Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 23352953 | [Disease-modifying treatment for inflammatory rheumatism in sub-Saharan Africa: outcome at | 2012 Oct | RATIONALE: Few data are available on the treatment of rheumatoid arthritis (RA) in sub-Saharan Africa, where the diagnosis is often substantially delayed. Disease-modifying antirheumatic drugs (DMARDs) are more effective when started early. Biotherapies are not available. Given the socioeconomic constraints in sub-Saharan Africa, treatments must be selected based on locally available resources. The objective of this study was to evaluate outcomes 6 months after initiation of conventional DMARDs in Senegalese patients with RA. METHODS: We retrospectively studied consecutive RA patients seen at the rheumatology outpatient clinic of the Le Dantec Teaching Hospital, Dakar, Senegal, from January 2005 through June 2009. All patients met the ACR criteria for RA. ACR and EULAR response criteria were evaluated 6 months after treatment initiation. RESULTS: The study included 205 patients. Corticosteroids were used in 205 patients, hydroxychloroquine in 190, methotrexate in 137, and sulfasalazine in 11. Combined corticosteroid, methotrexate, and hydroxychloroquine therapy was used in 122 patients and combined corticosteroid and hydroxychloroquine therapy in 63. DMARD treatment was interrupted for at least 5 days per month for 26% of the patients, either because the drugs were out of stock at the local pharmacies and/or because the patients could not afford to purchase them. During the first 6 months of treatment, patients had a mean of 4 clinic visits, and 48% of patients missed at least one scheduled visit. After 6 months, all clinical variables had improved significantly, except the swollen joint count. The ACR20, 50, and 70 response criteria were met in 50%, 31%, and 6.9% of patients, respectively. The EULAR response was good in 53.9% of patients, moderate in 12.7%, and poor in 23.1%. DMARD therapy failed in 10.3% of patients. Half the patients had their treatment modified during the 6-month study period. DMARD therapy was discontinued in 10 patients for the following reasons: plans to become pregnant, n = 5; pregnancy during treatment, n = 2; and tuberculosis, n = 3. CONCLUSION: In Senegal, the treatment of RA relies chiefly on variable combinations of methotrexate, hydroxychloroquine, and corticosteroids. The six-month outcomes are satisfactory. Biotherapy is required in 7% to 10% of patients, a rate that could be decreased by optimizing patient follow-up. The management of chronic inflammatory joint disease couple be improved despite the limited financial resources in sub-Saharan Africa with better physician training and the incorporation of osteoarticular diseases within a vast information and education program for the general population. | |
| 22730417 | Factors associated with gastrointestinal perforation in a cohort of patients with rheumato | 2012 Dec | OBJECTIVE: To estimate the incidence and risk factors for gastrointestinal (GI) perforation among patients with rheumatoid arthritis (RA). METHODS: Claims from employer health insurance plans were used to identify RA patients and those hospitalized for upper or lower GI perforation. GI perforation cases were identified using both a sensitive and a specific definition. A Cox model using fixed and time-varying covariates was used to evaluate the risk of GI perforation. RESULTS: Among 143,433 RA patients, and using a maximally sensitive GI perforation definition, 696 hospitalizations with perforation were identified. The rate of perforation was 1.70 per 1,000 person years (PYs; 95% confidence interval [95% CI] 1.58-1.83), and most perforations (83%) occurred in the lower GI tract. The rate of perforation was lower when a more specific GI perforation definition was used (0.87; 95% CI 0.78-0.96 per 1,000 PYs). Age and diverticulitis were among the strongest risk factors for perforation (diverticulitis hazard ratio [HR] 14.5 [95% CI 11.8-17.7] for the more sensitive definition, HR 3.9 [95% CI 2.5-5.9] for the more specific definition). Among various RA medication groups and compared to methotrexate, the risk of GI perforation was highest among patients with exposure to nonsteroidal antiinflammatory drugs (NSAIDs), concomitant nonbiologic disease-modifying antirheumatic drugs, and glucocorticoids. Biologic agents without glucocorticoid exposure were not a risk factor for perforation. CONCLUSION: GI perforation is a rare but serious condition that affects patients with RA, most frequently in the lower GI tract. Clinicians should be aware of risk factors for GI perforation when managing RA patients, including age, history of diverticulitis, and use of glucocorticoids or NSAIDs. | |
| 22393128 | Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rh | 2012 Mar 6 | BACKGROUND: Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. OBJECTIVE: To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness. DESIGN: A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) SETTING: 7 hospitals in the Netherlands. PATIENTS: 236 patients with early RA (duration <1 year). INTERVENTION: Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. MEASUREMENTS: The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. RESULTS: Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. LIMITATION: A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. CONCLUSION: Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. PRIMARY FUNDING SOURCE: Catharijne Foundation. | |
| 21946458 | Methotrexate pneumonitis in rheumatoid arthritis: increased prevalence with increasing lat | 2011 Oct | BACKGROUND: There is an association between increasing prevalence and increasing latitude for some autoimmune diseases, including rheumatoid arthritis (RA). Furthermore, in RA patients, a geographical variation in methotrexate pneumonitis has been suggested at a regional level in New Zealand. OBJECTIVE: The objective of the study was to determine if there is an increased incidence of methotrexate pneumonitis with increasing latitude in New Zealand. METHODS: A search was conducted using the NZ Ministry of Health's National Minimum Data Set for patients with discharge codes for RA (M05, M06) or history of RA and drug-induced lung disease (J702, J703, J704) or other (J189, J680, J90, J984) and methotrexate (Y431), for the period July 1, 1999, to June 30, 2008. Anonymous data were provided by the Ministry of Health for the 43 patients fulfilling these coding criteria and also the latitude and population of each domicile code. A Poisson regression analysis was undertaken with latitude as a continuous variable, adjusting for the total population at different latitudes. RESULTS: The incidence rate ratio for methotrexate pneumonitis shows a 16% increase per 1 degree of latitude (95% confidence interval, 7%-27%; P = 0.02). CONCLUSIONS: There was a latitudinal gradient seen in the rate of patient discharges for methotrexate pneumonitis, in the defined period. This supports the hypothesis that there is a latitude-dependent risk factor for this disorder and raises questions regarding possible environmental cofactors. It also supports the growing pool of evidence that certain immune-mediated conditions are more common at higher latitudes. | |
| 22640174 | Cost utility of tumour necrosis factor-α inhibitors for rheumatoid arthritis: an applicat | 2012 Jul 1 | BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1.5 million people in the US. Tumour necrosis factor (TNF)-α inhibitors have been shown to effectively treat and maintain remission in patients with moderately to severely active RA compared with conventional agents. The high acquisition cost of TNF-α inhibitors prohibits access, which mandates economic investigations into their affordability. The lack of head-to-head comparisons between these agents makes it difficult to determine which agent is the most cost effective. OBJECTIVE: This study aimed to determine which TNF-α inhibitor was the most cost-effective agent for the treatment of moderately to severely active RA from the US healthcare payer's perspective. METHODS: A Markov model was constructed to analyse the cost utility of five TNF-α inhibitors (in combination with methotrexate [+MTX]) versus MTX monotherapy using Bayesian methods for evidence synthesis. The model had a cycle length of 3 months and an overall time horizon of 5 years. Transition probabilities and utility scores were based on published studies. Total direct costs were adjusted to year 2009 $US using the medical component of the Consumer Price Index. All costs and QALYs were discounted at a rate of 3% per year. Patient response to the different strategies was determined by the American College of Rheumatology (ACR)50 criteria. One-way and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case scenario. The base-case scenario was changed to ACR20 criteria (scenario 1) and ACR70 criteria (scenario 2) to determine the model's robustness. Cost-effectiveness acceptability curves and cost-effectiveness frontiers were used to estimate the cost-effectiveness probability of each treatment strategy. A willingness-to-pay (WTP) threshold was defined as three times the US GDP per capita ($US139,143 per additional QALY gained). Primary results were presented as incremental cost-effective ratios (ICERs). RESULTS: Etanercept+MTX was the most cost-effective treatment strategy in the base-case scenario up to a WTP threshold of $US2 185,497 per QALY gained. At a WTP threshold of greater than $US2 185,497 per QALY gained, certolizumab+MTX was the most cost-effective treatment strategy. One-way analyses showed that the base-case scenario was sensitive to the probability of achieving ACR50 criteria for MTX and each TNF-α inhibitor, and changes in the utility score for patients who achieved the ACR50 criteria. With the exception of infliximab, all of the TNF-α inhibitors were sensitive to drug cost per cycle. In the scenario analyses, certolizumab+MTX was a dominant treatment strategy using ACR20 criteria, but etanercept+MTX was a dominant treatment strategy using ACR70 criteria. CONCLUSIONS: Etanercept+MTX was a cost-effective treatment strategy in the base-case scenario; however, the model was sensitive to parameter uncertainties and ACR response criteria. Although Bayesian methods were used to determine transition probabilities, future studies will need to focus on head-to-head comparisons of multiple TNF-α inhibitors to provide valid comparisons. | |
| 23136242 | Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global cl | 2013 Sep 1 | OBJECTIVES: Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA). METHODS: Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme. RESULTS: As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years' follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed. CONCLUSIONS: This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation. | |
| 21906492 | Cutaneous melanoma in patients in treatment with biological therapy: review of the literat | 2011 Aug 15 | Herein we report a case of a melanoma arising in a patient receiving adalimumab and methotrexate for rheumatoid arthritis. A limited number of studies reported melanoma growth in patients undergoing treatment with biologics. This case report with a brief review of literature suggests that patients under treatment with biologics should be counseled to identify new pigmented lesions or changes in preexisting nevi. Clinicians' collaboration will facilitate recognition and timely diagnosis of early melanoma. If there is any doubt, excision for histological evaluation should be considered. Pending new studies, careful observation is encouraged. | |
| 21647867 | Implementation of a treat-to-target strategy in very early rheumatoid arthritis: results o | 2011 Oct | OBJECTIVE: Clinical remission is the ultimate therapeutic goal in rheumatoid arthritis (RA). Although clinical trials have proven this to be a realistic goal, the concept of targeting at remission has not yet been implemented. The objective of this study was to develop, implement, and evaluate a treat-to-target strategy aimed at achieving remission in very early RA in daily clinical practice. METHODS: Five hundred thirty-four patients with a clinical diagnosis of very early RA were included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Treatment adjustments were based on the Disease Activity Score in 28 joints (DAS28), aiming at a DAS28 of <2.6 (methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with biologic agents in case of persistent disease activity). The primary outcome was disease activity after 6 months and 12 months of followup, according to the DAS28, the European League Against Rheumatism (EULAR) response criteria, and the modified American College of Rheumatology (ACR) remission criteria. Secondary outcomes were time to first DAS28 remission and outcome of radiography. RESULTS: Six-month and 12-month followup data were available for 491 and 389 patients, respectively. At 6 months, 47.0% of patients achieved DAS28 remission, 57.6% had a good EULAR response, and 32.0% satisfied the ACR remission criteria. At 12 months, 58.1% of patients achieved DAS28 remission, 67.9% had a good EULAR response, and 46.4% achieved ACR remission. The median time to first remission was 25.3 weeks (interquartile range 13.0-52.0). The majority of patients did not have clinically relevant radiographic progression after 1 year. CONCLUSION: The successful implementation of this treat-to-target strategy aiming at remission demonstrated that achieving remission in daily clinical practice is a realistic goal. | |
| 22390484 | Twelve years' experience with etanercept in the treatment of rheumatoid arthritis: how it | 2012 Mar | Etanercept is approved for the treatment of patients with moderate-to-severe active rheumatoid arthritis (RA), polyarticular juvenile RA, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. Randomized clinical trials have shown that it improves the signs and symptoms of early and long-standing RA and other inflammatory arthritides, prevents radiographic progression and improves the patients' health-related quality of life. It is more effective when combined with methotrexate than alone. It is generally well tolerated, and seems to be relatively safe in the short term, as confirmed by clinical trials, long-term observational studies and postmarketing surveillance over 12 years' use in clinical practice. It slightly increases the risk of serious infections. The incidence of malignancies during clinical trials and postmarketing surveillance is no different from that expected in the general population, except for the greater frequency of lymphoma. However, this is closely related to current RA activity and therefore suggests that it is not directly related to the drug. This article considers the published data in terms of clinical practice and changes in the progression of RA. | |
| 22463799 | TNF-alpha antagonism and cancer risk in rheumatoid arthritis: is continued vigilance warra | 2012 Mar | Rheumatoid arthritis (RA) is a chronic, systemic inflammatory arthritis that can lead to significant damage and dysfunction of involved joints. Prior to 1998, treatment options were limited to disease modifying anti-rheumatic drugs, commonly referred to as DMARDs like methotrexate, sulfasalazine, hydroxychloroquine, and gold salts. Tumor necrosis factor alpha (TNF-α) is a central cytokine that drives the inflammation in RA; hence inhibition of TNF-α offers an attractive treatment strategy in RA. The introduction of TNF-α inhibitors, a class of biologic DMARDs, has dramatically changed the treatment of RA as these are highly effective therapies. Medication-related adverse events remain a major problem in health care. This is true of the TNF-α antagonists as well, with particular concerns about increased risks of infections and malignancy. Because clinical trials performed prior to medication approval are limited by the number and clinical complexity of participants and the duration of the trials, post-marketing surveillance is critical in identifying adverse events. In order to better clarify the safety issues related to the use of TNF-α inhibitors in RA, several studies using large observational registries along with pooled meta-analyses of these studies have been published. This review will summarize the data from these recent studies on the question of malignancy risk associated with TNF-α inhibitor use in RA. It is comforting that the data from these studies do not support an increased risk of cancer, except non-melanoma skin cancer, with the use of TNF-α antagonists in adults with RA. | |
| 23055694 | Kinase inhibitors: a new class of antirheumatic drugs. | 2012 | The outlook for patients with rheumatoid arthritis has improved significantly over the last three decades with the use of disease-modifying antirheumatic drugs. However, despite the use of methotrexate, cytokine inhibitors, and molecules targeting T and B cells, a percentage of patients do not respond or lose their response over time. The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. In the past decade, small molecules targeting several kinases, such as p38 MAPK, Syk, and JAK have been developed. Several p38 MAPK inhibitors proved ineffective in treating rheumatoid arthritis. The Syk inhibitor, fostamatinib, proved superior to placebo in Phase II trials and is currently under Phase III investigation. Tofacitinib, a JAK1/3 inhibitor, was shown to be efficacious in two Phase III trials, while VX-509, a JAK3 inhibitor, showed promising results in a Phase II trial. Fostamatinib and tofacitinib were associated with increased rates of infection, elevation of liver enzymes, and neutropenia. Moreover, fostamatinib caused elevations of blood pressure and diarrhea, while tofacitinib was associated with an increase in creatinine and elevation of lipid levels. | |
| 22891404 | Clinical efficacy and adverse effects of golimumab in the treatment of rheumatoid arthriti | 2012 Jun | Golimumab is a fully human monoclonal antibody targeting tumor necrosis factor-alpha (TNFalpha), an important cytokine in the pathogenesis of rheumatoid arthritis (RA) and other arthritides. Golimumab was approved for the treatment of rheumatoid arthritis with methotrexate (MTX) and with or without MTX for psoriatic arthritis and ankylosing spondylitis. Administration is by monthly subcutaneous injection. In this review we present some of the major clinical trials evaluating the efficacy of golimumab with or without concomitant MTX in RA patients, including patients resistant to previous biologic treatments. In addition, we collected data on safety and adverse effects encountered in clinical trials. Current data show golimumab to be an effective and safe choice for the treatment of various inflammatory arthritides. | |
| 22045840 | Biological drug treatment of rheumatoid arthritis and spondyloarthritis: effects on QT int | 2012 Jan | OBJECTIVE: Tumor necrosis factor-α (TNF-α) antagonists bring about significant improvement in chronic inflammatory diseases such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). There is some evidence that they can also have negative myocardial effects, but to date this issue has not been clarified. We evaluated changes in electrocardiographic measures [QT interval, corrected, dispersion, and dispersion corrected (QT, QTc, QTd, QTdc, respectively)] in patients with RA or SpA treated with anti-TNF agents (infliximab and etanercept), those treated with other biological agents (rituximab), and with methotrexate. METHODS: We studied 38 consecutive patients with RA (21 patients) or SpA (19 patients) being treated with TNF-α antagonists, 8 patients with RA being treated with rituximab, and 13 patients (8 with RA and 5 with SpA) taking methotrexate. Electrocardiographs (ECG) were performed on all participants at baseline and 12 months after initiation of treatment, and the QT, QTc, and QTd were calculated with standard procedures. RESULTS: After 12 months of treatment, significant increases over baseline values were observed in the mean QT (p < 0.009), QTd (p < 0.0001), and QTdc (p < 0.0001) of the anti-TNF group, but no significant changes were observed in those taking rituximab. QT changes in the anti-TNF group were unrelated to the disease (RA vs SpA) or drug (infliximab vs etanercept), and none were associated with clinical manifestations of cardiac disease. CONCLUSION: In patients with RA and SpA, TNF-α antagonists seem to increase the QT and QTd measures. Although these changes were completely asymptomatic, ECG may be indicated in patients being considered for anti-TNF therapy to identify those at risk for cardiac complications. | |
| 20950126 | The number needed to treat for second-generation biologics when treating established rheum | 2011 Jan | OBJECTIVE: To evaluate the number needed to treat (NNT) and the number needed to harm (NNH) of the second-generation biologics abatacept, certolizumab, golimumab, rituximab, and tocilizumab in patients with established rheumatoid arthritis (RA) taking concomitant methotrexate (MTX). METHODS: A systematic literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane Register of Controlled Trials was conducted up to 1 November 2009. We selected any published randomized, double-blind, MTX-controlled study including RA patients with a mean disease duration of at least 5 years before entering a pivotal trial on second-generation biological therapy. Studies eligible for inclusion involved patients, who had previously shown inadequate response to conventional disease-modifying anti-rheumatic drug (DMARD) therapy. Pre-specified binary outcomes were extracted with a preference for 1-year data (6-month data were used if no data were available for 1 year). Two reviewers independently extracted the data necessary to estimate the absolute measures in a non-responder intention-to-treat (ITT) analysis. RESULTS: Five randomized controlled trials, one for each of the drugs, were selected and data extracted according to published data at endpoint for American College of Rheumatology 50% (ACR50)-responding patients, and withdrawals due to adverse events. NNT ranged from four to six treated patients to achieve one ACR50 response, while withdrawals due to adverse events were few and non-significant compared to the placebo group, except for rituximab administered as 1000 mg. CONCLUSION: Comparable efficacy was shown by the five biological agents studied, with few adverse events. However, for rituximab, tocilizumab, and golimumab, only 6-month data were available, hampering the external validity with regard to long-term efficacy and tolerability. A low dose (500 mg) of rituximab may be as effective as the recommended dose of 1000 mg. | |
| 21478189 | Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of | 2011 Jul | OBJECTIVES: To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). METHODS: Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). RESULTS: In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 μg/ml) at 3 and 6 mg/kg but were greater than 2 μg/ml at 10 mg/kg, whereas the levels were approximately 1 μg/ml for each dosage group in TNF-low patients. CONCLUSION: In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab. | |
| 22281228 | Progressive multifocal leukoencephalopathy in autoimmune diseases. | 2012 Jul | Progressive multifocal leukoencephalopathy (PML) is a subacute central nervous system infection due to reactivation of the JC virus. Most reported cases occurred in HIV-infected patients (80% of cases), patients with lymphoid malignancies (13%) and transplant recipients taking immunosuppressants (5%). Less often, PML has been described in patients with chronic inflammatory joint diseases associated with autoimmune disorders (lupus, rheumatoid arthritis [RA] and vasculitis) (2%). Magnetic resonance imaging of the brain shows suggestive changes and confirmation of the diagnosis is obtained by performing PCR tests to identify the JC virus in the cerebrospinal fluid or, when necessary, a brain biopsy. No treatments have been proven effective. Most patients experience progressive disease that is fatal within a few months or induces incapacitating neurological impairments. The risk of PML is 0.4/100,000 in patients with RA. In the few case-reports of PML in RA patients, the treatments used included methotrexate (five cases) combined with a biological agent such as infliximab (one case), rituximab (four cases), or leflunomide (two cases including one with concomitant rituximab). PML is an extremely rare but devastating complication. Rituximab therapy is associated with an increased prevalence of PML in RA patients (4/100,000), who should be informed of this risk. In patients with lupus, the risk of PML is higher than in RA (4/100,000) and 40% of cases of PML occur during low-dose glucocorticoid therapy without immunosuppressive therapy. | |
| 21618198 | Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK. | 2011 Sep | OBJECTIVE: Low-dose methotrexate (MTX) is an effective therapy for rheumatoid arthritis (RA), yet its mechanism of action is incompletely understood. The aim of this study was to explore the induction of apoptosis by MTX. METHODS: Flow cytometry was performed to assess changes in the levels of intracellular proteins, reactive oxygen species (ROS), and apoptosis. Quantitative polymerase chain reaction was performed to assess changes in the transcript levels of select target genes in response to MTX. RESULTS: MTX did not directly induce apoptosis but rather "primed" cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways, by a JNK-dependent mechanism. Increased sensitivity to apoptosis was mediated, at least in part, by MTX-dependent production of ROS, JNK activation, and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocked these MTX-induced effects. Patients with RA who were receiving low-dose MTX therapy expressed elevated levels of the JNK target gene, jun. CONCLUSION: Our results support a model whereby MTX inhibits reduction of dihydrobiopterin to tetrahydrobiopterin, resulting in increased production of ROS, increased JNK activity, and increased sensitivity to apoptosis. The finding of increased jun levels in patients with RA receiving low-dose MTX supports the notion that this pathway is activated by MTX in vivo and may contribute to the efficacy of MTX in inflammatory disease. | |
| 21441823 | Hydroxychloroquine use and decreased risk of diabetes in rheumatoid arthritis patients. | 2011 Apr | BACKGROUND/OBJECTIVES: Several studies have associated hydroxychloroquine use with decreased risk of diabetes mellitus (diabetes) or improved glycemic control in rheumatoid arthritis patients, but the studies were small or used data from self-report. The present study sought to replicate this protective relationship in a health system using electronic health records with laboratory data and physician diagnoses. METHODS: This study is a retrospective cohort of 1127 adults with newly diagnosed rheumatoid arthritis and no diabetes within the Geisinger Health System between January 1, 2003, and March 31, 2008. Patients were classified as ever users (n = 333) or never users (n = 794) of hydroxychloroquine. Incident diabetes cases were defined using 2010 American Diabetes Association criteria. RESULTS: The median follow-up times for the ever and never hydroxychloroquine users were 26.0 and 23.0 months, respectively (P = 0.28). The median duration of hydroxychloroquine exposure was 14.0 months. Of the 48 cases developing diabetes during observation, 3 were exposed to hydroxychloroquine at time of development and 45 were nonexposed, yielding incidence rates of 6.2 and 22.0 per 1000 per year (P = 0.03), respectively. In time-varying Cox proportional hazards regression models adjusting for sex, age, body mass index, positive rheumatoid factor and anti-cyclic citrullinated peptide antibodies, erythrocyte sedimentation rate, and nonsteroidal anti-inflammatory drug, glucocorticoid, methotrexate, and tumor necrosis factor α inhibitor use, the hazard ratio for incident diabetes among hydroxychloroquine users was 0.29 (95% confidence interval, 0.09-0.95; P = 0.04) compared with nonusers. CONCLUSIONS: Our findings support the potential benefit of hydroxychloroquine in attenuating the risk of diabetes in rheumatoid arthritis patients. Further work is needed to determine its potential preventive role in other groups at high risk for diabetes. | |
| 21917824 | Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthr | 2012 Jan | OBJECTIVES: To assess the effect of a temporary interruption in subcutaneous (SC) abatacept on immunogenicity, safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial. METHODS: Following a 12-week open-label introduction (period I; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg), patients were randomised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks (period II). At the end of period II, patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept (12-week open-label period III). The co-primary end points were ELISA-detected immunogenicity rate and safety at the end of period II. Efficacy was also monitored. RESULTS: Of 167 patients entering period I, 72% qualified for period II; during periods II and III, three patients discontinued treatment. Mean (SD) disease duration was 6.6 (6.5) years and Disease Activity Score 28 was 4.8 (0.8). The primary end point was met, with a non-significant increase in immunogenicity upon withdrawal (7/73 placebo vs 0/38 abatacept in period II; p=0.119) which was reversed upon reintroduction of SC abatacept (2/73 vs 1/38, end period III). Safety was comparable regardless of withdrawal, with no unexpected events upon reintroduction. Two patients experienced reactions at the SC injection site. On withdrawal, patients experienced slight worsening in efficacy which improved following reintroduction. CONCLUSIONS: Overall immunogenicity to SC abatacept is low, consistent with intravenous abatacept, and is not significantly affected by a 3-month interruption and reintroduction. This stop-start schedule was well tolerated, with little impact on safety and efficacy. These are important considerations for the clinical use of SC abatacept. CLINICALTRIALS: gov Identifier NCT00533897. | |
| 21211590 | The cellular immune response to influenza vaccination is preserved in rheumatoid arthritis | 2011 Feb 11 | OBJECTIVES: Yearly vaccination against influenza is currently recommended to patients with rheumatoid Arthritis (RA). Antibody and cell-mediated responses are both involved in the defense against influenza. Humoral responses to influenza vaccine are impaired in RA patients treated with rituximab (RTX). The objectives of this study were to comparatively assess cell mediated and humoral responses to influenza vaccination in RA patients with or without RTX-induced CD20 B-cell depletion. METHODS: Trivalent influenza subunit vaccine was administered to 46 RA patients and to 16 healthy controls. The RA group included 29 patients treated by RTX and 17 on conventional disease-modifying anti-rheumatic drugs (DMARDs), mostly methotrexate. Peripheral blood mononuclear cells and sera were obtained immediately before and 4-6 weeks after vaccination. Cell-mediated response to influenza antigens was evaluated by flow cytometry for activated CD4 T-cells. Humoral response was evaluated by haemagglutination inhibition assay. RESULTS: Cellular response: Cell-mediated responses were comparable in RTX-treated vs. DMARDs-treated patients. The recall postvaccination CD4+ cellular response was similar in RA patients and healthy controls. A positive correlation was found between CD19+ cell count on the day of vaccination and cellular response in RTX-treated RA patients. Humoral response: The antibody response rate was significantly impaired in the RTX group: being 26.4%, 68.4% and 47.1% in RTX-treated, DMARDs-treated and controls, respectively. CONCLUSION: Cellular immunity to influenza vaccination in RTX-treated patients was similar to DMARDs-treated patients and healthy controls, while humoral immunity was severely impaired. The preservation of cellular immunity may explain the relatively low rate of infection among B-cell depleted patients. |