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19404957 Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoi 2009 May OBJECTIVE: To assess the efficacy and safety of VX-702, a p38 MAPK inhibitor, in patients with active, moderate-to-severe rheumatoid arthritis (RA). METHODS: Two 12-week, double-blind, placebo-controlled studies of VX-702 were conducted in patients with active, moderate-to-severe RA. In the VeRA study, 313 patients received placebo or 2 daily doses of VX-702. In Study 304, 117 patients received placebo, daily VX-702, or twice weekly VX-702 in addition to concomitant methotrexate (MTX). Study end points included the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (an ACR20 response), ACR50 and ACR70 responses, changes in the serum levels of biomarkers of inflammation, and safety assessments. RESULTS: The numerically superior ACR20 response rates among patients receiving VX-702 compared with those receiving placebo in both studies did not reach pairwise statistical significance at the highest doses in either study. At week 12 in the VeRA study, ACR20 response rates were 40%, 36%, and 28% among patients receiving 10 mg of VX-702, 5 mg of VX-702, and placebo, respectively. In Study 304, the response rates were 40%, 44%, and 22% for patients receiving 10 mg VX-702 daily plus MTX, 10 mg VX-702 twice weekly plus MTX, and placebo, respectively. Reductions in the levels of C-reactive protein, soluble tumor necrosis factor receptor p55, and serum amyloid A were observed as early as week 1 in both studies, but these levels rapidly returned to baseline values by week 4. The overall frequency of adverse events was similar between the VX-702 and placebo groups. In the VeRA study, serious infections were more frequent in the VX-702 groups compared with the placebo group (2.4% versus 0%) but not in Study 304 (2.6% versus 4.9%). CONCLUSION: The modest clinical efficacy plus the transient suppression of biomarkers of inflammation observed in this study suggest that p38 MAPK inhibition may not provide meaningful, sustained suppression of the chronic inflammation seen in RA.
20542718 TNFα antagonist therapy does not increase the Epstein-Barr virus burden in patients with 2010 Oct OBJECTIVE: The risk of non-Hodgkin lymphoma is increased in rheumatoid arthritis (RA) but not in ankylosing spondylitis (AS). In RA, the degree of inflammation is closely associated with the lymphoma risk. Whether immunosuppressants such as methotrexate and TNFα antagonists affect the lymphoma risk in RA is unclear. The Epstein-Barr virus (EBV) may contribute to the pathogenesis of RA and may be involved in the development of lymphoma in patients taking methotrexate and/or TNFα antagonists, although these points remain debated. EBV load monitoring during immunosuppressive treatment may predict the occurrence of EBV-related lymphoma. Here, our objective was to prospectively measure the EBV load in patients receiving TNFα antagonists for RA or AS. METHODS: We prospectively studied patients with RA or AS before and after TNFα antagonist therapy initiation. The EBV load was measured in blood samples using the EBV R-gene Quantification Kit. Disease activity at the time of blood sampling was evaluated by determining the Disease Activity Score 28 (DAS28) in RA patients and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in AS patients. RESULTS: We included 46 patients with RA (82.6% women; mean age, 52.7 ± 11.3 years) and 27 with AS (men, 81.5%; mean age, 45.1 ± 12.7 years). In the RA group, the EBV load was measured at baseline and 9.72 ± 5.7 months later. The baseline EBV load was undetectable in 33 (70.2%) patients; mean EBV load in the 13 remaining patients was 9389 copies/ml (3.47 log₁₀ ± 0.45). Baseline EBV load did not correlate with disease activity (DAS28). At the follow-up assay, the EBV load became positive in five patients and increased significantly in one patient (four patients on etanercept, one on adalimumab, and one on infliximab); it became negative in six patients (five on adalimumab and one on etanercept) and showed non-significant changes in six patients. Mean EBV load in patients positive at follow-up was 3.63 ± 0.52 log₁₀ copies/ml. Mean DAS28 was 4.78 ± 1.1 at baseline and 2.94 ± 1.24 at follow-up. At follow-up, a good EULAR response was noted in 33 (71.7%) patients and a moderate EULAR response in seven (15.2%) patients. In the AS group, the baseline EBV load measurement occurred after 12.9 ± 10.6 months. Baseline EBV load was undetectable in 25 (92.6%) patients; mean load in the remaining two patients was 4.15 ± 0.46 log₁₀ copies/ml. At follow-up, the EBV load became positive in two patients (one on adalimumab and one on infliximab) and became negative in one patient (on adalimumab). Mean load in positive patients was 3.33 ± 0.24 log₁₀ copies/ml. Mean BASDAI was 55.1 ± 16.2 at baseline and 17.88 ± 18.62 at follow-up. A positive EBV load was significantly more common in the RA group than in the AS group (P = 0.039). EBV load changes did not differ significantly between the RA and AS groups or across TNFα antagonists. No cases of lymphoma were recorded. CONCLUSION: Introducing TNFα antagonist therapy does not affect the EBV load in patients with RA or AS. EBV load monitoring is probably unnecessary in patients given TNFα antagonists for RA or AS.
19999184 [Copernican revolution in the therapy of rheumatoid arthritis: the contribution of anti-TN 2009 Apr TNFalpha has a key role in cell recruitment, proliferation and death, expression of adhesion molecules and immune responses. In RA, TNFalpha is involved in matrix degradation and osteoclastogenesis. TNFalpha inhibitors are either soluble receptors (etanercept) or monoclonal antibodies (infliximab and adalimumab; golimumab and certolizumab are in development). TNFalpha antagonists, alone or in combination with methotrexate, reduce bone erosions and thinning of cartilage, but they differ as regards ligand binding, pharmacokinetics, pharmacodynamics, and clinical indications. Etanercept is the only TNFalpha antagonist that also neutralises LFT-alpha. Infliximab and adalimumab are more immunogenic. Cytotoxicity and cellular lysis are also higher with infliximab and adalimumab. Etanercept slows progression of joint damage in recently diagnosed RA when given alone, but much more when given with methotrexate; anti-TNF monoclonal antibodies also were shown to slow progression alone and in combination with methotrexate. Patients with early and long-standing RA treated with etanercept have now shown improvement in ACR scores, inflammation and disability for up to 9 years. Outcomes with infliximab and adalimumab are similar to those with etanercept, but only in combination with methotrexate. As a result of neutralizing antibodies, increasing doses of anti-TNFalpha antibodies may be required to maintain clinical response. As regards side effects, opportunistic infections seem more frequent with monoclonal antibodies. TNFalpha antagonists produce more QALYs than traditional DMARDs, counteracting higher costs. The efficacy, safety, and quality of life benefits of TNFalpha antagonists suggest using them possibly earlier than today, even in clinically moderate RA. Thanks to its overall profile, etanercept might be considered as one of the first-choices in TNFalpha antagonism in RA management.
20191470 Adherence to disease-modifying antirheumatic drugs and the effects of exposure misclassifi 2010 May OBJECTIVE: To describe the effect of different exposure classification strategies for disease-modifying antirheumatic drugs (DMARDs) on drug-outcome associations. METHODS: We studied the association between DMARD initiation and all-cause hospitalizations in patients with rheumatoid arthritis (RA), 1995-2005. Initiators of DMARDs and oral glucocorticoids were followed for < or =180 days. We compared 2 strategies for exposure classification: a persistent exposure required (PER) approach, in which followup stopped when the regimen changed; and a persistent exposure ignored (PEI) approach, in which followup continued despite regimen changes. For PEI, adherence was assessed using the medication possession ratio. All-cause hospitalization risk was compared among RA regimen initiators using Cox models and methotrexate as the reference. RESULTS: We identified 28,906 episodes of medication initiation. In PER analyses, tumor necrosis factor alpha antagonists did not increase hospitalization risk compared with methotrexate, whereas leflunomide did (hazard ratio [HR] 1.36, 95% confidence interval [95% CI] 1.1-1.67). Glucocorticoids increased hospitalization risk (HR 1.29, 1.54, and 2.03 for low, medium, and high doses, respectively). PEI results were similar to PER except that infliximab initiation increased the risk of hospitalization compared with methotrexate (HR 1.46, 95% CI 1.19-1.8), and most other effects were closer to the null. In PEI, adherence ranged from 73% for etanercept to 6% for glucocorticoids and adherence to methotrexate was 59%. CONCLUSION: Compared with methotrexate initiation, leflunomide or glucocorticoid initiation consistently increased all-cause hospitalizations in the first 180 days of use. Most PER and PEI estimates were similar; observed differences in risk between these methods were likely due to differences in adherence.
20974317 Subset analysis of patients experiencing clinical events of a potentially immunogenic natu 2010 Aug BACKGROUND: Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody directed against the interleukin-6 receptor. In Europe, TCZ is approved for use in combination with methotrexate in the treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have failed to respond to or were unable to tolerate previous therapy with one or more disease-modifying antirheumatic drugs or tumor necrosis factor (TNF) antagonists; in the United States, it is approved for the treatment of adult patients with moderate to severe active RA who have failed to respond to one or more TNF antagonists. As part of the Phase III clinical development program, the immunogenicity of TCZ was evaluated using a bridging ELISA; however, this assay is considered limited in detecting low-affinity or immunoglobulin G4 subisotype antidrug antibodies (ADAs). OBJECTIVE: This study assessed the validity of the ELISA for detecting anti-TCZ ADAs by using complementary bioanalytic assays to test samples from a subgroup of patients with clinical adverse events (AEs) of a potentially immunogenic nature, who were considered highly likely to have ADAs. The goal was to determine whether use of these additional assays led to detection of ADAs not found on the ELISA, thus minimizing the risk of false-negative results. METHODS: The Phase III program for TCZ consisted of 5 core studies in which adult patients with RA received either TCZ 4 or 8 mg/kg IV or control every 4 weeks, with or without concomitant antirheumatic therapy. Blood samples obtained at baseline and at regular intervals thereafter were tested using the ELISA for ADA screening and confirmation. Regardless of the results on ADA screening, samples from patients who developed clinical AEs of a potentially immunogenic nature (ie, falling within predefined system organ classes, occurring during or within 24 hours of TCZ infusion, considered related to TCZ therapy, or leading to study withdrawal) were subjected to additional testing with a surface plasmon resonance (SPR) assay for isotyping and epitope localization and a standard ImmunoCAP immunoglobulin E (IgE) assay made specific for TCZ. RESULTS: The 5 core studies and their open-label, longterm extension studies enrolled a total of 4199 adult patients with RA (82.1% female; 74.0% white; mean age, 52.0 years [range, 18-89 years]; mean weight, 73.4 kg [range, 35-150 kg]); 2928 patients received TCZ and 1271 received control. Of the 2816 samples from TCZ-treated patients tested, 64 (2.3%) had samples that tested positive at least once on the ELISA screening and confirmation assay, 48 (75.0%) of them at baseline. A clinical AE of a potentially immunogenic nature occurred during TCZ treatment in 21 patients, 8 of whom had an anaphylactic reaction. Eleven of the samples from these 21 patients had tested negative for AD As on the screening ELISA. Only 1 of these 11 patients tested positive for ADAs on both additional assays; all others tested negative. The results of the ELISA, SPR, and IgE assays were consistent for 16 of 18 tested patients (88.9%) who provided data on at least 2 of the 3 assays. CONCLUSIONS: Based on the findings of this analysis in a relevant patient population, the bridging-type screening and confirmation ELISA was a valid method of detecting anti-TCZ ADAs. Immunogenicity testing of samples from patients with clinical AEs of a potentially immunogenic nature using assays complementary to the ELISA added valuable information about the incidence and character of ADAs.
19126559 Comparative effectiveness of tumour necrosis factor alpha inhibitors in combination with e 2009 Dec OBJECTIVE: The objective of this study was to compare the effectiveness of a combination of tumour necrosis factor alpha (TNFalpha) inhibitors with either methotrexate or leflunomide in the treatment of patients with rheumatoid arthritis in a real-world setting. METHODS: Data from 1769 outpatients enrolled in the German biologics register RABBIT who were treated with one of the TNFalpha inhibitors adalimumab, etanercept, or infliximab in combination with either methotrexate (n = 1375) or leflunomide (n = 394) were included in the analysis. Clinical status including disease activity as well as treatment data were documented by the treating rheumatologist at baseline and at 3, 6, 12, 18, 24, 30 and 36 months of follow-up. RESULTS: Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide. CONCLUSION: The current clinical practice is to use methotrexate as a first choice for the combination with TNFalpha antagonists. In a number of patients methotrexate has to be replaced by another disease-modifying antirheumatic drug. Our data support the view that leflunomide is a useful alternative if methotrexate is contraindicated.
20666701 Does the p38 MAP kinase inhibitor pamapimod have potential for the treatment of rheumatoid 2010 Oct Methotrexate alone or in combination with other agents is the standard treatment for moderate-to-severe rheumatoid arthritis. As biological agents are expensive, they are not usually used until methotrexate has failed to give a good response. Thus, there is scope for the development of cheaper drugs that can be used instead of methotrexate or in addition to methotrexate. Pamapimod is a p38α inhibitor being developed for use in the treatment of rheumatoid arthritis. The objective of this review was to evaluate the recent clinical trials of pamapimod in subjects with rheumatoid arthritis. There is no clear-cut evidence that pamapimod alone or in the presence of methotrexate is efficacious in subjects with rheumatoid arthritis but it does cause adverse effects. It is unlikely that pamapimod will be useful in the treatment of rheumatoid arthritis.
21234291 Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis. 2010 Dec 19 Recent years have seen many exciting developments in the treatment of rheumatoid arthritis. Tocilizumab (TCZ) is a monoclonal antibody which inhibits the interleukin-6 receptor. After initial studies in Japan, it has been extensively studied in five multicentre clinical trials. This report summarises the key efficacy and toxicity findings from the major clinical trials. TCZ works quickly and effectively in rheumatoid arthritis either as monotherapy or in combination with other agents in early disease, DMARD inadequate responders, seronegative disease and after anti-TNF failure. The toxicity profile is manageable but includes infections (most notably skin and soft tissue), increases in serum cholesterol, transient decreases in neutrophil count and abnormal liver function tests (especially in combination with methotrexate). In summary, there is sufficient evidence to make TCZ a first line biologic therapy for rheumatoid arthritis especially for those who are unable to take methotrexate or who fail anti-TNF therapy.
27789984 The clinical efficacy and safety of certolizumab pegol (CZP) in the treatment of rheumatoi 2009 Rheumatoid arthritis can cause chronic pain, disability, fatigue and loss of productivity both in the workplace and at home. Fatigue, not joint pain, swelling or that there may be radiographic damage, is frequently mentioned by patients as their most debilitating problem. In the era prior to biologic therapy in rheumatoid arthritis, it was reported that 40% to 50% of individuals reported work loss within 10 years of the onset of their disease. Rheumatoid arthritis is not just associated with chronic pain and inability to function normally; there is a significant economic burden caused by the disease which affects society as well the individual. Work disability in individuals with rheumatoid arthritis occurs early and increases over time. Early, aggressive treatment has now become the norm in clinical practice with changes of medication dictated by measuring the presence of continued disease activity. The combination of adequately dosed methotrexate and a biologic agent, especially a TNFα inhibitor, has been shown to be far more effective than traditional disease modifying anti-rheumatic drugs in early and long-standing disease, with respect to clinical, radiologic and functional outcomes. Unfortunately, not all patients respond to all medications equally; indeed a patient may fail a number of medications, either alone or in combination, and then respond to another medication. For this reason, there is room in our therapeutic armamentarium for additional effective agents such as certolizumab pegol. The results of up to 100 weeks of treatment with certolizumab pegol with an emphasis on functional outcomes, is the focus of this review.
19814865 Therapeutic index of methotrexate depends on circadian cycling of tumour necrosis factor-a 2009 Oct OBJECTIVES: Rheumatoid arthritis is an autoimmune disorder of unknown aetiology. Morning stiffness, a characteristic feature of rheumatoid arthritis, shows a 24-h rhythm. Noticing this rhythm, we hypothesized the presence of a similar rhythm for a rheumatoid arthritis indicator, in addition to dosing-time dependency of the anti-rheumatic effect of methotrexate in arthritis induced by collagen in rats and mice, which reflect the symptomatology of rheumatoid arthritis patients. METHODS: To measure tumour necrosis factor (TNF)-alpha concentration, blood was taken at different times (2, 6, 10, 14, 18 or 22 h after the light was turned on (HALO)) in collagen-induced arthritic mice. Methotrexate was administered at two different dosing times based on these findings to estimate arthritis. KEY FINDINGS: The arthritis score was significantly lower in the 22 HALO-treated group than in the control and 10 HALO-treated groups in collagen-induced arthritic rats and mice. Plasma TNF-alpha concentrations showed obvious 24-h rhythms, with higher levels at light phase and lower levels at dark phase after rheumatoid arthritis crisis. Arthritis was relieved after administration of methotrexate during the dark phase in synchronization with the 24-h rhythm. CONCLUSIONS: Our findings suggest that choosing an optimal dosing time associated with the 24-h cycling of TNF-alpha could lead to effective treatment of rheumatoid arthritis by methotrexate.
21701629 Safety and clinical efficacy of golimumab in the treatment of arthritides. 2010 Golimumab is a human anti-tumor necrosis factor (TNF)-alpha monoclonal antibody that was recently approved for the treatment of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. This review covers the published clinical trial data on the use of golimumab for the approved indications mentioned above with respect to efficacy and safety. The various ongoing trials for golimumab have yielded promising results in terms of efficacy and safety in methotrexate-naive and -resistant patients with rheumatoid arthritis, as well as in patients who were previously treated with other anti-TNF agents. In addition, the efficacy of golimumab in psoriatic arthritis and ankylosing spondylitis has also been demonstrated. The real safety information will be available only once the drug has been used in many more patients, who frequently have comorbid conditions.
21189905 Evaluation of efficacy of combination of methotrexate and hydroxychloroquine with leflunom 2010 Dec BACKGROUND: Several new drugs for rheumatoid arthritis are available including leflunomide. Comparative studies of treatment with leflunomide (against methotrexate) report a better quality of life. AIM: This study was designed to evaluate the efficacy of combination of methotrexate and hydroxychloroquine with leflunomide, a new disease modifying antirheumatoid drug. Analysis was of intent to treat group. MATERIALS AND METHODS: This was an open labeled, randomized, comparative clinical trial in the department of rheumatology and immunology, at a tertiary care center in Bangalore. Patients who have diagnosed with rheumatoid arthritis as per American College of Rheumatology aged between 18 and 60 years were recruited and randomized to receive leflunomide (10 mg/day p.o.) or a combination of methotrexate and hydroxychloroquine (7.5 mg/week p.o. and 200 mg/day p.o., respectively) along with folate supplementation for 12 weeks. The European League Against Rheumatism criteria of improvement according to disease activity score 28 was considered as the primary efficacy variable. Baseline and end of study values were evaluated. The duration of the study period was 1 year. Analysis of variance (ANOVA) and Wilcoxon Signed rank test were used for statistical analysis. RESULTS: After 12 weeks, improvement noted in patients treated with leflunomide was similar to those treated with a combination of methotrexate and hydroxychloroquine. There was no statistical significance in improvement in disease activity between the two groups (P = 0.377). CONCLUSION: Combination of methotrexate and hydroxychloroquine is equivalent to leflunomide in terms of efficacy in reducing disease activity in the initial treatment of severe rheumatoid arthritis.
27789979 Efficacy, safety, and tolerability of abatacept in the management of rheumatoid arthritis. 2009 The management of rheumatoid arthritis (RA) has undergone an impressive transformation over the past few decades. Further understanding of the pathophysiology of the disease process has resulted in the development of biologic agents that target proinflammatory cytokines and both B and T lymphocytes. By blocking an important costimulatory pathway, abatacept leads to a dramatic reduction in T cell stimulation and proliferation. Multiple clinical trials have revealed consistent benefit with regards to clinical and radiographic efficacy, quality of life, and disability in patients suffering from RA who have had inadequate responses to methotrexate or tumor necrosis factor inhibitors. The possibility of remission when used early in the disease course has also been demonstrated. Importantly, abatacept has been very well tolerated with a low rate of serious infections and no apparent increase in malignancies to date. Continued surveillance of the benefits and risks will help to better define its place amongst the other biologic agents in the treatment of RA.
27789989 Bioboosters in the treatment of rheumatic diseases: a comprehensive review of currently av 2009 Immunologic research has clarified many aspects of the pathogenesis of inflammatory rheumatic disorders. Biologic drugs acting on different steps of the immune response, including cytokines, B- and T-cell lymphocytes, have been marketed over the past 10 years for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). Randomized controlled trials (RCTs) of anti-cytokine agents in RA (including the anti-tumor necrosis factor alpha (TNFα) drugs infliximab, etanercept, adalimumab, golimumab, certolizumab, anti-interleukin (IL)-1 anakinra, and anti-IL-6 tocilizumab) demonstrated a significant efficacy compared to traditional therapies, if combined with methotrexate (MTX), as measured by ACR 20, 50 and 70 response criteria. The new therapies have also been demonstrated to be superior to MTX in slowing or halting articular damage. RCTs have shown the efficacy of anti-TNFα in AS patients through significant improvement of symptoms and function. Trials of anti-TNFα in PsA patients showed marked improvement of articular symptoms for psoriasis and radiological disease progression. More recent studies have demonstrated the efficacy of B-cell depletion with rituximab, and T-cell inactivation with abatacept. All these drugs have a satisfactory safety profile. This paper reviews the different aspects of efficacy and tolerability of biologics in the therapy of RA, AS, and PsA.
27789995 Effects of low-dose tacrolimus therapy in combination with methotrexate in patients with m 2010 The aim of the present clinical trial was to determine the efficacy and safety of low-dose administration of tacrolimus in combination with methotrexate (MTX) in rheumatoid arthritis (RA) patients with an insufficient clinical response to MTX alone. Eleven patients with active RA, despite treatment with MTX, were enrolled and given tacrolimus in combination with MTX for 24 weeks. The primary endpoint was the assessment of clinical improvement using the European League against Rheumatism criteria. Administration of tacrolimus to RA patients with an insufficient response to MTX produced significant improvement in the Disease Activity Score 28 after 8-24 weeks. In addition, after 24 weeks, 50% and 25% of patients had achieved moderate and good responses, respectively, and there were significant reductions in the Modified Health Assessment Questionnaire, the rheumatoid factor and serum matrix metalloproteinase-3 levels. The present preliminary study suggests that low-dose tacrolimus in combination with MTX is well tolerated and provides both clinical and economic benefits.
24179373 Methotrexate-induced acute leukemia: report of three cases and review of the literature. 2009 For many years, methotrexate has been used in the treatment of certain chronic medical disorders e.g. rheumatoid arthritis and psoriasis as well as a number of malignant disorders e.g. acute lymphoblastic leukemia, certain types of lymphoma and breast carcinoma. Its use has been associated with various systemic toxicities and complications. The association between methotrexate therapy and the development of lymphoma and pseudolymphoma is well established. In patients treated with methotrexate, the development of leukemia has been attributed to either the primary disorder e.g. rheumatoid arthritis or to other drugs used concomitantly e.g. cyclophosphamide. Reported here are two patients with rheumatoid arthritis and one patient with psoriasis treated with low dose methotrexate for variable periods of time. Two of these patients developed acute myeloid leukemia on myelodysplastic syndrome background, while the third patient developed pre-B acute lymphoblastic leukemia that expressed few myeloid markers and had a positive philadelphia chromosome. To our knowledge, these are the first reported cases of methotrexate-induced acute leukemia.
23555393 Acute palmer digital artery occlusion treated using endoscopic ablation of the thoracic sy 2010 Acute occlusion of the digital arteries frequently causes painful infarction requiring digital amputation. We describe a 55-year-old male patient who presented with acute onset of digital ischemia with impending gangrene on the right hand. Because angiography revealed bypass surgery was not feasible, he underwent thoracoscopic sympathectomy (TS) one week after onset of the symptom, which resulted in rapid pain resolution. He was diagnosed, thereafter, with malignant rheumatoid arthritis and methotrexate was administered. Postoperative angiography revealed that the occluded digital artery had become recanalized. Timely TS is therefore a treatment of choice for acute digital ischemia.
22915918 Prefilled certolizumab pegol (Cimzia(®)) syringes for self-use in the treatment of rheuma 2010 A new anti-tumor necrosis factor alpha (TNF-α) inhibitor with a novel mechanism of action has entered phase 3 trials in rheumatoid arthritis (RA). Certolizumab pegol (Cimzia(®)) is a humanized Fab' antibody fragment against TNF-α with a polyethylene glycol tail that prevents complement-dependent and antibody-dependent cell-mediated cytotoxicity or apoptosis. Four randomized clinical trials have been published so far. Reported results are similar to those published in previous studies with other TNF-α inhibitors, with ACR20, ACR50, and ACR70 responses of around 60%, 40%, and 20%, respectively, when combined with methotrexate and slightly lower when used as monotherapy. Safety was shown to be similar to that seen with TNF-α blockers and some cases of tuberculosis were seen in the trials, stressing the importance of a complete screening in these patients. Although we still need effectiveness and safety data in larger numbers of patients and longer follow-up, this new TNF inhibitor is a welcome addition to our current armamentarium for the treatment of RA.
27789998 Reappraisal of the clinical use of leflunomide in rheumatoid arthritis and psoriatic arthr 2010 Leflunomide is a disease-modifying antirheumatic drug (DMARD) that has been in routine clinical use for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis for a decade. In RA, clinical trials of up to two years' duration showed that leflunomide monotherapy was equivalent to methotrexate in clinical and radiographic disease outcomes (tender and swollen joint counts, physician and patient global assessments, American College of Rheumatology and Disease Activity Score responses, slowing or halting of radiographic progression). In a number of studies, quality of life measurements indicated that leflunomide is superior to methotrexate. Leflunomide has been studied in combination with methotrexate and shows efficacy in patients only partly responsive to this agent. Recent trials have shown that leflunomide can be used safely with biologic DMARDs, including antitumor necrosis factor agents and rituximab as part of the treatment algorithm in place of methotrexate as a cotherapy. Leflunomide has demonstrated efficacy as a monotherapy in psoriatic arthritis, and it also has a beneficial effect in psoriasis. Postmarketing studies have shown that retention on treatment with leflunomide is equal to methotrexate and superior to other DMARDs. In general, its side effect profile is acceptable compared with other DMARDS, with nausea, diarrhea, and hair fall occurring commonly, but only rarely leading to discontinuation. Liver toxicity is the most significant problem in clinical use although it is uncommon. Peripheral neuropathy, hypertension, pneumonitis, and cytopenia occur more rarely. Leflunomide is contraindicated in pregnancy and should be used with caution in women during child-bearing years. In this review, the place of leflunomide in therapy is discussed and practical advice informed by evidence is given regarding dosing regimens, safety monitoring, and managing side effects. Leflunomide remains one of the most useful of the nonbiologic DMARDs.
19707407 Infliximab in the treatment of rheumatoid arthritis. 2009 Infliximab was the first monoclonal antibody to human necrosis factor alpha (TNFalpha) developed for treating rheumatoid arthritis (RA). This chimeric antibody binds with high affinity to both soluble and trans-membrane TNF and is able to reduce synovial inflammation, bone resorption and cartilage degradation. The efficacy of infliximab has been observed in active RA despite treatment with multiple disease modifying anti-rheumatic drugs (DMARDs), and in early disease with no prior treatment by methotrexate (MTX). Infliximab has been shown to reduce joint inflammation and to slow radiographic progression, in both clinical and non-clinical responders. Recent data suggest that using infliximab early in RA treatment increases the percentage of clinical remission and allows infliximab discontinuation. The recommended dosage of 3 mg/kg could be increased up to 10 mg/kg with partial efficacy of the dose escalation. Antibodies to infliximab have been observed in 7% to 61% of patients and are associated with a low trough level of infliximab and secondary response failure. Their occurrence could be prevented by co-medication with MTX. The combination of DMARDs other than MTX with infliximab was found to be safe and efficacious. Infections, principally tuberculosis, are increased in treated patients, and the risk is greater at higher dose. Even if the treatment is generally safe and well tolerated, patients treated with infliximab should be closely monitored.