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ID PMID Title PublicationDate abstract
18815725 Methotrexate for the treatment of juvenile idiopathic arthritis: process to approval for J 2009 Methotrexate (MTX), the primary treatment for the articular-type juvenile idiopathic arthritis (JIA), is effective and brings about radiological improvement. Patient compliance is good, and it is recognized that its known side effects, namely, disruption of liver function and induction of pulmonary lesions, are unlikely to be severe at the low MTX doses that are administered. In Japan, MTX was granted approval in 1999 by the then Ministry of Health and Welfare specifically for treating rheumatoid arthritis in adult patients, allowing it be generally used in medical institutions for patients having National Health Insurance. However, in the pediatric field, its use outside the indications has so far been unavoidable, and has been left to the discretion of the physician. Finally, at the present conference, expansion of the indications of MTX for JIA was approved in Japan. It is noteworthy that this expansion of indications was achieved without requiring clinical trials on children sponsored by the pharmaceutical company: it was achieved rather by collecting necessary information through ongoing efforts (including collection and analysis of information about approval status in foreign countries, adequate evidence from the literature, implementation of a clinical use survey in Japan, etc.). It also merits attention that the maximum dose (10 mg/m2) was set on the basis of pharmacokinetic data from children, rather than relying on the dosing method and dose for adults.
19505409 Successful treatment with etanercept of a patient with psoriatic arthritis after adalimuma 2009 Apr Inhibitors of tumor necrosis factor (TNF) alpha (infliximab, etanercept, adalimumab) are nowadays widely used for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), not responding to conventional therapies. Anti-TNF alpha drugs have demonstrated great efficacy in slowing the disease, however, to date, concern still remains regarding acute and long-term toxicity related to TNF block. Increase in liver tests may be observed during treatment with anti-TNF agents, more often related to concomitant drugs (i.e. NSAIDS, methotrexate) or to reactivation of chronic HBV or HCV infections. However, liver damage directly induced by the drug has been described in patients treated with infliximab or adalimumab. To our knowledge, no cases of liver injury closely related to etanercept have been reported so far. We report the case of a patient with PsA who presented liver dysfunction during adalimumab, subsequently successfully treated with etanercept.
20477007 Discussion: DMARDs and biologic therapies in the management of inflammatory joint diseases 2009 May Therapy for inflammatory joint diseases, such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, includes various conventional disease-modifying antirheumatic drugs (DMARDs). These therapeutic agents are termed DMARDs because they have the potential to reduce or prevent joint damage and preserve joint integrity and function. Conventional DMARDs are used as monotherapy or in combination and include methotrexate, leflunomide, azathioprine, ciclosporin, hydroxychloroquine, sulfasalazine, gold and minocycline. Biologic response modifiers, which are based on proteins made by living cells, are newer agents available for the treatment of various inflammatory joint diseases. Biologic therapies now approved for use in inflammatory joint diseases are TNF inhibitors, T-cell modulators and B-cell depleters. They have all been shown to have clinical efficacy and are able to retard structural damage. However, all current immune-modulating therapies also have potential side effects, and the decision to use a particular agent for treatment should be based on a thorough discussion of the benefits and risks with the patient. Newer biologic response modifiers and other immunologic therapies are currently being developed for the treatment of inflammatory joint diseases and are discussed in this review.
21199465 Psoriatic arthritis: a systematic review. 2010 Oct Psoriatic arthritis is an inflammatory rheumatic disorder of unknown etiology occurring in patients with psoriasis. The Classification Criteria for Psoriatic Arthritis study group has recently developed a validated set of classification criteria for psoriatic arthritis with a sensitivity of 91.4% and a specificity of 98.7%. Three main clinical patterns have been identified: oligoarticular (≤ 4 involved joints) or polyarticular (≥ 5 involved joints) peripheral disease and axial disease with or without associated peripheral arthritis. In this context distal interphalangeal arthritis and arthritis mutilans may occur. According to other reports, also in our centre, asymmetric oligoarthritis is the most frequent pattern at onset. Axial disease has been estimated between 5% and 36% of patients. It is characterized by an irregular involvement of the axial skeleton with a predilection for the cervical spine. Recurrent episodes of enthesitis and dactylitis represent a hallmark of psoriatic arthritis. In around 20% of cases distal extremity swelling with pitting edema of the hands or feet is observed. Unilateral acute iridocyclitis, usually recurrent in alternate fashion, is the most frequent extra-articular manifestation, and accelerated atherosclerosis is the prominent comorbidity. The clinical course of peripheral and axial psoriatic arthritis is usually less severe than rheumatoid arthritis and ankylosing spondylitis, respectively. Local corticosteroid injections and non-steroidal anti-inflammatory drugs are recommended in milder forms. Sulphasalazine and methotrexate are effective in peripheral psoriatic arthritis. Recent studies have provided evidence on the efficacy of anti-tumor necrosis factor-α drugs to control symptoms and to slow or arrest radiological disease progression.
20120426 Atypical presentation of histoplasmosis in a patient with psoriasis and psoriatic arthriti 2010 Jan Infliximab is a chimeric monoclonal antibody to TNF-alpha which acts on both the soluble and transmembrane forms of TNF-alpha. It has been used successfully for the treatment of psoriasis and psoriatic arthritis, rheumatoid arthritis, Crohn's disease and ankylosing spondylitis either as monotherapy or in combination with drugs such as methotrexate. To date, over 20,440 patients with moderate-to-severe psoriasis have been treated with infliximab worldwide. Opportunistic infections and reactivation of underlying latent infections are an area of concern with the use of infliximab particularly when used in conjunction with other immunosuppresants. The authors report a case of histoplasmosis presenting with signs of severe hypercalcemia and renal failure in a patient on infliximab for approximately three years in combination with low dosages of methotrexate and prednisone. This report stresses the importance of maintaining a high index of suspicion for unusual pathogens while managing patients receiving TNF-alpha inhibitors, particularly when used in combination with other immunosuppressants. In addition, the authors emphasize the role of a multi-disciplinary approach and appropriate coordination among caregivers.
21048388 [Remarkable improvement of the hip joint lesion in a patient with rheumatoid arthritis by 2010 22-year old woman who was previously diagnosed as having juvenile idiopathic arthritis (JIA) was treated with anti-TNF-α agents. Her disease activity was assessed as Stage IV and Class III by Steinbrocker's classification and resistant to steroids and methotrexate. Initially clinical findings responded well to infliximab (IFX), but polyarthritis recurred 15 months after the start of the treatment, and IFX was switched to etanercept (ETN) with good response. On the other hand, effects on the osteoarticular lesions were continuously observed through the period of the treatment with these two biologics. It was thought very rare that weight-bearing joint like the hip joint was restored as was seen in this case, while its mechanism is unknown. Because mechanism for inhibition of inflammation or joint destruction might be independent, we should investigate further the relationship between inflammation and joint destruction in the future.
19801257 [Severe tularaemia mimicking glandular tuberculosis during adalimumab therapy]. 2009 Oct BACKGROUND: Tularaemia is an anthropozoonosis, transmitted by small mammals (hares) and arthropods (ticks, horseflies). The causative agent is Francisella tularensis, a facultatively intracellular Gram-negative bacillus. We report a case of tularaemia in its ulceroglandular form occurring during methotrexate and adalimumab treatment (Humira) for rheumatoid arthritis. PATIENTS AND METHODS: A 58-year-old man with a history of primary tuberculosis receiving adalimumab in combination with methotrexate for rheumatoid arthritis for almost 1 year consulted for a febrile inflammatory plaque on the left leg with a small central necrotic area. An enlarged left inguinal lymph node was present. Doxycycline has previously been prescribed for a tick bite. The lymphadenopathy gradually became enlarged resulting in skin fistulisation. After surgical excision, histopathology revealed epithelioid granulomas accompanied by giant cells and central necrosis. Mycobacterial cultures were negative. Positive tularaemia serology at significant titres suggested a diagnosis of tularaemia, with probable transmission via a tick bite. The diagnosis was confirmed by F. tularensis DNA amplification using PCR on a lymph node biopsy. Doxycycline was continued for a further 6 weeks. One year later, no relapse had occurred. DISCUSSION: A febrile adenopathy presenting the histological features of necrotic granulomas in a patient receiving anti-TNF alpha treatment initially suggested reactivation of tuberculosis. However, the history of tick bite and failure to isolate mycobacteria from different tissue specimens prompted screening for a tick-borne disease, finally leading to a diagnosis of tularaemia. We discuss the possible relationship between immunosuppression and the clinical course of this rare infection.
20127436 [Chlorambucil treatment of Behçet's syndrome. Retrospective evaluation of two cases]. 2010 Jan BACKGROUND: Behçet's syndrome rarely occurs in North America and Central Europe (incidence: 1 : 500,000), whereas it is more frequently seen in Japan and Mediterranean countries (incidence: 1 : 10,000). The diagnosis is based on the detection of symptoms and clinical signs. Orogenital aphthosis, anterior and posterior uveitides that frequently cause loss of vision are considered to be primary symptoms. Dermatologic manifestations, i.e., erythema nodosum, vascular lesions (angio-Behçet's syndrome), gastrointestinal ulcers and neurologic involvement, can be observed. HLA B5 is found in some of the patients with Behçet's syndrome. Administration of chlorambucil, a cytotoxic compound, is an effective form of treatment of symptoms and complications of Behçet's syndrome. CASE REPORTS: The present article describes the course of a female and a male patient who were 39 and 23 years old when Behçet's syndrome was diagnosed for the first time. Treatment with chlorambucil was started in the early 1990s and continued for a period of 9 1/2 and 3(3/4) years, respectively, with the symptoms remitting during and after this therapy. Approximately 10 years after the start of treatment with chlorambucil, the patients' symptoms changed. The female patient who was first diagnosed having Behçet's syndrome at the age of 39 years developed rheumatoid arthritis with joint destruction. Her symptoms could be controlled in the long term by oral administration of prednisone, at doses below the Cushing threshold combined with methotrexate. The male patient who was first diagnosed having Behçet's syndrome at the age of 23 years developed systemic vasculitis remitting during low-dose treatment with prednisone. CONCLUSION: Immunosuppressive therapy with chlorambucil administered over several years often induces remission of Behçet's syndrome. However, both case reports indicate that symptoms can change from Behçet's syndrome to systemic vasculitis or rheumatoid arthritis.
20037747 Marked effect and steroid-sparing ability of anakinra on a patient with refractory adult-o 2010 Apr We report a case of refractory adult-onset Still's disease (AOSD) successfully controlled with anakinra, an interleukin-1 (IL-1) receptor antagonist. The patient was a 23-year-old Japanese woman with AOSD who could not be induced into remission despite of two courses of pulsed methylprednisolone followed by high-dose glucocorticoid administration in conjunction with high-dose intravenously administered gamma-globulin and methotrexate. To the best of our knowledge, this is the first case report in Japan of AOSD remission induced with anakinra.
19758231 Treatment of rat adjuvant arthritis with flavonoid (Detralex), methotrexate, and their com 2009 Sep In both adjuvant arthritis and rheumatoid arthritis, edema and inflammation appear in synovial joints. Edema or effusion reflects an imbalance in lymph dynamics. Purified micronized flavonoid fraction is mainly used in the treatment of chronic venous insufficiency. This compound improves lymphatic drainage with a significant increase in lymphatic flow and lymphatic pulsality. It is suggested that the beneficial effect of purified micronized flavonoid fraction may be involved in the treatment of adjuvant arthritis in rats. In this study treatment of adjuvant arthritis in rats with Detralex, methotrexate, and their combination were evaluated. Groups of rats with adjuvant arthritis were treated with methotrexate (0.6 mg/kg/week), Detralex (20 mg/kg/day), and their combination for 50 days from adjuvant application. Hind paw swelling, arthrogram scores, serum albumin level, serum nitrite/nitrate concentrations, and whole-body mineral density were evaluated as markers of inflammation and destructive changes associated with arthritis. Long-term prophylactic treatment with low-dose methotrexate significantly inhibited the markers of both inflammation and arthritis. Detralex administered alone slightly decreased both the hind paw swelling and the arthritic score. Other inflammatory and arthritic markers were not significantly influenced. However, Detralex combined with methotrexate markedly potentiated the beneficial effects of methotrexate, which resulted in a more significant reduction in hind paw swelling, arthritic scores, and serum concentrations of nitrite/nitrate. Interestingly, the arthritis-induced decrease of bone mineral density in AA rats was significantly lower only in the group treated with the combination of Detralex and methotrexate. Our results indicate that Detralex increased the therapeutic efficacy of methotrexate basal treatment in AA. We suggest that this may be related to the beneficial effect of Detralex on microcirculation, especially on venules and lymphatic vessels.
20237125 Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyart 2010 Apr OBJECTIVE: To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA). METHODS: Patients eligible for the open-label extension (OLE, weeks 52-204) received infliximab 3-6 mg/kg every 8 weeks plus methotrexate. RESULTS: Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively. CONCLUSIONS: In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate.
19156421 Methotrexate treatment ameliorated testicular suppression and anorexia related leptin redu 2009 Aug Methotrexate (MTX) has been frequently used in the treatment of rheumatoid arthritis (RA). However, its action on arthritis associated male hypogonadism, or anorexia related low leptin production has not yet been studied. The well-established model of human RA is rat adjuvant-induced arthritis (AA). In the present series we aimed at the evaluation of the effects of MTX on AA induced inflammatory parameters, testosterone suppression, and anorexia associated lowered leptin release. AA was induced in male Lewis rats by intradermal injection of heat killed Mycobacterium butyricum in incomplete Freund's adjuvant in the base of the tail. Arthritic rats were treated with two doses of MTX: 0.3 and 0.5 mg/kg twice a week orally for the period of 28 days. The evaluated parameters were body mass, hind-paw swelling, arthrogram scores, serum albumin, total testosterone and leptin on days 14, 21 and 28 of AA. MTX treatment ameliorated all parameters studied dose dependently. Higher dose of MTX induced a significant reduction in the hind-paw swelling, arthritic score, and an increase in serum albumin in all examined time intervals of AA. This dose also significantly improved the suppressed testosterone and leptin levels found in arthritic rats. Prophylactic MTX treatment of rats with AA improved all inflammatory and arthritic parameters studied indicating its clear anti-inflammatory effects. The significant improvement of testosterone and leptin shows beneficial effects of MTX on reproduction and anorexia related leptin reduction during chronic AA.
21029481 The effect of immunomodulators on the immunogenicity of TNF-blocking therapeutic monoclona 2010 Therapeutic monoclonal antibodies have revolutionized the treatment of various inflammatory diseases. Immunogenicity against these antibodies has been shown to be clinically important: it is associated with shorter response duration because of diminishing concentrations in the blood and with infusion reactions. Concomitant immunomodulators in the form of methotrexate or azathioprine reduced the immunogenicity of therapeutic antibodies in rheumatoid arthritis, Crohn disease, and juvenile idiopathic arthritis. The occurrence of adverse events does not increase when immunomodulators are added to therapeutic antibodies. The mechanism whereby methotrexate and azathioprine influence immunogenicity remains unclear. Evidence-based consensus on prescribing concomitant immunomodulators is needed.
21413195 2009 Feb July 2018: NICE has made new recommendations on treat-to-target strategy, initial pharmacological management, symptom control and monitoring. The recommendations and evidence in chapters 7 and 8 have been stood down and replaced. There are over 400,000 people with rheumatoid arthritis (RA) in the UK. Although this makes it a common disorder, there are numerous other conditions ahead of it in terms of numbers, and indeed as causes of excess mortality. What this does not capture however, is the dreadful morbidity associated with the disease. The synovitis of RA affects multiple sites causing widespread pain, and the subsequent destruction of the joints can lead to severe disability affecting all aspects of motor function from walking to fine movements of the hand. Furthermore, RA is not simply a disease of the joints but can affect many other organs causing, for example, widespread vasculitis or severe lung fibrosis. More recently it has become apparent that RA is associated with an increased prevalence of coronary artery disease and significant increased risk of premature mortality. Fortunately there are a considerable number of disease-modifying and anti-inflammatory agents which can significantly reduce the impact of RA. Some of these, for example corticosteroids, sulphasalazine or methotrexate, have been available for many years, and rheumatologists are well used to balancing the benefits and side-effects of these drugs. More recently, targeted diseasemodifying and anti-inflammatory therapies, particularly the anti-TNF agents, have emerged, and have proved effective in many patients. While it is encouraging that there is such a wide range of treatment available, the choice brings with it difficult questions concerning the best sequencing of therapy. Moreover, the newer drugs are expensive. The high impact of the disease and the need to make best use of the available treatment make RA a highly suitable subject for a NICE guideline, which it is now my pleasure to introduce. I have already touched on the exciting therapeutic options for RA, but this guideline addresses many other aspects of management. Because established RA has so many classical features it is easy to forget that at presentation the diagnosis may not be readily apparent, yet early intervention may be important. The guideline offers advice on this problem, including a consideration of the place of newer serological markers of the disease, particularly anti-CCP antibodies. The role of objective measures in the monitoring of disease activity is also considered, as an important component of achieving and maintaining control. The importance of non-pharmacological management of RA is also emphasised, including the many therapeutic interventions which are usually supervised by physiotherapists, occupational therapists and podiatrists; as is the crucial role of the multidisciplinary team including these professionals as well as specialist nurses and doctors.
19799829 Safety of conventional systemic agents and biologic agents in the treatment of psoriasis. 2009 Sep For many years, the mainstays of psoriasis therapy were conventional oral immunosuppressants (eg, cyclosporine and methotrexate) and retinoids. Recently, six biologic agents were approved for the treatment of psoriasis in Canada and the United States: alefacept, efalizumab, etanercept, infliximab, adalimumab, and ustekinumab. Biologic agents exert their therapeutic effect in psoriasis through inhibition of various pathways. Although these treatments are new to the management of psoriasis, many have been used in other disease states, such as rheumatoid arthritis, psoriatic arthritis, and Crohn's disease. Long-term safety data are available from the treatment of these diseases. Both conventional and biologic treatments are effective in the treatment of psoriasis, but they are associated with serious adverse events, ranging from organ toxicity to serious infections, birth defects, and malignancies. This article reviews the safety profiles of both classes of treatments.
19714630 Long-term safety and effectiveness of etanercept in children with selected categories of j 2009 Sep OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS: Patients ages 2-18 years with rheumatoid factor (RF)-positive or RF-negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (> or =10 mg/m(2)/week [ approximately 0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open-label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment. RESULTS: A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure-adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient-years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient-years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study. CONCLUSION: These data confirm the findings of other long-term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.
19902549 A novel high-performance liquid chromatography/mass spectrometry method for improved selec 2009 Dec The folate antagonist methotrexate is commonly used in low dose for treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Therapeutic effects are attributed to intracellular levels of various methotrexate polyglutamates. The present methodology, combining a simple preparation step with ion-pairing reversed-phase liquid chromatography and electrospray ionization mass spectrometry, is suitable for the measurement of methotrexate and its polyglutamates(2-7), in human red blood cells. Sample preparation consists of perchloric acid protein precipitation followed by solid-phase extraction. Baseline separation of all analytes was achieved within 10 min using a Phenomenex Synergy C18 column together with a gradient solvent program obtained from blending acetonitrile with pH 7.5, 5 mM aqueous dimethylhexylamine. Seven methotrexate polyglutamates were detected using multiple reaction monitoring, with the mass spectrometer operating in positive ion mode. Using 20 microL injection volumes, limits of detection were 2.5 nM for individual methotrexate polyglutamates, while large volume (100 microL) injections led to detection limits of 0.5 nM and linear calibration from 0.5 to 100 nM for individual analytes. Finally, the presented methodology was applied for the analysis of methotrexate and its polyglutamates in red blood cells obtained from patients being treated for juvenile idiopathic arthritis with methotrexate. Significantly, the methodology proved suitable for determination of long-chain methotrexate polyglutamates(5-7) and further, appears to be superior with respect to sensitivity, selectivity and speed as compared to all previously described approaches.
21686950 Lymphoproliferative disorder due to sulphasalazine. 2009 We present the case of a 57-year-old man who had been on sulphasalazine for 20 years for seropositive non-erosive rheumatoid arthritis and developed a lymphoproliferative disorder, which resolved completely on cessation of sulphasalazine. This is the first report of lymphoproliferative disorder secondary to sulphasalazine. Lymphoproliferative disorders are well recognised with methotrexate and cyclosporine, and recognition of this disorder is critical due to the fact that a number of patients' symptoms will resolve completely with discontinuation of the drug and will not need further treatment. This case report discusses the literature on lymphoproliferative disorders as well as differential diagnoses like drug rash with eosinophilia and systemic symptoms (DRESS) syndrome.
19565504 Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate dise 2009 Jul OBJECTIVE: To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent-onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures. METHODS: Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG-U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance-weighted discrimination normalization. RESULTS: Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor beta-inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets. CONCLUSION: Gene expression signatures in PBMCs from patients with recent-onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.
20637063 Rare incidence of methotrexate-specific lesions in liver biopsy of patients with arthritis 2010 INTRODUCTION: The present study objective was to evaluate the incidence of methotrexate (MTX)-specific liver lesions from the analysis of a liver biopsy of inflammatory arthritis patients with elevated liver enzymes. METHODS: A case-control study was performed with 1,571 arthritis patients on long-term low-dose MTX therapy. Results of liver biopsy were analyzed in 41 patients with elevated liver enzymes. The expression of autoimmune markers was also assessed. This population was compared with 41 disease control subjects obtained from the same database, also on MTX but without elevated liver enzymes, matched for age, sex and rheumatic disease. RESULTS: Compared with the disease controls, patients with liver biopsy showed lower disease duration and lower MTX exposure, weekly and cumulative doses, reflecting shorter treatment duration due to liver abnormalities. Liver biopsies showed 17 autoimmune hepatitis-like (AIH-like) lesions, 13 nonalcoholic steatohepatitis-like lesions, seven limited liver lesions, and two primary biliary cirrhoses. However, MTX-specific lesions with dystrophic nuclei in hepatocytes were seen in only two cases. Liver biopsy lesions were associated with autoimmune markers (P = 0.007); notably, AIH-like lesions were associated with rheumatoid arthritis and with the presence of the HLA-DR shared epitope. CONCLUSIONS: MTX-specific liver lesions are rarely observed in arthritis patients under long-term MTX therapy and elevated liver enzymes.