tacrolimus and Lupus-Erythematosus--Systemic

The safety of multitarget treatments is of concern. This study aimed to evaluate the effectiveness and safety of multitarget therapy as an induction treatment for lupus nephritis in comparison with monotherapy.. This study included randomized controlled trials (RCTs) that evaluated the effectiveness and safety of multitarget therapies, such as voclosporin+mycophenolate mofetil (MMF), tacrolimus+MMF, or belimumab+standard of care in comparison with MMF or cyclophosphamide (CYC) monotherapy for induction treatment of lupus nephritis. We performed a meta-analysis of the efficacy and safety of multitarget therapy as an induction treatment for lupus nephritis in comparison with monotherapy.. Six RCTs, including 1,437 participants, met the inclusion criteria. The complete remission rate was significantly higher in the multitarget therapy group than in the monotherapy group (odds ratio, 2.155; 95% CI, 1.695-2.739;. Multitarget therapy showed a higher complete remission rate than monotherapy; however, cases of infection and pneumonia were numerically more elevated in the multitarget therapy group than in the monotherapy group.

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic; Remission Induction; Tacrolimus; Treatment Outcome

Topics: Adult; Alopecia; Azetidines; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinase Inhibitors; Lupus Erythematosus, Systemic; Mycophenolic Acid; Prednisolone; Purines; Pyrazoles; Retreatment; Risk Assessment; Sulfonamides; Tacrolimus; Treatment Outcome

Moyamoya syndrome (MMS) is a chronic cerebrovascular disorder characterized by occlusion or stenosis of the internal carotid arteries with the formation of abnormal collateral vascular networks. Moreover, the development of MMS, which is a distinct category from "moyamoya disease," is attributed to the underlying disease, while some cases of MMS related to systemic lupus erythematosus (SLE) have been previously reported. Herein, we present the case of a 29-year-old Japanese woman with SLE in whom intracranial hemorrhage ascribable to MMS developed during pregnancy. Craniotomy was performed to remove hematoma, and prednisolone, tacrolimus, and hydroxychloroquine were consecutively administered. She ultimately achieved remission and childbearing without the relapse of cerebrovascular event. To our knowledge, this is the first report of MMS associated with SLE in pregnancy. Through reviewing published English articles and our case, it was suggested that the pathogenesis of SLE is implicated in the development of moyamoya vasculopathy leading to cerebrovascular events. Moreover, pregnancy may affect the bleeding from the fragile collateral vessel wall.

Topics: Adult; Carotid Artery, Internal; Female; Humans; Lupus Erythematosus, Systemic; Moyamoya Disease; Pregnancy; Tacrolimus

With advancement in our understanding of pathogenic mechanisms in systemic lupus erythematosus (SLE), there is tremendous enthusiasm in examining drugs, old and new, to improve outcomes. This review highlights recent trials' successes and impasses that have come to fore.. Among B-cell therapies, belimumab continues its run of successes with sustained safety and tolerability documented in a long-term extension as well as the likely approval of a subcutaneous formulation in the near future. With greater antibody-dependent cytotoxicity and less immunogenicity, there is hope for obinituzumab to succeed where its anti-CD 20 predecessors have failed. Drugs targeting type I interferons - sifalimumab and anifrolumab - have been efficacious albeit with an increase in incidence of Herpes zoster infections. There is also renewed interest in evaluating the efficacy of calcineurin inhibitors, specifically tacrolimus in the induction and maintenance of lupus nephritis. Introspection into clinical trial designs have highlighted the effects of entry criteria, end points, background medications and geographical differences on study outcomes.. There are at least 50 drugs and targets being evaluated in SLE. In addition to developing new drugs to treat lupus, future trials have to focus on more effective study designs to improve chances of trial success.

Topics: Abatacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; B-Lymphocytes; Clinical Trials as Topic; Cyclosporine; Herpes Zoster; Humans; Immunosuppressive Agents; Interferon Type I; Lupus Erythematosus, Systemic; Lupus Nephritis; Maintenance Chemotherapy; Peptide Fragments; Plasma Cells; Quinolones; Recombinant Fusion Proteins; Remission Induction; T-Lymphocytes; Tacrolimus; Treatment Outcome

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

Moyamoya syndrome (MMS) is a rare, chronic progressive cerebrovascular occlusive disease that is characterized by a stenosis or occlusion of the bilateral internal carotid arteries and the circle of Willis arteries leading to the development of collateral vessels as visualized by cerebral angiography. We report a case of a 24-year-old woman with nephrotic syndrome whose biopsy showed membranous nephropathy. Ten months after the diagnosis she suffered sudden right hemiplegia and seizure. She was diagnosed with MMS by angiogram seven months ago and received decompressive craniotomy. The patient was admitted to our hospital and a diagnosis of systemic lupus erythematosus (SLE) was made. Glucocorticoids and tacrolimus were used to control the symptoms of SLE. Following one month of immunosuppressant treatment, the patient died of brain hemorrhage. This case alongside another six reviewed cases shows that an underlying cerebrovascular lesion of moyamoya in the vessels of patients with SLE is susceptible to cerebrovascular accidents.

Topics: Craniotomy; Fatal Outcome; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Intracranial Hemorrhages; Lupus Erythematosus, Systemic; Moyamoya Disease; Nephrotic Syndrome; Tacrolimus; Young Adult

A 69-year-old woman, who had been diagnosed as having Sjögren's syndrome at 37 years old and mixed connective tissue disease at 42 years old, was under treatment with oral prednisolone. In 2009, she was diagnosed as having active systemic lupus erythematosus, and started on treatment with tacrolimus at 3 mg/day. In 2010, para-aortic lymphadenopathy and superficial multiple lymphadenopathy were detected. Tacrolimus was discontinued. Axillary lymph node biopsy revealed Epstein-Barr (EB) virus-negative CD5-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified into clinical stage IIIA and as being at high risk according to the international prognostic index. After the discontinuation of tacrolimus, the lymph nodes reduced temporarily in size. In January 2011, the lymphadenopathy increased again, and the patient received a total of 8 courses of therapy with rituximab, pirarubicin, vincristine, cyclophosphamide and prednisolone, followed by intrathecal injection to prevent central nervous system infiltration, which was followed by complete remission. In February 2012, fluorodeoxyglucose positron emission tomography showed relapse in multiple lymph nodes and central nervous system infiltration. The patient was considered to have iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the WHO, and this is the first reported case of CD5-positive DLBCL and central nervous system infiltration following administration of the drug. The patient was considered to have a poor prognosis as EB virus was negative, discontinuation of tacrolimus was ineffective and there was evidence of central nervous system infiltration.

Topics: Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; CD5 Antigens; Cyclophosphamide; Doxorubicin; Female; Herpesvirus 4, Human; Humans; Iatrogenic Disease; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphoma, Large B-Cell, Diffuse; Mixed Connective Tissue Disease; Prednisolone; Rituximab; Sjogren's Syndrome; Tacrolimus; Vincristine

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with involvement of both B cells and cytotoxic T lymphocytes and several cytokines aberrations. Standard therapy for SLE has its limitations. Tacrolimus, a novel calcineurin inhibitor with potent immunosuppressive effects, has been shown in the recent years to be effective in SLE therapy. This paper serves to collate the experimental and clinical data on the efficacy of tacrolimus in the treatment of SLE and lupus nephritis. Tacrolimus as a key component of multitarget therapy in SLE is also discussed. The immunocytokine modulatory effects of tacrolimus are also reviewed with reference to SLE. It can be concluded that tacrolimus has an established role in the management of SLE.

Topics: Cytokines; Estrogens; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Tacrolimus; Treatment Outcome

Pimecrolimus is a non-steroidal immunosuppressant derived from ascomycin. This drug inhibits the action of calcineurin phosphatase and blocks the production of inflammatory substances that are thought to be important in causing skin lesions in inflammatory diseases. Pimecrolimus 1% cream (Elidel, Novartis Pharma, East Hanover, NJ, USA) was approved in the European Union, the United States and Japan as second-line therapy for the short- term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children aged 2 years and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable. This topical immunomodulator has also an enormous potential as topical treatment for numerous inflammatory skin diseases like psoriasis and vitiligo. Recently, some authors reported its efficacy in the treatment of skin manifestations of Lupus erytematosus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphocyte Activation; Molecular Structure; Pain; Psoriasis; T-Lymphocytes; Tacrolimus; Vitiligo

Lupus erythematosus (LE) shows a broad range of cutaneous symptoms, including acute, subacute and chronic lesions. The gold standard of established topical treatment consists of medium- to high-potency corticosteroids. Because face and neck are often involved, adverse effects of prolonged corticosteroid use are not uncommon. There is a need of steroid-free topical treatment in LE. With the development of topical calcineurin inhibitors, tacrolimus and pimecrolimus, there is an alternative available. The present study reviews the literature data on topical tacrolimus and pimecrolimus for malar rash, subacute lesions and discoid chronic lesions among others. The present data argue for an efficacy of these compounds in acute and subacute cutaneous LE manifestations with a rapid response and only minor side-effects when used as an adjunct to systemic treatment. In chronic discoid LE, hypertrophic plaques do not well respond because of limited penetration. The primary target seems to be the decrease or blocking of cytokine production by activated T lymphocytes.

Topics: Administration, Topical; Calcineurin Inhibitors; Cytokines; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Tacrolimus

In this review we summarize selected articles that have been published about immunosuppressive agents in the past year. These studies fall into three major categories: 1) use of pulse cyclophosphamide in autoimmune diseases other than systemic lupus erythematosus; 2) use of newer immunosuppressive agents such as cyclosporine and FK506 in a variety of rheumatic diseases; and 3) toxicity.

Topics: Adult; Arthritis, Juvenile; Azathioprine; Behcet Syndrome; Child; Cladribine; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Granulomatosis with Polyangiitis; Humans; Hydroxychloroquine; Immunosuppressive Agents; Liver; Lung; Lung Injury; Lupus Erythematosus, Systemic; Methotrexate; Pemphigoid, Benign Mucous Membrane; Retina; Tacrolimus; Thalidomide

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

Background Pulsed cyclophosphamide or mycophenolate mofetil for lupus nephritis has limited efficacy. We previously reported a case of mixed-class IV + V lupus nephritis successfully treated with cyclophosphamide and tacrolimus. This study assessed the efficacy and safety of multitarget therapy with cyclophosphamide and tacrolimus for the treatment of lupus nephritis. Methods In a prospective, single-arm, open label pilot study, we recruited 15 patients aged 18-64 years with active lupus nephritis who met the American College of Rheumatology criteria for a diagnosis of systemic lupus erythematosus (1997). The treatment protocol was a starting dose of prednisolone of 0.6-1.0 mg/kg/day for 2 weeks and then tapered to a maintenance dose, intravenous cyclophosphamide (500 mg biweekly for 3 months) and tacrolimus (3.0 mg/day). Tacrolimus was continued as maintenance therapy. Complete remission was defined as a spot urine protein/creatinine ratio of < 0.5 g/gCr with no active urine casts and a serum creatinine level that was either normal or within 30% of a previously abnormal baseline level. We retrospectively compared results for the study patients with those of 18 historical controls conventionally treated with cyclophosphamide and prednisolone. Results At baseline, the mean patient age was 41.5 ± 14.6 years (male:female ratio 2:13), urine protein/creatinine ratio 3.9 ± 2.3 g/gCr and serum creatinine 84.6 ± 34.6 µmol/L. Lupus nephritis classifications included classes IV ( n = 8), III + V ( n = 1), IV + V ( n = 5) and unclassified ( n = 1). Eleven patients completed the treatment protocol and four withdrew. At 6 months, 12 of 15 (80.0%) had achieved complete remission using intention-to-treat analysis, significantly more than historical controls (seven of 18 patients, 38.9%). A transient increase in serum creatinine and gastric symptoms occurred in three cases. One patient withdrew due to cytomegalovirus antigenemia and severe diabetes, and one patient died of thrombotic microangiopathy. Conclusions Multitarget therapy with cyclophosphamide and tacrolimus can be a therapeutic option for lupus nephritis. Clinical trials registration Combination therapy of tacrolimus and intravenous cyclophosphamide for remission induction of lupus nephritis, UMIN: 000004893, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005830&language=E . Date of registration: 18 January 2011.

Topics: Administration, Intravenous; Adult; Creatinine; Cyclophosphamide; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Japan; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisolone; Prospective Studies; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus (TAC) in various manifestations of systemic lupus erythematosus (SLE) patients in daily clinical practice. Each of the 21 TAC-treated patients with SLE in our care over 2 years was enrolled in this open-label trial. Patients were administered TAC at a dosage of 1-6 mg once daily, followed up for 24 weeks. Efficacy and safety were evaluated utilizing clinical and laboratory findings. As treatment targets, TAC was preferentially used with oral corticosteroid administration for mild active manifestations such as arthritis, skin eruptions, or asymptomatic nephritis. In efficacy, the mean value of the SLE disease activity index was significantly reduced to 4.1, 2.7, 1.8, and 1.2 (N=21, 20, 16 and 13) at 0, 4, 12, and 24 weeks, respectively. In eight cases, treatment was discontinued within 24 weeks due to insufficient effects (6 cases) and side effects (2 cases). Non-serious side effects were observed in only five cases (23.8%) over 24 weeks. TAC can be considered both effective and safe for the treatment of various manifestations of SLE.

Topics: Adolescent; Adult; Aged; Drug Therapy, Combination; Female; Glucocorticoids; Health Status; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome; Young Adult

To determine the efficacy of tacrolimus ointment 0.1% on resistant cutaneous lesions in patients with lupus erythematosus.. Twelve patients with skin manifestations were studied. Six had discoid lupus (DL), four subacute cutaneous lupus erythematosus (SCLE) and two systemic lupus erythematosus (SLE). All patients had extensive skin lesions refractory to previous treatment. Patients received topical tacrolimus 0.1% for a minimum of 6 weeks and response was evaluated by physicians' and patients' assessment and documented with photographs at baseline and at the end of the treatment.. Eleven of 12 patients completed the therapy. One patient with DL discontinued because of side--effects-peeling and a burning sensation. Six patients were clearly improved, one patient had a minor remission of his face lesion while in four the rashes remained the same. Two patients with SCLE had significant regression of their lesions while the other two had no improvement. In DL, two had certain improvement, one minor improvement and two were without response. The patients with SLE had significant amelioration of their extensive photosensitive rash.. Tacrolimus ointment 0.1% may be an effective alternative in patients with severe resistant cutaneous manifestations in lupus erythematosus.

Topics: Adult; Aged; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Male; Middle Aged; Ointments; Tacrolimus; Treatment Outcome

Topical treatment of cutaneous lupus erythematosus usually includes potent glucocorticosteroids. However, prolonged use causes adverse side effects including skin atrophy as the foremost concern. In contrast to glucocorticosteroids, the anti-inflammatory and immunosuppressive macrolactam pimecrolimus has no atrophogenic potential. Affected areas of 11 patients with different forms of lupus erythematosus were treated with pimecrolimus 1% cream under semiocclusive conditions twice daily for 3 weeks. Skin involvement before and after therapy was assessed by means of a clinical score. In all patients, significant regression of skin lesions was observed after therapy (P <.001). This was an open and uncontrolled study on a limited number of cases. We suggest that pimecrolimus 1% cream could be an efficacious and safe treatment option for cutaneous lupus erythematosus.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Child; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Male; Middle Aged; Patient Acceptance of Health Care; Tacrolimus; Treatment Outcome

A 26-year-old woman with tuberous sclerosis complex (TSC) received outpatient treatment for the complication of systemic lupus erythematosus (SLE) at our hospital. She visited our hospital with a chief complaint of pitting oedema in bilateral lower legs for 3 days. The urinalysis showed massive proteinuria with a lot of white blood cell casts. The blood tests revealed hypoalbuminaemia, hypercholesterolaemia, hypocomplementaemia, and elevated anti-double-stranded DNA antibody titre. Renal biopsy was not performed because of multiple renal angiomyolipomas, which was one of the features of TSC. She was diagnosed with a nephrotic state due to lupus nephritis. Although she had a standard therapy with high-dose corticosteroid and mycophenolate mofetil and tacrolimus, complete remission had not been achieved leading to a steroid-dependent nephrotic syndrome. During the follow-up, the angiomyolipomas became larger and had a risk of rupture at the age of 29 years. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was started for the treatment of angiomyolipomas, and mycophenolate mofetil and tacrolimus were terminated instead. The activity of lupus nephritis was surprisingly ameliorated, and the amount of corticosteroid successfully tapered. Everolimus has been continued for 6 years without severe side effects. Accumulating evidence suggests that the activated mTOR pathway plays a key role in the pathogenesis of SLE. We reported the long-term efficacy and safety of everolimus for refractory SLE in a patient with TSC for the first time. This case suggests that everolimus can be a promising option for the treatment of lupus nephritis.

Topics: Adult; Angiomyolipoma; Everolimus; Female; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Tacrolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Tacrolimus is one of the drugs that can be used in pregnancies complicated with systemic lupus erythematosus (SLE), but there are still few reports on its pregnancy outcomes. Although tacrolimus has been reported to cause adverse events, such as increased blood pressure, abnormal glucose metabolism, and susceptibility to infection, there have been no studies on the impact of tacrolimus in SLE pregnancies at these points. We performed a retrospective observational study of pregnancies complicated by SLE at St Luke's International Hospital in Tokyo from April 2003 to August 2021.. Basic clinical information on SLE, pregnancy outcomes, disease activity before and after pregnancy, laboratory results, blood pressure, blood glucose levels, treatment regimens, and presence of infection was extracted from electronic medical records. We defined overall adverse pregnancy outcomes (APOs) as follows: (1) fetal death after 10 gestational weeks, (2) preterm delivery, (3) delivery due to hypertensive disorders of pregnancy, preeclampsia, or placental insufficiency, or (4) the diagnosis of small for gestational age infants. We also examined whether there was a statistical difference in APO incidence between patients treated with and without tacrolimus.. Pregnancy outcomes were obtained for 48 patients with a total of 60 pregnancies complicated by SLE. In 20 (33.3%) of these pregnancies, the patients took tacrolimus, and 28 (46.7%) of the pregnancies had APOs. APO incidence did not statistically differ between the tacrolimus and non-tacrolimus groups in the multivariate analysis (. Tacrolimus did not significantly affect pregnancy outcomes, blood pressure, or glucose levels. Further research is required to confirm its effects in a larger population.

Topics: Female; Humans; Infant; Infant, Newborn; Japan; Lupus Erythematosus, Systemic; Placenta; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Tacrolimus

The risk of COVID-19 infection is increased in patients with systemic lupus erythematosus (SLE) versus those without SLE. Some immunosuppressive medications increase COVID-19 infection and decrease the efficacy of vaccination. Consensus documents have suggested management strategies for handling immunosuppressive medications to increase vaccine efficacy, but the benefit of such strategies has not been proven. The current study was undertaken to determine the effect of immunosuppressive drugs on vaccine response in SLE.. We collected information on COVID-19 infection, vaccination history, and COVID-19 antibodies in the Hopkins Lupus Cohort. A cohort of health care workers was used for comparison. Outcome measures included SARS-CoV-2 antibody IgG levels after vaccination over time in both cohorts and effect of immunosuppressive medications on postvaccination IgG levels in SLE patients.. The analysis was based on 365 observations from 334 different patients in the SLE cohort, and 2,235 observations from 1,887 different health care workers. SLE patients taking immunosuppressive medications had lower vaccine IgG levels than SLE patients who were not; but both groups had lower levels than health care workers. Holding mycophenolate for 1 week after vaccination increased postvaccine IgG levels significantly without leading to clinical flares. In multiple variable models, mycophenolate mofetil, tacrolimus, and belimumab all significantly reduced antibody response to vaccination.. SLE patients, regardless of background immunosuppressive therapy, had lower vaccine IgG levels than health care workers. Mycophenolate, tacrolimus, and belimumab significantly reduced IgG response to vaccination. Holding mycophenolate for 1 week improved vaccine efficacy, providing clinical benefit on vaccine response without leading to clinical flares.

Topics: Antibodies, Viral; Antibody Formation; COVID-19; COVID-19 Vaccines; Humans; Immunoglobulin G; Immunosuppressive Agents; Lupus Erythematosus, Systemic; SARS-CoV-2; Tacrolimus; Vaccination

Topics: Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Tacrolimus; Treatment Outcome

We aimed to reveal the effectiveness of hydroxychloroquine (HCQ) compared with tacrolimus (TAC), an immunosuppressive agent, in patients with systemic lupus erythematosus (SLE) with persistent activity on standard treatment.. We retrospectively compared the efficacy and safety of the treatment between 18 patients receiving HCQ and 27 patients receiving TAC. None of the patients were in the lupus low disease activity state (LLDAS) at the beginning of this study. The efficacy end points were the cumulative incidence of LLDAS attainment without additional immunosuppressive agents, drug continuation rate, and treatment failure-free survival. The safety end point was the frequency of adverse events.. Eight (44.4%) patients in the HCQ group and 10 (37.0%) patients in the TAC group achieved LLDAS during the follow-up period; thus, the cumulative incidences of LLDAS attainment of the two treatments were nearly identical. The drug continuation and treatment failure-free survival rates were also not different between the two groups. The frequency of adverse events showed no clear differences between the two groups.. The efficacy and safety of an add-on treatment with HCQ are similar to those with TAC. Patients with persistently active SLE can benefit from HCQ in efforts to achieve at least low disease activity.

Topics: Antirheumatic Agents; Humans; Hydroxychloroquine; Lupus Erythematosus, Systemic; Retrospective Studies; Tacrolimus

The effectiveness and safety of sirolimus for SLE treatment have been shown in some uncontrolled studies. However, a comparison of sirolimus with other classic immunosuppressants has not been reported. We conducted the study to compare the effectiveness and safety of sirolimus versus tacrolimus for SLE treatment.. A real-world cohort study was conducted. Patients with clinically active SLE who were prescribed sirolimus or tacrolimus were enrolled. Propensity score matching was used to ensure equivalent disease conditions and background medications. SLE disease activity indices, serological parameters, steroid doses, modification of other immunosuppressants, renal effectiveness and adverse events were compared between the two groups at 3-month, 6-month, 9-month and 12-month follow-up visits.. Data from 52 patients in each of the sirolimus and tacrolimus groups were analysed. Indices regarding the effectiveness of sirolimus, including Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, physician's global assessment (PhGA) scores, and proportion of patients with SLEDAI-2K reduction of ≥4 and PhGA increase of <0.3, were equivalent to those of tacrolimus at all follow-up timepoints (all p≥0.05). Greater improvements in complement levels were observed in the sirolimus group at 3 and 6 months. Higher percentages of patients with prednisone doses ≤7.5 mg/day were observed in the sirolimus group at all timepoints. Seventeen adverse events in the sirolimus group were recorded. None was severe or led to drug discontinuation.. Overall, sirolimus was as effective as tacrolimus in the treatment of SLE. Sirolimus had better effects on serological improvement and glucocorticoid tapering. Sirolimus was well tolerated in patients with SLE.

Topics: Cohort Studies; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Sirolimus; Tacrolimus

Glucocorticoid discontinuation, a challenge in systemic lupus erythematosus (SLE), might be achievable with the advent of new therapeutic options.. This single-center study included 31 children with newly diagnosed pediatric SLE between 2002 and 2021, after the exclusion of patients who were followed for less than 1 year after treatment initiation and those lost to follow-up. Patient characteristics, clinical course including flares, treatment, glucocorticoid discontinuation, and outcomes were retrospectively analyzed.. Glucocorticoids could be discontinued in 19 (61%) patients during a median observation period of 105.5 (range, 17-221) months. Of these, 5 (26%), 12 (63%), and 18 (95%) patients could discontinue glucocorticoids in 3, 5, and 10 years from treatment initiation, respectively. Additionally, 18 of the 19 patients did not experience flares after glucocorticoid discontinuation during a median duration of 37.2 (7.2-106.8) months. Three of the nineteen patients achieved drug-free remission. At last follow-up, all patients achieved low disease activity with or without glucocorticoids and 19, 8, and 1 patient were receiving mycophenolate mofetil (MMF), MMF plus tacrolimus, and MMF plus ciclosporin A, respectively. Flares were observed in 15 patients during the observation period. MMF as initial immunosuppressant (P = 0.01) and shorter interval between therapy initiation and achieving maintenance prednisolone dose of 0.1-0.15 mg/kg/day (P = 0.001) were associated with significantly reduced flare risk. Femoral head necrosis was observed in two patients.. Despite the small sample size, these results support glucocorticoid discontinuation as a therapeutic target in pediatric SLE.

Topics: Child; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Belimumab combined with mycophenolate mofetil has been proven to be effective for treating systemic lupus erythematosus (SLE) in several randomized controlled trials. Calcineurin inhibitors are also useful in controlling the activity of SLE. However, the safety and effectiveness of belimumab-calcineurin inhibitor combination therapy have not been addressed. Therefore, the current single-center retrospective study aimed to analyze the safety/efficacy profile of belimumab-tacrolimus (B-T) combination therapy in patients with SLE.. Patients with SLE administered tacrolimus and belimumab during treatment were included in the study. Samples were analyzed for the drug retention rate, SLE flare rate, infection incidence rate, and glucocorticoid-sparing effect of the B-T combination therapy.. Thirty-three patients with SLE were treated with B-T combination therapy at our institution. Four patients discontinued treatment due to insufficient response or adverse events. The drug retention rate was over 90% at week 52 and approximately 80% at day 1000. Only one patient developed serious infection. The lupus low disease activity state (LLDAS) achievement ratio was 9.1% on the day of initiation and improved to 64.0% at 52 weeks after initiation. SLE flares were observed in three patients (9.1%) in the first 52 weeks after initiation, and in five patients (15.2%) throughout the study period. A glucocorticoid-reducing effect was also observed in patients treated with B-T combination therapy.. In most patients with SLE, B-T combination therapy is well tolerated with a good efficacy profile and glucocorticoid-reducing effect. Thus, B-T combination therapy represents a feasible option for patients with refractory lupus. Key Points • The safety and effectiveness of belimumab-calcineurin inhibitor combination therapy have not been addressed. • The drug retention rate of belimumab-tacrolimus combination therapy was over 90% at week 52 and around 80% on day 1000 • Almost none of the patients suffered from severe infection after the initiation of belimumab-tacrolimus combination therapy. • Belimumab-tacrolimus combination therapy is efficacious in suppressing lupus activity and achieving LLDAS.

Topics: Calcineurin Inhibitors; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topics: Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Tacrolimus; Treatment Outcome

BACKGROUND Nephrotic syndrome caused by minimal mesangial lupus nephritis is considered rare. Nephrotic syndrome can be caused by minimal mesangial lupus nephritis with diffuse epithelial foot-process effacement and lupus podocytopathy. CASE REPORT A 23-year-old Japanese woman diagnosed with mixed connective tissue disease was admitted because of weight gain and generalized edema for 2 weeks prior to admission. She had butterfly-shaped erythema on her cheeks, proteinuria, leukocytopenia with lymphocytopenia, and hypoalbuminemia. She was positive for antinuclear antibodies, and specific autoantibodies were only positive for the ribonucleoprotein (RNP) antigen. She was diagnosed with systemic lupus erythematosus. Renal biopsy showed minor glomerular abnormalities, and immunofluorescence revealed peripheral deposits of IgM and complement C3c. Electron microscopy revealed diffuse podocyte foot-process effacement of >80% of the capillary loop surfaces, with only a few subendothelial deposits. Consequently, we diagnosed minimal mesangial lupus nephritis with lupus podocytopathy. On hospital day 4, we administered 1000 mg/day of methylprednisolone for 3 days, followed by prednisolone 50 mg/day, but proteinuria persisted. On day 12, we administered tacrolimus (3 mg/day). Proteinuria improved and then disappeared on day 17. Prednisolone was gradually tapered and stopped after 3 years, although tacrolimus 3 mg/day was continued. No flare-up was observed 4 years after admission. CONCLUSIONS Tacrolimus showed good efficacy in this case of minimal mesangial lupus nephritis with lupus podocytopathy. Prospective and randomized controlled trials should be conducted to demonstrate the efficacy of tacrolimus for this indication.

Topics: Adult; Female; Humans; Induction Chemotherapy; Lupus Erythematosus, Systemic; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Prospective Studies; Proteinuria; Tacrolimus; Young Adult

Topics: Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Glomerulonephritis; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

Topics: Abdominal Pain; Aged; Fatigue; Female; Humans; Lupus Erythematosus, Systemic; Pancytopenia; Panniculitis, Lupus Erythematosus; Panniculitis, Peritoneal; Prednisolone; Tacrolimus; Tomography, X-Ray Computed

Tacrolimus, an immunosuppressant, has been used to treat paediatric systemic lupus erythematosus, but the optimal initial regimen is not clear. The purpose of this study was to explore the optimal initial dose of tacrolimus for children with systemic lupus erythematosus using population pharmacokinetics and pharmacogenomics.. Clinical information, tacrolimus concentrations and related genetic polymorphisms were incorporated into a model using non-linear mixed-effects modelling (NONMEM) analysis.. The results showed that weight, the CYP3A5 genotype and combined treatment with Wuzhi capsule can affect tacrolimus clearance in children with systemic lupus erythematosus. Furthermore, at the same weight, the ratios of tacrolimus clearance were 1:2.49:0.57:1.4193 from people who were CYP3A5*3/*3 and did not take Wuzhi capsule, people who had the CYP3A5*1 allele and did not take Wuzhi capsule, people who were CYP3A5*3/*3 and took Wuzhi capsule, and people who had the CYP3A5*1 allele and took Wuzhi capsule, respectively. In addition, we found that 0.10 mg/kg split into two doses was suitable for people with weights from 10 to 60 kg who were CYP3A5*3/*3 and did not take Wuzhi capsule, who were CYP3A5*3/*3 and took Wuzhi capsule, and who had the CYP3A5*1 allele and took Wuzhi capsule. In people who had the CYP3A5*1 allele and did not take Wuzhi capsule, 0.15 mg/kg split into two doses was appropriate for those with weights from 10 to 40 kg and 0.10 mg/kg split into two doses was appropriate for those with weights from 40 to 60 kg.. This study is the first study to recommend an optimal initial regimen of tacrolimus for children with systemic lupus erythematosus based on the CYP3A5 polymorphism and coadministration of Wuzhi capsule.

Topics: Adolescent; Alleles; Child; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Models, Biological; Nonlinear Dynamics; Pharmacogenetics; Polymorphism, Genetic; Retrospective Studies; Tacrolimus

Indeterminate cell histiocytosis (ICH) is an extremely rare clonal proliferative disorder of dendritic cells which presents with skin lesions in the majority of cases. Although extra-cutaneous manifestations are very rare, ICH may involve the mucosa, cornea, and conjunctiva as well as the visceral organs. Since the clinical appearance of cutaneous lesions of ICH is not distinctive, it is diagnosed with histopathological and immunohistochemical findings after clinical suspicion. Herein, we report a 27-year-old man with a two-year history of asymptomatic reddish papules and papulonecrotic lesions on his face, arms and buttocks. He was previously diagnosed with systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS), and he had been treated with hydroxychloroquine and low-dose aspirin. Diffuse dermal infiltration of a mixture of histiocytes and lymphocytes accompanied with multinuclear giant cells, the positive CD68 and Factor XIIIa and negative Langerin immunoreactions, along with the positive staining with CD1a and S100, led us to the diagnosis of ICH. To the best of our knowledge, this is the first case of ICH associated with SLE and APS.

Topics: Administration, Topical; Adult; Antiphospholipid Syndrome; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Skin Diseases; Tacrolimus

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

Topics: Aftercare; Anti-Infective Agents; Biopsy; Brachyspira; Colonoscopy; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Intestinal Diseases; Lupus Erythematosus, Systemic; Medication Therapy Management; Middle Aged; Prednisolone; Radiography, Abdominal; Spirochaetales Infections; Tacrolimus; Tomography, X-Ray Computed

Topics: Antifungal Agents; Bronchiolitis; Cellulitis; Cryptococcosis; Female; Humans; Immunocompromised Host; Lupus Erythematosus, Systemic; Middle Aged; Prednisolone; Tacrolimus

To assess the renal and non-renal efficacy of mycophenolate mofetil (MMF) in Japanese patients with systemic lupus erythematosus (SLE).. We conducted a retrospective study to assess the renal and non-renal efficacies of MMF in Japanese patients with systemic lupus erythematosus (SLE). We analyzed 14 patients with lupus nephritis (LN) who were given MMF, and 13 patients who received monthly intravenous cyclophosphamide (IVCY) as induction therapy, and a further 19 patients without LN who were treated with MMF, and 13 patients who took tacrolimus (TAC) to reduce glucocorticoid dosages. We assessed the therapeutic effects of each therapeutic regime on renal and non-renal disease manifestations over a six-month period after treatment initiation.. Median urine protein to creatinine ratios in the MMF and IVCY groups significantly decreased from 2.2 to 0.7 g/gCr and from 3.3 to 0.5 g/gCr, respectively. Significant improvements in serum immunological variables (serum complements C3 and C4 and the anti-double stranded DNA antibody) and reductions in the SLE disease activity index (SLEDAI) and daily prednisolone dosages were observed in each group with LN. MMF and TAC significantly improved SLEDAI and serum immunological variables and reduced daily prednisolone dosages in patients without LN.. The present results demonstrated that MMF might be an effective treatment for renal and non-renal manifestations in Japanese patients with SLE and has potential as a good therapeutic alternative and steroid-sparing agent.

Topics: Administration, Intravenous; Adult; Antibodies, Antinuclear; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Japan; Kidney Function Tests; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

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Topics: Capsule Endoscopy; Drug Therapy, Combination; Enteritis; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Prednisolone; Tacrolimus; Young Adult

Objective We evaluated the efficacy and safety of tacrolimus in systemic lupus erythematosus patients with refractory thrombocytopenia. Methods We retrospectively reviewed the data for 20 systemic lupus erythematosus patients with refractory thrombocytopenia and treated with tacrolimus during the period January 2013 to January 2015. In addition to glucocorticoids, all patients were treated with tacrolimus, 1 mg taken twice daily. The clinical effect of tacrolimus treatment in patients was evaluated by analysis of platelet counts at baseline and after one, three and six months of tacrolimus treatment. Levels of anti-double-stranded DNA antibodies and complement C3, C4 were determined individually. Results After one month of tacrolimus treatment, three patients (15%) did not respond, three patients (15%) achieved a complete response and the other 14 patients (75%) achieved a partial response. After three months of tacrolimus treatment, the platelet counts of all patients were significantly improved. A partial response was seen in 14 patients (75%) and the complete response rate increased to 25% (five patients). After six months, all patients attained partial response or complete response without relapse, and the rate of complete response increased to 75%. Compared to pretreatment, anti-double-stranded DNA antibody levels and the disease activity index score were markedly decreased after tacrolimus treatment. The levels of serum C3 and C4 were increased significantly ( P < 0.05). Conclusions Our survey revealed that a six-month course of tacrolimus is a safe and effective treatment for systemic lupus erythematosus patients with refractory thrombocytopenia.

Topics: Adult; Calcineurin Inhibitors; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Platelet Count; Retrospective Studies; Tacrolimus; Thrombocytopenia

Macrophage activation syndrome (MAS), a variant of secondary hemophagocyticlymphohistiocytosis, is a potentially life-threatening complication of inflammatory and autoimmune diseases. We present a case of MAS as a rare manifestation of systemic lupus erythematosus. Although initial treatment with corticosteroid, with or without cyclosporine A, is justified in patients with MAS, evidence regarding the effectiveness of this treatment protocol remains to be clarified. Our patient was successfully treated with a combination of intravenous immunoglobulin therapy and intravenous methyl predonisolone pulse therapy, which was followed by a course of oral prednisolone and oral tacrolimus. Based on our experience, we propose tacrolimus to provide a more useful adjuvant treatment to corticosteroid therapy than cyclosporine A.

Topics: Administration, Oral; Adult; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Macrophage Activation Syndrome; Prednisolone; Pulse Therapy, Drug; Tacrolimus

Topics: Adult; Ascites; Chronic Disease; Cyclophosphamide; Female; Humans; Lupus Erythematosus, Systemic; Mycophenolic Acid; Peritonitis; Prednisolone; Severity of Illness Index; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

A 49-year-old man was admitted to our hospital with pancreatitis. He was diagnosed with systemic lupus erythematosus at 34 years of age and was being treated with oral tacrolimus (3 mg/day) and predonine (10 mg/day) for the past 15 months. The computed tomography (CT) scan showed the mass lesion had invaded the pancreatic head via thickening of the duodenal wall. Upper gastrointestinal endoscopy showed the all-round ulcerative lesion from the superior duodenal angle to the descending portion. Histological examination confirmed the diagnosis of diffuse large B cell lymphoma (DLBCL). Tacrolimus therapy was stopped due to the possibility of immunodeficiency-related lymphoproliferative disease; however, the lesion did not improve. Consequently, he was administered rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). After six courses of R-CHOP therapy, a partial response was confirmed on CT. One month after the completion of chemotherapy, a gastrojejunal anastomosis was performed because of duodenal stenosis. He has since been well without recurrence. It was difficult to identify the risk factor for DLBCL; therefore, both the disease activity and immunosuppressive therapy should be taken into consideration as carrying a risk. In the present case, the symptom of pancreatitis enabled an early diagnosis of DLBCL.

Topics: Acute Disease; Anti-Inflammatory Agents; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Duodenal Neoplasms; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Pancreatitis; Prednisolone; Prednisone; Rituximab; Tacrolimus; Vincristine

Systemic lupus erythematosus (SLE) involves multiple organ systems and primarily affects women during their reproductive years. Pregnancy in a woman with SLE may lead to higher rates of disease flares. Little is known regarding which medications are safe to maintain remission and/or treat flares throughout such pregnancies. Here we retrospectively analyzed the efficacy of tacrolimus (TAC) in the pregnancy outcomes of SLE patients. We studied the 54 deliveries of 40 SLE patients over an eight-year period from 2008 to 2016. We used analyses of covariance with adjustments for the propensity score and inverse probability of treatment weights to compare the patient backgrounds between the TAC users and non-TAC users. TAC was administered to the patient in 15 of the 54 (27.8%) pregnancies, and these patients had a significantly higher dose of prednisolone, hypocomplementemia, lower estimated glomerular filtration rate, past history of lupus nephritis, and complication with antiphospholipid syndrome. In the adjusted background of the TAC deliveries, the risks of decreased fetal body weight, low birth weight infant, non-reassuring fetal status (NRFS), and preterm birth were not increased compared to the non-TAC deliveries. Thrombocytopenia and hypertension during the pregnancy were extracted as independent predictive risk factors for decreased fetal body weight and NRFS, respectively. We had anticipated that the maternal and fetal outcomes in the TAC-use deliveries would be poor before the analysis; however, the TAC-use group showed no significant difference in risks contributing to outcomes compared to the non-TAC group, suggesting that adjunct TAC treatment corrected various risk factors during the lupus pregnancies.

Topics: Adolescent; Adult; Antiphospholipid Syndrome; Female; Humans; Immunosuppressive Agents; Japan; Lupus Erythematosus, Systemic; Prednisolone; Pregnancy; Pregnancy Outcome; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Different population pharmacokinetics (PPK) models of tacrolimus have been established in various populations. However, the tacrolimus PPK model in paediatric systemic lupus erythematosus (PSLE) is still undefined. This study aimed to establish the tacrolimus PPK model in Chinese PSLE.. A total of nineteen Chinese patients with PSLE from real-world study were characterized with nonlinear mixed-effects modelling (NONMEM). The impact of demographic features, biological characteristics, and concomitant medications was evaluated. Model validation was assessed by bootstrap and prediction-corrected visual predictive check (VPC).. A one-compartment model with first-order absorption and elimination was determined to be the most suitable model in PSLE. The typical values of apparent oral clearance (CL/F) and the apparent volume of distribution (V/F) in the final model were 2.05 L/h and 309 L, respectively. Methylprednisolone and simvastatin were included as significant.. The first validated tacrolimus PPK model in patients with PSLE is presented.

Topics: Adolescent; Asian People; Child; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Metabolic Clearance Rate; Nonlinear Dynamics; Tacrolimus

We investigated the efficacy and safety of tacrolimus (TAC) by monitoring its serum concentration for mothers and infants in pregnant patients with systemic lupus erythematosus (SLE).. We measured trough concentrations of TAC in 25 pregnant patients with SLE to assess influence of TAC on the disease activity. Additionally, we measured the concentrations of TAC in umbilical arterial blood, breast milk, and breastfed infants to investigate the safety of TAC for the mothers and infants.. The trough concentrations of TAC in the mothers significantly decreased in the second trimester as compared with those before pregnancy. However, the decrease in the trough concentrations of TAC did not lead to the deterioration of SLE. When examined, the doses of TAC were significantly lower in the second trimester and postpartum in the deteriorating group than those in the non-deteriorating group. There were no adverse events by TAC in mothers and fetuses. The concentrations of TAC in the umbilical cord blood were lower than those in the maternal blood. The relative infant dose in breastfed infants of TAC was < 1%. The level of TAC in infant bloods was below detectable limits.. These findings suggest that TAC is one of the most effective and safest immunosuppressive drugs for use in pregnant patients with SLE.

Topics: Adult; Breast Feeding; Female; Fetal Blood; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Japan; Lactation; Lupus Erythematosus, Systemic; Milk, Human; Pregnancy; Severity of Illness Index; Tacrolimus

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

We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients.. The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a ≥ 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders.. There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p = 0.085). A mean dose of 1.6 mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7 mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p = 0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7 mg/day vs. 7.1 mg/day, p < 0.05). Only one patient discontinued tacrolimus because of fatigue after three months.. Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.

Topics: Adult; Disease Progression; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Medical Records; Middle Aged; Retrospective Studies; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome

Topics: Azathioprine; Cyclophosphamide; Female; Glomerulonephritis; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Mycophenolic Acid; Prednisone; Tacrolimus

Morphea is an uncommon connective tissue disease with the most prominent feature being thickening or fibrosis of the dermal without internal organ involvement. It is also known as a part of localized scleroderma. Based on clinical presentation and depth of tissue involvement, morphea is classified into several forms, and about two thirds of adults with morphea have plaque type. Overproduction of collagen production by fibroblast is the cause of abnormality in morphea, and the hyperactivity mechanism of fibroblast is still unknown, although there are several mechanisms already proposed. Plaque type morphea is actually a benign and self limited. Plaque type morphea that mimicking systemic lupus erythematosus in clinical appearance, such as alopecia and oral mucosal ulcers, is uncommon. A case of plaque type morphea mimicking systemic lupus erythematosus in a 20 year old woman was discussed. The patient was treated with local and systemic immunosuppressant and antioxydant. The patient's condition is improved without any significant side effects.

Topics: Abdomen; Adult; Anemia; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Lung; Lupus Erythematosus, Systemic; Radiography; Scleroderma, Localized; Tacrolimus; Ultrasonography; Young Adult

Systemic lupus erythematosus (SLE) is frequently accompanied by gastrointestinal symptoms. Although all parts of the gastrointestinal tract may be affected, colonic involvement is quite rare. Colonic ulceration, particularly in the rectum, is associated with a high mortality rate in patients with SLE, despite immunosuppressive therapy. While a standard regimen for treating rectal ulcers as a complication of SLE has not been established, combination therapy with steroids and immunosuppressive agents is necessary because of the associated high mortality rate. In this report, we describe a patient with SLE whose condition was complicated with ulcerative lesions in the rectum and sigmoid colon; the lesions were successfully treated with a combination of corticosteroids and tacrolimus therapy. Tacrolimus could be a useful additional or alternative modality for treating rectal involvement in SLE.

Topics: Adrenal Cortex Hormones; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Rectal Diseases; Tacrolimus; Treatment Outcome; Ulcer

A 57-year old male patient was admitted to our hospital because of severe vomiting and abdominal pain with massive ascites. He had been diagnosed as mixed connective tissue disease in 1997 and lupus nephritis ISN III (A/C) + V in 2003. Treatment was started with intravenous steroid pulse therapy combined with an immunosuppressant resulting in improvement of his proteinuria and serological activity. In 2008, the disease activity flared and he was admitted to our hospital with nephrotic syndrome. Hemodialysis was unavoidable, despite treatment with intravenous steroid pulse therapy and plasma exchange. We continued to treat him with oral prednisolone and tacrolimus. However, for personal reasons, he terminated tacrolimus treatment and massive ascites remained because of insufficient hemodialysis. Since the end of 2011, he suffered repeated abdominal pain with ileus and encapsulating peritoneal sclerosis (EPS) was detected. In February 2013, he underwent synechotomy for EPS. Here, we present a rare case of EPS in a hemodialysis patient.

Topics: Ascites; Chronic Disease; Digestive System Surgical Procedures; Humans; Ileus; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mixed Connective Tissue Disease; Peritoneal Fibrosis; Prednisolone; Renal Dialysis; Tacrolimus; Tomography, X-Ray Computed

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects women of childbearing years. Pregnancy with SLE is associated with an increase risk of adverse maternal and fetal outcomes. Recently, tacrolimus has been used for steroid-resistant SLE. However, because of limited information regarding the use of immunosuppressants during pregnancy, many SLE patients give up pregnancy. We report two SLE patients receiving tacrolimus who hoped to become pregnant. Patient 1 was a 31-year-old woman diagnosed with SLE 6 years earlier and treated with tacrolimus for 3 years because her symptoms were not controlled with other immunosuppressants. Patient 2 was a 28-year-old woman diagnosed with SLE 13 years earlier and treated with tacrolimus for 3 years because her symptoms were not controlled with prednisolone alone. The medical ethics board in our hospital approved the use of tacrolimus during pregnancy and lactation, and informed consent was obtained from the patients. Both patients were well controlled during pregnancy with prednisolone (Patient 1: 12 mg/day and Patient 2: 10 mg/day) and tacrolimus therapy (3 mg/day). They had healthy newborns and continued breastfeeding with tacrolimus therapy. The blood concentrations of tacrolimus 12 hours after taking tacrolimus was 3.0 ng/ml in Patient 1 and 2.9 ng/ml in Patient 2, and their newborns' blood concentrations of tacrolimus 1 hour after breastfeeding were 0.2 ng/ml and 0.5 ng/ml, respectively. Both newborns are healthy for at least 3 years after birth. This is the first report on the safety of tacrolimus for pregnancy and lactation in patients with SLE.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Japan; Lactation; Lupus Erythematosus, Systemic; Prednisolone; Pregnancy; Pregnancy Outcome; Tacrolimus; Treatment Outcome

A substantial number of patients with lupus nephritis (LN) are refractory to conventional glucocorticoid (GC) treatment. Although many of these patients respond to immunosuppressive drugs such as intravenous cyclophosphamide (IVCY), azathioprine (AZA), mizoribine, tacrolimus, cyclosporine A (CSA) and mycofenolate mofetil (MMF), some remain refractory to such therapies. Recent studies of multi-target therapies have reported effective outcomes for immunosuppression following renal transplantation and refractory LN when therapy consists of two or more immunosuppressive drugs with different mechanisms of action. We herein report a case of LN unresponsive to IVCY that was successfully treated with the addition of tacrolimus and discuss the usefulness of multi-target therapy for LN.

Topics: Adolescent; Antihypertensive Agents; Biphenyl Compounds; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Infusions, Intravenous; Irbesartan; Lupus Erythematosus, Systemic; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Pulse Therapy, Drug; Recurrence; Ribonucleosides; Severity of Illness Index; Tacrolimus; Tetrazoles

A 36-year-old woman was diagnosed with systemic lupus erythematosus (SLE). Seven days after beginning glucocorticoid treatment, she developed reduced visual acuity, and atypical severe central serous chorioretinopathy (CSC) was confirmed. Since glucocorticoid use is an important risk factor for CSC, the PSL was reduced, tacrolimus was added, and the visual acuity improved rapidly. Reduction in glucocorticoid combined with the use of immunosuppressive agents is one option for preventing a deterioration in atypical severe CSC while still controlling SLE.

Topics: Adult; Central Serous Chorioretinopathy; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Methylprednisolone; Prednisolone; Recovery of Function; Tacrolimus; Treatment Outcome; Vision Disorders; Visual Acuity

Topics: Child; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Prednisolone; Ribonucleosides; Tacrolimus; Treatment Outcome

Hemophagocytic syndrome (HPS) is an unusual disorder associated with systemic lupus erythematosus (SLE). A 64-year-old woman was admitted because of fever and urticarial vasculitis. Laboratory data revealed pancytopenia and immunological abnormalities, suggesting elevated disease activity. Prednisolone monotherapy failed to improve the pancytopenia despite the amelioration of other clinical findings. Because her condition was suggestive of HPS, tacrolimus at 2-3 mg/day was added to the prednisolone regimen. Eventually, the pancytopenia improved and prednisolone could be effectively tapered. Tacrolimus could be an additional or alternative modality for treating refractory HPS.

Topics: Bone Marrow; Dose-Response Relationship, Drug; Female; Fever; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphohistiocytosis, Hemophagocytic; Middle Aged; Pancytopenia; Prednisolone; Remission Induction; Tacrolimus; Treatment Failure; Treatment Outcome; Urticaria; Vasculitis

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

Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.. We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.. All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine.. This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.

Topics: Adrenal Cortex Hormones; Adult; Aged; Creatinine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Methylprednisolone; Middle Aged; Pilot Projects; Prednisolone; Proteinuria; Remission Induction; Retrospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome

The prognosis of lupus nephritis (LN) has improved since the introduction of immunosuppressant therapies, but the safety and effectiveness of treatments can also be improved. We retrospectively assessed the treatment courses of 12 patients with systemic lupus erythematosus who were treated with glucocorticoid, mizoribine (MZR) and tacrolimus. This regimen was used as initial therapy for active LN in six patients (mean glucocorticoid dose, 66.6 mg); four of these six patients also received pulse methylprednisolone therapy. The starting doses of MZR and tacrolimus were 150 and 3 mg, respectively, and they were titrated as required. Five of six patients achieved complete remission and one achieved partial remission at 6 months. Five patients who completed 12-month analysis achieved complete remission. Another six patients were given the combination regimen for treating minor flares or for steroid sparing. The mean prednisolone doses were reduced from 11.0 mg at baseline to 6.6 mg at 12 months. Six patients experienced minor adverse events, including three minor infections. One patient stopped tacrolimus because of suspected toxicity. All 12 patients were successfully treated, and none experienced severe adverse events. Multitarget therapy combining glucocorticoid, MZR and tacrolimus may have the potential to become a treatment option which is effective and safe.

Topics: Adult; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Remission Induction; Retrospective Studies; Ribonucleosides; Tacrolimus; Time Factors; Treatment Outcome

We describe the first reported case of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) induced by low-dose tacrolimus in a patient with autoimmune disease. A 41-year-old man with systemic lupus erythematosus (SLE) developed hyponatremia induced by SIADH after administration of tacrolimus (0.06 mg/kg per day). In this case, the hyponatremia promptly resolved upon withdrawal of tacrolimus. This case strongly suggests that SIADH is a potentially important complication of tacrolimus administration, irrespective of dosage, and should be borne in mind whenever the drug is used.

Topics: Adult; Humans; Hyponatremia; Immunosuppressive Agents; Inappropriate ADH Syndrome; Lupus Erythematosus, Systemic; Male; Tacrolimus; Withholding Treatment

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that affects multiple organs. Neuropsychiatric SLE develops during the course of the disease in 50% to 74% of SLE patients. The pathogenesis of CNS manifestations is multifactorial. The most common neuropathological finding has, in various studies, been multifocal infarcts. The cerebral vascular lesions in SLE that can cause cerebral infarction can be categorized into thromboembolism and vasculitis. On the other hand, tacrolimus is an immunosuppressive drug used for several autoimmune diseases, which inhibits the calcineurin pathway in T cells and reduces accompanying inflammatory cytokine production. We experienced that treatment of a patient with SLE with tacrolimus and steroid pulse therapy yielded improvement of vasculitis of brain vessels on magnetic resonance angiography. We suggest that tacrolimus may play an important role in the treatment of vasculitis of SLE.

Topics: Adult; Brain; Calcineurin; Cerebrovascular Circulation; Female; Fever; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Magnetic Resonance Angiography; Magnetic Resonance Imaging; T-Lymphocytes; Tacrolimus; Treatment Outcome; Vasculitis

Topics: Antirheumatic Agents; Antiviral Agents; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Hydroxychloroquine; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Lupus Erythematosus, Systemic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Tacrolimus; Treatment Outcome

Topics: Drug Resistance; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Middle Aged; Prednisone; Protein-Losing Enteropathies; Tacrolimus; Tomography, X-Ray Computed

The effects of a water-soluble tacrolimus-PEG conjugate (KI-102) on insulin-dependent diabetes mellitus and systemic lupus erythematosus were investigated. KI-102 was stable at pH 4.0-4.5 and 4°C. The area under the concentration-time curve, the time of maximum concentration, and the maximum concentration were 43.4 ng·h/mL, 0.85 h, and 8.1 ng/mL, respectively, similar to those of FK506. Mice that administered KI-102 at 4.32 mg/kg had the plasma glucose concentrations that decreased to 7.5 mmol/L after 170 days, similar to that of mice administered FK506 at 0.6 mg/kg. There were no incidences of diabetes when KI-102 was administered at 86.4 mg/kg after 24 weeks. The group that administered 43.2 mg/kg had decreases in the concentrations of β-hydroxybutyrate (60%), triglyceride (24%), and cholesterol (30%). KI-102 administered at 180 mg/kg reduced serum anti-dsDNA antibody activity by 64% compared with a control. Urinary albumin concentration in the same group decreased 81% compared with the control. These results indicate that KI-102 may be practically applicable as prodrug of FK506.

Topics: Administration, Oral; Albumins; Animals; Antibodies, Antinuclear; Blood Glucose; Capsules; Cholesterol; Diabetes Mellitus, Type 1; DNA; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Compounding; Drug Delivery Systems; Drug Evaluation, Preclinical; Drug Stability; Female; Freeze Drying; Hydrogen-Ion Concentration; Immunosuppressive Agents; Insulin; Lupus Erythematosus, Systemic; Mice; Polyethylene Glycols; Prodrugs; Rats; Rats, Sprague-Dawley; Tacrolimus; Triglycerides

The present case is the first report of a systemic lupus erythematosus patient which has been induced Parkinsonism with the administration of tacrolimus (TAC). A 50-year-old woman was diagnosed as lupus nephritis on September 2003. The patient had been prescribed initially 40 mg/day of prednisolone, then cyclosporine was added on May 2005. One year later, she developed severe headache, so cyclosporine was stopped, and she was prescribed tacrolimus on February 2007. However her severe headache had been disappeared, she experienced rigidity and tremor around September 2007. The Dopamine-transporter-imaging examination reavealed that she had Parkinson's disease. The gene analysis on the genetic background showed her case was the sporadic type? Parkinson's disease. Washing out of Tacrolimus, her Parkinsonism was partially improved. This fact suggested that her Parkinsonism was drug-induced type Parkinsonism. In lupus nephritis patients who have been treated with TAC, a very careful observation should be considered because neurological disorders inducing Parkinsonism may occur.

Topics: Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Middle Aged; Parkinsonian Disorders; Tacrolimus

We conducted a pilot study to investigate whether tacrolimus was effective for treating patients with systemic lupus erythematosus (SLE) without renal involvement. Ten SLE patients with symptoms such as arthritis and erythema, but no active nephritis, were treated with tacrolimus. They included 8 women and 2 men aged from 24 to 62 years [mean +/- standard deviation (SD): 42.1 +/- 11.3 years]. Tacrolimus was administered at doses of 1-3 mg daily, and efficacy was assessed from the SLE Disease Activity Index (SLEDAI) after 1 year. Two patients ceased treatment due to adverse reactions (after 4 days for chest pain and 7 months for recurrent infections). The other 8 patients completed 1 year of treatment, and significant improvement of disease activity was observed in 6 of them. The mean (+/-SD) SLEDAI showed a significant decrease after 1 year of tacrolimus therapy, from 6.8 +/- 3.1 to 3.4 +/- 0.9; p < 0.05 by Student's paired t test. The mean (+/-SD) dose of prednisolone also decreased significantly, from 16.8 +/- 8.6 to 9.3 +/- 4.6 mg/day; p < 0.05. Although a prospective controlled study will be necessary to confirm, tacrolimus might be a treatment option for active SLE without renal involvement.

Topics: Adult; Anti-Inflammatory Agents; Cohort Studies; Complement C3; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Patient Selection; Pilot Projects; Prednisolone; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

The treatment of pure membranous (class V) lupus nephropathy remains unsatisfactory. We studied the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE.. We recruited 18 consecutive SLE patients (tacrolimus group) with recently confirmed biopsy-proven class V lupus nephritis. They were treated with a tailing dose of oral prednisolone and tacrolimus 0.1-0.2 mg/kg/day for 6 months, followed by maintenance prednisolone and AZA. The rate of resolution of proteinuria and SLEDAI were compared with 19 historical controls treated with oral cyclophosphamide or AZA (control group). All patients were followed for 12 months.. Baseline clinical characteristics were comparable between the groups. For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). However, tacrolimus group had faster resolution of proteinuria than the control group by the general linear model with repeated measures (P = 0.032). At 12 weeks, proteinuria was reduced by 76.2 +/- 17.0% for the tacrolimus group and 47.1 +/- 51.1% for the control group (P = 0.028). Serial change in renal function and SLEDAI score did not differ between the groups. During the study period, four patients of the tacrolimus group, and 11 of the control group, developed lupus flare (P = 0.027). There was no serious adverse effect in the tacrolimus group.. A 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. The long-term effect and optimal regimen of tacrolimus require further study.

Topics: Adult; Case-Control Studies; Chi-Square Distribution; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Prednisolone; Recurrence; Tacrolimus; Treatment Outcome

We present a 47-year-old Caucasian female who initially presented with mild discoid lupus erythematosus that evolved into systemic lupus erythematosus with subacute cutaneous LE and treatment-recalcitrant lupus panniculitis. Conventional therapy with antimalarials, systemic steroids, azathioprine, cyclophosphamide, methotrexate, and pulse doses of methylprednisolone did not control the course of the disease. Cyclosporin-A treatment led to clinical improvement and maintained remission.

Topics: Antimalarials; Azathioprine; Cyclophosphamide; Cyclosporine; Disease Progression; Drug Therapy, Combination; Female; Humans; Hydroxychloroquine; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Methotrexate; Methylprednisolone; Middle Aged; Panniculitis, Lupus Erythematosus; Pulse Therapy, Drug; Tacrolimus; Treatment Failure

It has been reported that aggressive immunosuppressive treatment is effective for controlling the disease activity of refractory systemic lupus erythematosus (SLE). However, little information on a regimen including tacrolimus (TL) for the treatment of refractory SLE has been available. We report a successful low dose TL treatment of a 25-year-old male patient with refractory SLE. He developed SLE with proliferative lupus nephritis(WHO class IVb) at the age of 11 years. During the past 4 years, despite aggressive immunosuppressive treatment consisting of methylprednisolone pulse therapy, mizoribine pulse therapy, cyclosporine A and intravenous cyclophosphamide pulse therapy, frequent flares associated with presumptive hypercytokinemia i.e., increased levels in the serum C-reactive protein, ferritin and soluble IL-2 receptor, occurred. Hence, administration of low-dose TL at 3 mg per day, was initiated. The blood levels of TL at approximately 12 hours post-dosing were maintained at between 3 and 5 ng/mL. Within 3 weeks following TL administration, the serum levels of C3, C4 and CH50 began to increase rapidly, and the prednisolone dose could be successfully tapered. No adverse effects of TL were observed. We suggest that TL may be the treatment of choice for selected patients with refractory SLE.

Topics: Adult; Drug Administration Schedule; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Prednisolone; Recurrence; Tacrolimus; Treatment Outcome

A 23-year-old woman presented with recurrence of lupus cystitis, which had been in remission under daily administration of a single corticosteroid over a period of 8 years. She was treated with increased doses of corticosteroid and immunosuppressants, i.e., cyclosporin, cyclophosphamide, azathioprine, and salazosulfapyridine, but the cystitis remained active. Since her condition became critical by the complication of intestinal pseudo-obstruction, tacrolimus was administered. This agent induced a remission promptly without significant adverse events in this patient, suggesting an efficacy to lupus cystitis refractory to corticosteroid and other immunosuppressants.

Topics: Adrenal Cortex Hormones; Adult; Cystitis; Female; Humans; Hydronephrosis; Immunosuppressive Agents; Intestinal Pseudo-Obstruction; Lupus Erythematosus, Systemic; Radiography; Tacrolimus; Ultrasonography

Topics: Adult; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Mycophenolic Acid; Red-Cell Aplasia, Pure; Tacrolimus

There is only limited experience in patients with systemic lupus erythematosus (SLE) with drugs that have developed for immunosuppression after organ transplantation, namely calcineurin inhibitors (CI). The aim of this study is to determine the effect of these drugs on disease activity after kidney transplant in patients affected by SLE.. Between January 1990 to March 2003, 13 patients with end- stage renal disease secondary to SLE received 14 kidney transplants. The outcome variables assessed include graft and patient survival as well as clinical and serological lupus activity.. All received CI-based immunosuppression (cyclosporine or tacrolimus). Actuarial patient and graft survivals at 5 yr were 100 and 93%, respectively. Recurrence of clinical or serological disease was never detected.. To date, only anecdotal experience with CI in the treatment of SLE has been reported. The favorable response observed in our patients suggests that CI at low-doses are effective in preventing SLE-reactivation. Further studies focused on calcineurin inhibitor treatment in SLE patients who fail to respond to standard medical management should be conducted.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Secondary Prevention; Severity of Illness Index; Tacrolimus

We report a patient with systemic lupus erythematosus (SLE) who developed fulminant pulmonary hemorrhage. This patient also showed liver dysfunction, bicytopenia and hyperferritinemia, with an increase in serum levels of interleukin (IL)-1 beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) at the onset of pulmonary symptoms, probably indicating an associated hemophagocytic syndrome. Despite an acute progressive course temporarily requiring mechanical ventilation the patient was successfully treated with continuous drip infusion of tacrolimus, plasmapheresis and intravenous high-dose immunoglobulin and corticosteroid. In this patient increased inflammatory cytokines ascribable to activation of macrophages and/or helper T cells were considered to play an important role in the pathogenesis of the pulmonary hemorrhage. Because this complication is frequently fatal in SLE, intensive therapy, including immunosuppressants and plasmapheresis, should be actively considered as early as possible after onset.

Topics: Adrenal Cortex Hormones; Adult; Female; Hemorrhage; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Lung Diseases; Lupus Erythematosus, Systemic; Plasmapheresis; Tacrolimus; Treatment Outcome

In a 30-year-old male patient systemic lupus erythematosus was diagnosed based on the presence of 8 out of 11 ARA criteria. Disease onset was acute and included renal function impairment with biopsy-proven lupus nephritis (WHO class IV) requiring renal replacement therapy. Although conventional immunosuppressive therapy regimens proved effective in controlling disease activity, all of the administered drugs were accompanied by serious side effects: bilateral femur head necrosis with corticosteroids, allergic skin reaction in response to azathioprine, nephrotoxicity with cyclosporine, nausea and abdominal pain with mycophenolate mofetil and life-threatening septicemia with cyclophosphamide treatment. In search for alternative treatment options, tacrolimus (FK506, trough serum levels 3-6 ng/ml) was started. FK506 was well-tolerated and lupus activity completely resolved within 7 months after initiation of therapy. During 36 months of follow-up no arthritic complaints occurred and renal function stabilized at a serum creatinine of 2.1 mg/dl with negative anti-ds-DNA antibodies and ANA titers. In conclusion, FK506 may be considered as alternative immunosuppressive for maintenance treatment in patients with severe lupus erythematosus and side effects to conventional regimens.

Topics: Adult; Drug Eruptions; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Tacrolimus

Thrombotic microangiopathy is a well-known problem in patients following renal transplantation. In postrenal transplantation, thrombotic microangiopathy is often a reflection of hemolytic uremic syndrome. We aimed to determine the causes of thrombotic microangiopathy in a population of renal transplantation recipients and discuss the literature.. We investigated the causes of thrombotic microangiopathy during a 1-year period, from June 2003 to June 2004, at the King Fahad National Guard Hospital in Riyadh, Saudi Arabia, by reviewing the slides of all transplant biopsies (n=25) performed during this interval. Pre- and posttransplant crossmatching was done when possible.. Five cases of thrombotic microangiopathy were found. Three of these cases were from the 25 transplantations performed at King Fahad National Guard Hospital, while the other 2 transplantations had been performed abroad and were referred to us for follow-up. Three cases were related to cyclosporine, and 1 case was secondary to both cyclosporine and tacrolimus. The fifth case had features of thrombotic microangiopathy related to an antiphospholipid syndrome in a patient with systemic lupus erythematosus.. In the literature, the most-frequent cause of hemolytic uremic syndrome in patients following renal transplantation is recurrence of the hemolytic uremic syndrome. Other causes include drug-related (cyclosporine, tacrolimus) toxicity, procoagulant status, and antibody-mediated rejection. We found that the most-frequent cause of thrombotic microangiopathy was drug related, secondary mainly to cyclosporine. In the current study, the frequency of thrombotic microangiopathy was similar to the percentage reported in the literature (20%).

Topics: Acute Disease; Adult; Antiphospholipid Syndrome; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Microcirculation; Middle Aged; Postoperative Period; Retrospective Studies; Tacrolimus; Thrombosis

The rash of systemic lupus erythematosus (SLE) is usually treated with topical corticosteroids, but prolonged use causes adverse cutaneous side-effects. We assessed the efficacy of topical tacrolimus for treating the skin lesions of SLE. Three patients with SLE affecting their facial skin applied 0.1% tacrolimus ointment on one side of their face twice daily for 3 weeks, in conjunction with a sunscreen cream. After 3 weeks, erythema on the treated side was ameliorated in all three patients compared with the untreated side. Although the study is preliminary, the results demonstrate that topical tacrolimus may be useful for treating the malar rash of SLE.

Topics: Adult; Anti-Bacterial Agents; Exanthema; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Ointments; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Chronic Disease; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Middle Aged; Scalp Dermatoses; Tacrolimus

To evaluate the effectiveness of renal transplantation in systemic lupus erythematosus (SLE).. A total of 97 SLE patients who underwent renal transplantation between January 1984 and September 1996 were selected for study and were matched with a group of non-SLE controls (1 control for each SLE patient) who also received transplants during that period. SLE patients and controls were matched on 6 covariates: age, sex, race, type of allograft (cadaveric versus living-related), number of previous transplants, and year of transplantation. All study subjects received either cyclosporine or FK-506/tacrolimus as part of their immunosuppressive regimen. In a rigorous medical records review, the status of each allograft and the cause of each graft loss was determined. Using a stratified Cox proportional hazards model, the transplantation outcomes of the SLE patients were compared with those of the controls. The effects of 9 individual variables on transplantation outcomes were also examined, and the statistically significant variables were compared in a stratified, multivariate Cox proportional hazards model.. The control group included patients with 20 different causes of end-stage renal disease (ESRD). The mean followup times for the SLE patients and controls were 323 weeks and 320 weeks, respectively. During the followup period, 52 SLE patients and 37 controls lost their allografts. The 1-, 2-, 5-, and 10-year allograft survival probabilities for the 2 groups (SLE versus controls) were as follows: 81.7% versus 88.2% (1-year); 74.7% versus 84.4% (2-year); 45.9% versus 75.0% (5-year); and 18.5% versus 34.8% (10-year). In the multivariate model, the relative hazard of allograft loss associated with SLE as the cause of ESRD was 2.1 (95% confidence interval 1.06-4.06, P = 0.0328). The total number of HLA mismatches, smoking status, and delayed allograft function were also associated with allograft loss in the multivariate model.. Compared with matched controls, renal transplant patients with SLE had inferior transplantation outcomes, with more than twice the risk of allograft loss.

Topics: Adult; Antirheumatic Agents; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Multivariate Analysis; Probability; Proportional Hazards Models; Survival Analysis; Tacrolimus; Treatment Outcome

Topics: Adult; Anti-Bacterial Agents; Autoantibodies; Autoimmune Diseases; Cyclosporine; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Tacrolimus

An analysis of the efficacy of tacrolimus treatment in three patients with difficult and severe systemic lupus erythematosus (SLE) whose active disease had been previously poorly controlled by cyclosporine and cyclophosphamide.. A review of patient notes.. Two patients are well controlled after six and nine months of treatment with tacrolimus 0.06 mg/kg/day and 0.18 mg/kg/day. Previous persistent vasculitis had resolved and other features of active disease were controlled. The third patient's vasculitis had not improved significantly after two months of treatment and tacrolimus 0.17 mg/kg/day was discontinued because of nephrotoxicity.. Tacrolimus may be a useful additional immunosuppressive agent in some patients whose SLE is not well controlled by conventional treatments.

Topics: Adolescent; Adult; Drug Administration Schedule; Evaluation Studies as Topic; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney; Lupus Erythematosus, Systemic; Male; Tacrolimus

Groups of female MRL/MpJ-lpr/lpr mice received either saline or FK506 (tacrolimus; 2 mg/kg intraperitoneally) three times weekly, cyclophosphamide (CY; 20 mg/kg) once monthly, or both drugs from 8 weeks of age. Median survival for untreated and CY-treated mice was 26 weeks, and for FK506- and FK506 + CY-treated groups was > or = 44 weeks. Severity of skin lesions and lymph node hyperplasia was markedly reduced by the drug combination, whereas either drug alone was less effective. FK506 or CY alone delayed the onset of proteinuria, but by 24 weeks all of these animals were positive. In contrast, drug combination reduced the prevalence of proteinuria to < or = 60% throughout the 44 weeks of study. Sequential monitoring of peripheral blood lymphocytes revealed that combination therapy but not monotherapy markedly reduced the proportion of atypical CD3+ B220+ and CD3+CD4-CD8- T cells. Neither FK506 nor CY affected the reduction in IL-2 and IL-4 mRNA levels observed in lymph nodes of diseased animals compared with normals. Although the drug combination also did not affect IL-2 mRNA levels, IL-4 mRNA transcripts were increased six-fold compared with saline-treated controls. IL-10 and interferon-gamma (IFN-gamma) mRNAs were induced by FK506, CY and by the drug combination. Serum levels of anti-dsDNA antibodies were reduced in all treatment groups. These data demonstrate improved efficacy of combined T and B cell-directed immunosuppression in murine lupus, associated with marked inhibition of atypical T cells and selective augmentation of IL-4 within the affected lymphoid tissue.

Topics: Animals; Antibodies, Antinuclear; Antigens, Surface; Base Sequence; CD3 Complex; CD4 Antigens; CD8 Antigens; Cyclophosphamide; Cytokines; DNA Primers; Female; Gene Expression; Kidney; Leukocyte Common Antigens; Lupus Erythematosus, Systemic; Mice; Mice, Mutant Strains; Molecular Sequence Data; Proteinuria; Survival Analysis; T-Lymphocyte Subsets; Tacrolimus

We examined the effects of gamma-interferon (gamma-IFN) and the new immunosuppressant FK506 on resting B cell proliferation of New Zealand black/white F1 hybrid (B/W F1) mice, an animal model of human systemic lupus erythematosus (SLE). gamma-IFN and FK506 inhibited in a dose-dependent manner both B cell proliferation and autoantibody production of resting B cells respectively. There was a synergistic interaction between gamma-IFN and FK506 in their inhibition and they did not exhibit cell cytotoxicity. This in vitro synergism of gamma-IFN and FK506 may have clinical application in that low doses of gamma-IFN and FK506 combinations may be effective to correct polyclonal B cell activation of patients with SLE.

Topics: Animals; B-Lymphocytes; Cytotoxicity, Immunologic; DNA; Drug Synergism; Female; Hybridization, Genetic; Interferon-gamma; Interleukin-4; Lipopolysaccharides; Lupus Erythematosus, Systemic; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred NZB; Tacrolimus

A novel immunosuppressive compound extracted from the fermentation broth of Streptomyces tsukubaensis belongs to the macrolide family. We gave this drug (FK-506) to MRL/lpr and NZB X NZW F1 (B/W F1) mice, an animal model of human systemic lupus erythematosus (SLE), to investigate its effect on the course of the disease. This drug showed potential to prolong the lifespan, to reduce proteinuria, and to prevent the progression of nephropathy. Appreciable differences in the levels of anti-dsDNA antibodies between treated and control animals were nil.

Topics: Animals; Autoantibodies; DNA; Immunoglobulin G; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Proteinuria; Pyridines; Spleen; Tacrolimus