Long-term experience with low dose methotrexate in rheumatoid arthritis

Summary One hundred twenty-six patients with rheumatoid arthritis (RA) were treated with weekly low doses of methotrexate (MTX) for a mean period of 36.8 months (range 13–110 months). The overall probability of continuing with MTX therapy was 72% at 2 and 3 years, 67% at 4 years and 65% at 5–7 years. Seronegative patients had a higher probability of continuing therapy than seropositive patients (P<0.05). Out of the whole group, 8% showed no improvement, 16% showed mild improvement, and 30% showed moderate improvement, and 45% experienced marked improvement. Eight patients (6%) of the latter group achieved complete clinical remission. In the course of the follow-up period there was a significant decrease in the mean daily dosage of prednisone and NSAIDs. Minor side effects were common (68%), but therapy was discontinued in only 27 patients (21%) because of major complications. In most of them (25 out of 27) these occured within the first 24 months of therapy. Although malignancy was revealed in 5 patients during the follow-up period, its occurrence did not differ from expected rates.     

Rheumatoid arthritis: Perioperative management of biologics and DMARDs

ObjectiveArthroplasty remains prevalent for patients with rheumatoid arthritis (RA), but outcomes are not equivalent to patients with osteoarthritis, and complications including infection are increased. The objective of this article is to review the current evidence supporting perioperative medication management. Challenges are discussed such as continuing potent disease-modifying therapy (DMARDs) and biologics, which may increase infection risk, versus withholding these medications, which may result in disease flares.MethodsPublished literature regarding arthroplasty in RA has been reviewed and discussed.ResultsSome DMARDs such as methotrexate and hydroxychloroquine appear safe in the perioperative period. Anti-TNFα biologics should be withheld due to increase in infection risk, while the impact of rituximab and abatacept on infection risk has not been as clearly defined.ConclusionThis article provides an overview of arthroplasty in RA, summarizes the evidence supporting perioperative medication management including corticosteroids, and identifies areas where further study is needed.     

Whole exome sequencing (WES) of methotrexate response/adverse event profile in rheumatoid arthritis patients

Aim of the workTo preliminary study polymorphisms in a set of genes of relevance to methotrexate (MTX) response based on the Drug Bank database in Egyptian rheumatoid arthritis (RA) patients.Patients and methodsThe study included 10 consecutive adult female RA patients categorized according their response and adverse events (AEs) to MTX; patients with good response, ACR50 after 4 weeks was considered. Variant Call Format files were annotated and filtered via Drug Bank (11/9/2017) database in MTX. Accordingly, the following set of genes most related for RA MTX response were considered: SLC16A1, SLC7A11, SLC22A7, TBXAS1, PTK2B, ABCC2, ABCC4, SNORD13G, SLCO3A1, ABCC1, SLC46A1, SARM1, ABCB1, SLC19A, ATIC and SLCO1C1. Human genome DNA was assessed using Ion Ampliseq Exome Panel. Single-nucleotide variants (SNVs) and short insertions/deletions were identifiedResultsThe mean age of the patients was 39 ± 12.5 years and disease duration 9.8 ± 7.4 years. AEs were present in 4 (2 poor and 2 good responders). 6 patients showed a good response with no AEs. Of the 16 studied genes, 19 variants were revealed. 18 SNVs and one deletion were detected. The C allele of ABCB1 was dominant in 7 out of 8 good responders’ (87.5%). The G of ATIC was present in 20% with AEs and poor response. The T and G of SLCO1C1 were in 60% of good responders.ConclusionIn Egyptian RA patients, there is evidence of a possible influence of a set of gene variants on the disease pathogenesis while others were related to MTX AEs and response.     

Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid arthritis

The objective of this study was to evaluate the efficacy and safety of an additive combination of a disease-modifying antirheumatic drug (DMARD) actarit and low-dose methotrexate (MTX) in patients with active rheumatoid arthritis (RA) unresponsive to MTX. Thirty-four patients with active RA, who had been unsuccessfully treated with MTX for at least 3 months were enrolled on a 24-week course of actarit (300 mg/day) and MTX (2.5–10 mg/week). Disease activity was evaluated by physical global assessments using conventional measures (Japan Rheumatism Association), and the American College of Rheumatology (ACR) criteria of improvements in RA. Thirty-two patients completed this study. No severe adverse drug reactions were seen. Patients whose RA did not respond to MTX alone responded to the combination therapy, with a significant improvement in the duration of morning stiffness, grip strength, swollen joint counts, patient's articular pain score, modified health assessment questionnaire (M-HAQ) score, score of both patient's and physician's global assessments, and C-reactive proteins (CRP). Sixteen patients (50.0%) and 9 patients (31.0%) showed a significant improvement in overall conventional measures, and ACR response criteria, respectively, and 60.0% of RA patients who received MTX for more than 1 year showed improvement in ACR definition. Patients who responded to the combination treatment within the first 12 weeks showed persistent improvement for the remaining part of the 24 week period. Our results indicate that the additive combination of actarit and MTX is safe, and without serious adverse effects, and has an excellent efficacy in patients with active and refractory RA. Received: July 28, 1999 / Accepted: January 28, 2000     

Durability of treatment with methotrexate in Venezuelan patients with rheumatoid arthritis

A multicenter, national, retrospective, and cross-sectional study of 219 hospital-based Venezuelan patients with rheumatoid arthritis (RA) was aimed to evaluate the probability of continuity of treatment with oral methotrexate (MTX). Treatment survival decreased from 92% at 12 months to 42% at 180 months, as assessed by life table analysis and the Kaplan–Meier method. Forty-seven patients stopped treatment and adverse effects (29.7%) and lack of continuous access to medication (19.1%) were the most common causes for withdrawal. MTX survival was decreased in the group with combined MTX plus leflunomide therapy, as shown by the log-rank test. Venezuelan patients with RA have a probability of continuing treatment with oral MTX comparable to non-Hispanic patient populations. However, concomitant use of leflunomide may increase the risk of interruption of MTX treatment in this RA population.     

Leukocytoclastic vasculitis induced by adalimumab biosimilar in an elderly female with rheumatoid arthritis: A case-based review

BackgroundAdalimumab is one of the most frequently used tumor necrosis factor (TNF) inhibitors considered in the treatment of several autoimmune diseases including rheumatoid arthritis (RA). There have been reports of being adversely associated with the development of lupus and vasculitis. Leukocytoclastic vasculitis (LCV) is the most common form of cutaneous vasculitis that could be associated with different medications including TNF inhibitors.Case presentationA 64-year-old Iranian female with RA for 11 years presented to the rheumatology clinic, Imam Reza Hospital, Kermanshah University, complaining of erythematous patches, plaques, and erosions on her lower extremities for 20-days. She had been receiving methotrexate (MTX) for 11 years (on 5 mg/week) and adalimumab biosimilar 40 mg every other week for nine months prior to developing the skin lesions. There were no signs of RA activity. The routine laboratory tests and immunological workup including anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibody (ANCA) and serum complements were within normal limits. Abdominopelvic sonography showed no pathological finding. A skin biopsy confirmed the diagnosis of LCV. Adalimumab and MTX were discontinued and she was started on prednisolone (5 mg/day) and mycophenolate mofetil (2 g/day). Gradual improvement was observed. Similar reported cases of adalimumab-related LCV are presented.ConclusionLeukocytoclastic vasculitis could be a possible adverse event of TNF inhibitors. Complete improvement occurs after withdrawal of the culprit drug in most cases while corticosteroids and immunosuppressive medications are required in some cases. LCV associated with adalimumab biosimilar should raise the awareness of rheumatologists about this possible complication for appropriate management.     

Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs

Modern therapy for rheumatoid arthritis (RA) is based on knowledge of the severity of the natural history of the disease. RA patients are approached with early and aggressive treatment strategies, methotrexate as an anchor drug, biological targeted therapies in those with inadequate response to methotrexate, and "tight control," aiming for remission and low disease activity according to quantitative monitoring. This chapter presents a rationale for current treatment strategies for RA with antirheumatic drugs, a review of published reports concerning treatments in clinical cohorts outside of clinical trials, and current treatments at 61 sites in 21 countries in the QUEST-RA database.     

Efficacy of low-dose tacrolimus added to methotrexate in patients with rheumatoid arthritis in Japan: a retrospective study

Abstract

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

Efficacy of low-dose tacrolimus added to methotrexate in patients with rheumatoid arthritis in Japan: a retrospective study

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

甲氨蝶呤单用或联合柳氮磺胺吡啶治疗类风湿关节炎的疗效和安全性的再评价

目的：系统评价单独使用甲氨蝶呤(MTX)与联合柳氮磺胺吡啶(SSZ)治疗类风湿关节炎(RA)的疗效及安全性。方法：采用主题词和自由词相结合方法,检索Pubmed、EMBASE、OVID和CNKI全文期刊网,收集疗程大于半年的相关随机及半随机对照临床试验,对其逐个进行质量评价及系统分析。结果：总计纳入4个临床试验,共318例RA患者。MTX单独或联合SSZ治疗RA的总有效性没有差别：采用随机效应模型比较4个试验共306例RA患者,合并后的比值比(OR)为0．75．95% Cl 0．44～1．27;采用美国风湿病学会(ACR)标准进行评价,MTX单独或联合SSZ治疗RA的缓解率没有差异：采用固定效应模型比较208例RA患者的OR为0．77．95% CI 0．43～1．38;采用欧洲风湿病学会联盟(EULAR)标准进行评价,MTX单独或联合SSZ治疗RA的缓解率没有差异,固定效应模型OR为1．04．95%Cl 0．60～1．82;联合治疗的不良事件发生率要远高于单独使用MTX：共3个试验264例RA患者,合并后的OR 0．40,95%Cl 0．20～0．78。其中两种治疗方案在神经系统的不良反应发生率相似,2个试验208例患者合并后的OR为0．56,95%Cl 0．25～1．27;联合用药的消化道不良反应发生率远高于单独使用MTX,2个试验208例患者合并后的OR 0．27,95%Cl 0．15～0．49。结论：联合MTX及SSZ与单用MTX治疗RA相比,联合治疗的不良反应发生率显著增加,而疗效并未相应增加,提示今后临床治疗RA应慎重考虑MTX与SSZ联合治疗的效益和安全性。     

Osteoporosis evaluation and treatment recommendations in rheumatoid arthritis

In this chapter, we emphasize among rheumatoid arthritis (RA) patients, whom and how to screen for osteoporosis. We highlight certain modalities, advancements in technology, secondary osteoporosis workup, and laboratory testing as well as their caveats. Finally, we discuss current guidance on how to direct the laboratory and radiology testing in the context of the individual patient with RA to guide and select from the osteoporosis treatment options currently available.     

Primary cervical epidural malignant lymphoma with rheumatoid arthritis: a case report

We report a case of primary cervical epidural malignant lymphoma with rheumatoid arthritis. Because of the acute progression of paralysis in both legs, surgical decompression and stabilization of the cervical spine were performed. The resected specimen showed proliferation of lymphoblastic cells diagnosed as malignant lymphoma. Four series of chemotherapy were administered after surgery, and the patient recovered from paralysis.     

Personalized medicine in rheumatoid arthritis: Combining biomarkers and patient preferences to guide therapeutic decisions

The last few decades have seen major therapeutic advancements in rheumatoid arthritis (RA) therapeutics. New disease-modifying antirheumatic drugs (DMARDs) have continued to emerge, creating more choices for people. However, no therapeutic works for all patients. Each has its own inherent benefits, risks, costs, dosing, and monitoring considerations. In parallel, there has been a focus on personalized medicine initiatives that tailor therapeutic decisions to patients based on their unique characteristics or biomarkers. Personalized effect estimates require an understanding of a patient's baseline probability of response to treatment and data on the comparative effectiveness of the available treatments. However, even if accurate risk prediction models are available, trade-offs often still need to be made between treatments. In this paper, we review the history of RA therapeutics and progress that has been made toward personalized risk predictive models for DMARDs, outlining where knowledge gaps still exist. We further review why patient preferences play a key role in a holistic view of personalized medicine and how this links with shared decision-making. We argue that a “preference misdiagnosis” may be equally important as a medical misdiagnosis but is often overlooked.     

A prospective analysis of liver biopsies in rheumatoid arthritis patients receiving long term methotrexate therapy

Summary Baseline and sequential liver biopsies were performed in ten patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) for more than 4 years. Liver biopsies were performed in all patients before the initiation of MTX therapy and were repeated after reaching a cumulative dose of 1500 mg or more. In four patients a third biopsy was performed 3 years after the first one. No significant worsening of hepatic architecture was found in any of our patients after 4 to 71/2 years of MTX therapy. No correlations between histologic findings and various clinical or pharmacological variables could be found. Our results suggested that prolonged MTX administration in RA patients did not cause severe hepatic abnormalities.     

Plasma and synovial fluid concentrations of sulphasalazine and two of its metabolites in rheumatoid arthritis

Summary A study was made of plasma and synovial fluid levels of sulphasalazine, one of its dissociation products — sulphapyridine and a metabolite of the latter — acetyl sulphapyridine in patients with rheumatoid arthritis (RA) who were in a steady state on sulphasalazine therapy. Combined sulphapyridine levels were significantly higher than those of sulphasalazine both in plasma and synovial fluid. Synovial fluid levels of both drugs correlated with their plasma levels and were generally slightly lower. Some patients accumulated sulphasalazine and sulphapyridine in the synovial fluid and the mean concentration of sulphasalazine was higher in the fluid than in the plasma. The explanation for this is uncertain. The concentration of combined sulphapyridine in synovial fluid was related to local joint inflammation and more active systemic disease. No consistent association was found between sulphasalazine levels and local or systemic activity. The higher sulphapyridine levels in synovial fluid found in this study suggest the possibility that this moiety could play a more active role in RA than it does in inflammatory bowel disease.     

Inhibition of neutrophil chemotaxis in methotrexate-treated rheumatoid arthritis patients

Summary Polymorphonuclear cell (PMN) chemotaxis was assessed using the in vitro under agarose assay in ten rheumatoid arthritis patients prior to and following a single 10-mg dose of methotrexate (MTX). PMNs obtained from patients after MTX showed a decreased chemotactic migration response to both zymosan activated serum (P<0.005) and N-formyl-L-methionyl-L-phenylalanine (P<0.01). In similar conditions, no significant difference in chemotactic migration could be detected in six rheumatoid arthritis patients not on MTX. In contrast to the in vivo effects of MTX, there was no inhibition of normal PMN chemotactic migration following a 30-min in vitro incubation of the cells with MTX (P<0.99).     

Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: A systematic literature review

Objective

To review published cases of induced or exacerbated interstitial lung disease (ILD) in rheumatoid arthritis (RA) associated with non-biologic disease-modifying antirheumatic drugs (nbDMARDs) and biologics and to discuss clinical implications in daily practice.

Methods

We performed a systematic literature review from 1975 to July 2013 using Medline, Embase, Cochrane, and abstracts from the ACR 2010–2012 and EULAR 2010–2013 annual meetings. Case reports and series that suggest a causative role of nbDMARDs (methotrexate [MTX], leflunomide [LEF], gold, azathioprine [AZA], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) and biologic agents (TNF inhibitors [TNFi], rituximab [RTX], tocilizumab [TCZ], abatacept [ABA], and anakinra) in causing ILD or worsening a pre-existing ILD in RA patients were included. Results from observational and postmarketing studies as well as reviews on this topic were excluded from the qualitative analysis but still considered to discuss the implication of such drugs in generating or worsening ILD in RA patients. Comparisons were made between MTX-induced ILD in RA and the cases reported with other agents, in terms of clinical presentation, radiological features, and therapeutic management and outcomes.

Results

The literature search identified 32 articles for MTX, 12 for LEF (resulting in 34 case reports), 3 for gold, 1 for AZA, 4 for SSZ, 27 for TNFi (resulting in 31 case reports), 3 for RTX, 5 for TCZ (resulting in 8 case reports), and 1 for ABA. No case was found for HCQ or anakinra. Common points are noted between LEF- and TNFi-related ILD in RA: ILD is a rare severe adverse event, mostly occurs within the first 20 weeks after initiation of therapy, causes dyspnea mostly in older patients, and can be fatal. Although no definitive causative relationship can be drawn from case reports and observational studies, these data argue for a pulmonary follow-up in RA patients with pre-existing ILD, while receiving biologic therapy or nbDMARDs.

Conclusion

As previously described for MTX, growing evidence highlights that LEF, TNFi, RTX, and TCZ may induce pneumonitis or worsen RA-related pre-existing ILD. Nonetheless, identifying a causal relationship between RA therapy and ILD-induced toxicity clearly appears difficult, partly because it is a rare condition.     

Expression and citrullination of keratin in synovial tissue of rheumatoid arthritis

Keratin is the main component of cellular intermediate filaments, and its post-translational modification plays an important role in cell differentiation and apoptosis, as well as disease states. The conversion of peptidylarginine to citrulline, termed citrullination, is particularly involved in the pathogenesis of rheumatoid arthritis (RA). Immunohistochemistry using an antibody mixture that broadly recognized various keratin forms detected cytokeratin in many cells in the area lining the synovial membrane of RA. Furthermore, double immuno-florescent labeling showed that the cells expressing cytokeratin were also positive for citrulline when they were in the vicinity of extracellular deposits or approached the exterior of the synovial membrane. Western blot analysis demonstrated citrullination of keratin purified from RA synovial tissue by immuno-precipitation. The above results indicate the presence of citrullinated cytokeratin in synovial membranes in RA.