tacrolimus and Arthritis--Rheumatoid

To evaluate the efficacy and safety of tacrolimus in adult patients with rheumatoid arthritis (RA) by using the GRADE approach.. We searched PubMed, Japana Centra Revuo Medicina Web (Ichu-shi web), and the Cochrane Database of Systematic Reviews. Articles fulfilling the predefined inclusion criteria were appraised and used for meta-analysis. The primary outcomes were American College of Rheumatology 20 (ACR20) and serum creatinine elevation. Other outcomes included ACR50, ACR70, changes in C-reactive protein, modified Health Assessment Questionnaire Disability Index, gastrointestinal disorders, metabolic and nutritional disorders, and infections and infestations.. We identified five randomized controlled studies, four of which compared tacrolimus to placebo and were included in the meta-analysis. The risk ratio of ACR20 achievement was 1.71 (95% confidence interval [CI] 1.20-2.42) for 1-2 mg/day and 2.30 (95% CI 1.79-2.96) for 3 mg/day. The risk ratio of creatinine elevation was 1.95 (95% CI 1.18-3.23) for 1-2 mg/day and 3.81 (95% CI 2.43-5.99) for 3 mg/day.. Tacrolimus is effective with acceptable safety in the management of RA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Tacrolimus; Treatment Outcome

We aimed to assess the relative efficacy and tolerability of monotherapy with leflunomide or tacrolimus at recommended dosages in rheumatoid arthritis (RA) patients. Randomized controlled trials (RCTs) examining the efficacy and tolerability of leflunomide 20 mg, leflunomide 10 mg, tacrolimus 3 mg, tacrolimus 1.5-2 mg, and placebo, based on the number of withdrawals of RA patients, were included. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs. Six RCTs including 1510 patients met the inclusion criteria. The proportion of patient withdrawals owing to lack of efficacy was significantly lower in the leflunomide 20 mg (OR 0.17, 95% credible interval (CrI) 0.08-0.34); leflunomide 10 mg (OR 0.16, 95% CrI 0.02-0.75); and tacrolimus 3 mg (OR 0.41, 95% CrI 0.21-0.74) groups than in the placebo group. Rank probability based on the surface under the cumulative ranking curve (SUCRA) values indicated that leflunomide 20 mg had the highest probability of being the best treatment based on the number of withdrawals owing to lack of efficacy (SUCRA = 0.8530), followed by leflunomide 10 mg (SUCRA = 0.8321), tacrolimus 3 mg (SUCRA = 0.4965), tacrolimus 1.5-2 mg (SUCRA = 0.3035), and placebo (SUCRA = 0.0150). Patient withdrawals owing to adverse events did not differ significantly among the groups; however, withdrawals in the placebo group were fewer than those in the leflunomide 20 mg group (OR 0.22, 95% CrI 0.07-0.74). Placebo had the highest probability of being the most tolerable treatment (SUCRA = 0.8161) followed by tacrolimus 3 mg (SUCRA = 0.6490), tacrolimus 1.5-2 mg (SUCRA = 0.4857), leflunomide 10 mg (SUCRA = 0.4651), and leflunomide 20 mg (SUCRA = 0.0841). Leflunomide 20 mg, leflunomide 10 mg, and tacrolimus 3 mg were more efficacious than placebo, while leflunomide 20 mg was less tolerable than placebo. Leflunomide is likely to be more efficacious but less tolerable than tacrolimus for RA treatment.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Bendamustine Hydrochloride; Humans; Isoxazoles; Leflunomide; Network Meta-Analysis; Randomized Controlled Trials as Topic; Tacrolimus

This paper aims to study the background and clinical characteristics of tacrolimus (TAC)-induced lung disease. A case of a rheumatoid arthritis (RA) patient who developed TAC-induced interstitial lung disease (TAC-ILD) is reported. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) website was searched for cases of TAC-ILD and its prevalence among all cases of TAC-related adverse events. As for cases of TAC-ILD, its underlying disease, preexisting lung diseases, and fatal outcome were also searched. Literature review of TAC-ILD cases was added. A 65-year-old female RA patient with preexisting bronchiectasis developed near-fatal TAC-ILD. Amelioration of RA, ground-glass opacities in the upper, anterior, and central lung fields, and decrease in peripheral blood lymphocyte count were the major findings in this patient. A search of the PMDA website revealed the following: the prevalence of TAC-ILD was 3 % of all cases of TAC-related adverse events, 56 out of 85 RA cases (66 %), and one out of 15 other cases had a preexisting lung disease; the prevalences of fatal outcome in RA and other cases were 24 and 38 %, respectively. A few cases in the literature had preexisting ILD and developed diffuse alveolar damage. In our case, preexisting bronchiectasis, arthritis remission, newly developed ground-glass opacities (GGOs) in the upper, anterior, and central lung fields, and decrease in peripheral blood lymphocyte count were the major findings. From the search of the PMDA website, about one fourth of the cases with TAC-related lung injury had a fatal outcome, and among RA patients, two thirds had preexisting lung diseases.

Topics: Aged; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Lung Diseases; Tacrolimus

Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) other than methotrexate (MTX: anchor csDMARDs) are effective for single use, reinforcement of MTX, biologics and induction and maintenance of biologics-free condition. Newly developed iguratimod (IGU) does not suppress immunological reaction, therefore, it is useful for single use or combination with other csDMARDs in patients with complications. IGU can be used as a first csDMARDs before MTX use during the screening for MTX. IGU might be effective for reinforcement of MTX, biologics and induction and maintenance of biologics-free condition just like other csDMARDs. IGU can be used in wide variety of situation of the treatment of rheumatoid arthritis and it is desired that after the all-case surveillance condition for approval, IGU become a standard csDMARDs all over the world which was made in Japan.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Chromones; Cysteine; Drug Discovery; Drug Interactions; Drug Substitution; Drug Therapy, Combination; Drugs, Generic; Female; Humans; Male; Ribonucleosides; Sulfasalazine; Sulfonamides; Tacrolimus

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.

Topics: Adrenal Cortex Hormones; Arthritis, Psoriatic; Arthritis, Rheumatoid; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporine; Drug Resistance; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Tacrolimus

Disease-modifying antirheumatic drugs (DMARDs) have largely contributed to recent paradigm shift of rheumatoid arthritis (RA) treatment strategy. DMARDs can be indicated for all RA patients and early use of DMARDs after diagnosis of RA is recommended. Individual DMARDs have common characteristics. Understanding these characteristics is very important in treating RA. As for safety, the pattern of adverse reactions (ADRs) associated with DMARDs has been generally understood. It is necessary to select DMARDs and follow up patients with recognition of the pattern of ADRs. Regular monitoring is also essential to ensure the safety of DMARDs. This chapter deals with some major DMARDs in Japan, including methotrexate, which is indispensable in current RA treatment; salazosulfapyridine and bucillamine; tacrolimus, which is recently increasing in use; and iguratimod, which became available in 2012.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cysteine; Humans; Japan; Methotrexate; Sulfasalazine; Tacrolimus

The primary goal in the treatment of rheumatoid arthritis (RA) is to maintain good quality of life by preventing joint destruction and avoiding disability. For this purpose, all patients with the diagnosis of RA should be treated by disease-modifying antirheumatic drugs (DMARDs) including biologic DMARDs and non-biologic DMARDs. All DMARDs are expected to prevent the progression of bone and cartilage destruction of RA patients from the results of in vitro research, and prevention of joint destruction is confirmed in vivo in all biologic DMARDs, but not in all non-biologic DMARDs. In this chapter, we would like to review the results of basic researches and clinical studies to demonstrate the prevention of joint destruction by non-biologic DMARDs that have been frequently used I daily practice.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bone and Bones; Cartilage; Clinical Trials as Topic; Cysteine; Humans; Isoxazoles; Joints; Leflunomide; Methotrexate; Sulfasalazine; Tacrolimus

Topics: Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Tacrolimus

The aim of this study was to assess the efficacy and safety of tacrolimus in patients with active rheumatoid arthritis (RA).. We surveyed randomized controlled trials (RCTs) and open-label studies that examined the efficacy and toxicity of tacrolimus in disease-modifying anti-rheumatic drug (DMARD)--and methotrexate (MTX)-resistant or -intolerant patients with active RA patients using Medline, the Cochrane Controlled Trials Register, and by performing manual searches. Meta-analysis of RCTs was performed to determine treatment efficacy and safety outcomes. The results are presented as risk ratios (RRs), weighted mean differences (WMDs), or standardized mean differences (SMDs). Open-label studies were included in the systematic review.. The four RCTs included 1014 DMARD-resistant or -intolerant patients with DMARD-resistant or -intolerant RA. Median follow-up duration was 6 (range 4-6) months. American College of Rheumatology 20, 50, and 70% (ACR20, ACR50, and ACR70) response rates were significantly higher in the tacrolimus 3 mg/day group (n = 390) than in the controls (n = 402) [primary efficacy outcome, ACR50; risk ratio (RR) 2.583, 95% confidence interval (CI) 1.095-6.092, p = 0.030], and efficacies in the tacrolimus 1.5-2 mg/day group showed a similar pattern. Patients treated with tacrolimus withdrew from treatment because of adverse events (n = 222) (primary safety outcome, withdrawals due to adverse events; RR 1.475, 95% CI 0.895-2.187, p = 0.053) more frequently than controls (n = 231), although this was not significant. All four open-label studies found that tacrolimus was safe, well-tolerated, and provided clinical benefits.. Tacrolimus, at dosages of 1.5-3 mg/day, was found to be effective in DMARD-resistant or -intolerant patients with active RA.

Topics: Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

Because of a paradigm shift in the therapeutic strategy of RA by biologics, the goal of RA therapy became not only the clinical remission, but also the imaging remission. From the results of randomized controlled clinical trials of disease modifying anti-rheumatic drugs (DMARDs), decreased radiographic progression has been documented. In particular, methotrexate (MTX) is described as "anchor drug" of RA therapy because inhibitory effects of MTX on radiographic progression are proved by many clinical trials. Although DMARDs can slow down the radiographic progression with the achievement of clinical remission in RA, some patients still have subclinical synovitis detected by imaging technique. Such subclinical inflammation may explain the observed discrepancy between disease activity and radiographic progression in RA during DMARD therapy.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cyclosporine; Cysteine; Disease Progression; Drug Therapy, Combination; Gold Sodium Thiomalate; Humans; Isoxazoles; Leflunomide; Methotrexate; Penicillamine; Radiography; Randomized Controlled Trials as Topic; Sulfasalazine; Tacrolimus

Topics: Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Glucocorticoids; Humans; Infliximab; Pharmacogenetics; Risk Assessment; Tacrolimus

Since joint destruction, the most important problem in rheumatoid arthritis (RA) , progress rapidly at the onset of the disease, initial treatment using appropriate disease-modifying anti-rheumatic drug DMARD such as methotrexate (MTX) is strongly recommended in order to retard progression of joint damage. However, not a few patients are resistant to MTX and/or intolerant of MTX. Oral tacrolimus 1.5-3 mg/day, an immunosuppressive drug, was approved in Japan for the treatment of RA insufficient to other DMARD. The properties of tacrolimus have the much potential of inhibition of T cell activation, suppressing the production of pro-inflammatory cytokines, improvement of joint inflammation, retarding bone and cartilage destruction, overcoming drug-resistance and so on and, thereby, tacrolimus can be the best alternative to MTX and biologics in RA patients who are refractory to or intolerant of these other drugs.

Topics: Arthritis, Rheumatoid; Calcineurin; Clinical Trials as Topic; Humans; Immunosuppressive Agents; Interleukin-2; Joints; Lymphocyte Activation; NFATC Transcription Factors; T-Lymphocytes; Tacrolimus

The calcineurin inhibitors cyclosporine and tacrolimus are important treatments for patients with active rheumatoid arthritis, especially in cases of resistance or intolerance to methotrexate or other disease-modifying antirheumatic drugs. Here, we discuss the mechanism, efficacy and safety of cyclosporine and tacrolimus in the treatment of rheumatoid arthritis.. Recent clinical trials of cyclosporine have shown the advantages of its combination with methotrexate, glucocorticoids and leflunomide in the treatment of active rheumatoid arthritis. In Japan, tacrolimus monotherapy was found to be quite effective and combination therapy with methotrexate had positive results in an American study. The inhibitory effects of both drugs not only on T lymphocytes, but also on human osteoclast formation, have been demonstrated in basic studies.. Cyclosporine and tacrolimus are clinically available disease-modifying antirheumatic drugs. Numerous clinical studies have shown the usefulness of these calcineurin inhibitors in monotherapy and also when combined with methotrexate. Although these drugs have similar effects, there are some differences in adverse reactions.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Glucocorticoids; Humans; Immunosuppressive Agents; Methotrexate; Safety; T-Lymphocytes; Tacrolimus; Tacrolimus Binding Proteins

We encountered the rare case of a 50-year-old woman who developed rheumatoid arthritis (RA) while suffering from Takayasu's arteritis of arch vessel type. prednisolone (PSL) therapy was continued at a maintenance dose of 7.5 mg due to recurring inflammation. She was affected with RA for 7 years after Takayasu's arteritis. Disease-modifying antirheumatic drugs (DMARDs) were unusable because of side effects. In the summer of 2005, RA activity increased, and treatment with tacrolimus hydrate at 1.5 mg was started; thereafter, the activity of RA and Takayasu's arteritis was relieved, especially MRA findings. We report that therapy with tacrolimus hydrate markedly relieved two disorders, and review the literature.

Topics: Angiography; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Middle Aged; Tacrolimus; Takayasu Arteritis

Tacrolimus is an immunosuppressive drug that has been used widely in organ transplantation and topically for atopic dermatitis. Tacrolimus exerts its immunosuppressive effects by the inhibition of calcineurin, leading to interference with T-cell activation. As T-cell activation plays a major role in the pathogenesis of rheumatoid arthritis, there has been an interest in the use of tacrolimus for the treatment of rheumatoid arthritis. The pharmacological properties of tacrolimus have the potential of suppressing the production of inflammatory cytokines, improvement of joint inflammation, improvement of bone and cartilage destruction, improvement of functional status and relief from arthritic pain. This article reviews the pharmacodynamics, pharmacokinetics, clinical efficacy, safety and role of tacrolimus in the treatment of rheumatoid arthritis.

Topics: Animals; Arthritis, Rheumatoid; Humans; Tacrolimus

Tacrolimus (FK506) is an immunosuppressive drug, widely used for organ transplantation and atopic dermatitis. Tacrolimus exerts its immunosuppressive effects primarily by interfering with the activation of T cells, via inhibition of calcineurin. Recent clinical studies have also demonstrated the efficacy of tacrolimus in the treatment of rheumatoid arthritis (RA), an autoimmune disease in which T cells play a pivotal role in pathogenesis. Inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 are involved in development of the disease. Recently, modes of action of tacrolimus on RA have been intensively studied in in vitro and animal arthritis models, demonstrating that tacrolimus exerts various novel actions as an anti-rheumatic drug. The pharmacological action of tacrolimus suggests that it has potential to specifically suppress the production of pathogenic inflammatory cytokines with a low frequency of infection, improve joint inflammation and bone/cartilage destruction, fully recover loss of functional status, exert rapid relief in arthritic pain, and promote osteogenic and chondrogenic differentiation. Here we review the action of tacrolimus on experimental models of RA, with a focus on our recent studies, and provide further insight into experimental models used for identifying efficacious anti-rheumatic drugs.

Topics: Analgesics; Animals; Arthritis, Rheumatoid; Cartilage; Cytokines; Disease Models, Animal; Humans; Tacrolimus

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; DNA-Binding Proteins; Humans; Interleukin-2; Japan; NFATC Transcription Factors; Nuclear Proteins; T-Lymphocytes; Tacrolimus; Transcription Factors; United States

Tacrolimus, a hydrophobic macrolide with immunosuppressant properties, has recently been evaluated as a new treatment for adults with active rheumatoid arthritis. Oral tacrolimus 3mg once daily was significantly more effective than placebo in patients with rheumatoid arthritis (RA) who were refractory or intolerant to disease-modifying antirheumatic drugs (DMARDs), according to results from a 6-month, phase III trial; American College of Rheumatology 20 (ACR20) response rates were 27% and 10%. Tacrolimus 3mg once daily was effective in the same patient group in a 12-month, open-label trial; the ACR20 response rate was 38%. Oral tacrolimus 3 mg once daily was effective in combination with established methotrexate therapy in patients with RA in a 6-month, open-label trial. The ACR20 response rate was 53%. Oral tacrolimus 3 mg once daily was generally well tolerated by patients with active RA refractory or intolerant to previous DMARD treatment or when administered as combination therapy in patients with RA on established methotrexate therapy.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Tacrolimus

Cyclosporin A(CsA) and tacrolimus (FK506) are important immunosuppressants to inhibit rejection of transplanted organs and to treat various immunological disorders, however those drugs produce major side effects. Those drugs form complexes with cellular proteins, immunophilins (cyclophilin for CsA and FKBP for tacrolimus) and inhibit Ca-calmodulin dependent phosphatase calcineurin through direct binding. Calcineurin dephosphorylates various substrates including NFAT family proteins required for the expression of immunoregulatory molecules especially cytokines. NFAT-calcineurin pathway offers a good model system to apply new technology to develop drugs. Enzyme-substrate interaction could be an important target to develop drugs with high specificity accompanied with less side effects.

Topics: Arthritis, Rheumatoid; Calcineurin; Cyclosporine; DNA-Binding Proteins; Immunophilins; NFATC Transcription Factors; Nuclear Proteins; Tacrolimus; Transcription Factors

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Arthritis, Rheumatoid; Clinical Trials as Topic; Drug Approval; Drug Costs; Drug Design; Etanercept; Humans; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Isoxazoles; Leflunomide; Receptors, Tumor Necrosis Factor; Tacrolimus

Rheumatoid arthritis (RA) is a chronic immune-mediated disease characterised by chronic synovitis, which leads to cartilage damage and joint destruction. It is generally a progressive disease with radiographic evidence of joint damage, functional status decline and premature mortality. Proinflammatory cytokines, such as interleukin 1 and tumour necrosis factor alpha, play an important role in maintaining the chronicity of RA and mediating tissue damage. New approaches in the therapy of RA with anticytokine biological agents, which neutralise or block cytokines or their receptors, are now the first generation antirheumatic drugs in clinical practice. A better understanding of the signal transduction systems and gene regulation by transcription factors involved in cytokine production has opened the way for the discovery of novel therapeutic compounds useful in treating patients with RA. Overactivation of selective kinases or aberrant function of downstream transcription factors could help convert a normal immune response to a chronic disease state. This provides a unique opportunity for novel therapeutic interventions, since specific signal transduction or transcription factor targets might interrupt the perpetuation mechanisms in RA. The availability of potent and selective p38 mitogen activated protein kinase inhibitors provide a means in further dissecting the pathways implicated in cytokine production, which in turn maintain the chronicity of RA. Many studies conclude that these compounds are very useful in the treatment of chronic synovitis and therefore are very promising for RA treatment.

Topics: Animals; Arthritis, Rheumatoid; Cyclosporine; Cytokines; Gene Expression Regulation; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Mitogen-Activated Protein Kinases; Mycophenolic Acid; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Sirolimus; Tacrolimus

Immunomodulatory agents represent a unique group of therapies that are not biologics and have relatively specific, noncytotoxic effects on the immune system. Cyclosporine has been the most widely tested of the immunomodulatory agents and shown efficacy in a variety of autoimmune diseases as well as monotherapy in established rheumatoid arthritis. FK-506 and rapamycin, agents similar to cyclosporine, are being tested in human transplantation, with only arthritis studies having been done in animals. Tilomisole, imuthiol, and mycophenolate mofetil have been studied in limited rheumatoid arthritis trials with positive effects. Although more specific and with manageable short-term side effects, this group of therapies requires more studies to establish their efficacy and long-term safety.

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Clinical Trials as Topic; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Polyenes; Sirolimus; Tacrolimus

Tapering or stopping biological disease-modifying anti-rheumatic drugs has been proposed for patients with rheumatoid arthritis (RA) in remission, but it frequently results in high rates of recurrence. This study evaluates the efficacy and safety of tacrolimus (TAC) as maintenance therapy in patients with established RA in remission after receiving combination therapy with tumor necrosis factor inhibitor (TNFi) and methotrexate (MTX).. This 24-week, prospective, open-label trial included patients who received TNFi and MTX at stable doses for ≥24 weeks and had low disease activity (LDA), measured by Disease Activity Score-28 for ≥12 weeks. Patients selected one of two arms: maintenance (TNFi plus MTX) or switched (TAC plus MTX). The primary outcome was the difference in the proportion of patients maintaining LDA at week 24, which was assessed using a logistic regression model. Adverse events were monitored throughout the study period.. In efficacy analysis, 80 and 34 patients were included in the maintenance and switched arms, respectively. At week 24, LDA was maintained in 99% and 91% of patients in the maintenance and switched arms, respectively (odds ratio, 0.14; 95% confidence interval, 0.01-1.59). Drug-related adverse effects tended to be more common in the switched arm than in the maintenance arm (20.9% versus 7.1%, respectively) but were well-tolerated.. This controlled study tested a novel treatment strategy of switching from TNFi to TAC in RA patients with sustained LDA, and the findings suggested that TNFi can be replaced with TAC in most patients without the patients experiencing flare-ups for at least 24 weeks.. Korea CDC CRIS, KCT0005868 . Registered 4 February 2021-retrospectively registered.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Humans; Methotrexate; Prospective Studies; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

To investigate the efficacy and safety of tacrolimus (TAC) versus leflunomide (LEF) when combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients.. This was a 24-week multi-center, double-blind, randomized, non-inferiority study targeting RA patients with moderate to severe Disease Activity Score of 28 joints (DAS28 > 3.2) who showed inadequate response to MTX. Patients were randomized into TAC or LEF (add-on to MTX) groups. Initial daily doses of TAC and LEF were 1.5 and 10 mg, respectively, for 4 weeks and then doubled until the end of the study. The primary endpoint was DAS28 comparison at 24 weeks.. Eighty-seven patients were screened in 10 centers and 75 patients were randomized into two groups. Baseline demographics were comparable between TAC + MTX and LEF + MTX groups. The TAC + MTX group was non-inferior to the LEF + MTX group in terms of DAS28 at 24 weeks (mean difference of DAS28: -0.1812, 95% confidence interval: -0.8073, 0.4450). There was a greater number of adverse events in the LEF + MTX group (66 in LEF + MTX and 49 in TAC + MTX). Six patients presented with transaminitis in the LEF + MTX group compared with two patients in the TAC + MTX group.. The efficacy of TAC combined with MTX was non-inferior to LEF + MTX. It had a reasonable safety profile in RA patients with moderate to severe disease activity (http://cris.nih.go.kr; KCT0000781).

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Leflunomide; Male; Methotrexate; Middle Aged; Republic of Korea; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs).. Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs.. Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24.. TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Humans; Japan; Male; Middle Aged; Product Surveillance, Postmarketing; Tacrolimus

To analyze the effectiveness of tacrolimus (TAC) in comparison with methotrexate (MTX) or biologics in propensity score (PS)-matched rheumatoid arthritis (RA) patients.. RA patients with moderate or high disease activity as defined by the 28-joint disease activity score (DAS28) and who had completed at least two successive biannual RA cohort surveys were analyzed. Patients were assigned in a stepwise fashion to one of four groups (Biologics, MTX, TAC, or Control) according to medication changes during a 6-month period. A PS was generated for each of three conditions (Biologics, MTX or Control group versus the TAC group, respectively), followed by the assignment of PS-matched patients. At 1 year, the DAS28 in each treatment versus TAC group was analyzed using a mixed effect model with repeated measures.. Compared with the respective PS-matched TAC group, the difference in DAS28 at 1 year was -0.398 [95% confidence interval (CI) - 0.660 to -0.136, p < 0.005] in the Biologics group (N = 120), -0.045 (95% CI -0.222 to 0.133, p = 0.622) in the MTX group (N = 465), and 0.182 (95% CI 0.010 to 0.353, p < 0.05) in the Control group (N = 462).. TAC may provide a potential therapeutic option for RA patients with moderate to high disease activity.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Female; Humans; Male; Methotrexate; Middle Aged; Propensity Score; Tacrolimus; Treatment Outcome

To determine the efficacy and safety of low-dose tacrolimus in Korean rheumatoid arthritis (RA) subjects with an inadequate response to methotrexate (MTX).. This was a multicenter, open-label study conducted at five Korean sites. Fifty-six patients with active RA, despite treatment for ≥ 1 month with a stable, maximally tolerated dosage of oral MTX (median dosage, 15 mg/wk), were enrolled and received 1.5 mg/day of tacrolimus as a single oral dose once per day for 16 weeks while continuing to receive MTX. All other disease-modifying anti-rheumatic drugs were discontinued, whereas stable dosages of nonsteroidal anti-inflammatory drugs and oral corticosteroids (≤ 10 mg/day of prednisone or an equivalent corticosteroid) were allowed. The primary clinical response criterion was the American College of Rheumatology's definition of 20% improvement (ACR20) at the end of treatment.. The ACR20 response rate was 42.9% (24 of 56 patients) in patients who had received tacrolimus at least once. The overall ACR50 and ACR70 responses at the end of treatment for all patients were 30.4% and 10.7%, respectively. Throughout the treatment period, 37 patients experienced 71 adverse events (AEs) in total, and four patients left the study because of AEs. In addition, 15 patients in total experienced treatment-related AEs. Throughout the treatment period, two patients were reported to experience two serious AEs, and one patient left the study because of a serious AE.. In patients whose active RA persists despite treatment with MTX, low-dose tacrolimus in combination with MTX appears to be safe and well tolerated, and provides clinical benefit.

Topics: Administration, Oral; Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Calcineurin Inhibitors; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Remission Induction; Republic of Korea; Tacrolimus; Time Factors; Treatment Outcome

In rheumatoid arthritis (RA) patients receiving immunosuppressive treatments, vaccination against Streptococcus pneumoniae is recommended. The objective of the study was to evaluate the effects of tacrolimus (TAC) on immune response following administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) in patients with established RA.. Patients with RA (n = 133) were vaccinated with PPSV23. Patients were classified into TAC (n = 29), methotrexate (MTX) (n = 55), control (n = 35), and TAC/MTX (n = 14) treatment groups. We measured the concentrations of pneumococcal serotypes 6B and 23F by using an enzyme-linked immunosorbent assay and determined antibody functionality by using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI), before and 4 to 6 weeks after vaccination. A positive antibody response was defined as at least a twofold increase in the IgG concentration or as at least a 10-fold increase in the OI.. IgG concentrations and OIs were significantly increased in all treatment groups after PPSV23 vaccination. The TAC treatment group appears to respond in a manner similar to that of the RA control group in terms of 6B and 23F serotype concentration and function. In contrast, the MTX group had the lowest immune response. Patients who received a combination of TAC and MTX (TAC/MTX) also had a diminished immune response compared with those who received TAC alone.. TAC monotherapy does not appear to impair PPSV23 immunogenicity in patients with RA, whereas antibody production and function may be reduced when TAC is used with MTX. Thus, PPSV23 administration during ongoing TAC treatment should be encouraged for infection-prone TAC-treated patients with rheumatic diseases.. University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.

Topics: Aged; Antibodies, Bacterial; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Male; Methotrexate; Middle Aged; Pneumococcal Vaccines; Tacrolimus

A multicenter, randomized, double-blind, placebo-controlled study of the oral calcineurin inhibitor tacrolimus was performed in patients with early rheumatoid arthritis who had responded poorly to disease-modifying antirheumatic drugs (DMARDs), and factors related to suppression of joint destruction were investigated.. The change in the total Sharp score (∆TSS) was assessed by univariate analysis in patients with X-ray films to identify the main determinant of a ∆TSS of <0.5 in week 52. Patients with this factor were then investigated further.. Univariate analysis showed that a baseline C-reactive protein (CRP) level of <1.5 mg/dL was the major determinant of ∆TSS <0.5 at week 52 in the tacrolimus group. Detailed analysis of patients with a baseline CRP of <1.5 mg/dL revealed no significant differences in background factors between the two groups. In week 52, ∆TSS was significantly smaller in the tacrolimus group than in the placebo group (2.67 ± 5.40 vs. 8.05 ± 10.32, respectively, p = 0.017). Both groups had a similar incidence of adverse reactions.. Adding tacrolimus to DMARDs significantly suppressed disease activity and joint destruction in patients with early rheumatoid arthritis, a disease duration ≤3 years, a CRP <1.5 mg/dL, and a poor response to oral DMARDs.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Double-Blind Method; Drug Therapy, Combination; Female; Hand Joints; Humans; Male; Methotrexate; Middle Aged; Radiography; Severity of Illness Index; Tacrolimus; Treatment Outcome

Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities. The purpose of this study was to determine the inhibitory effects of FK506 (tacrolimus) on GLS production in rheumatoid arthritis (RA). We investigated the modulation of serum GLS by FK506 therapy and the effect of FK506 on the production of GLS in fibroblast-like synoviocytes (FLSs). Serum samples were collected from 11 RA patients with active disease at baseline and after 12 weeks of FK506 treatment. Serum concentrations of GLS and matrix metalloproteinase (MMP)-3 were measured by ELISA and found to be down-regulated in responders evaluated with a disease activity score. Patient FLSs were cultured and stimulated by tumor necrosis factor (TNF)-α with or without FK506. The expression levels of GLS were determined using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme immunoassay and shown to be significantly increased. GLS levels in TNF-α-stimulated FLSs were reduced by FK506 treatment. Our data show a novel mechanism for the action of physiological concentrations of FK506 in RA that regulates the production of GLS in FLSs.

Topics: Aged; Arthritis, Rheumatoid; Cells, Cultured; Female; Fibroblasts; Humans; Immunosuppressive Agents; Male; Middle Aged; Synovial Membrane; Tacrolimus; Thymidine Phosphorylase; Tumor Necrosis Factor-alpha

In this trial, we investigated the safety and efficacy of tacrolimus used in addition to standard antirheumatic drugs in patients with rheumatoid arthritis. Tacrolimus 3 mg or placebo was orally administered once daily for 52 weeks in a double-blind manner to patients with early active rheumatoid arthritis receiving other disease-modifying antirheumatic drugs (DMARDs). A total of 123 patients were randomized to the tacrolimus group (61 patients) and to the placebo group (62 patients). In the tacrolimus group, 70.5% achieved a clinical response according to American College of Rheumatology (ACR) 20 criteria, whereas 45.2% in the placebo group did so (P = 0.005). The tacrolimus group also showed significant improvement in terms of the European League Against Rheumatism (EULAR) response criteria of "good or moderate" versus the placebo group (86.9 vs. 56.5%, respectively). Likewise, significantly more patients in the tacrolimus group versus the placebo group achieved remission of the Disease Activity Score in 28 joints (DAS28) (45 vs. 21%). The mean changes in the Total Sharp Score and erosion score were lower in the tacrolimus group, but the differences between the two groups were not significant. There was no significant difference between the two groups in the incidence of adverse events. Based on these results, we can conclude that the additional use of tacrolimus in patients with early rheumatoid arthritis with inadequate response to other DMARD treatments is useful, and this could become one of the treatment options for these rheumatoid arthritis patients.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Cysteine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Joints; Male; Methotrexate; Middle Aged; Severity of Illness Index; Sulfasalazine; Tacrolimus; Treatment Outcome

The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus for treating rheumatoid arthritis (RA) patients in clinical practice. Fifty-five active RA patients who had been resistant or intolerant to other disease-modifying antirheumatic drugs were enrolled in this open-label trial. Patients were administered tacrolimus at a dosage of 1, 2 or 3 mg once daily, and followed up for 24 weeks. They were divided into three groups according to their dosage. Efficacy and safety were evaluated utilizing clinical and laboratory findings. Eighty percent of the patients had moderate or high disease activity; 55% were elderly and 53% had complications; 65% of the patients were started on tacrolimus as a monotherapy. Moderate or good response rates were achieved as follows: 38.2% (4 weeks); 41.8% (12 weeks); and 45.6% (24 weeks). Adverse events were observed in seven cases (12.7%). Only one case required hospitalization due to severe hyperglycemia caused by a high tacrolimus concentration (24.2 ng/ml); we suspected a drug interaction in this subject. Mean concentrations were dose-dependent in the 1, 2, and 3 mg/day groups (2.96, 4.29, and 8.32 ng/ml, respectively). Four cases of high concentration (over 10 ng/ml), without any signs or symptoms, were observed in the 3 mg/day group; in these cases, doses were decreased and no severe adverse events occurred. Tacrolimus was found to be both effective and safe in treating active RA patients with complicated backgrounds in clinical practice. Blood concentration measurements and dose adjustments should be performed to prevent severe adverse events in a 3 mg/day group.

Topics: Administration, Oral; Aged; Arthritis, Rheumatoid; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hyperglycemia; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

In this study we focused on the safety of long-term tacrolimus therapy in non-elderly patients with rheumatoid arthritis who were treated with tacrolimus or mizoribine in a previous double-blind study. The patients received oral tacrolimus at a dose < or =3 mg once daily for 76 weeks. The safety analysis population included 115 patients aged 20-64 years. Adverse drug reactions presented as symptomatic events in 39 patients (33.9%), laboratory abnormalities in 38 patients (33.0%), and infections in 19 patients (16.5%). The major reactions were gastrointestinal disorders and hypertension as symptomatic events, increases of creatinine, urinary N-acetyl-beta-D-glucosamidase and hemoglobin A1C as laboratory abnormalities, and the common cold syndrome as infections. After 76 weeks of tacrolimus treatment, the ACR20 response rates of patients who had also received tacrolimus during the preceding double-blind study was 61.5% (compared with the status at baseline in the preceding study). The corresponding response rate for patients who had previously received mizoribine was 66.0%. The mean blood concentration of tacrolimus was 3.8-4.8 ng/mL. In conclusion, safety profiles of tacrolimus treatment for long-term seems to be similar to those of previous studies in patients with rheumatoid arthritis.

Topics: Adult; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Middle Aged; Tacrolimus; Young Adult

The aim of this study was to assess if low-dose tacrolimus is efficacious for the treatment of rheumatoid arthritis (RA) when combined with methotrexate (MTX). The clinical courses of 32 RA patients who received tacrolimus plus MTX were analyzed retrospectively. Disease activity and clinical response were evaluated by DAS28 (disease activity score of 28 joints) and EULAR (European League Against Rheumatism) response criteria. Tacrolimus was started at 1 mg/day in five patients, 1.5 mg/day in 24 patients, and three mg/day in 3 patients. At six months, tacrolimus was continued at 1-2 mg/day in 27 of 32 patients, but was discontinued in five cases who showed no or inadequate response. Of the 32 patients, 47% were evaluated as having a moderate or good response at one month of tacrolimus therapy, and 72% at six months. No serious adverse events were observed. Our results suggest that the addition of tacrolimus at low dose to MTX for the treatment of patients with moderately active RA appears to be highly efficacious. Further studies are required for the appropriate use of this expensive immunosuppressant in the treatment of RA.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

To compare the efficacy and safety of tacrolimus and mizoribine in patients with rheumatoid arthritis (RA).. Adult patients with RA with an insufficient response to at least one disease modifying antirheumatic drug (DMARD) were randomized to receive 28 weeks of double-blind treatment with tacrolimus 3 mg once daily or mizoribine 50 mg three times daily. The primary efficacy endpoint was the American College of Rheumatology 20% (ACR20) response. Safety was evaluated by adverse events.. A total of 204 patients were enrolled for study (103 in the tacrolimus group, 101 in the mizoribine group). Significantly more patients receiving tacrolimus achieved an ACR20 response compared with mizoribine (48.5 vs 10.0%, respectively; p = 0.001). Tacrolimus was also superior to mizoribine in ACR50 and ACR70 response rate, tender and painful joint counts, swollen joint counts and patient and physician assessments of pain, disease activity, and patient's physical function assessment based on the Modified Health Assessment Questionnaire (p < 0.001). Adverse events were more frequent in the tacrolimus group than the mizoribine group (65.0 vs 59.4%); however, there were no statistically significant differences between treatment groups.. Tacrolimus improves RA symptoms to a significantly greater extent than mizoribine in patients with RA inadequately controlled with at least one prior DMARD. Tacrolimus has the potential to be a useful and highly effective treatment for RA.

Topics: Arthritis, Rheumatoid; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ribonucleosides; Tacrolimus; Treatment Outcome

To evaluate the efficacy and safety of tacrolimus (FK506) in patients with active rheumatoid arthritis (RA) exhibiting resistance to disease modifying antirheumatic drug (DMARD) therapy, and to determine the optimal dosage.. A total of 212 patients with DMARD-resistant RA were enrolled in this double blind, multicenter, randomized, placebo controlled study and allocated to 3 groups. Patients were administered tacrolimus at a dosage of 1.5 mg/day (68 patients) or 3 mg/day (70 patients), or placebo (74 patients), for 16 weeks. They were allowed to continue taking prednisolone (< or = 5 mg/day) and/or one nonsteroidal antiinflammatory drug (NSAID) during the study. Clinical assessment was based on the American College of Rheumatology (ACR) 20% criteria.. ACR 20% response rates were higher in both tacrolimus groups (3 mg: 48.3%; 1.5 mg: 24.6%) than in the placebo group (14.1%), with the rate in the 3 mg group significantly higher. There were no significant differences between the tacrolimus groups and placebo group in the incidence of adverse events. The main adverse events in the tacrolimus groups, especially in the 3 mg group, were renal function abnormalities and gastrointestinal symptoms. However, no significant differences were observed among the 3 groups in the incidence of any adverse event except decrease in serum Mg level.. Our findings demonstrate excellent dose-dependent efficacy of tacrolimus in patients with DMARD-resistant RA and strongly suggest the usefulness of tacrolimus for treatment of RA. The optimal dosage appears to be 3 mg/day in terms of efficacy and safety.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Placebos; Prednisolone; Tacrolimus; Treatment Outcome

To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active despite treatment with MTX.. This was a multicenter open-label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for >/=1 month with a stable, maximally tolerated dosage of oral MTX (/=30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6-63.4%).. In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well-tolerated and provides clinical benefit.

Topics: Administration, Oral; Arthritis, Rheumatoid; Creatinine; Drug Therapy, Combination; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney; Male; Methotrexate; Middle Aged; Tacrolimus; Treatment Outcome

To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA).. This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg.. A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by >/=40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients.. Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates.

Topics: Administration, Oral; Arthritis, Rheumatoid; Double-Blind Method; Drug Resistance; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Treatment Outcome

To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA).. This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes.. ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups.. Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Health Status; Hospitals, Community; Hospitals, University; Humans; Immunosuppressive Agents; Joints; Male; Methotrexate; Middle Aged; Prednisolone; Severity of Illness Index; Tacrolimus; Treatment Outcome

To determine if tacrolimus (FK506) has potential as a therapeutic agent in patients with severe and/or refractory rheumatoid arthritis (RA).. Twelve patients with RA who had severe and active disease and had failed an average of 5.3 disease modifying antirheumatic drugs (DMARD) were treated with tacrolimus 2-6 mg/day in an open label study. Patients were assessed monthly with respect to RA outcomes and drug related toxicities.. Of the 12 patients, 7 were able to complete 6 months of treatment. In these 7 patients, significant improvements were seen in tender joint count (from 26.4 +/- 4.2 to 11.7 +/- 3.2; p = 0.007), swollen joint count (from 17.7 +/- 2.5 to 4.1 +/- 1.3; p = 0.001), and other RA outcomes. All 7 patients achieved the 20% response criteria of the American College of Rheumatology (ACR), and 5 of 7 patients met the ACR 50% response criteria. The other 5 patients withdrew in the first 3 months of treatment due to gastrointestinal symptoms (3), chest pain (1), and neuropathic pain (1). Serum creatinine levels were unchanged in all patients, and hypertension was not seen.. Tacrolimus was tolerated by only 7 of 12 patients, but in 5 of these 7 patients with severe and refractory disease, the clinical responses were very good.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Middle Aged; Outcome Assessment, Health Care; Tacrolimus

The study aimed to investigate the effectiveness and tolerance of biological disease-modifying antirheumatic drugs (bDMARDs) therapy administered concomitantly with tacrolimus (TAC) treatment in patients with rheumatoid arthritis.. 2792 patients who underwent therapy with five bDMARDs (etanercept: ETN, adalimumab, golimumab, tocilizumab, and abatacept: ABT) were enrolled. Among the study subjects, 1582 were concomitant methotrexate (MTX group), 147 were concomitant TAC (TAC group), and 1063 were non-concomitant MTX and TAC (non-MTX/TAC group). The primary outcome was the incident rate of discontinuation of bDMARDs by adverse events (AEs) or loss of efficacy.. Concerning the analysis for each reasons of discontinuation, including AEs and loss of efficacy, the hazards ratio (HR) was significantly lower in the TAC group than in non-MTX/TAC groups (AEs: HR = 0.39, 95% confidence interval, 0.23-0.68, loss of efficacy: HR = 0.49, 95% confidence interval, 0.30-0.78). The loss of efficacy with the use of ETN and ABT was lower in the TAC group than in non-MTX/TAC groups. Concomitant TAC did not induce elevated risk for discontinuation of AEs in all bDMARD analyses.. Concomitant TAC with ABT or ETN showed higher retention rates than bDMARDs therapy without TAC or MTX. AEs did not increase over long-term observation.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Etanercept; Humans; Methotrexate; Tacrolimus; Treatment Outcome

To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD).. The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure.. Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression.. None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Leflunomide; Lung Diseases, Interstitial; Male; Methotrexate; Tacrolimus

Deciding which drug to choose for targeted therapy is an important step in sequential treatment for rheumatoid arthritis (RA). This study aimed to identify factors for selecting Janus kinase inhibitors (JAKis) rather than biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with RA in real-world practice.. We selected RA patients starting JAKis or bDMARDs from single-center prospective cohorts in Korea. Patients were divided into JAKi, tumor necrosis factor (TNF) inhibitor, and non-TNF inhibitor groups. We performed multinomial logistic regression analyses to identify factors associated with selecting JAKis.. 145, 205, and 89 patients were included in the JAKi, TNF inhibitor, and non-TNF inhibitor groups. In multinomial regression analysis, the JAKi group was older than the TNF inhibitor group (OR 1.03, 95% confidence interval [CI] 1.01-1.05) but younger than the non-TNF inhibitor group (OR 0.97, CI 0.95-1.00). The JAKi group was less likely to have chronic pulmonary diseases compared with the TNF inhibitor group (OR 0.07, CI 0.01-0.56) or the non-TNF inhibitor group (OR 0.06, CI 0.01-0.50). Higher disease activity assessed by physician (OR 1.80, CI 1.51-2.38) and previous tacrolimus use (OR 2.05, CI 1.20-3.51) were factors suggesting selection of JAKis than TNF inhibitors.. Age, pulmonary comorbidities, previous tacrolimus use, and high disease activity assessed by physician were factors influencing the selection of JAKis for RA patients in Korea.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Comorbidity; Humans; Janus Kinase Inhibitors; Prospective Studies; Tacrolimus; Tumor Necrosis Factor Inhibitors

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its incidence, prognosis, and risk factors remain unclear. In this retrospective study, we evaluated the actual incidence, prognostic impact, and risk factors of MTX-LPD. Of the 986 patients with RA treated with MTX, 90 patients experienced 95 new malignancies (NMs), with LPD as the most frequent in 26 patients. The cumulative LPD incidences were 1.3% and 4.7% at 5 and 10 years after MTX initiation, respectively. Among the 24 patients who discontinued MTX after developing LPD, 15 showed sustained regression, without difference in overall survival between patients with LPD and without NM. Inflammatory markers and absolute lymphocyte counts were not useful for early LPD development detection, but most of the patients with LPD had persistently elevated erythrocyte sedimentation ratios. Regarding concomitant drugs, tacrolimus increased the risk only if patients were not receiving biological disease-modifying antirheumatic drugs (bDMARDs). bDMARDs did not increase the risk for any of the drugs or the number of classes used. The number of LPD cases was lower in patients with IL-6A even after a long period after MTX, although with no statistically significant difference. Thus, approximately 1 in 20 patients with RA developed MTX-LPD over the 10 years of MTX treatment, but it did not affect the survival of patients with RA. Tacrolimus increased the risk of developing LPD for certain patients and should be used with caution.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Lymphoproliferative Disorders; Methotrexate; Retrospective Studies; Tacrolimus

Insufficient evidence exists regarding the efficacy of Janus kinase inhibitors (JAKis), a class of targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs), in the treatment of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). Herein, we present a case of RA-ILD refractory to previous treatments that exhibited favorable response to upadacitinib. A 69-year-old man, former smoker, was diagnosed with RA-ILD based on persistent symmetric polyarthritis, elevated C-reactive protein levels and erythrocyte sedimentation rate, reduced diffusing capacity for carbon monoxide/alveolar volume (D

Topics: Aged; Arthritis, Rheumatoid; Dyspnea; Humans; Lung Diseases, Interstitial; Male; Methotrexate; Prednisolone; Tacrolimus

We experienced a patient in her 30s with rheumatoid arthritis (RA) who achieved delivery with the use of certolizumab pegol (CZP) and tacrolimus (TAC) during pregnancy. She developed RA in X - 3 year and was treated with salazosulfapyridine (SASP). In X - 2 year, she became pregnant and discontinued SASP and had a normal delivery despite joint pain during pregnancy. She restarted SASP in X - 1 year and became pregnant again in X year. She experienced a flare-up of RA and was referred to our rheumatic centre. We introduced CZP and TAC, and she discontinued these agents and started prednisolone just before delivery. There is reportedly minimal placental transfer of CZP because of its Fc-free structure, since the Fc part of CZP is replaced by polyethylene glycol. TAC was contraindicated during pregnancy until 2018, but its usage in such patients is now approved. Despite the flare-up of RA during pregnancy, we were able to reduce the disease activity by introducing CZP and TAC during pregnancy. We believe that the present findings support the efficacy of this approach for treating RA flare during pregnancy.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Certolizumab Pegol; Female; Humans; Methotrexate; Placenta; Pregnancy; Tacrolimus; Treatment Outcome

To compare infectious risk between leflunomide versus TNF inhibitors (TNFi), and between tacrolimus versus TNFi among rheumatoid arthritis (RA) patients receiving methotrexate (MTX).. Using Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating TNFi, leflunomide, or tacrolimus. The primary outcome was any serious infections defined as a composite endpoint of serious bacterial, opportunistic, and herpes zoster infections. Secondary outcomes were individual components of the primary outcome. Propensity-score fine-stratification (PSS) and weighting were applied to adjust for confounding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing leflunomide versus TNFi, and tacrolimus versus TNFi.. Among 72,516 RA patients receiving MTX, we identified 3,336 TNFi initiators, 11,122 leflunomide initiators, and 5,136 tacrolimus initiators. Two study cohorts were 10,992 leflunomide initiators PSS-weighted on 1,623 TNFi initiators and 5,126 tacrolimus initiators PSS-weighted on 2,521 TNFi initiators. The incidence rate per 100 person-years of herpes zoster infection (3.70-4.27) was beyond 3-times that of serious bacterial infection (1.12-1.36), but opportunistic infection was relatively rare (0.11-0.23). The PSS-weighted HR [95% CI] for any serious infection was 1.03 [0.89-1.22] comparing leflunomide versus TNFi, and 0.91 [0.77-1.08] comparing tacrolimus versus TNFi. Analyses on the secondary outcomes showed consistent results.. In this nation-wide cohort study, we did not find a significant difference in the risk of serious infections (i.e., serious bacterial, opportunistic, and herpes zoster infections) between leflunomide versus TNFi, and between tacrolimus versus TNFi among RA patients receiving background MTX.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cohort Studies; Herpes Zoster; Humans; Infections; Leflunomide; Methotrexate; Tacrolimus; Tumor Necrosis Factor Inhibitors

Topics: Abatacept; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Humans; Methotrexate; Retrospective Studies; Tacrolimus; Treatment Outcome

To evaluate whether combinatorial use of abatacept (ABT) and tacrolimus (Tac) increases the risk of adverse events compared to their individual use in Japanese rheumatoid arthritis (RA) patients. We conducted a retrospective cohort study of RA patients using the Japanese multicenter database and analyzed the data of RA patients registered from April 2010 to March 2019 by comparing three treatment groups who received Tac, ABT, or a combination of both. We included patients who had initiated treatment with ABT or Tac and excluded patients who used tumor necrosis factor inhibitors, IL-6 inhibitors, and Jak inhibitors in the first year of our study. The primary outcome was the occurrence of adverse events such as infections that required hospitalization, newly diagnosed malignancy, or death from any cause after initiation of ABT or Tac. Of the 27,032 RA patients in the registry, 2009 patients were included. The Tac, ABT, and combination groups consisted of 1328, 563, and 118 patients, respectively. Primary outcome occurred in 149 (13.4%), 62 (13.5%), and 14 (13.9%) patients of the Tac, ABT, and combination groups, respectively. The incidence of adverse events between groups was not significantly different (p = 0.638). A Cox regression analysis which was adjusted for potential confounders such as age, disease activity, and concomitant use of prednisolone revealed no significant differences between groups. The combinatorial use of ABT and Tac, or ABT alone does not increase the risk of adverse events when compared to the use of Tac alone in RA patients in Japan. Key Points • This study included Japanese rheumatoid arthritis data and found that there was no significant risk when patients were treated with a combination of Tac and ABT or each drug alone.

Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Japan; Neoplasms; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Aged; Arthritis, Rheumatoid; Calcinosis; Female; Finger Joint; Glucocorticoids; Hand Joints; Humans; Immunosuppressive Agents; Injections, Intra-Articular; Prednisolone; Tacrolimus; Triamcinolone Acetonide

Tacrolimus (TAC) is a powerful immunosuppressive agent whose therapeutic applicability is confined owing to its systemic side effects.. Herein, we harnessed a natural polymer based bioconjugate composed of maltodextrin and α-tocopherol (MD-α-TOC) to encapsulate TAC as an attempt to overcome its biological limitations while enhancing its therapeutic anti-rheumatic efficacy.. The designed TAC loaded maltodextrin-α-tocopherol nano-micelles (TAC@MD-α-TOC) were assessed for their physical properties, safety, toxicological behavior, their ability to combat arthritis and assist bone/cartilage formation.. Overall, our designed bioconjugate micelles offered an excellent approach for improved TAC safety profile with enhanced anti-arthritic activity and unique bone formation characteristics.

Topics: Animals; Arthritis, Rheumatoid; Bone Regeneration; Chlorocebus aethiops; Humans; Micelles; Nanostructures; Polysaccharides; Tacrolimus; Tocopherols; Vero Cells

We aimed to evaluate the obstetric complications and the risk factors for these events in pregnant women with rheumatic diseases (RDs).. A single-center retrospective study of women with RDs at Hokkaido University Hospital between 2007 and 2016 was conducted. Clinical features and maternal and fetal outcomes were retrospectively collected. The rate of pregnancy complications was compared with the general obstetric population (GOP) in Japan.. Overall, 132 pregnancies in 95 women with RDs were recorded. Underlying RDs were systemic erythematosus (SLE) (. Pregnancies with RDs were at increased risk of having both maternal complications and adverse neonatal outcomes, indicating these pregnancies should be closely monitored.

Topics: Adult; Antibodies, Antinuclear; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Arthritis, Rheumatoid; Cesarean Section; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant, Newborn; Japan; Lupus Erythematosus, Systemic; Perinatal Mortality; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Rheumatic Diseases; Risk Factors; Tacrolimus

Abatacept (ABT) demonstrates good clinical efficacy and retention in rheumatoid arthritis (RA) patients. However, no rescue treatment option against inadequate response to ABT exists. Since tacrolimus (TAC) and ABT suppress T lymphocytes via different mechanisms and a combination of these agents could potentially be effective, this study aimed to examine the efficacy and safety of add-on TAC therapy in RA patients with inadequate response to ABT.. Of 550 patients treated with ABT and registered in a Japanese multicenter registry, 25 consecutive patients who underwent add-on TAC therapy and were followed for longer than 24 weeks were included in this study.. Mean patient age was 67.0 years, disease duration was 16.2 years, and duration of ABT treatment was 1.2 years at the initiation of add-on TAC therapy. Mean TAC dose was 1.2 mg/d at baseline and 1.6 mg/d at week 24. Mean Disease Activity Score of 28 joints - erythrocyte sedimentation rate was significantly improved at week 24 (3.35) relative to baseline (4.97). The proportion of patients who achieved low disease activity or remission was 40.0%, and the European League Against Rheumatism moderate or good response was 72.0%. ABT retention rate was 92.0% at week 24, as calculated by Kaplan-Meier analysis. Only one patient discontinued add-on TAC therapy due to an adverse event (itching sensation).. This is the first report describing the efficacy and safety profile of add-on TAC therapy with a focus on RA patients with inadequate response to ABT. Our findings suggest that add-on TAC therapy is a worthwhile complementary treatment option in daily clinical practice.

Topics: Abatacept; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Registries; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome; Tumor Necrosis Factor Inhibitors

In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-

Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Bone Resorption; Disease Progression; Etanercept; Humans; Male; Matrix Metalloproteinase 3; Mice; Mice, Inbred C57BL; Mice, Transgenic; Tacrolimus; Tumor Necrosis Factor-alpha

Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies are frequently detected in amyopathic dermatomyositis with rapidly progressive interstitial lung disease (RP-ILD). However, the presence of anti-MDA5 antibodies in other connective tissue diseases is not well known. We herein report a case of rheumatoid arthritis complicated with refractory anti-MDA5 antibody-positive ILD. A 75-year-old Japanese woman was referred to our hospital for refractory ILD. Serological testing was positive for anti-MDA5 antibody without any muscle or skin lesions. Immunosuppressive therapy (prednisolone and tacrolimus) ameliorated her symptoms as well as ILD. Anti-MDA5 antibody-positive ILD, as well as dermatomyositis with RP-ILD, can occur in patients with rheumatoid arthritis.

Topics: Aged; Arthritis, Rheumatoid; Autoantibodies; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Prednisolone; Radiography; Tacrolimus; Tomography, X-Ray Computed

The targeted delivery of therapeutics to sites of rheumatoid arthritis (RA) has been a long-standing challenge. Inspired by the intrinsic inflammation-targeting capacity of macrophages, a macrophage-derived microvesicle (MMV)-coated nanoparticle (MNP) was developed for targeting RA. The MMV was efficiently produced through a novel method. Cytochalasin B (CB) was applied to relax the interaction between the cytoskeleton and membrane of macrophages, thus stimulating MMV secretion. The proteomic profile of the MMV was analyzed by iTRAQ (isobaric tags for relative and absolute quantitation). The MMV membrane proteins were similar to those of macrophages, indicating that the MMV could exhibit bioactivity similar to that of RA-targeting macrophages. A poly(lactic- co-glycolic acid) (PLGA) nanoparticle was subsequently coated with MMV, and the inflammation-mediated targeting capacity of the MNP was evaluated both in vitro and in vivo. The in vitro binding of MNP to inflamed HUVECs was significantly stronger than that of the red blood cell membrane-coated nanoparticle (RNP). Compared with bare NP and RNP, MNP showed a significantly enhanced targeting effect in vivo in a collagen-induced arthritis (CIA) mouse model. The targeting mechanism was subsequently revealed according to the proteomic analysis, indicating that Mac-1 and CD44 contributed to the outstanding targeting effect of the MNP. A model drug, tacrolimus, was encapsulated in MNP (T-RNP) and significantly suppressed the progression of RA in mice. The present study demonstrates MMV as a promising and rich material, with which to mimic macrophages, and demonstrates that MNP is an efficient biomimetic vehicle for RA targeting and treatment.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cytochalasin B; Disease Models, Animal; Erythrocytes; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Hyaluronan Receptors; Macrophage-1 Antigen; Macrophages; Mice; Nanoparticles; Polyesters; Polylactic Acid-Polyglycolic Acid Copolymer; Proteomics; Tacrolimus

Membranous nephropathy (MN) caused by disease-modifying antirheumatic drugs is relatively common in patients with rheumatoid arthritis (RA). However, MN rarely occurs due to RA itself. We describe a 61-year-old woman with RA who showed nephrotic syndrome. She was admitted because of systemic edema and severe arthritis. She had a long history of RA successfully treated with methotrexate (MTX), but discontinued all treatments 4 years before hospitalization. She had never been treated with bucillamine or gold. Laboratory test results were positive for anti-cyclic citrullinated peptide antibody and negative for anti-nuclear antibody. Renal pathologic findings were compatible with MN. Immunofluorescence microscopy showed IgG, IgA, κ, λ, and C3 along the glomerular capillary wall, whereas deposition of IgM or C1q was not detected. In terms of the IgG subclasses, only IgG2 findings were positive. Results for glomerular antigen and serum antibody for M-type phospholipase A2 receptor and thrombospondin type 1 domain-containing 7A were negative. HLA type did not include the HLA-DQA1 gene that is a concern in primary MN (PMN). She responded to intensive immunosuppressive therapy consisting of prednisolone, tacrolimus, and MTX with a parallel reduction of proteinuria. Based on assessments for differentiating PMN from secondary MN (SMN), the diagnosis of the present case was incompatible with PMN. Taken together, we consider that SMN in the present case was due to RA itself rather than drug-induced MN.

Topics: Anti-Citrullinated Protein Antibodies; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Female; Glomerulonephritis, Membranous; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Methotrexate; Middle Aged; Nephrotic Syndrome; Prednisolone; Proteinuria; Tacrolimus; Treatment Outcome

This study aimed to evaluate the relationships between concomitant biologic disease-modifying anti-rheumatic drugs (DMARDs) and prednisolone administration and blood tacrolimus exposure or serum CYP3A4/5-related markers in rheumatoid arthritis (RA) patients without severe disease activity.. Forty-six RA patients treated with oral tacrolimus once daily for maintenance of clinical remission to moderate disease activity were enrolled. The blood concentrations of tacrolimus and its major metabolite were determined at 12 h after the evening dosing. Blood samples for determination of serum markers including 4β-hydroxycholesterol (4β-OHC), 25-hydroxyvitamin D (25-OHD) and interleukin-6 (IL-6), and CYP3A5 genotype were collected.. Most enrolled patients had RA with clinical remission to mild disease activity. Concomitant tocilizumab or low-dose prednisolone administration did not alter the blood tacrolimus exposure. Serum 4β-OHC level was lower in tocilizumab co-treated patients than in the biologic DMARD non-treated patients. The blood tacrolimus concentration was inversely correlated with the serum level of 25-OHD, but not 4β-OHC and IL-6. The serum level of 4β-OHC was positively associated with that of 25-OHD. No correlations were observed between the serum levels of CYP3A4/5 activity markers and IL-6. The patients with the homozygous CYP3A5*3 had the higher blood tacrolimus concentration, while CYP3A5*3 allele was not associated with the serum levels of 4β-OHC and 25-OHD.. Concomitant use of tocilizumab or low-dose prednisolone had no effect on the pharmacokinetics of tacrolimus, while tocilizumab lowered serum 4β-OHC. Blood tacrolimus exposure was negatively associated with serum 25-OHD in RA patients with clinical remission to moderate disease activity.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Cytochrome P-450 CYP3A; Female; Humans; Hydroxycholesterols; Immunosuppressive Agents; Limit of Detection; Male; Middle Aged; Prednisolone; Tacrolimus; Vitamin D

A 71-year-old woman being treated with methotrexate (MTX) and tacrolimus (TAC) for rheumatoid arthritis (RA) was admitted to our hospital and underwent surgery for gastric perforation and peritonitis. An endoscopic examination six days post-surgery showed an extensive ulcer in the stomach, and a biopsy revealed diffused large B-cell lymphoma. We diagnosed her with immunodeficiency-associated lymphoproliferative disorder (LPD) and discontinued the MTX and TAC. She underwent gastrectomy due to stenosis approximately two months after the first operation, but the histopathological findings of lymphoma had disappeared. LPD should be considered as a potential cause of gastric perforation during RA treatment.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biopsy; Female; Humans; Iatrogenic Disease; Lymphoproliferative Disorders; Methotrexate; Peptic Ulcer Perforation; Tacrolimus

To assess the long-term efficacy and safety of adding tacrolimus for patients with active rheumatoid arthritis (RA) despite anti-tumor necrosis factor (TNF) therapy with methotrexate.. Consecutive patients who were treated with adding tacrolimus onto anti-TNF therapy with methotrexate for active RA despite anti-TNF therapy with methotrexate, were retrospectively analyzed in terms of treatment response, achieving remission, subsequent treatment tapering and adverse events.. Fifteen patients could be analyzed. Median symptom duration was 2.9 years and prior duration of anti-TNF therapy was 40 weeks. Median value of Disease Activity Score in 28 joints was 4.6. Five, eight and two were on infliximab, etanercept and adalimumab at the onset of tacrolimus, respectively. At 2 years, the proportions of patients achieving responses of American College of Rheumatology 50, 70 and 90, were 80%, 73% and 40%, respectively, and those achieving remission as defined by Simplified Disease Activity Index ≤ 3.3 were 67%. All patients could discontinue oral glucocorticoids and 10 had been successfully withdrawn from anti-TNF therapy for more than 1 year at the final observation.. Adding tacrolimus onto anti-TNF therapy is a promising therapeutic option with sustained benefit for refractory RA patients despite treatment with anti-TNF therapy combined with methotrexate.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Remission Induction; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Integrin, alpha9 subunit (hereinafter, alpha9) has been identified as a novel putative therapeutic target for rheumatoid arthritis (RA). Support for this target comes from the observations that alpha9 is overexpressed both in the joints of RA patients and in animal models of arthritis. In the experimental models, the increase in alpha9 expression precedes the onset of arthritic symptoms. The current study presents data on the pharmacological profile of an anti-alpha9 antibody in a collagen-induced arthritis (CIA) mouse model. Administration of an alpha9-blocking antibody in CIA mice suppressed the development of arthritis and significantly decreased plasma level of activated fibroblast-like synoviocyte (FLS)-derived biomarkers without reducing the formation of anti-type II collagen antibodies. While anti-alpha9 antibody administration significantly suppress the accumulation of immune cells in arthritic joints it had no effect on immune cell number in the spleen. Furthermore, in non-arthritic mice, alpha9 had no inhibitory effect in either a mixed lymphocyte reaction (MLR) or in a delayed type hypersensitivity (DTH) reaction. These results suggest that blocking alpha9 exerts its anti-arthritic effect through suppression of FLS-activation via a non-immune mediated mechanism. Finally, therapeutic administration of anti-alpha9 antibody alleviated established arthritis in CIA mice. Our data provide evidence that alpha9 blockade is a promising therapy for joint inflammation with minimal systemic immunomodulation.

Topics: Animals; Antibodies; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Biomarkers; Cells, Cultured; Collagen Type II; Humans; Immunomodulation; Integrins; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Tacrolimus; Treatment Outcome

Tacrolimus (TAC) is an important drug for inflammatory diseases. However, TAC has several limitations, such as variable trough concentrations among individuals and a high medication frequency. In this study, we created NK61060, a novel micellar TAC formulation, to circumvent these disadvantages.. Immunosuppressive activity of NK61060 was determined in the collagen-induced arthritis rat model, mannan-induced arthritis mouse model and dextran sodium sulfate-induced colitis mouse model. The pharmacokinetics and toxicology of NK61060 were evaluated in those models.. In arthritis and colitis models, NK61060 exhibited superior immunosuppressive activity compared with that of TAC. Pharmacokinetic and toxicological analyses indicated that NK61060 had a wider safety margin and could be administered at a reduced medication frequency.. NK61060 mitigates the trough concentration variability and the medication frequency and it may be a safer and more effective option for use in clinical settings. Further studies are needed to determine its clinical usefulness.

Topics: Animals; Area Under Curve; Arthritis, Experimental; Arthritis, Rheumatoid; Colitis, Ulcerative; Collagen; Dextran Sulfate; Drug Administration Schedule; Drug Carriers; Drug Evaluation, Preclinical; Female; Humans; Immunosuppressive Agents; Mannans; Mice; Mice, Inbred ICR; Micelles; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Tacrolimus

To investigate the drug survival rate of tacrolimus (TAC) and analyze the potential predictors of this rate in patients with rheumatoid arthritis (RA) in routine care.. In this retrospective longitudinal study, we enrolled 102 RA patients treated with TAC from April 2009 to January 2014 at a tertiary center in South Korea. The causes of TAC discontinuation were classified as lack of efficacy (LOE), adverse events (AEs), and others. The drug survival rate was estimated using the Kaplan-Meier method and the predictors of this rate were identified by Cox-regression analyses.. TAC was discontinued in 27 of 102 RA patients (26.5%). The overall 1-, 2-, 3-, and 4-year TAC continuation rates were 81.8%, 78.4%, 74.2%, and 69.1%, respectively and the median follow-up period from the start of TAC was 32.5 months. The number of TAC discontinuations due to LOE, AEs, and others were 15 (55.6%), 11 (40.7 %), and 1 (3.7%), respectively. The baseline high disease activity was a significant risk factor for TAC discontinuation after adjusting for confounding factors (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.16 to 5.35;. In our study, TAC showed a good overall survival rate in patients with RA in real clinical practice. This suggests that the long-term TAC therapy has a favorable efficacy and safety profile for treating RA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Republic of Korea; Retrospective Studies; Tacrolimus; Treatment Outcome; Withholding Treatment

The purpose of this study was to describe the impact of sex and cytochrome P450 3A5 (CYP3A5) variant on the blood concentration of tacrolimus in patients with systemic lupus erythematosus or rheumatoid arthritis. The blood concentration of tacrolimus (ng/mL) divided by the daily dose of tacrolimus (mg/day) and the patient's weight (kg) (C/D) was obtained from 55 patients. The C/D value was analysed according to genetic variation in CYP3A5 or ATP binding cassette subfamily B member 1 (ABCB1), sex, and age. The C/D value in the CYP3A5*3/*3 group was significantly higher than in the CYP3A5*1/*1 and *1/*3 groups (p < 0.05, effect size: d = 1.40). In the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in men than in women (p < 0.05, effect size: d = 1.78). Furthermore, in the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in women aged over 50 years than in women aged under 50 years (p < 0.05, effect size: d = 1.18). In contrast, ABCB1 genetic variations did not show any significant effect on the C/D value. Since the blood concentration of tacrolimus in patients with CYP3A5*3/*3 varies depending on sex and age, these factors should be considered when studying the difference of sex in CYP3A.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Biomarkers; Cytochrome P-450 CYP3A; Female; Gene Expression Regulation, Neoplastic; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Sex Factors; Tacrolimus; Tissue Distribution; Young Adult

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Betamethasone; Drug Eruptions; Female; Humans; Immunosuppressive Agents; Middle Aged; Tacrolimus

  A 65-year-old woman with a 17-year history of polymyositis and 8-year history of rheumatoid arthritis who was treated with a low dose of prednisolone and tacrolimus (Tac) was admitted to our hospital because of general malaise and hypertension. Blood tests showed thrombocytopenia, hemolytic anemia with fragmented erythrocytes, and hypercreatinemia. Based on these clinical features, she was diagnosed with thrombotic micro-angiopathy (TMA). Thrombocytopenia and hemolytic anemia with fragmented erythrocytes improved with the discontinuation of Tac and plasma exchange; however, hypertension and renal dysfunction persisted. TMA due to calcineurin inhibitor (CNI) nephropathy was suspected based on the histopathological findings of renal biopsy. However, the condition was atypical of a CNI nephropathy because the trough level of Tac was lower than that reported previously and renal dysfunction persisted after drug discontinuation. She had mild sclerodactylia and Raynaud's symptoms, although the diagnostic criteria for systemic sclerosis (SSc) were not satisfied. Moreover, the patient tested positive for anti PL-7 antibody. The relationship between anti PL-7 antibody and pathogenesis of SSc has been reported. In this case, it was suspected that CNI nephropathy worsened because of the potential basic factors of SSc. These findings indicate that TMA may occur in patients testing positive for anti PL-7 antibody who are treated with Tac.

Topics: Aged; Amino Acyl-tRNA Synthetases; Arthritis, Rheumatoid; Autoantibodies; Biomarkers; Calcineurin Inhibitors; Female; Humans; Plasma Exchange; Polymyositis; Tacrolimus; Thrombotic Microangiopathies; Withholding Treatment

To describe the efficacy of adding tacrolimus to maintain remission in patients with rheumatoid arthritis (RA) on methotrexate after discontinuation of tumor necrosis factor inhibitor (TNFi) therapy.. Consecutive patients with RA, who resumed a TNFi to treat flares after initial TNFi-free remission and discontinued a TNFi again after achieving remission and adding tacrolimus were enrolled. The lengths of remission after discontinuation of TNFi without or with tacrolimus were analyzed.. Thirteen TNFi-free periods in six patients, in which seven were without and six were with tacrolimus were analyzed. All were seropositive females with a median age of 46 years and symptom duration of 1.2 years at the onset of TNFi therapy. Two were treated with infliximab and four were with etanercept. The median dose of tacrolimus was 2 mg/day with trough level of 4.5 ng/ml. The length of time to flare after discontinuation of TNFi therapy with tacrolimus was significantly longer than those without tacrolimus (median 107 weeks [range 4-207] versus 13 weeks [2-36]). After adding tacrolimus, only one patient resumed TNFi therapy and three had no flare until final observation.. Add-on tacrolimus was effective in maintaining TNFi-free remission in patients with RA who ever relapsed after TNFi-free remission.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Monitoring; Etanercept; Female; Humans; Infliximab; Japan; Longitudinal Studies; Male; Medication Therapy Management; Methotrexate; Middle Aged; Remission Induction; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha; Withholding Treatment

Tocilizumab (TCZ) shows good retention in patients with rheumatoid arthritis (RA), but no previous reports demonstrated hopeful treatment options against inadequate response to TCZ. Tacrolimus (TAC) has proved to show efficacy against inadequate response to tumor necrosis factor alpha inhibitors, yet its add-on effects on TCZ remain unknown.. Twenty patients with RA (17 women, age 58.6 years, disease duration 12.1 years, prior TCZ duration 2.6 years, 18 intravenous [8 mg/kg/month] and 2 subcutaneous [324 mg/month] TCZ treatments, methotrexate 6.1 mg/week [70.0%]) who showed an inadequate response to TCZ (clinical disease activity index [CDAI] ≥ 5.8, 18 secondary non-responders) were additionally treated with TAC (1.1 mg/day), and enrolled in this 24-week, prospective study.. Seventeen patients (85.0%) continued the treatment for 24 weeks. Statistically significant decreases in outcome measures were as follows: disease activity score based on 28 joints with C-reactive protein (DAS28-CRP) from 3.3 at baseline to 2.1 at week 24 (p < 0.001), CDAI from 17.7 to 7.6 (p < 0.001), and serum matrix metalloproteinase-3 levels from 232.8 to 66.2 ng/ml (p < 0.001). About 15 patients (75%) achieved low disease activity or remission (DAS28-CRP ≤2.7 or CDAI ≤10) at week 24.. Adding low-dose TAC to inadequate responders to TCZ may be a promising complementary treatment option.

Topics: Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Drug Monitoring; Female; Humans; Japan; Male; Matrix Metalloproteinase 3; Middle Aged; Patient Acuity; Prospective Studies; Remission Induction; Severity of Illness Index; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Administration, Oral; Aged; Alopecia Areata; Arthritis, Rheumatoid; Female; Hair; Humans; Immunosuppressive Agents; Tacrolimus

The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8 months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bone Resorption; Cathepsin K; Cell Differentiation; Drug Therapy, Combination; Female; Humans; Male; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Methotrexate; Middle Aged; Osteoclasts; Prospective Studies; Real-Time Polymerase Chain Reaction; Ribonucleosides; Severity of Illness Index; Tacrolimus

Albumin is considered an attractive dug carrier for hydrophobic drugs to target inflamed joints of rheumatoid arthritis. This study focused on the pharmaceutical potential of albumin-based nanoparticles (NPs) on delivery of tacrolimus (TAC) to enhance targetability and anti-arthritic efficacy. TAC-loaded human serum albumin (HSA) nanoparticles (TAC HSA-NPs) were prepared using the nab™ technology. The resulting NPs were 185.8 ± 6.8 nm in diameter and had a zeta potential value of -30.5 ± 1.1 mV, as determined by dynamic light scattering. Particles were uniformly spherical in shape as determined by transmission electron microscopy. The encapsulation efficacy of TAC was 79.3 ± 3.7% and the water solubility was over 46 times greater than that of free TAC. TAC was gradually released from NPs over 24h, which is sufficient time for targeting and treatment of the NPs in inflamed arthritis via intravenous injection. In vitro study using splenocytes excised from spleens of mice following induction of arthritis using collagen clearly demonstrated the anti-proliferative activity of TAC HSA-NPs on activated T cells compared with non-activated T cells. Furthermore, TAC HSA-NPs displayed significantly more anti-arthritic activity than TAC formulations including intravenously administered TAC solution or oral TAC suspension, as reflected by the incidence of arthritis and clinical score (1.6 vs. 3.2 and 5.0, respectively). These improvements were due to the targetability of HSA that facilitated the accumulation of TAC HSA-NPs at inflamed arthritis sites. TAC HSA-NPs are a promising drug delivery system to enhance water solubility and increase accumulation in joints for treatment of rheumatoid arthritis.

Topics: Administration, Intravenous; Animals; Arthritis, Rheumatoid; Cell Proliferation; Collagen; Drug Carriers; Drug Liberation; Humans; Joints; Male; Mice; Nanoparticles; Particle Size; Serum Albumin; Solubility; T-Lymphocytes; Tacrolimus

We retrospectively investigated the inhibitory effect on radiographic joint damage (RJD) for non-biological disease-modifying antirheumatic drug (non-bioDMARD) monotherapy or methotrexate (MTX) combination therapy for rheumatoid arthritis (RA) in the disease activity score with 28 joint counts with erythrocyte sedimentation rate (DAS28) remission.. Eighty-four patients (55 cases of monotherapy, 29 cases of MTX-combination therapy) in DAS28 remission (DAS28 ≤ 2.6) were investigated from 538 RA patients newly registered between February 2007 and August 2010. The patients were analyzed for radiological assessments using the modified total Sharp score/year (mTSS/y).. The remission rates and ΔmTSS/y for each agent using monotherapy were 7.1% and 0.17 for sulfasalazine; 11.9% and 0.49 for bucillamine (BUC); and 23.9% and 2.06 for MTX. Those using combination therapy were 6.8% and 1.39 for MTX + BUC; 23.5% and -1.64 for MTX + leflunomide; and 8.0% and 0.31 for MTX + tacrolimus. The cumulative distribution in the single and combination therapy groups showed improvement of percentages in structural remission from baseline to 1-year treatment, 34.1% to 60.9% (P < 0.05) and from 0% to 56.7%(P < 0.0001), respectively. Baseline mTSS (r = 0.67, P < 0.0001), disease duration (r = 0.40, P < 0.01), swollen joint counts (r = 0.33, P < 0.05), and anti-cyclic citrullinated peptide antibody (r = 0.31, P < 0.05) were useful predictors of RJD for non-bioDMARD monotherapy, but not for combination therapy.. Satisfactory inhibition of RJD was observed in the DAS28 remission cases of monotherapy or MTX combination therapy with a non-bioDMARD.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Disease Progression; Drug Therapy, Combination; Female; Foot Joints; Hand Joints; Humans; Isoxazoles; Leflunomide; Male; Methotrexate; Middle Aged; Radiography; Retrospective Studies; Tacrolimus; Treatment Outcome

Tacrolimus (TAC) and abatacept (ABT) inhibit T-cells via different mechanisms and, in combination, may be effective against rheumatoid arthritis. However, they may also disrupt normal immune functions. We compared the efficacy and safety of ABT administered to patients in combination with TAC, methotrexate (MTX), or other drugs.. This was a retrospective multicenter study conducted to compare the efficacy and safety of ABT in 211 patients: the drug was administered together with TAC (ABT+ TAC group; 22 patients), MTX (ABT+ MTX group; 102 patients), or patients treated without concomitant MTX or TAC (ABT mono group; 87 patients). The disease activity, treatment continuation rate, and reason for discontinuation of treatment were investigated.. The retention rate at Week 24 was similar in the three groups. There were no cases of discontinuation related to the appearance of adverse events in the ABT+ TAC group. At Week 24, according to the European League Against Rheumatism response criteria, the "good" response rates were 33.3%, 13.4%, and 13.4% in the ABT+ TAC, ABT+ MTX, and ABT mono groups, respectively. Statistically significant decreases in various disease activity scores/indices were observed in all the groups as early as Week 4.. Although the sample size was small, the results of this retrospective study suggest that the ABT+ TAC combination therapy has at least comparable safety and efficacy to those of the ABT+ MTX combination, and that it can thus be a useful option for patients who cannot take MTX.

Topics: Abatacept; Adult; Aged; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Male; Methotrexate; Middle Aged; Registries; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

This study aimed to evaluate the blood exposure of and clinical responses to tacrolimus based on genetic variants of CYP3A5 and ABCB1 in patients with rheumatoid arthritis.. Seventy rheumatoid arthritis patients treated with oral tacrolimus once daily were enrolled. Blood concentrations of tacrolimus and its major metabolite 13-O-demethylate at 12h after dosing were determined. The relationships between the tacrolimus pharmacokinetics and efficacy, renal function, and CYP3A5 and ABCB1 genotypes were evaluated.. Dose-normalized blood concentration of tacrolimus was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. A lower metabolic ratio of 13-O-demethylate to tacrolimus was observed in the CYP3A5*3/*3 group. The ABCB1 3435TT group had higher dose-normalized blood concentrations of tacrolimus and 13-O-demethylate. The blood tacrolimus concentration was inversely correlated with the estimated glomerular filtration rate (eGFR). ABCB1 C3435T but not CYP3A5 genotype had decreased eGFR. Patients lacking the CYP3A5*3 allele had a higher incidence of tacrolimus withdrawal.. CYP3A5*3 increased the blood exposure of tacrolimus through its metabolic reduction. ABCB1 C3435T led to a higher blood exposure of tacrolimus and its major metabolite. The ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affected renal function in rheumatoid arthritis patients.

Topics: Administration, Oral; Aged; Alleles; Arthritis, Rheumatoid; ATP Binding Cassette Transporter, Subfamily B; Biotransformation; Cytochrome P-450 CYP3A; Drug Monitoring; Female; Gene Frequency; Humans; Immunosuppressive Agents; Kidney; Kidney Function Tests; Male; Middle Aged; Polymorphism, Single Nucleotide; Tacrolimus; Treatment Outcome

This observational retrospective study examined whether abatacept efficacy could be augmented with concomitant methotrexate (MTX) or tacrolimus (TAC) in patients with rheumatoid arthritis (RA) who experienced failure with prior biological disease-modifying antirheumatic drugs (DMARDs) and in whom favorable therapeutic efficacy is difficult to achieve. All patients with a prior biological DMARD history who were treated with abatacept for 52 weeks and registered in a Japanese multicentre registry were included. Clinical efficacy and safety of abatacept according to the concomitant drug used, i.e., none (ABT-mono), MTX (ABT-MTX), and TAC (ABT-TAC), were compared. A greater mean percent change of DAS28-ESR was observed in the ABT-TAC group compared with the ABT-mono group at weeks 12 (-20.5 vs. -5.4 %, p = 0.035) and 24 (-25.0 vs. -11.0 %, p = 0.036). ABT-MTX and ABT-TAC groups had a significantly higher proportion of patients who achieved low disease activity (LDA) within 52 weeks compared with the respective baselines, while no significant change was observed in the ABT-mono group. A higher proportion of patients in the ABT-TAC group achieved EULAR moderate response compared with the ABT-mono group at week 52 (66.7 vs. 35.0 %, p = 0.025). Multivariate logistic regression analysis revealed that concomitant TAC use was independently associated with the achievement of LDA and EULAR response at 52 weeks, while concomitant MTX use was not. Concomitant TAC use may offer a suitable option for RA patients treated with abatacept after prior biological DMARD failure, likely because both abatacept and TAC affect T cell activation.

Topics: Abatacept; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Methotrexate; Middle Aged; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

Polyomavirus nephropathy is commonly seen in the renal allograft setting but is uncommon in native kidneys. This paper describes polyomavirus nephropathy that developed in the native kidneys of a patient following immunosuppressive therapy for rheumatoid arthritis/Sjögren's syndrome associated lung disease. The patient presented with dyspnoea and a slow steady rise in serum creatinine. Owing to chronic immunosuppression, calcineurin-inhibitor toxicity was suspected. However, renal biopsy revealed polyomavirus nephropathy. The treatment of choice, lowered immunosuppression, was complicated by exacerbation of the patient's lung disease. This case highlights features of polyomavirus nephropathy in the native kidney, as well as the difficulty in its treatment when immunosuppressive treatment is necessary for medical comorbidities.

Topics: Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Polyomavirus; Polyomavirus Infections; Pulmonary Fibrosis; Tacrolimus

Tacrolimus (TAC) is an immunosuppressive macrolide that blocks T-cell activation by specifically inhibiting calcineurin. TAC was approved in Japan for the treatment of rheumatoid arthritis (RA) in 2005. However, the safety and effectiveness of TAC adding on to biological disease-modifying anti-rheumatic drugs (DMARDs) in the real clinical setting may not be clear enough.. We report here the interim results of post marketing surveillance (PMS) of TAC adding on to biological DMARDs in RA patients who failed to show an adequate response to biological DMARDs.. Patients who had an inadequate response to biological DMARDs were enrolled. An inadequate response to biological DMARDs was defined as that all of the following conditions were met: a Simplified Disease Activity Index (SDAI) score of >3.3 when TAC was started; both the tender joint count and swollen joint count were the same or increased compared with those at 4-8 weeks prior to TAC; and biological DMARDs were used for at least 8 weeks prior to TAC. This study was conducted in compliance with the ministerial ordinance on "Good Post-Marketing Study Practice" (GPSP).. The safety data collection and evaluation for 172 patients and effectiveness data collection and evaluation for 165 patients were reported. The mean age was 61.9 years. Adverse drug reactions occurred in 18 patients. The mean SDAI decreased from 20.1 at baseline to 11.7 at week 24.. TAC is well tolerated and effective when added on to biological DMARDs in RA patients who failed to achieve an adequate response to biological DMARDs.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Resistance; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Product Surveillance, Postmarketing; Tacrolimus

To examine the inhibitory effect of tacrolimus on radiographic joint damage in patients with rheumatoid arthritis (RA).. Thirty-eight patients with RA resistant or intolerant to conventional disease-modifying anti-rheumatic drugs were administered tacrolimus and analyzed retrospectively. Disease activity and clinical response were evaluated by Disease Activity Score in 28 joints and C-reactive protein (DAS28-CRP) and European League Against Rheumatism (EULAR) response criteria. The progression of joint destruction was evaluated by an estimated yearly change in modified Total Sharp Score (mTSS).. Good or moderate response rate according to EULAR response criteria was seen in 63.2%, 63.2%, 73.7% and 65.8% of patients at 3, 6, 12, and 24 months, respectively. The rate of patients with low disease activity or remission reached 47.3% and 50.0% at 12 and 24 months, respectively. Progression of joint damage, evaluated as yearly change in mTSS (ΔmTSS), significantly decreased from 11.4 at baseline to 2.63 in the first year and 0.69 in the second year of tacrolimus treatment.. These findings suggest tacrolimus has the potential to inhibit progression of joint damage in established RA.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Arthrography; Disease Progression; Female; Humans; Joints; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome

A post-marketing surveillance (PMS) program was implemented to assess the safety and effectiveness of tacrolimus (TAC) in Japanese rheumatoid arthritis (RA) patients and to identify risk factors related to adverse drug reactions (ADRs).. Patients were registered centrally and monitored for all adverse events (AEs) for 24 weeks. Effectiveness was evaluated using the Disease Activity Score 28-CRP (DAS28-CRP).. Data from 3,172 patients (mean age 62.2 years) were evaluated in the safety analysis. Of the safety population, 78.5 %were female and 25.9 % were in Steinbrocker's functional class 3 or 4. TAC was prescribed as monotherapy in 52.5 % and the most common concomitant disease modifying antirheumatic drug (DMARD) was methotrexate, used in 28.9 % of the patients. The incidence of AEs, serious AEs (SAEs), ADRs and serious ADRs were 41.2, 6.4, 36.0, and 4.9 %, respectively. The most frequent serious ADR category was infections and infestations. Age ≥ 65 years, concurrent renal dysfunction, and concurrent diabetes mellitus were identified as significant risk factors for ADR. Based on EULAR response criteria, 65.4 % of the patients showed moderate or good response.. The results demonstrate that TAC is well tolerated by Japanese patients with active RA, including those receiving concomitant methotrexate, in the real world.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Asian People; Drug Therapy, Combination; Female; Humans; Male; Methotrexate; Middle Aged; Product Surveillance, Postmarketing; Risk Factors; Severity of Illness Index; Tacrolimus; Treatment Outcome

To describe current trends in the numbers of rheumatoid arthritis (RA)-related surgeries.. The number of operations was determined for patients with RA in a large observational cohort [Institute of Rheumatology, Rheumatoid Arthritis (IORRA)] enrolled from 2001 to 2012.. The total number of operations peaked in 2002 and gradually decreased thereafter, but began to increase again in 2008. The number of total knee replacements has decreased since 2003, while the number of wrist and foot arthroplasties and the number of artificial finger prosthesis surgeries have increased gradually.. Our results suggest that the number of orthopedic surgeries may change in response to changes in the drug therapy for RA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Chromones; Cohort Studies; Databases, Factual; Female; Humans; Japan; Joints; Male; Orthopedic Procedures; Piperidines; Pyrimidines; Pyrroles; Quality of Life; Sulfonamides; Tacrolimus

This study investigated whether the calcineurin inhibitor, tacrolimus, suppresses receptor activator of NF-κB ligand (RANKL) expression in fibroblast-like synoviocytes (FLS) through regulation of IL-6/Janus activated kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling (SOCS3) signaling.. The expression of RANKL, JAK2, STAT3, and SOCS3 proteins was assessed by western blot analysis, real-time PCR and ELISA in IL-6 combined with soluble IL-6 receptor (sIL-6R)-stimulated rheumatoid arthritis (RA)-FLS with or without tacrolimus treatment. The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum. Immunofluorescent staining was performed to identify the effect of tacrolimus on RANKL and SOCS3. The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.. We found that RANKL expression in RA FLS is regulated by the IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. Inhibitory effects of tacrolimus on RANKL expression in a serum-induced arthritis mice model were identified. Tacrolimus inhibits RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing STAT3. Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus. As compared to dexamethasone and methotrexate, tacrolimus more potently suppresses RANKL expression in FLS. By up-regulating SOCS3, tacrolimus down-regulates activation of the JAK-STAT pathway by IL-6/sIL-6R trans-signaling, thus decreasing RANKL expression in FLS.. These data suggest that tacrolimus might affect the RANKL expression in IL-6 stimulated FLS through STAT3 suppression, together with up-regulation of SOCS3.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Blotting, Western; Calcineurin Inhibitors; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Humans; Interleukin-6; Janus Kinase 2; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; RANK Ligand; Real-Time Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Synovial Membrane; Tacrolimus

Tacrolimus is an immunosuppressive drug used to prevent acute rejection following organ transplantation and to treat autoimmune disease. Tacrolimus is usually prescribed in such situation at a dose of 3.0 mg/day. Pneumocystis pneumonia induced by this dose of tacrolimus has been reported in many cases; however, we encountered a rare case of Pneumocystis pneumonia induced by low-dose tacrolimus and methylprednisolone.. We herein report the case of an 82-year-old Asian Japanese female with rheumatoid arthritis and Pneumocystis pneumonia who was being treated with low-dose tacrolimus and low-dose methylprednisolone therapy. She was diagnosed with rheumatoid arthritis at 52 years of age and was administered oral low-dose methylprednisolone and salazosulfapyridine. Her condition had been stable under this treatment for 30 years. However, her arthralgia worsened three months before admission. The salazosulfapyridine was changed to tacrolimus (0.5 mg/day) by her physician, and her arthralgia almost completely disappeared. She was admitted to our hospital for Pseudomonas pneumonia, and her symptoms improved almost completely with intravenous ceftazidime therapy. However, on the 14th day of admission, she developed acute respiratory failure due to Pneumocystis pneumonia and died on the 17th day of admission in spite of adequate treatment.. Our report highlights the importance of providing prompt prevention, diagnosis and treatment of Pneumocystis pneumonia in rheumatoid arthritis patients under tacrolimus and low-dose methylprednisolone therapy.

Topics: Aged; Aged, 80 and over; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Female; Humans; Methylprednisolone; Pneumonia, Pneumocystis; Tacrolimus

We report two cases of falsely elevated levels of Tacrolimus (TAC) measured by affinity column mediated immunoassay (ACMIA). Potential reasons for this are herein explored. Patient 1, a post-renal transplantation patient, was treated by TAC, while patient 2, a patient with rheumatoid arthritis, was not. TAC levels measured by ACMIA of patients 1 and 2 were greater than 40 and 20 ng/ml, respectively. In patient 2, rheumatoid factor (RF) levels were constantly higher than 1,000 IU/ml, and levels of TAC were shown to be correlated with RF. Results of immunoglobulin adsorption tests and gel filtration suggested that the false positivities for TCA were induced by IgG of patient 1 and IgM of patient 2. After the addition of anti-TAC antibody, levels of TAC decreased to an undetectable range in both cases. TAC levels also became undetectable after the addition of MAK33-Framework IEP in patient 1 and IIR in patient 2. In patient 2, the addition of HBR-1 and MAK absorbent prevented the false positive phenomenon. In both cases, human anti mouse antibodies (HAMAs) reacted to anti-TAC mouse monoclonal antibodies within the reagent and produced falsely elevated results. These results were inhibited by MAK33-Framework IEP binding to the hyper-variable region of immunoglobulin; therefore, the causative agent of this phenomenon in patient 1 was likely an anti-idiotype antibody against the mouse monoclonal anti-TAC antibody used in the assay. Furthermore, a close relationship between measured levels of TAC and RF, along with the finding that the addition of HBR-1 and IRR prevents false positive results, suggests that RF produced false positive results through IgM-HAMA activity in patient 2. These data indicate that false positive results of TAC can be due to the presence of HAMAs with different specificities.

Topics: Antibodies, Anti-Idiotypic; Arthritis, Rheumatoid; Chromatography, Affinity; Chromatography, Gel; Female; Humans; Immunoassay; Immunoglobulin M; Middle Aged; Tacrolimus

Tacrolimus is a calcineurin inhibitor, and it is used for the treatment of rheumatoid arthritis (RA). It works by inhibiting nuclear factor of activated T cells and inducting immunosuppression. This study aims to evaluate the influence of tacrolimus on the bone metabolism of patients with RA. Twenty-eight RA patients in three centers received tacrolimus 3 mg once daily for 24 weeks. Blood samples for evaluating bone metabolism and cytokines were collected at Weeks 0 and 24. We measured the serum C-telopeptide of type I collagen (sCTx-I), osteocalcin and inflammatory cytokines. We analyzed the data using the Kruskal-Wallis test and Spearman's correlation. IL-2 and IL-6 were significantly decreased after the administration of tacrolimus (p = 0.027 and p = 0.024). There was no significant difference in the serum level of sCTx-I before and after treatment. The level of serum osteocalcin at Week 24 was significantly increased compared to the level at Week 0 (p = 0.002). The increase of osteocalcin was correlated with the reductions of IL-2 and IFN-γ (r = 0.405, p = 0.033 and r = 0.380, p = 0.046, respectively). Tacrolimus treatment increased bone formation markers in RA patients. This suggests that tacrolimus may play a role to inhibit bone erosion by increasing bone formation as well as improving the clinical symptoms of RA.

Topics: Adult; Aged; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Interleukin-2; Interleukin-6; Male; Middle Aged; Osteocalcin; Osteogenesis; Tacrolimus

To identify the value of magnetic resonance imaging (MRI)-proven bone edema in patients with very early rheumatoid arthritis (RA).. All of the 13 patients included in the study were positive at entry for MRI-proven bone edema of the wrist and finger joints and anti-cyclic citrullinated peptide antibodies or IgM-rheumatoid factor. A tight control approach was applied for 12 months. Plain MRI and radiographs of both wrist and finger joints were examined every 6 months. MRI was scored by the RA MRI scoring (RAMRIS) technique and plain radiographs were scored using the Genant-modified Sharp score. Variables that were correlated with plain radiographic changes at 12 months were examined.. Simplified disease activity index (SDAI) remission was achieved in 7 patients, and a significant reduction in the RAMRIS bone edema score, which declined to <33 % as compared with the baseline, was achieved in 8 out of 13 patients. Four patients showed plain radiographic progression while 9 patients did not. Significant reductions in the RAMRIS bone edema score (p = 0.007) and the time-integrated SDAI (p = 0.031) were the variables involved in plain radiographic progression.. Improvement in bone edema may be associated with protection against structural damage in very early RA patients managed using the tight control approach.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Bone Diseases; Disease Progression; Edema; Female; Finger Joint; Humans; Magnetic Resonance Imaging; Male; Methotrexate; Middle Aged; Radiography; Sulfasalazine; Tacrolimus; Treatment Outcome; Wrist Joint

To assess the long-term safety and efficacy of tacrolimus (TAC) used in combination with oral methotrexate (MTX) in patients with rheumatoid arthritis (RA) whose disease remains active despite treatment with MTX alone. The clinical courses of 24 RA patients who received TAC added to MTX from a single center were analyzed retrospectively. The disease activity was evaluated by the DAS28-ESR(3) every 12 months after the addition of TAC, and side effects were evaluated for 3 years. At 3 years after starting the treatment, TAC was still being used by 19 patients (79 %). The causes of discontinuation were an inadequate response (3 cases), oral ulcers and elevation of creatinine (1 case), and worsening of interstitial pneumonia (1 case). No death was registered. The DAS28-ESR(3) was decreased from 4.81 to 3.41 after 3 years of treatment. The doses of prednisolone were decreased from 5.1 mg/day to 3.2 mg/day after 3 years. In patients whose active RA persists despite treatment with MTX, TAC in combination with MTX is safe and well tolerated and provided clinical benefit for a long time in this single-center retrospective study. Further studies are required to confirm the safety and efficacy of this combination therapy.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Male; Methotrexate; Middle Aged; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

We aimed to assess the efficacy of tacrolimus (TAC) as an add-on therapy in patients with rheumatoid arthritis (RA) who were previously treated with methotrexate (MTX) but not with biologics.. The study group (MTX + TAC group) consisted of 157 patients (selected from among the patients in the Institute of Rheumatology, Rheumatoid Arthritis [IORRA] RA cohort from April 2005 to October 2009) who received add-on therapy with TAC in addition to MTX, but without biologics. A propensity score (PS) for the use of TAC was derived, and 471 PS-matched patients who received MTX alone or MTX with other non-biologic disease-modifying antirheumatic drugs (except for TAC), but not with biologics, were selected and served as the control group. Changes in disease activity in the two groups during three consecutive IORRA phases were analyzed by adjusting for confounding factors.. The median 28-joint disease activity score (DAS28) decreased from 4.58 to 3.70 in the MTX + TAC group and from 4.12 to 3.61 in the control group. After adjusting for confounding factors, the decrease in the DAS28 score in the MTX + TAC group was significantly larger (by 0.273 points) than that in the control group (P < 0.05).. This study demonstrated the efficacy of add-on therapy with TAC to MTX in patients with RA in daily practice.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Retreatment; Severity of Illness Index; Tacrolimus; Treatment Outcome

Depression in rheumatoid arthritis (RA) patients is more severe than in healthy people. Herein, we report improved depression in RA patients using biologic agents. We examined whether depression was improved by tacrolimus combination therapy when biologic agents were ineffective.. The study included 13 RA patients who used biologic agents. The following methods were used before the initiation of tacrolimus combination therapy and at 14 and 30 weeks after treatment initiation: the Zung self-rating depression scale (SDS) to evaluate depression state, disease activity score 28/erythrocyte sedimentation rate (DAS28), tender joint counts, swollen joint counts, a patient global assessment to evaluate RA disease activity, and the modified health assessment questionnaire (mHAQ) to evaluate quality of life.. The SDS scores before the initiation of tacrolimus combination therapy and at 14 and 30 weeks after treatment initiation were 45.2 ± 10.6, 44.8 ± 12.8, and 41.6 ± 11.2 (p = 0.047), respectively, indicating significant improvement. The DAS28 was 5.0 ± 1.3 prior to treatment, 3.8 ± 1.3 at 14 weeks, and 3.5 ± 0.9 at 30 weeks, demonstrating significant improvement at both 14 and 30 weeks (p < 0.001). The mHAQ score changed from 0.60 ± 0.45 at baseline to 0.54 ± 0.52 and 0.38 ± 0.43 at 14 and 30 weeks, respectively. The mHAQ score was significantly lower at 30 weeks when compared to baseline (p = 0.013).. Tacrolimus combination therapy does not directly improve depression in RA patients, but it is possible that the observed improvement in depression accompanies the improvement in the secondary failure of RA.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Depression; Drug Therapy, Combination; Female; Health Status; Humans; Male; Middle Aged; Severity of Illness Index; Surveys and Questionnaires; Tacrolimus; Treatment Outcome

Incidents of new-onset vitiligo attributed to infliximab therapy for rheumatoid arthritis and ulcerative colitis have been reported. Reported cases share a common theme in that symptoms manifested in close proximity to the initiation or significant dose increase of the medication. This case describes the presentation of infliximab-induced vitiligo in a patient using it for long-term treatment of stable pityriasis rubra pilaris. The patient was initiated and titrated to a stable dose of infliximab totaling 27 months' duration. He was able to achieve near-complete resolution of symptoms before developing depigmented patches consistent with vitiligo. Infliximab was discontinued. Tacrolimus 0.1% ointment and narrow-band ultraviolet B light successfully repigmented the patches. The association of discontinuing infliximab and resolution of vitiligo suggests infliximab had a role in this case. Though the mechanism of involvement is undetermined, infliximab may have induced an autoimmune process by paradoxically activating lymphocytes. Alternatively, infliximab antibodies may have led to the process by disrupting the normal balance of cytokines.

Topics: Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Diabetes Mellitus, Type 2; Gout; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Pityriasis Rubra Pilaris; Tacrolimus; Ultraviolet Therapy; Vitiligo

This study aimed to identify the regulatory effect of tacrolimus on the interleukin-1β (IL-1β)-induced expressions of angiopoietin-1 (Ang-1), Tie-2 receptor (Tie-2), and vascular endothelial growth factor (VEGF) in human rheumatoid fibroblast-like synoviocytes (FLS) and to determine the regulatory mechanism in the mitogen-activated protein kinases (MAPKs) signaling pathway.. IL-1β-induced Ang-1, Tie-2, and VEGF expressions with and without tacrolimus were measured in cultured FLS using real time-polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining. The effect of tacrolimus on the regulation of Ang-1, Tie-2 and VEGF expressions through the MAPK signaling pathway was identified by Western blotting and immunofluorescence staining.. IL-1β appeared to induce marked expressions of Ang-1, Tie-2, and VEGF in cultured FLS. Tacrolimus significantly inhibited Ang-1, Tie-2, and VEGF mRNA and protein in cultured FLS treated with 10 ng/ml IL-1β. In addition, expressions of these angiogenic molecules were shown to involve all three of the studied MAPK signaling pathways, including ERK, JNK, and p38. However, the inhibitory effects of tacrolimus on Ang-1, Tie-2, and VEGF proteins were regulated by blocking the phosphorylations of JNK and p38 MAPK, but not that of ERK.. This study demonstrates that tacrolimus inhibits the expressions of Ang-1, Tie-2, and VEGF by blocking the activations of the IL-1β-mediated JNK and p38 MAPK pathways in human FLS. This suggests that tacrolimus contributes to the suppression of angiogenesis in the pathogenesis of RA.

Topics: Angiopoietin-1; Arthritis, Rheumatoid; Cells, Cultured; Fibroblasts; Humans; Immunosuppressive Agents; Interleukin-1beta; MAP Kinase Kinase 4; Neovascularization, Pathologic; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Receptor, TIE-2; RNA, Messenger; Signal Transduction; Synovial Membrane; Tacrolimus; Vascular Endothelial Growth Factor A

To retrospectively evaluate the efficacy and safety of combination therapy with tacrolimus (TAC) and other disease-modifying antirheumatic drugs (DMARDs). One hundred fifteen rheumatoid arthritis (RA) patients treated with tacrolimus were enrolled in this retrospective analysis. We collected clinical information, including patient background, treatment efficacy (evaluated using the DAS score), and adverse events observed. Multiple logistic regression analysis was conducted to analyze factors contributing to clinical response and adverse effects. The disease activity score of 28 joints (DAS28) improved significantly at 24 weeks, and continuation rate at 1 year was 57.9%. There was no difference in continuation rate between different DMARD combinations, and not only methotrexate (MTX) but also bucillamine (BUC) and salazosulfapyridine (SSZ) were effective combination partners with TAC. No serious adverse events were observed, and no different inefficacy or safety was observed between non-elderly (<65 years old) and elderly (≥65 years old) RA patients. By conducting multiple logistic regression analysis, combination therapy with MTX and TAC, the number of baseline DMARDs (specifically, ≥3), and old age were identified as risk factors for adverse events. Our findings indicate that TAC is a valuable DMARD for second-line combination therapy in RA.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cysteine; Disease Progression; Drug Therapy, Combination; Female; Humans; Male; Methotrexate; Middle Aged; Retrospective Studies; Risk Factors; Severity of Illness Index; Sulfasalazine; Tacrolimus; Treatment Outcome

Tacrolimus (TAC) suppresses immune-inflammation by an intermediary inhibition of calcineurin activation in the treatment of rheumatoid arthritis (RA). Various combination therapies for RA have been reported to be superior to monotherapies. The aim was therefore to study add-on TAC in a combination with biologics (BIO) and/or non-BIO disease-modifying anti-rheumatic drugs (DMARDs) in treatment-resistant patients. In eight RA patients, TAC was added on to BIO (TAC/BIO group) and in forty-one to non-BIO DMARDs (TAC/non-BIO group). The mean C-reactive protein (CRP) decreased from 33 mg/l at the baseline to 16 mg/l at first year in the TAC/BIO group (P < 0.05), from 41 to 14 mg/l in the TAC/non-BIO group (P < 0.05); the mean DAS28-CRP (28 joint count) disease activity score decreased from 5.3 to 4.4 in the TAC/BIO group (P < 0.05) and from 5.0 to 3.9 in the TAC/non-BIO group (P < 0.05). The median of Δ modified total Sharp score decreased from 43 during the year preceding the baseline to 3 during the first year of the follow-up in the TAC/BIO group (P < 0.05) and from 22 to 0 during the second year in the TAC/non-BIO group (P < 0.05). Twenty-six adverse events occurred in this study in 26 patients (53% in all); however, the only severe adverse event was one case of an atypical mycobacterial disease (2%). The combination therapy of TAC with BIO or non-BIO DMARDs represents an effective and relatively safe mode of therapy in treatment-resistant RA.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Arthrography; Biological Products; Disease Progression; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Treatment Outcome

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Infliximab; Male; Middle Aged; Retreatment; Tacrolimus; Treatment Outcome

We report a 37-year-old female of intractable rheumatoid arthritis (RA) complicated by systemic lupus erythematosus (SLE), who was successfully treated with a combination of tocilizumab (TCZ) and tacrolimus. She was diagnosed with RA when she was 21 years old, and was administered oral prednisolone, injectable gold and salazosulfapyridine, but deformity of her hands gradually developed. She developed high fever and thrombocytopenia when she was 35 years old. Renal involvement, pericarditis, positive antinuclear antibody and high level of anti-double-stranded DNA antibody were found and the patient was diagnosed with SLE. Polyarthritis and immunological abnormalities developed despite aggressive immunosuppressive therapy including high-dose corticosteroids and intravenously administered cyclophosphamide. Tacrolimus (TAC) therapy gave only partial improvement of joint symptoms. After the initiation of combination therapy with TCZ, not only was a complete remission of RA obtained, but also the serum levels of SLE markers dramatically decreased. Our report suggests the possibility that this combination therapy is effective in treating SLE as well as RA.

Topics: Adult; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Tacrolimus

Although the effects of tacrolimus on T cells are well-known, direct effects on rheumatoid synovial fibroblasts (RSF) remain unclear. We studied the effects of tacrolimus on RSF by a DNA microarray analysis.. Tacrolimus and interleukin (IL)-1β were added to cultured RSF. Total RNA was prepared from the cells and the gene expression profile was analyzed by a DNA microarray screening system. mRNA expressions influenced by tacrolimus in the screening system were confirmed by real-time PCR. The effects of tacrolimus on nuclear translocation of nuclear factor-κB (NF-κB) were also examined.. The mRNA expressions of CCL3, CCL4, and CXCL8 were up-regulated by IL-1β and down-regulated by tacrolimus. The levels of these IL-1β-induced chemokines in culture supernatant were decreased by a therapeutic concentration of tacrolimus. Tumor necrosis factor-α as well as IL-1β induced these chemokines, while tacrolimus inhibited their production and mRNA expression. Chemotaxis of polymorphonuclear cells in response to IL-1β was also inhibited by tacrolimus. Nuclear translocation of p50 and p65 NF-κB in response to IL-1β was decreased by tacrolimus.. IL-1β-induced chemokine expressions were down-regulated by tacrolimus, suggesting that tacrolimus exerts its anti-inflammatory effect partly through inhibiting chemokine production by RSF.

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Cells, Cultured; Chemokines; Down-Regulation; Fibroblasts; Humans; Immunosuppressive Agents; Interleukin-1beta; NF-kappa B; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Synovial Membrane; Tacrolimus

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cysteine; Female; Humans; Methotrexate; Sulfasalazine; Tacrolimus

Kaposi's sarcoma (KS) is a vascular lesion of low-grade malignant potential caused by the complex interactions between geographic, genetic, environmental, and immunological factors. We recently experienced a rare case of KS associated with rheumatoid arthritis in a patient receiving corticosteroids and tacrolimus; the KS demonstrated unusually aggressive clinical behavior. We herein report the details of the clinical course and discuss the possible contribution of corticosteroids and tacrolimus to the development of aggressive KS in the present case.

Topics: Adrenal Cortex Hormones; Aged; Arthritis, Rheumatoid; Bone Neoplasms; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

The aim of this study was to evaluate the suitability of chemiluminescent enzyme immunoassay (CLIA) for the monitoring of whole-blood tacrolimus concentrations in rheumatoid arthritis (RA) patients.. Sixty-three RA patients and 47 renal transplant (RT) patients treated with tacrolimus were enrolled. Tacrolimus concentrations in spiked blood and patient blood were measured by CLIA and HPLC-MS/MS. The cross-reactivity in CLIA was evaluated using 13-O-demethylated or 31-O-demethylated tacrolimus.. Tacrolimus concentrations measured by CLIA correlated with those measured by HPLC-MS/MS. Bland-Altman analysis revealed the 95% confidence intervals between CLIA and HPLC-MS/MS in RA and RT patients were -20.7 to 109.9% and -5.0 to 74.1%, respectively. While 31-O-demethylated tacrolimus cross-reaction amounted to an equivalent of 120% tacrolimus in CLIA, 13-O-demethylated tacrolimus did not cross-react.. CLIA values should be carefully interpreted in RA patients, especially those receiving a low dose of tacrolimus.

Topics: Arthritis, Rheumatoid; Chromatography, High Pressure Liquid; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Luminescence; Reproducibility of Results; Tacrolimus; Tandem Mass Spectrometry

Tacrolimus (TAC) was approved in Japan in 2005 for rheumatoid arthritis (RA) patients having inadequate response to other disease-modifying anti-rheumatic drugs. As of May 2007, spontaneous reports identified twenty-seven cases of exacerbation or new development of interstitial pneumonia among RA patients given TAC in Japan.. To describe the clinical and radiological characteristics of TAC-induced pulmonary injury (TIPI).. Eleven RA patients diagnosed with de novo pulmonary injury or exacerbation of IP during treatment with TAC were identified. Clinical, radiological, and laboratory data of ten of these cases were retrospectively analyzed.. Baseline data for the ten patients were a mean age of 69.7 years; gender, 70% female; mean RA disease duration, 9.1 years; and pulmonary comorbidities, 90%. Six cases were classified as presumptive TAC-induced pulmonary injury (TIPI) and four as probable TIPI. Among the six presumptive cases, TIPI developed at an average of 84 days after initiation of treatment (n = 5) or four days after reinstitution of TAC (n = 1). Five cases were an exacerbation of pre-existing interstitial pneumonia and one was a de novo pulmonary injury. Radiological patterns of thoracic computed tomography (CT) scans of patients in the presumptive TIPI cases were hypersensitivity pneumonia like-pattern (n = 3), ground-glass opacity (n = 2), and organizing pneumonia-pattern (n = 1). All patients with presumptive TIPI were treated with high dosage glucocorticosteroids and one received concomitant immunosuppressants. Two of the six presumptive TIPI patients died.. Rheumatologists should be aware of this rare but potentially life-threatening adverse event in RA patients receiving TAC.

Topics: Aged; Aged, 80 and over; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Lung; Male; Middle Aged; Radiography, Thoracic; Tacrolimus; Tomography, X-Ray Computed

Stiffness and cytokine in blood levels show 24-h rhythms in rheumatoid arthritis (RA) patients. We previously revealed that higher therapeutic effects were obtained in RA patients and RA model animals when the dosing time of methotrexate was chosen according to the 24-h rhythms to cytokine. In this study, we examined whether a dosing time-dependency of the therapeutic effect of tacrolimus (TAC) could be detected in collagen-induced arthritis (CIA) and MRL/lpr mice. To measure the levels of cytokines and serum amyloid A (SAA), blood was collected from CIA mice at different times. TAC was administered at two different dosing times based on these findings and its effects on arthritis and toxicity were examined. Plasma tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and SAA concentrations showed obvious 24-h rhythms with higher levels during the light phase and lower levels during the dark phase after RA crisis. The arthritis score and leukocyte counts were significantly lower in the group treated at 2 h after the light was turned on (HALO) than in the control and 14 HALO-treated groups. Our findings suggest that choosing an optimal dosing time could lead to the effective treatment of RA by TAC.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Collagen Type II; Drug Chronotherapy; Immunosuppressive Agents; Interleukin-6; Leukocyte Count; Leukocytosis; Male; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Mice, Inbred MRL lpr; Renal Insufficiency; Serum Amyloid A Protein; Severity of Illness Index; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Fingers; Humans; Methotrexate; Radiography; Tacrolimus

To explore the effect of additional administration of tacrolimus to rheumatoid arthritis patients treated with biologics, in whom the effect of biologics is unsatisfactory.. Tacrolimus was administered if the effect of biologics was unsatisfactory for 24 weeks at least in terms of laboratory data or DAS28 level: ESR, CRP level and DAS28 level were not below 15 mm/h, 0.2 mg/dl or 2.6, respectively.. Tacrolimus administered in addition to biologics was significantly effective for suppressing the activity of rheumatoid arthritis in our study. The significant effect of tacrolimus appeared at the 4th week. The effect of tacrolimus achieved quite significant level at the 54th week (p< 0.0001).. Tacrolimus may be a promising candidate to suppress the disease activity of rheumatoid arthritis refractory to the conventional treatment with biologics.

Topics: Aged; Arthritis, Rheumatoid; Biological Products; Blood Sedimentation; C-Reactive Protein; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Tacrolimus

Macrophagic myofascitis (MMF) is an unusual inflammatory myopathy characterized by muscle infiltration by macrophages and lymphocytes. Here, we describe a case of MMF which is associated with rheumatoid arthritis. A 53-year-old Japanese rheumatoid arthritis (RA) patient presented with focal tenderness of lower extremities. Magnetic resonance imaging showed evidence of myofascitis involving fascias of anterior tibialis muscle. Muscle biopsy showed a unique pathological pattern of MMF. MMF is known to be associated with vaccination containing aluminum. However, our case was not related to aluminum containing vaccinations and etiologies are unknown. The possible link needs to be discussed.

Topics: Arthritis, Rheumatoid; Biopsy; Fascia; Female; Gait Disorders, Neurologic; Humans; Immunosuppressive Agents; Leg; Macrophages; Magnetic Resonance Imaging; Middle Aged; Muscle Weakness; Muscle, Skeletal; Myofascial Pain Syndromes; Myositis; Prednisolone; Tacrolimus; Treatment Outcome

A 60-year-old man who had been diagnosed as rheumatoid arthritis admitted to our hospital by dysesthesia on his legs with edema. Nerve conduction velocity test led to diagnosis of mononeuritis multiplex. Magnetic resonance imaging (MRI) of lower legs showed high intensity in slow tau inversion recovery. Typical vasculitis with neutrophil-dominant cell infiltration was observed by muscle biopsy without inflammatory myopathy or fascitis. Diagnosis was made by rheumatoid vasculitis found in crural muscles. Intravenous cyclophosphamide with oral tacrolimus effectively improved dysesthesia with reduction of inflammatory response.

Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; Biopsy; Cyclophosphamide; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Injections, Intravenous; Magnetic Resonance Imaging; Male; Middle Aged; Muscle, Skeletal; Muscular Diseases; Neural Conduction; Neutrophils; Paresthesia; Tacrolimus; Treatment Outcome; Vasculitis

Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA.. One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio).. The disease activity of enrolled patients was 5.8 +/- 1.2 (mean +/- SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/M ratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes.. Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment.

Topics: Aged; Arthritis, Rheumatoid; ATP Binding Cassette Transporter, Subfamily B, Member 1; Calcineurin Inhibitors; Case-Control Studies; CD4-Positive T-Lymphocytes; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Treatment Outcome

The objective of this study was to assess the usefulness of tacrolimus (TAC) for rheumatoid arthritis (RA) patients. The first 101 consecutive RA patients in whom TAC treatment was initiated were prospectively registered and their data analyzed. Clinical variables were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The 101 patients included 85 females and 16 males. Average doses of TAC were 1.62 mg/day at entry and 2.13 mg/day at month 12. The average doses of concomitantly prescribed prednisolone (6.92 mg/day) and methotrexate (MTX; 8.59 mg/week) were higher than those in all RA patients in the IORRA cohort. At month 12, 57 patients remained on TAC therapy; 18 patients had discontinued TAC due to side effects, and 16 patients had discontinued due to inefficacy. Adverse reactions responsible for discontinuation included gastrointestinal symptoms, renal dysfunction, and infection. According to the European League Against Rheumatism (EULAR) response criteria, 56.5% of the patients who continued TAC at 12 months experienced "good" or "moderate" responses. Through the use of last observation carried forward (LOCF) methodology, the average Disease Activity Score (DAS) 28 significantly improved. We confirmed the usefulness of TAC for the treatment of RA and found that TAC is suitable for RA patients who are unable to use biologic agents or to tolerate a high dose of MTX because of their complications or background factors.

Topics: Arthritis, Rheumatoid; Drug Resistance; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Health Status; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Prednisolone; Prospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Leg Ulcer; Middle Aged; Ointments; Tacrolimus; Time Factors; Treatment Outcome; Wound Healing

We report a Japanese male patient with intractable rheumatoid arthritis (RA), in whom tacrolimus was effective ultimately. Five years before the admission he was diagnosed as RA, which was resistant to various disease-modifying anti-rheumatic drugs (DMARDs). Two years before, administration of infliximab was initiated although the medicine failed to control RA. In spite of the multiple joint replacement, the RA disease activity worsened. Tacrolimus (1.5 mg/day) was administered. Twenty-four weeks of tacrolimus treatment reduced the disease activity score for 28 joints-erythrocyte sedimentation rate from 7.44 to 3.65. Herein, we present a patient with RA, who was successfully treated by tacrolimus, and in whom infliximab was not effective. Tacrolimus may be one of the drugs for RA patients refractory to the conventional treatments including methotrexate or tumor necrosis factor inhibitors.

Topics: Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Disease Progression; Drug Resistance; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Retreatment; Tacrolimus; Treatment Outcome

In the present study, we retrospectively evaluate the efficacy of low dose tacrolimus (TAC) as add-on therapy in refractory rheumatoid arthritis (RA) despite a combination of tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) using consecutive case series of five patients with active RA (mean disease duration 2.3 years) despite MTX and TNF inhibitors for at least 3 months (mean 9.5 months) treated with low dose TAC (1.5-2 mg/day) for at least 6 months (mean 1.8 years). Clinical and radiographic efficacy was assessed according to the European league against rheumatism response criteria and the modified Sharp method, respectively. At 1 year, three patients reached to remission. The mean yearly progression of radiographic joint damage of all five patients after the onset of TAC was significantly decreased compared to that observed during anti-TNF therapy without TAC (p = 0.04). One patient temporally discontinued the treatment because of herpes zoster. In RA patients with inadequate response to MTX and a TNF inhibitor, additions of low dose TAC markedly improved clinical variables including radiographic scores without remarkable detrimental effects. It seems that TAC in combination with MTX and TNF inhibitors may be a hopeful treatment option for RA patients with inadequate response to anti-TNF therapy.

Topics: Adult; Aged; Antibodies, Monoclonal; Arthritis, Rheumatoid; Drug Therapy, Combination; Etanercept; Female; Humans; Immunoglobulin G; Infliximab; Male; Methotrexate; Middle Aged; Receptors, Tumor Necrosis Factor; Retrospective Studies; Tacrolimus; Tumor Necrosis Factor-alpha

Although serum amyloid A (SAA) has been used as a marker of inflammation, its role in leucocyte recruitment and angiogenesis has not been well established in RA. CCL20 is a chemokine involved in the migration of CCR6-expressing Th17 cells. To study the contribution of SAA to the recruitment of Th17 cells, we investigated the effects of SAA on CCL20 production by RA synoviotytes.. Synoviocytes isolated from RA patients were stimulated with recombinant SAA and cellular supernatants were analysed by CCL20-specific ELISA. CCL-20 mRNA expression was analysed by RT-PCR.. SAA is a most potent inducer of CCL20 secretion in RA synoviocytes compared with other inflammatory cytokines (IL-1beta, TNF-alpha and IL-17A). SAA stimulation induced CCL20 mRNA expression in RA synoviocytes, which was not affected by polymyxin B pre-treatment. SAA-induced CCL20 production was down-regulated by NF-kappaB inhibition and partially by c-jun N-terminal kinase (JNK) inhibition. SAA-induced CCL20 production was also suppressed by dexamethasone or FK506.. These findings suggest that SAA may be implicated in the recruitment of lymphocytes, including CCR6-expressing Th17 cells, in RA synovium by up-regulating CCL20 production in synoviocytes.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cells, Cultured; Chemokine CCL20; Chemotaxis, Leukocyte; Cytokines; Dexamethasone; Extracellular Signal-Regulated MAP Kinases; Humans; Immunoassay; NF-kappa B; Protein Array Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serum Amyloid A Protein; Statistics, Nonparametric; Stimulation, Chemical; Synovial Membrane; Tacrolimus

Topics: Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Middle Aged; Tacrolimus; Treatment Outcome; Urticaria

We attempted to determine what baseline variables are responsible for the efficacy of tacrolimus at 6 months in Japanese patients with rheumatoid arthritis (RA). One hundred and six RA patients treated with tacrolimus for 6 months were entered in this study. The outcome was set as the achievement of Disease Activity Score 28 C-reactive protein (DAS28-CRP) remission at 6 months. We examined the association of gender, DAS28-CRP at baseline, concomitant use of methotrexate (MTX), and concomitant use of prednisolone with the achievement of DAS28-CRP remission at 6 months by logistic regression analysis. Twenty-three of 106 patients (21.7%) achieved DAS28-CRP remission at 6 months. There was concomitant use of MTX by 20 patients (18.9%), prednisolone by 93 (87.7%), and prednisolone [5 mg/day by 43 (40.6%) at baseline. Logistic regression analysis showed that male gender (first) and moderate disease activity at baseline (second) are independent predictors toward achieving DAS28-CRP remission at 6 months. Maximum tacrolimus dosage administrated for patients over a 6-month period appeared not to be predictive for the DAS28-CRP remission at 6 months. In conclusion, we revealed for the first time that good outcome in RA patients treated with tacrolimus can be predictive by some baseline variables. That is clinically valuable for daily practice in the choice of disease-modifying antirheumatic drugs (DMARDs), especially tacrolimus.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Chi-Square Distribution; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Predictive Value of Tests; Prednisolone; Regression Analysis; Remission Induction; Severity of Illness Index; Sex Factors; Statistics, Nonparametric; Tacrolimus; Treatment Outcome

Recently, there has been an interest in the use of tacrolimus for the treatment of rheumatoid arthritis (RA). The role of rheumatoid factor (RF) as a cause of immunoassay interferences is well known. This study is the first to investigate the susceptibility of a tacrolimus immunoassay to interference by RF. Tacrolimus apparent concentrations were determined using the antibody conjugated magnetic immunoassay (ACMIA) run on the Dimension RxL Immunoassay System in 100 randomly selected samples previously submitted for routine diagnostic or monitoring of RA in patients not receiving tacrolimus. Fifty of them had an RF concentration exceeding 100 IU/L and 50 had an RF concentration below 20 IU/L. Samples with tacrolimus apparent whole-blood concentrations above 2.3 ng/mL (limit of quantification of the ACMIA assay alleged by the vendor) were considered as potential false positives. No positive tacrolimus result was found among the 50 samples with serum RF < 20 IU/mL. Among the 50 selected samples from patients with RF > 100 IU/mL (RF range 110-2650 IU/mL), 2 were positive for tacrolimus with ACMIA. In both cases, the pretreatment of these samples with an immunoglobulin blocking agent reduced the apparent tacrolimus concentrations to below the limit of detection. This was confirmed using the alternative and reference tacrolimus assays, both of which reported results below their respective limits of detection. The measured human anti-mouse antibodies levels were found to be elevated. These results show that certain patients with positive RF can have false-positive tacrolimus results using the tacrolimus ACMIA-Flex immunoassay on a Dimension RXL analyzer, which was not the case with 2 other techniques. The interference with the tacrolimus ACMIA results was suppressed after preincubation with an immunoglobulin blocking reagent.

Topics: Antibodies, Blocking; Arthritis, Rheumatoid; Artifacts; Cross Reactions; Female; Humans; Immunoenzyme Techniques; Male; Rheumatoid Factor; Tacrolimus

We assessed the safety of tacrolimus therapy for rheumatoid arthritis. Forty-two patients who started tacrolimus therapy between April 2005 and July 2006 were investigated retrospectively using data from their medical records up to June 2007. The cumulative treatment continuation rate was assessed by the Kaplan-Meier method. Fisher's exact test was used to compare gastrointestinal symptoms between different tacrolimus doses and between the presence and absence of each concomitant medication. The mean (+/-SD) observation period was 288 +/- 238 days. The cumulative treatment continuation rate was, respectively, 59.5% and 38.1% at 6 months and 1 year after the patients started treatment. Tacrolimus was discontinued in 28 patients, and was discontinued because of adverse reactions in 21 patients. Gastrointestinal symptoms were the most common adverse reactions (45.2% = 19/42 patients), followed by infections and hyperglycemia. Tacrolimus was discontinued in 9/19 patients with gastrointestinal symptoms, and was discontinued within 60 days of starting treatment in seven of them. Nausea and vomiting led to discontinuation in seven patients (within 60 days of starting treatment in six of them). The incidence of gastrointestinal symptoms was higher in patients receiving a daily dose >or=2 mg than in those receiving <2 mg/day. During treatment of rheumatoid arthritis by oral tacrolimus therapy, gastrointestinal symptoms were common, early, and dose-dependent. However, these symptoms were not severe and did not cause any serious safety problems.

Topics: Aged; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Retrospective Studies; Tacrolimus

We report a case of rheumatoid arthritis (RA) complicated by myelodysplastic syndrome (MDS) successfully treated by tacrolimus. A 57-year-old woman had persistent pain and swelling in bilateral wrist and knee joints, in addition to severe anemia and leukopenia. She was diagnosed with MDS and RA based on the results of bone marrow aspiration and the criteria of RA. Combination therapy with tacrolimus (1.5 mg day(-1)) and prednisolone (10 mg day(-1)) improved her bicytopenia and polyarthralgia.

Topics: Anemia, Refractory; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Middle Aged; Prednisolone; Tacrolimus

Topics: Administration, Oral; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Middle Aged; Rheumatoid Nodule; Skin; Tacrolimus

A 74-year-old woman was experiencing rheumatoid arthritis complicated with interstitial pneumonitis (IP), and tacrolimus treatment was started. She presented with dyspnea. Chest X-ray and computed tomography (CT) showed ground-glass opacity and IP. Although tacrolimus was stopped, she died of respiratory failure. At autopsy, both the upper and lower lung fields showed usual IP and the organizing stage of diffuse alveolar damage. The former is common, but the latter is uncommon, suggesting tacrolimus may cause severe alveolar damage.

Topics: Aged; Arthritis, Rheumatoid; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Respiratory Insufficiency; Tacrolimus

A 64-year-old woman had been treated with prednisolone (PSL) for interstitial pneumonia (IP) of unknown origin since 1988. The IP progressed gradually, however, and home oxygen therapy was instituted in 1993. In 2002, persistent arthritis of the hands appeared and diagnosis of rheumatoid arthritis (RA) was finally established based on radiological and pathological findings. Salazosulfapyridine was given with only partial effect. On October 2002, she was hospitalized because of back pain followed by dyspnea. Chest X-ray revealed multiple giant bullae on bilateral upper lung fields, accompanied by deterioration of IP. Methyl-prednisolone pulse therapy followed by 30 mg/day of PSL was instituted and the bullae were diminished with gradual improvement of IP and synovitis. On the 55th hospital day, she complained of chest oppression, and chest X-ray revealed a complication of pneumomediastinum. Since IP was still active and serum KL-6 remained high, 3 mg/day of tacrolimus was added to control IP further and to reduce the dosage of PSL which was recognized as one of the aggravation factors of pneumomediastinum. As a result, pneumomediastinum disappeared gradually along with amelioration of IP. PSL was successfully tapered to 15 mg/day by the 87th hospital day and the patient was discharged. Although the efficacy of tacrolimus on IP complicated with polymyositis / dermatomyositis and other autoimmune diseases has been reported, this case first suggests its efficacy on IP associated with RA.

Topics: Arthritis, Rheumatoid; Blister; Female; Humans; Immunosuppressive Agents; Lung Diseases; Lung Diseases, Interstitial; Mediastinal Emphysema; Middle Aged; Tacrolimus

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by progressive joint destruction that requires aggressive treatment using appropriate disease-modifying antirheumatic drugs (DMARDs). RA patients with renal failure, however, are intolerant to most DMARDs due to the potential toxicity. In Japan, tacrolimus was approved for the treatment of RA in 2005. Based on its pharmacokinetics, tacrolimus may be administered to the patients undergoing hemodialysis. We report two cases of RA patients on hemodialysis treated effectively and safely with tacrolimus.

Topics: Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Tacrolimus

Tacrolimus is an effective and well-tolerated treatment for rheumatoid arthritis (RA). We report three cases of strictly sleep-associated myoclonus in RA patients treated with tacrolimus. Although the high-dosage administration of tacrolimus in transplantation is known to cause diverse neurotoxic adverse effects, including myoclonus, no previous cases of myoclonus in RA, especially in association with sleep, have been reported. We suggest that this is not a rare adverse effect, particularly in elderly RA patients.

Topics: Age Factors; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Macrolides; Male; Middle Aged; Nocturnal Myoclonus Syndrome; Sleep; Tacrolimus

A 68-year-old man with a 3-year history of rheumatoid arthritis (RA) developed gynecomastia 3 months after beginning oral low-dose methotrexate (MTX) therapy. Four months after MTX therapy was discontinued, the gynecomastia symptoms improved. Only eight cases of gynecomastia resulting from low-dose MTX administration have been reported worldwide, and no cases have previously been reported in Japan. Although it occurs infrequently, gynecomastia resulting from low-dose MTX therapy should be considered in male patients with RA.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Gynecomastia; Humans; Male; Methotrexate; Remission Induction; Tacrolimus; Withholding Treatment

To prospectively evaluate the safety of tacrolimus in active rheumatoid arthritis (RA) in elderly patients with insufficient response to disease-modifying antirheumatic drugs (DMARDs).. Fifty-seven patients aged > or =65 yr with RA for > or =6 months were enrolled in an open-label, non-controlled study. All DMARDs were discontinued and tacrolimus was administered orally once daily after the evening meal for 28 weeks. Tacrolimus, initiated at 1.5 mg/day, was increased to 3 mg/day after 6 weeks if no abnormal changes developed. Existing NSAID and oral corticosteroid (< or =7.5 mg/day prednisolone equivalent) therapy could be continued during the study. Safety was evaluated as clinical symptoms, abnormal changes in laboratory values and the development of infection. Treatment response was determined using the American College of Rheumatology (ACR) criteria for improvement. Whole blood concentrations of tacrolimus 12 h after administration were measured by high-performance liquid chromatography and tandem mass spectrometry.. Clinical adverse events developed in 25 patients (46.3%). Abnormal changes in laboratory values occurred in 25 patients (46.3%). Ten patients (18.5%) developed infection. An ACR20 response was achieved by 50.0% of efficacy-evaluable patients and ACR20 success rates (the proportion of patients achieving ACR20 response and completing the study) was 46.3%. The ACR50 response rate was 18.5% of evaluable patients. Mean blood concentration of tacrolimus was 3.3 and 5.3 ng/ml in patients receiving 1.5 and 3.0 mg daily, respectively. No relationship between its concentration and adverse reactions was observed.. In elderly patients with insufficient response to DMARD therapy, tacrolimus at 1.5-3.0 mg/day is safe and well-tolerated and provides clinical benefit.

Topics: Administration, Oral; Aged; Arthritis, Rheumatoid; Communicable Diseases; Creatinine; Humans; Immunosuppressive Agents; Prospective Studies; Tacrolimus; Treatment Outcome

In a dose-response study, there are frequently multiple goals and not all planned observations are realized at the end of the study. Subjects drop out and the initial design can be quite different from the final design. Consequently, the final design can be inefficient. Single- and multiple-objective Bayesian optimal designs that account for potentially missing observations in quantal response models were recently proposed in Baek (2005). In this work, we investigate the efficiencies of the conventional optimal designs that do not incorporate potential missing information relative to our proposed designs. Furthermore, we examine the impact of restricted dose range on the resulting optimal designs. As an application, we used missing data information from a study by Yocum et al. (2003) to design a study for estimating dose levels of tacrolimus that will result in a certain percentage of rheumatoid arthritis patients having an ACR20 response at 6 months.

Topics: Algorithms; Arthritis, Rheumatoid; Bayes Theorem; Clinical Trials, Phase II as Topic; Computer Simulation; Dose-Response Relationship, Drug; Humans; Logistic Models; Models, Statistical; Research Design; Tacrolimus; Treatment Outcome

To explore the effects of FK506 on the inhibition of cell proliferation and the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and their products PGE subset2 and NO in TNF-alpha-stimulated human rheumatoid arthritis synovial fibroblasts (RASF) treated with triptolide (TP), and to study the mechanisms involved when combining FK506 and TP in RA therapy.. RASF used in the experiments were obtained from the synovial tissue of patients with RA before being cultured. RASF were pretreated with FK506 (10 approximately 1000 nM) for 2 hours before being stimulated with TNF-alpha (20 ng/ml) in the presence or absence of TP (10 ng/ml) . RASF proliferation was determined by [3 supersetH]-TdR incorporation. Production of PGE subset2 and NO in culture supernatants of RASF was detected by competitive ELISA and enzymatic reduction of nitrate, respectively. Expressions of COX-2 and iNOS mRNA in RASF were analyzed by semi-quantitative RT-PCR. Expressions of COX-2 and iNOS protein were estimated by Western-blot and a cellular enzyme immunoassay. NFkappaB activity in whole-cell extract of treated RASF was also measured using an ELISA-based method.. Neither FK506 nor TP at a lower concentration (10 ng/ml) affected TNF-alpha-induced COX-2 and iNOS expressions or PGE subset2 and NO productions in synovial cells. Combined treatment of FK506 and a lower concentration of TP (10 ng/ml) reduced both COX-2 and iNOS mRNA and protein expression, and correspondingly reduced PGE subset2 and NO produced by synovial fibroblasts. This effect was highly correlated with FK506 concentration (10 approximately 1000 nM). NFkappaB activity in TNF-alpha-stimulated synovial cells was suppressed more profoundly by FK506 plus TP (10 ng/ml) than by TP (10 ng/ml) alone. However, no change was observed regarding the inhibition of synovial cell proliferation after combined treatment of FK506 and TP.. FK506 enhanced TP-mediated down-regulation of COX-2 and iNOS as well as their products PGE subset2 and NO in human TNF-alpha-stimulated RASF by more profoundly suppressing the activity of NFkappaB.

Topics: Arthritis, Rheumatoid; Base Sequence; Cell Line; Cyclooxygenase 2; Dinoprostone; Diterpenes; DNA Primers; Down-Regulation; Drug Synergism; Epoxy Compounds; Fibroblasts; Humans; Immunosuppressive Agents; Membrane Proteins; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phenanthrenes; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane; Tacrolimus; Tumor Necrosis Factor-alpha

The aim of this study was to determine whether FK506, which has been shown to be effective for the treatment of refractory RA, affects the synthesis of matrix metalloproteinases (MMPs) in rheumatoid synovial fibroblasts. Synovial fibroblasts isolated from rheumatoid synovium were incubated in 6-well culture plates for 24 h with FK506 and interleukin-1beta, alone and in combination. Samples of supernatants were assayed by ELISA or immunoblottings using anti-MMP-13 specific antibodies. In addition, synovial fibroblasts pretreated with FK506 were stimulated with IL-1beta for 10 min and cellular lysates were subjected to anti-phospho-specific mitogen-activated protein kinase (MAPK). Unstimulated synovial fibroblasts produced low levels of MMP-3 and 13. IL-1beta-induced substantial output of these MMPs into cell supernatants. FK506 had no detectable effects on IL-1beta-induced MMP-2 induction. FK506, however, significantly suppressed MMP-13 production from IL-1beta-stimulated synovial fibroblasts. FK506 also prevented IL-1beta-stimulated JNK activation and transcriptional activation of AP-1 in these cells. Our results indicate that FK506 is capable of regulating MMP-13 synthesis via JNK pathway in rheumatoid synonvium.

Topics: Arthritis, Rheumatoid; Cells, Cultured; Collagenases; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Humans; Interleukin-1; Matrix Metalloproteinase 13; RNA, Messenger; Synovial Membrane; Tacrolimus

To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA).. Patients with active RA who had discontinued all DMARDs for at least 2 weeks and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids.. 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67+/-19 micromol/l (0.76+/-0.22 mg/dl) at baseline to 75+/-26 micromol/l (0.85+/-0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had > or =30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a > or =30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints.. This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Pressure; Creatinine; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Long-Term Care; Male; Middle Aged; Tacrolimus; Treatment Outcome; Tremor

Topics: Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; T-Lymphocytes; Tacrolimus; Treatment Outcome

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Industry; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Failure; Treatment Outcome

To characterize rat collagen-induced arthritis (CIA) on the basis of levels of inflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in paw tissues, and further investigate the effect of FK506 (tacrolimus), a potent inhibitor of T cell activation, on cytokine levels.. CIA was induced in female Lewis rats. The volume of hindpaws was measured before and after collagen immunization. TNF-alpha, IL-1beta and IL-6 levels in paw tissue extracts were determined by ELISA. Proteoglycan contents of cartilage in femoral heads was measured as an indication of cartilage destruction. To assess the effect of FK506 on inflammatory cytokine levels, rats were orally treated with 5 mg/kg of FK506 from days 14-21.. TNF-alpha a level in paw tissues did not significantly change compared to levels found before collagen immunization, throughout development of CIA. In contrast, IL-1beta and IL-6 levels in paw tissues significantly increased between day 14 and day 28 after collagen imuninization, when the arthritis was at a developed stage. Therapeutic treatment with FK506 reduced the elevated level of IL-6, but not IL-1beta, in paw tissue. FK506 treatment was effective in suppressing paw swelling and also recovering the loss of proteoglycan contents in the cartilage.. Levels of IL-1beta and IL-6, but not TNF-alpha , in paw tissue were upregulated in association with the development of arthritis in rat CIA. These results suggest that IL-1beta and IL-6, rather than TNF-alpha , may play important roles at local inflammatory sites in producing joint destruction in rat CIA. FK506 may improve arthritis in established stages of CIA, by reducing the elevated level of IL-6.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Collagen; Cytokines; Female; Hindlimb; Immunosuppressive Agents; Inflammation; Interleukin-1; Interleukin-6; Rats; Rats, Inbred Lew; Tacrolimus; Treatment Outcome; Up-Regulation

To explore the effects of FK506 on the inhibition by triptolide (TP) of cell proliferation and expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and their inducing products PGE2, NO in human rheumatoid arthritis synovial fibroblasts (RASF), and to study the mechanisms of combination of FK506 and TP in RA therapy, RASF used in the experiments were obtained from synovial tissue of patients with RA and were cultured. RASF were pretreated with FK506(10-1000 nmol/L)for 2 h, then the cells were stimulated with TNF alpha(20 microg/L) in the presence or absence of TP (10 microg/L). The RASF proliferation was determined by [(3)H]-TdR incorporation, and the productions of PGE2 and NO in culture supernatants of RASF were detected with competitive ELISA and enzyme reduction of nitrate. Expression of COX-2 and iNOS mRNA in RASF were analyzed by semi quantitative RT-PCR. Expressions of COX-2 and iNOS protein were estimated by Western blot method and cellular enzyme immunoassay in synovial fibroblasts. NF-kappa B activity in whole-cell extract of RASF was also measured by an ELISA-based method. Results showed that neither FK506 nor TP at lower concentration (10 microg/L) alone affected TNF alpha-induced COX-2, iNOS expression and production of PGE2, NO in synovial cells. Combined treatment of FK506 and a lower concentration of TP (10 microg/L) down-regulated COX-2 and iNOS mRNA and protein expression, and their inducing products PGE2 and NO of synovial fibroblasts. This effect was positively correlated with FK506 concentrations (10-1000 nmol/L). NF-kappa B activity in TNF alpha-stimulated synovial cells was suppressed more profoundly by FK506 plus TP (10 microg/L) treatment than those with TP (10 microg/L) alone. No change was observed in inhibition of proliferation of synovial cells after combined treatment of FK506 and TP. In conclusion, FK506 enhanced TP-mediated down-regulation of COX-2, iNOS and their inducing products PGE2, NO in human RASF by suppressing the activity of NF-kappa B.

Topics: Arthritis, Rheumatoid; Blotting, Western; Cell Division; Cells, Cultured; Cyclooxygenase 2; Dinoprost; Diterpenes; Enzyme-Linked Immunosorbent Assay; Epoxy Compounds; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Immunosuppressive Agents; Isoenzymes; Membrane Proteins; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phenanthrenes; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Synovial Membrane; Tacrolimus; Tumor Necrosis Factor-alpha

To determine the direct effect of cyclosporin A (CSA) on the production of cytokines by rheumatoid synovial fibroblasts.. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis and cultured in the presence of CSA. The production of interleukin-10 (IL-10), IL-15, and tumor necrosis factor a (TNFalpha) by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The expression of IL-10, IL-15, and TNFalpha messenger RNA (mRNA) in FLS was determined by polymerase chain reaction (PCR).. CSA (1-1,000 ng/ml) increased the production of IL-10, but decreased in a dose-dependent manner the levels of IL-15 and TNFalpha that were spontaneously secreted from FLS. CSA also potently inhibited the production of IL-15 and TNFalpha stimulated with interferon-gamma, IL-1beta, or lipopolysaccharide. The inhibitory effect of CSA on IL-15 and TNFalpha production depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. In a semiquantitative PCR, CSA increased IL-10 mRNA expression but strongly suppressed IL-1beta-induced IL-15 and TNFalpha mRNA expression, indicating that the production of these cytokines by CSA was regulated at the transcriptional level. Results with the calcineurin inhibitor FK-506, but not with the immunosuppressant rapamycin, were similar to those with CSA. Agonists of cAMP displayed an additive effect on the changes produced in the IL-10, IL-15, and TNFalpha levels by CSA, while a cAMP antagonist almost completely abrogated the effect of CSA, suggesting that cAMP is the major intracellular signal that mediates cytokine regulation by CSA.. These results suggest that CSA differentially regulates the production of cytokines by rheumatoid synoviocytes via a cAMP-dependent pathway.

Topics: 1-Methyl-3-isobutylxanthine; Antimetabolites; Antirheumatic Agents; Arthritis, Rheumatoid; Bucladesine; Calcineurin Inhibitors; Cells, Cultured; Cyclic AMP; Cyclosporine; Cytokines; Dideoxyadenosine; Fibroblasts; Gene Expression; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-15; Phosphodiesterase Inhibitors; RNA, Messenger; Synovial Membrane; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Administration, Topical; Aged; Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Leg Ulcer; Retreatment; Tacrolimus

Prostaglandins (PG) formed by cyclooxygenase (COX) enzymes are important mediators of inflammation in rheumatoid arthritis. The contribution of the inducible COX-2 to inflammation in the rheumatoid synovium is well documented. We examined the regulation of COX-2 mRNA and protein expression in response to both glucocorticoids (GC) and FK506 using rheumatoid synovial fibroblasts. Combined treatment of FK506 and a low concentration of dexamethasone (DEX) (10(-9) M) down-regulated synovial COX-2 mRNA and protein expression. In contrast, neither FK506 nor DEX (10(-9) M) alone influenced COX-2 expression. Immunocytochemical studies showed that pretreatment with FK506 enhanced the nuclear translocation of the glucocorticoid receptor (GR) in synovial fibroblasts in the presence of low concentrations of DEX (10(-9) M). Transient transfection experiments showed that treatment of cells with FK506 enhanced the expression of glucocorticoid-responsive gene reporter in the presence of DEX (10(-9) M). NF-kappaB is known to mediate the transcriptional activation of the COX-2 gene. Electrophoretic mobility shift assay demonstrated that DNA-binding activity of NF-KB was suppressed more profoundly by FK506 plus DEX (10(-9) M) treatment with those of DEX (10(-9)M) alone in IL-1beta-stimulated synovial cells. Our results indicated that FK506-induced potentiation of GR-mediated repression of synovial COX-2 gene transcription is the result of increased translocation of GR to the nucleus and subsequent repression of NF-kappaB transactivation. Our results also suggest that FK506 may exert anti-inflammatory effects in the rheumatoid synovium by potentiating GR-mediated signal transduction.

Topics: Arthritis, Rheumatoid; Base Sequence; Cells, Cultured; Cyclooxygenase 2; Dexamethasone; DNA Primers; Down-Regulation; Fibroblasts; Fluorescent Antibody Technique, Indirect; Humans; Isoenzymes; Membrane Proteins; NF-kappa B; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases; Receptors, Glucocorticoid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Subcellular Fractions; Synovial Membrane; Tacrolimus; Transcription, Genetic

1. Staphylococcal enterotoxine B (SEB; superantigen) accelerated the onset of arthritis in mice preimmunized with type II collagen (SEB-potentiated collagen-induced arthritis). Cyclosporin A and FK-506 inhibited the induction and development of clinical signs and histopathological changes of SEB-potentiated collagen-induced arthritis in mice. 2. Simultaneously, both cyclosporin A and FK-506 inhibited the development of humoral and cellular immunity to type II collagen. 3. The expression of IL-2 receptor (CD25) by SEB on splenocyte T cells from collagen-preimmunized mice was inhibited by both agents in ex vivo experimentation.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Collagen; Cyclosporine; Enterotoxins; Immunosuppressive Agents; Male; Mice; Mice, Inbred DBA; Receptors, Interleukin-2; Superantigens; T-Lymphocytes; Tacrolimus

To investigate the effect of a new immunosuppressant, FK506, on interleukin 6 (IL-6) production by freshly prepared rheumatoid synovial cells.. Rheumatoid synovial cells were isolated from synovial tissue of patients with rheumatoid arthritis (RA) by using collagenase and DNase treatment. The surface phenotypes of the cells were analyzed by 2-color fluorescent analysis with FACScan. The levels of IL-6 in supernatant of cultured synovial cells were measured by enzyme immunoassay.. The synovial cells used were mainly composed 32 +/- 1% of HLA-DR+/LeuM3+ cells and 53 +/- 6% of HLA-DR-/LeuM3-cells. These synovial cells spontaneously produced a large amount of IL-6 in culture. This spontaneous production of IL-6 was significantly inhibited by FK506 at the concentration of 10(-8) to 10(-6) M in a dose dependent manner. In the preincubation study, FK506 required more than 12 h to inhibit IL-6 production by synovial cells.. These results suggest that FK506 may be beneficial for patients with RA via inhibiting IL-6 production in inflammatory joints.

Topics: Adult; Arthritis, Rheumatoid; Cells, Cultured; Female; Flow Cytometry; Humans; Immunoenzyme Techniques; Interleukin-6; Male; Middle Aged; Synovial Membrane; Tacrolimus