mycophenolic-acid and Arthritis--Rheumatoid

Oral manifestations of side effects of medications, such as methotrexate (MTX) for management of rheumatoid arthritis (RA) and mycophenolate mofetil (MMF) for solid organ transplant (SOT), are very rare. The known side effects include entities called other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) due to immunosuppression caused by these medications. While there has been an increased incidence of oral cavity LPD reported in the literature associated with MTX, oral presentations that involve MMF are rare. This case report will detail a 74-year-old man with scleroderma treated with MMF who developed Epstein-Barr virus + polymorphic B-cell lymphoproliferative disorder in the right maxillary gingiva presenting as osteonecrosis of the jaw (ONJ). His oral presentation was successfully treated with a combination of surgery and MMF dosage reduction with an oral presentation free of disease at 6 months follow-up. This is the first known case report of an oral manifestation of MMF-related OIIA-LPD.

Topics: Aged; Arthritis, Rheumatoid; Humans; Iatrogenic Disease; Lymphoproliferative Disorders; Male; Methotrexate; Mycophenolic Acid

Lung involvement in rheumatologic diseases has a broad spectrum of clinical and radiological presentations, from acute and inflammatory predominance to chronic and fibrotic lung disorders. Therapy has to be guided by the type of rheumatologic disease, the kind of lung involvement and the risk associated with the clinical state of the patient and prognostic factors. Although several therapeutic approaches have been used, the best treatment is still not certain; clinical trials are mandatory, which would require a better knowledge of the pulmonary pathogenesis of immunologic diseases. The following review is focused on the therapeutic options for those rheumatologic disorders that could present as a predominant interstitial lung disease which may confer a bad or life-threatening prognosis.

Topics: Adrenal Cortex Hormones; Antirheumatic Agents; Arthritis, Rheumatoid; Azathioprine; Cyclophosphamide; Humans; Immunosuppressive Agents; Lung Diseases; Lupus Erythematosus, Systemic; Mycophenolic Acid; Polymyositis; Rituximab; Scleroderma, Systemic; Sjogren's Syndrome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Bone Density; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mycophenolic Acid; Osteoporosis; Protein Kinase Inhibitors; Treatment Outcome

This review article describes our present understanding of interstitial lung disease (ILD) complicating rheumatoid arthritis (RA). It discusses its high prevalence and clinical relevance, our recent improvement in understanding both its pathology and physiology, and our expectations of ongoing research into the immunology and genetics of the disease. An important section relates to the effects of drugs routinely used in the treatment of the articular manifestations of RA on the lung, especially in the presence of ILD. The major focus of the article is on therapeutic intervention, and here we discuss traditional and often unsuccessful approaches to treatment, leading on to discuss newly introduced therapeutic options such as anticoagulation and oral N-acetylcysteine. In the later sections, we focus our attention on several promising new therapeutic agents, including mycophenolate and new monoclonal antibody therapies, reviewing the limited literature available to support the use of these agents, concluding with a number of other aspects of treatment that are worthy of consideration.

Topics: Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Lung Diseases, Interstitial; Lung Transplantation; Mycophenolic Acid; Practice Guidelines as Topic; Vaccination

Methotrexate (MTX) and mycophenolic acid (MPA) are used in the clinic for their immunosuppressive properties. MTX is widely used for the treatment of rheumatoid arthritis (RA). MPA is used to prevent graft rejection and is now experimentally used in systemic lupus erythematosis and RA. It is known that both drugs interfere with DNA synthesis. However, the precise mechanism of action is still debated. We have analysed the effect of the drugs on cytokine production in whole blood during short cultures. The production of T-cell cytokines was inhibited by both drugs. MTX inhibits cytokine production because MTX induces apoptosis in activated T-cells. MPA inhibits cytokine production by preventing T-cells to progress to the S-phase of the cell cycle. Cytokine production by monocytes was slightly decreased by the drugs. The reason for this inhibition is not clear. These results indicate that T-cells are the main target cells of the immunosuppressive drugs MPA and MTX.

Topics: Animals; Apoptosis; Arthritis, Rheumatoid; Cytokines; DNA; Dose-Response Relationship, Drug; Humans; Hypoxanthine; Immunosuppressive Agents; Lymphocytes; Methotrexate; Mycophenolic Acid; Nucleic Acid Synthesis Inhibitors

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

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

Leflunomide inhibits dihydro-orotate dehydrogenase with secondary effects on interleukin 2, transforming growth factor alpha and antibody production. Published data show that it is effective at 10-25 mg/day. Leflunomide's side-effects include gastrointestinal toxicity, a low incidence of alopecia, elevated liver function test abnormalities and weight loss. Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase with secondary decreases on guanine nucleotides, DNA synthesis and inhibition of natural killer cell activity. At 1 or 2 g daily it is effective clinically, although it has little effect on erythrocyte sedimentation rate. Incidences of toxicity obtained from transplantation experience are principally gastrointestinal but also include a probable increase in viral infections, some myelosuppression and occasional cholestasis or pancreatitis. Matrix metalloproteinase inhibitors (MMPIs) are a diverse group of enzymes that are rapidly induced by inflammatory mediators. Some MMPIs are effective in rheumatoid arthritis. Their toxicities include gastrointestinal toxicity, sun sensitivity and rare systemic lupus erythematosus-like syndromes.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibiotics, Antineoplastic; Arthritis, Rheumatoid; Enzyme Inhibitors; Humans; Isoxazoles; Leflunomide; Metalloendopeptidases; Mycophenolic Acid

The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following oral administration, mycophenolate mofetil was rapidly and completely absorbed, and underwent extensive presystemic de-esterification. Systemic plasma clearance of intravenous mycophenolate mofetil was around 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fell below the quantitation limit (0.4 mg/L) within 10 minutes of the cessation of infusion. Similar plasma mycophenolate mofetil concentrations were seen after intravenous administration in patients with severe renal or hepatic impairment, implying that the de-esterification process had not been substantially affected. Mycophenolic acid, the active immunosuppressant species, is glucuronidated to a stable phenolic glucuronide (MPAG) which is not pharmacologically active. Over 90% of the administered dose is eventually excreted in the urine, mostly as MPAG. The magnitude of the MPAG renal clearance indicates that active tubular secretion of MPAG must occur. At clinically relevant concentrations, mycophenolic acid and MPAG are about 97% and 82% bound to albumin, respectively. MPAG at high (but clinically realisable) concentrations reduced the plasma binding of mycophenolic acid. The mean maximum plasma mycophenolic acid concentration (Cmax) after a mycophenolate mofetil 1 g dose in healthy individuals was around 25 mg/L, occurred at 0.8 hours postdose, decayed with a mean apparent half-life (t1/2) of around 16 hours, and generated a mean total area under the plasma concentration-time curve (AUC infinity) of around 64 mg.h/L. Intra- and interindividual coefficients of variation for the AUC infinity of the drug were estimated to be 25% and 10%, respectively. Intravenous and oral administration of mycophenolate mofetil showed statistically equivalent MPA AUC infinity values in healthy individuals. Compared with mycophenolic acid, MPAG showed a roughly similar Cmax about 1 hour after mycophenolic acid Cmax, with a similar t1/2 and an AUC infinity about 5-fold larger than that for mycophenolic acid. Secondary mycophenolic acid peaks represent a significant enterohepatic cycling process. Since MPAG was the sole material excreted in bile, entrohepatic cycling must involve colonic bacterial deconjugation of MPAG. An oral cholestyramine interaction study showed that the mean contribution of entrohepatic cycling to t

Topics: Absorption; Arthritis, Rheumatoid; Drug Administration Routes; Drug Interactions; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Failure; Mycophenolic Acid; Protein Binding; Renal Insufficiency

Rheumatoid arthritis was considered for centuries to be a nuisance condition, limiting in its effects on an individual's range of motion and the source of considerable distress, but not a life-threatening disease. Recently, however, it has become apparent that patients with severe rheumatoid arthritis may have a decreased life span. Current pharmacologic therapies for patients with rheumatoid arthritis, which include nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, methotrexate, and corticosteroids, have been moderately successful in alleviating the discomforts associated with swollen, painful joints. Many practitioners have sought to improve use of these agents and slow joint destruction by challenging traditional treatment paradigms, altering the sequence in which drugs are given. Nevertheless, most standard medical approaches to treatment have had little or no impact on the course of rheumatoid disease. Innovative strategies, particularly those based on new concepts in the immunobiology of rheumatoid arthritis, are being developed to target cellular inflammatory mechanisms and actually prevent disease progression. Some agents, such as inhibitors of 5-lipoxygenase-omega-3 fatty acid and zileuton-may be most useful in treatment of milder disease manifestations such as moderate synovitis. Other agents, such as oral type II collagen, minocycline, subcutaneous interleukin-1ra, and anti-CD4 monoclonal antibodies, have produced such inconsistent results that substantial additional research will be required before any conclusions may be drawn about their value. Among the most promising agents, and the most extensively studied, are tumor necrosis factor-alpha monoclonal antibodies, immunosuppressive drugs such as cyclosporine and mycophenolate mofetil, and the novel compound tenidap, which has both cytokine-modulating and anti-inflammatory properties.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies; Antirheumatic Agents; Arthritis, Rheumatoid; CD4 Antigens; Collagen; Cyclosporine; Humans; Hydroxyurea; Immunosuppressive Agents; Interleukin-1; Minocycline; Mycophenolic Acid; Tumor Necrosis Factor-alpha

Evidence that was obtained in several experimental models and in strains of hypertensive rats indicates that infiltration of inflammatory cells and oxidative stress in the kidney play a role in the induction and maintenance of hypertension. Similar evidence is lacking in human hypertension, at least in part, because immunosuppressive treatment is unjustified in patients with hypertension. For addressing this issue, patients who were prescribed by their private physicians mycophenolate mofetil (MMF) for the treatment of psoriasis or rheumatoid arthritis and had, in addition, grade I essential hypertension and normal renal function were studied. Eight patients were studied before MMF was started, during MMF treatment, and 1 mo after MMF treatment had been discontinued. Other treatments and diet were unchanged in the three phases of the study. MMF therapy was associated with a significant reduction in systolic, diastolic, and mean BP. Urinary excretion of TNF-alpha was reduced progressively by MMF treatment and increased after MMF was discontinued. Reduction of urinary malondialdehyde, TNF-alpha, and RANTES excretion during MMF administration did not reach statistical significance but had a direct positive correlation with the BP levels. These data are consistent with the hypothesis that renal immune cell infiltration and oxidative stress play a role in human hypertension.

Topics: Aged; Arthritis, Rheumatoid; Blood Pressure; Chemokine CCL5; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Immunosuppressive Agents; Inflammation; Male; Middle Aged; Mycophenolic Acid; Psoriasis; Tumor Necrosis Factor-alpha

Membranoproliferative glomerulonephritis (MPGN) represents a heterogeneous group of diseases. The common feature of a membranoproliferative lesion pattern in the kidney biopsy can either be idiopathic/primary or-much more frequently-have a secondary cause. The historical classification into MPGN types I to III has largely been abandoned and replaced in recent years by a pathogenesis-oriented classification. A MPGN with C1q, C3 and/or C4 deposits on light microscopy is referred to as immune complex GN (IC-GN), while a MPGN with dominant C3 deposits is referred to as C3 glomerulopathy (C3G). C3G is further divided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). These diagnoses can only be made by a kidney biopsy. Possible causes of MPGN are chronic infections (especially hepatitis B and C, bacterial infections, infections with protozoa), autoimmune diseases (especially lupus, rheumatoid arthritis) or malignancies (especially hematological malignancies). Particularly in the case of C3G a comprehensive analysis of the complement system components is strongly recommended. Due to the low incidence and the heterogeneous clinical appearance of MPGN therapeutic decisions must be made individually; an optimal general therapy is unknown, except that supportive treatment as with other glomerular diseases should be optimized. In the case of a secondary MPGN it is generally recommended to treat the potential cause of the MPGN. If significant proteinuria persists and eGFR remains > 30 ml/min/1.73 m. Die membranoproliferative Glomerulonephritis (MPGN) repräsentiert eine heterogene Gruppe von Erkrankungen. Das gemeinsame Merkmal eines membranoproliferativen Läsionsmusters in der Histologie der Nierenbiopsie kann sowohl idiopathisch/primär auftreten, als auch – wesentlich häufiger – eine sekundäre Ursache haben. Die historische licht- und elektronenmikroskopische Einteilung in MPGN Typ I bis III wurde weitgehend verlassen und in den letzten Jahren durch eine Pathogenese-orientierte Einteilung ersetzt. Von einer Immunkomplex-GN (IK-GN) spricht man beim Vorliegen einer MPGN mit C1q, C3 und/oder C4 Ablagerungen, während eine MPGN mit dominanten C3-Ablagerungen als C3-Glomerulopathie (C3G) bezeichnet wird. Diese wird wiederum in eine C3-Glomerulonephritis (C3GN) und eine dense-deposit disease (DDD) eingeteilt. Diese Diagnosen können nur durch eine Nierenbiopsie gestellt werden. Mögliche Ursachen für eine MPGN sind chronische Infektionen (v. a. Hepatitis B und C, bakterielle Infektionen, Infektionen mit Protozoen). Autoimmunerkrankungen (v. a. Lupus, rheumatoide Arthritis) oder Malignome (v. a. hämatologische maligne Erkrankungen). Insbesondere im Falle einer C3G wird auch eine umfassende Abklärung des Komplementystems empfohlen. Therapeutische Entscheidungen sind aufgrund der niedrigen Inzidenz und des heterogenen klinischen Erscheinungsbildes einer MPGN individuell zu treffen, eine optimale generelle Therapie ist unbekannt. Im Falle einer identifizierten Ursache einer MPGN wird prinzipiell empfohlen diese zu behandeln, ebenso sollte die supportive Therapie, wie auch bei anderen Glomerulonephritiden optimiert werden. Bei anhaltender signifikanter Proteinurie und einer eGFR > 30 ml/min/1,73 m

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Glomerulonephritis, Membranoproliferative; Humans; Kidney Transplantation; Mycophenolic Acid

To characterize the utilization and discontinuation of medications before, during and after pregnancy among women with RA.. We used population-based administrative data to identify women with RA who had a singleton pregnancy ending in delivery between 1 January 2002 and 31 December 2012. We assessed the utilization of RA medications, namely, conventional synthetic DMARDs, biologics, glucocorticosteroids and NSAIDs, across six windows spanning 24 and 12 months before the start of pregnancy, each trimester of pregnancy and 12 months post-pregnancy. We defined medication discontinuation as no prescription in a given window following a prescription in the preceding window and evaluated predictors using logistic regression models, calculating adjusted odds ratios (ORs) and 95% CIs.. We studied 1730 pregnancies in 1301 women with RA (mean age at delivery 31.4 ± 5.4 years). We observed substantial medication discontinuation, particularly in the first trimester, with discontinuation of antimalarials in 57.3% of patients, azathioprine 59.1%, sulfasalazine 69.5% and biologics 50.8%. Factors inversely associated with discontinuation of antimalarials in the first trimester were maternal age [OR 0.90 (95% CI 0.86, 0.95)] and number of rheumatology visits [OR 0.86 (95% CI 0.75, 0.97)] and for biologics, prior adverse birth outcome [OR 0.22 (95% CI 0.05, 0.95)].. Our population-based study shows frequent discontinuation of medications for RA, particularly in the first trimester. Findings indicate a need to educate women with RA who are planning pregnancy on the benefits and risks of medications during pregnancy.

Topics: Abatacept; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Azathioprine; Biological Products; British Columbia; Chloroquine; Cohort Studies; Cyclophosphamide; Cyclosporine; Deprescriptions; Female; Glucocorticoids; Gold Compounds; Humans; Hydroxychloroquine; Interleukin 1 Receptor Antagonist Protein; Leflunomide; Logistic Models; Maternal Age; Methotrexate; Mycophenolic Acid; Odds Ratio; Preconception Care; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, First; Rheumatology; Rituximab; Sulfasalazine; Tumor Necrosis Factor Inhibitors

Visceral disseminated varicella zoster viral (VZV) infection is a rare but severe complication with a high mortality rate in immunosuppressed individuals, and an increased susceptibility to VZV has been reported in kidney transplant recipients who are treated with mycophenolate mofetil (MMF). In Japan, MMF is currently approved for patients with lupus nephritis (LN) and data to indicate its optimal dosage are still insufficient.. A 46-year-old Japanese woman with rheumatoid arthritis was diagnosed as having systemic lupus erythematosus (SLE) and LN class III (A/C). Although initial remission-induction therapy with prednisolone and tacrolimus was started, her serum creatinine level and urinary protein excretion were elevated. Methylprednisolone pulse therapy was added, and tacrolimus was switched to MMF. Two months after admission when she was taking 40 mg of PSL and 1500 mg of MMF daily, she suddenly developed upper abdominal pain and multiple skin blisters, and disseminated visceral VZV infection was diagnosed. Laboratory examinations demonstrated rapid exacerbation of severe acute liver failure and coagulation abnormalities despite immediate multidisciplinary treatment, and she died of hemorrhagic shock 7 days after the onset of abdominal pain. A serum sample collected at the time of admission revealed that she had recursive VZV infection.. MMF together with high-dose glucocorticoid therapy may increase the risk of VZV infection in Asian patients with SLE. Accumulation of evidence for parameters of safety, such as the area under the blood concentration-time curve of mycophenolic acid, should be urgently considered in order to establish a safer protocol for remission induction therapy in Asian patients with LN.

Topics: Arthritis, Rheumatoid; Enzyme Inhibitors; Fatal Outcome; Female; Herpes Zoster; Humans; Lupus Nephritis; Middle Aged; Mycophenolic Acid

Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon.. To query the association of cytotoxic, anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm.. This retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio.. Odds ratio (OR) assessment for AID-directed therapies.. Among the 86 patients who met inclusion criteria (49 men [57%]; 37 women [43%]; mean [SD] age, 72.3 [15.6] years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 [26.7%]), psoriasis (18 [20.9%]), and systemic lupus erythematosus (12 [14.0%]) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men [57.0%]; 74 women [43.0%]; mean [SD] age, 72.7 [13.8] years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio [OR], 7.05; 95% CI, 2.35- 21.13; P < .001). Notable but insignificant case cohort use among cytotoxic agents was found for exposure to cyclophosphamide (OR, 3.58; 95% CI, 0.91-14.11) followed by mitoxantrone hydrochloride (OR, 2.73; 95% CI, 0.23-33.0). Methotrexate sodium (OR, 0.60; 95% CI, 0.29-1.22), mercaptopurine (OR, 0.62; 95% CI, 0.15-2.53), and mycophenolate mofetil hydrochloride (OR, 0.66; 95% CI, 0.21-2.03) had favorable ORs that were not statistically significant. No significant association between a specific length of time of exposure to an agent and the drug's category was observed.. In a large population with primary AID, azathioprine exposure was associated with a 7-fold risk for myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti-tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.

Topics: Aged; Aged, 80 and over; Arthritis, Rheumatoid; Autoimmune Diseases; Azathioprine; Case-Control Studies; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Incidence; Leukemia, Myeloid, Acute; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Mycophenolic Acid; Myelodysplastic Syndromes; Odds Ratio; Psoriasis; Retrospective Studies; Risk Factors; United States

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

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

Previous studies informed an increased prevalence of cutaneous papillomavirus (cHPV) infection in patients with systemic lupus erythematosus (SLE). The main objective of our study was to evaluate factors associated with cHPV infection in patients with either rheumatoid arthritis (RA) or SLE, and to determine whether SLE itself is an independent risk factor for cHPV infection. We included 670 patients (in consecutive selection) in this cross-sectional study (550 with RA and 120 with SLE). All patients were evaluated by a dermatologist; patients with cHPV infection were selected as cases (63) and the other 607 patients were selected as controls. The prevalence of cHPV infection was increased 2.8-fold in SLE patients (20%) compared with RA patients (7.1%). When comparing cases with controls, bivariate analysis showed statistically significant differences for: age, having SLE, and treatment with mycophenolate mofetil (MMF). When all of the potential risk factors identified using bivariate analysis (age, having SLE, and MMF) were included into a multivariate model, independent risk factors for cHPV infection were: having SLE (odds ratio: 2.16, 95% confidence interval: 1.04-4.48) and MMF therapy (odds ratio: 2.91, 95% confidence interval: 1.18-7.14).

Topics: Adult; Arthritis, Rheumatoid; Case-Control Studies; Cross-Sectional Studies; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Papillomavirus Infections; Prevalence; Risk Factors; Skin Diseases, Viral; Young Adult

Topics: Acute Pain; Aged; Arthritis, Rheumatoid; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Inflammation; Interleukin-6; Male; Mycophenolic Acid; Protein Precursors; Withholding Treatment

The treatment of some inflammatory diseases, such as rheumatoid arthritis, remains an important target for studies because some patients are refractory to conventional treatment. Mycophenolate mofetil (MMF), an immunosuppressive drug, has been shown to have a beneficial effect on the therapy of inflammatory and autoimmune diseases. In the present study, we aimed to analyse the anti-inflammatory effect of MMF administered by oral route in the mouse carrageenan-induced air pouch model.. MMF significantly inhibited the influx of leukocytes, exudate concentrations (P<0.01), activities of myeloperoxidase (MPO) and adenosine deaminase (ADA), levels of nitrite/nitrate (NO(x)) and inducible nitric oxide synthase (iNOS) mRNA expression, as well as the levels of mRNA expression and proteins of tumor necrosis factor-alpha (TNF-α), Interleukin-beta (IL-1β) and vascular endothelial growth factor-alpha (VEGF-α) (P<0.05). These results provide evidence that MMF has an important anti-inflammatory effect in reducing the influx of leukocytes and exudate concentrations. These inhibitory effects are correlated with the inhibition of specific pro-inflammatory enzymes (MPO, ADA and iNOS), and the levels of mRNA expression and proteins of TNF-α, IL-1β and VEGF-α.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Carrageenan; Cell Movement; Cytokines; Disease Models, Animal; Humans; Immunosuppression Therapy; Inflammation Mediators; Leukocytes; Mice; Mycophenolic Acid; Nitric Oxide; Peroxidase; Vascular Endothelial Growth Factor A

To describe the clinical characteristics, histopathologic features, and outcomes of patients in whom vasculitis developed in association with use of tumor necrosis factor-α (TNF-α) inhibitors.. This is a retrospective review of patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1, 1998, through March 31, 2011, with a diagnosis of vasculitis induced by anti-TNF-α therapy.. Of 8 patients with vasculitis associated with anti-TNF-α therapy (mean age, 48.5 years), 6 (75%) were female. Four (50%) had rheumatoid arthritis, 1 (13%) had Crohn disease, and 3 (38%) had ulcerative colitis. Five (63%) were treated with infliximab, 2 (25%) with etanercept, and 1 (13%) with adalimumab. The mean duration of treatment before development of vasculitis was 34.5 months. The skin was the predominant organ affected (5 patients [63%]), with the most common cutaneous lesion being palpable purpura (4 of 5 [80%]). Two organs involved in systemic vasculitis were the peripheral nervous system (4 patients [50%]) and kidney (1 patient [13%]). All cases of vasculitis were histopathologically confirmed. Seven of 8 patients improved with discontinuation of therapy (mean time to resolution, 6.9 months) and adjuvant treatment (all 8 received prednisone; another agent was also used in 7); rechallenge with anti-TNF-α therapy was not attempted in any patient. At last follow-up, no patients had experienced a recurrence of vasculitis after therapy discontinuation.. Cutaneous small-vessel vasculitis was the most common finding, but systemic vasculitis, including peripheral nerve and renal vasculitis, was also frequently observed.

Topics: Adalimumab; Adult; Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Arthritis, Rheumatoid; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Etanercept; Female; Glucocorticoids; Hematuria; Humans; Immunoglobulin G; Immunologic Factors; Infliximab; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Polyneuropathies; Prednisone; Proteinuria; Receptors, Tumor Necrosis Factor; Retrospective Studies; Rituximab; Tumor Necrosis Factor-alpha; Vasculitis; Young Adult

Topics: Animals; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers, Pharmacological; Drug Discovery; Humans; Immunomodulation; Mycophenolic Acid; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Transforming Growth Factor beta1

Topics: Adalimumab; Adrenal Cortex Hormones; Adult; Alefacept; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Crohn Disease; Cyclosporine; Etanercept; Female; Humans; Immunoglobulin G; Methotrexate; Middle Aged; Mycophenolic Acid; Psoriasis; PUVA Therapy; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Treatment Outcome; Ustekinumab

We report a case of dermatomyositis associated with rheumatoid arthritis, Hashimoto thyroiditis, and diabetes mellitus responsive only to combination of rituximab with mycophenolate. A 42-year-old woman presented with proximal muscle weakness, myalgias, fever, night sweats, and shortness of breath. Creatinine kinase was 8155 IU/L, and muscle biopsy was diagnostic of dermatomyositis. She was started on glucocorticoids; her systemic symptoms improved, but her muscle weakness persisted. She was serially treated with intravenous immunoglobulin, azathioprine, and mycophenolate mofetil without improvement in her weakness. She responded dramatically to combination therapy with rituximab and mycophenolate, with improvement in strength and normalization of creatinine kinase. She has been well controlled on rituximab infusion every 6 months and maintenance mycophenolate mofetil.

Topics: Adult; Antibodies, Monoclonal, Murine-Derived; Antirheumatic Agents; Arthritis, Rheumatoid; Autoimmune Diseases; Dermatologic Agents; Dermatomyositis; Drug Therapy, Combination; Female; Hashimoto Disease; Humans; Mycophenolic Acid; Rituximab

Mycophenolate mofetil is an immunosuppressive agent approved for the prophylaxis of renal, cardiac and hepatic transplant rejection. With its proven immunosuppressive effects and favourable toxicity profile, mycophenolate mofetil was postulated as a potential candidate for treating rheumatoid arthritis.. To evaluate the efficacy and safety profile of mycophenolate mofetil in the treatment of adults with advanced refractory rheumatoid arthritis.. The effectiveness of mycophenolate mofetil (1 g twice daily) in the treatment of advanced refractory rheumatoid arthritis was assessed in three 24-week, randomized, double-blind, parallel-group trials (two placebo-controlled [n = 229 and n = 214] and one with ciclosporin 2.5-4 mg/kg/day as a comparator [n = 842]). Patients had American Rheumatism Association functional class II or III disease, a mean disease duration of 9.8-13 years, and had failed treatment with a median of three to four disease-modifying antirheumatic drugs. Overall, 959/1262 (76%) of patients in the main analysis group were female and 1189/1262 (94%) were Caucasian.. In the placebo-controlled trials, the American College of Rheumatology 20% responder index rate did not differ significantly between mycophenolate mofetil and placebo (19.7% [29/147] vs 13.0% [9/69] and 15.8% [22/139] vs 10.1% [7/69]; p > 0.05 for both studies). Consequently, the active-comparator trial was stopped prematurely before completion and efficacy analyses were not performed. Treatment-emergent adverse events were experienced by 51.6% (371/719), 73.1% (304/416) and 36.1% (53/147) of patients receiving mycophenolate mofetil, ciclosporin and placebo, respectively. Hypertension, increased serum creatinine, muscle cramps, hirsutism and hypertrichosis were more than twice as common with ciclosporin as with mycophenolate mofetil. In all three trials, the incidence of serious adverse events with mycophenolate mofetil was 12.1% (compared with 11.3% and 7.5% for ciclosporin and placebo, respectively).. Mycophenolate mofetil did not achieve a significant difference from placebo in terms of disease improvement in patients with refractory rheumatoid arthritis. A descriptive analysis of adverse events suggests mycophenolate mofetil was generally as well tolerated as ciclosporin in this patient population.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cyclosporine; Double-Blind Method; Early Termination of Clinical Trials; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Multicenter Studies as Topic; Mycophenolic Acid; Placebo Effect; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease in the United States, affecting 1% to 2% of the adult population. Although joints and synovium are the primary targets in this disorder, extra-articular manifestations involving the lungs can lead to significant morbidity and excess mortality. Among the various pulmonary complications that occur in RA, interstitial lung disease (ILD) is the most damaging, with effects ranging from subclinical inflammation/scarring to end-stage pulmonary fibrosis. New insights during the past several years have underscored the epidemiologic impact of clinically/functionally significant RA-associated ILD (RA-ILD) and have begun to identify factors contributing to the pathogenesis of this potentially devastating complication of RA. Despite these advancements, the complexity of RA-ILD and the lack of reliable predictors for disease progression highlight the need for improved biomarker development. Establishing such detailed molecular signatures will ultimately guide the application and timing of therapeutic agents that include immunomodulators as well as newly studied antifibrotic agents.

Topics: Adrenal Cortex Hormones; Antimetabolites; Arthritis, Rheumatoid; Biomarkers; Citrulline; Cyclophosphamide; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Mycophenolic Acid; Proteins; Pulmonary Fibrosis; Radiography; Smoking

Topics: Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Mycophenolic Acid; Polymyositis; Quality of Life; Scleroderma, Systemic; Synovitis; Treatment Outcome

Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.

Topics: Acridines; Administration, Oral; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Biological Availability; Cell Line; Cell Proliferation; Gastrointestinal Tract; Half-Life; Humans; IMP Dehydrogenase; Leukocytes, Mononuclear; Macaca fascicularis; Male; Piperazines; Rats; Rats, Inbred Lew; Stereoisomerism; Structure-Activity Relationship

We observed 10-year radiographic outcomes in patients with rheumatoid factor positive rheumatoid arthritis prospectively. Group I, II, and III comprised 87, 125, and 89 consecutive subjects with disease duration at presentation of less than 4, 4-24, and 25-255 months, respectively. Initial therapy was with combinations of pulse intravenous (i.v.) methylprednisolone (0-125 mg), cyclophosphamide (100-200 mg), methotrexate (MTX, 5-15 i.v. mg/week) and simultaneous oral cyclosporin A (CSA, 25 mg bid/tid). After disease was controlled i.v. therapy was tapered and switched to oral MTX + CSA. Outcomes from the Larsen Index and Erosive Joint Count were compared in cases and in dropouts with baseline and each other. Significant improvement in the Larsen Index and Erosive Joint Count was observed in Group I (p < 0.0001). In Group II and III the improvement or deterioration was not significant. The Larsen Index and Erosive Joint Count deteriorated significantly in the dropouts compared with baseline and cases (p < 0.0001). In conclusion, in early RA, in a Malayo-Polynesian patient sample, radiological progression could be halted with aggressive combination treatment.

Topics: Administration, Oral; Adolescent; Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Cyclophosphamide; Cyclosporine; Disease Progression; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infusions, Intravenous; Male; Methotrexate; Methylprednisolone; Middle Aged; Mycophenolic Acid; Prospective Studies; Pulse Therapy, Drug; Radiography; Remission Induction; Rheumatoid Factor; Treatment Outcome

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cost-Benefit Analysis; Disease Progression; Drug Approval; Drug Costs; Drug Therapy, Combination; Ethics, Medical; Germany; Humans; Immunosuppressive Agents; Insurance Coverage; Insurance, Pharmaceutical Services; Male; Methotrexate; Middle Aged; Mycophenolic Acid; National Health Programs; Refusal to Treat; Treatment Outcome

TINU syndrome probably is a frequently overlooked disease where uveitis occurs in association with acute tubulointerstitial nephritis. Diagnostic criteria have been published recently.. In this retrospective case series the charts of four consecutive patients with TINU syndrome (follow-up 36, 23, 17, and 12 months, respectively) were analysed, including comorbidity and complications, and the literature was reviewed.. Two patients were treated with methotrexate or ciclosporin A and mycophenolate mofetil. In one patient autoimmune thyroiditis was known. During the follow-up, symptoms indicative of rheumatoid arthritis were observed. Because of her uveitis she required methotrexate therapy. Three patients were obese (mean BMI 32.2 kg/m (2)). Ocular complications were posterior synechiae (two patients) and papillary and macular oedema (three patients). One patient developed cerebrospinal hypertension under ciclosporin A treatment which resolved after discontinuation of therapy.. Patients with definite TINU syndrome frequently suffer from other diseases and associated immune phenomena. The course of the disease can vary considerably. Complications do occur, despite overall good prognosis. Regional and systemic steroids may be sufficient; frequently steroid sparing immunosuppressives are necessary at least temporarily. Patients with this multiorgan disease do need to be followed by a paediatrician or a medical specialist.

Topics: Adolescent; Arthritis, Rheumatoid; Autoimmune Diseases; Child; Cyclosporine; Female; Follow-Up Studies; Humans; Male; Methotrexate; Mycophenolic Acid; Nephritis, Interstitial; Patient Care Team; Syndrome; Thyroiditis, Autoimmune; Treatment Outcome; Uveitis

1. Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is being developed for the prevention of rejection following solid organ transplantation. This crossover study investigated the effect of food and antacid (Maalox TC) on the plasma pharmacokinetics of MPA and its inactive glucuronide metabolite MPAG after giving single 2 g MMF doses orally to rheumatoid arthritis patients. 2. With food, the AUC of MPA in plasma was equivalent to that following an overnight fast. MPA tmax was slightly delayed and Cmax was lowered about 25%, consistent with delay in gastric emptying in the fed state. MPAG Cmax and AUC were higher in the fed relative to the fasting state, suggesting more complex processes involving changes in glucuronidation may also be occurring with food. 3. With antacid, AUC of MPA was lowered about 15% compared with fasting and Cmax was decreased 37%. Plasma MPAG parameters were similarly reduced. These parallel changes in MPA and MPAG are consistent with reduced absorption. 4. The changes in MPA with both food and antacid are small in comparison with the interpatient variability and are not likely to have clinically major effects; the changes in MPAG are of mechanistic interest.

Topics: Administration, Oral; Aged; Aluminum Hydroxide; Antacids; Area Under Curve; Arthritis, Rheumatoid; Cross-Over Studies; Drug Combinations; Fasting; Female; Food; Food-Drug Interactions; Humans; Immunosuppressive Agents; Magnesium Hydroxide; Male; Middle Aged; Mycophenolic Acid