Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra, rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.     

Evidence for early disease-modifying drugs in rheumatoid arthritis

Some research evidence supports early aggressive treatment of rheumatoid arthritis (RA) using combination therapy with two or more disease modifying anti-rheumatic drugs (DMARDs) plus steroids, or even DMARDs plus an anti-TNF. By contrast, conservatively delayed DMARD monotherapy, given after non-steroidal anti-inflammatory drugs have failed, has been criticised. However, recent long-term studies highlight the complexities in evaluating whether to abandon pyramidal treatment in favour of early DMARDs. Although patients given early DMARD therapy show short-term benefits, longer-term results show no prolonged clinical advantages from early DMARDs. By 5 years patients receiving early DMARDs had similar disease activity and comparable health assessment questionnaire scores to patients who received DMARDs later in their disease course. X-ray progression was persistent and virtually identical in both groups. These negative findings do not invalidate the case for early DMARD therapy, as it is gives sustained reductions in disease activity in the early years of treatment without excessive risks from adverse effects. However, early DMARDs alone do not adequately control RA in the longer term. This may require starting with very aggressive therapy or treating patients more aggressively after early DMARD therapy has been initiated.     

Evidence for early disease-modifying drugs in rheumatoid arthritis

Some research evidence supports early aggressive treatment of rheumatoid arthritis (RA) using combination therapy with two or more disease modifying anti-rheumatic drugs (DMARDs) plus steroids, or even DMARDs plus an anti-TNF. By contrast, conservatively delayed DMARD monotherapy, given after non-steroidal anti-inflammatory drugs have failed, has been criticised. However, recent long-term studies highlight the complexities in evaluating whether to abandon pyramidal treatment in favour of early DMARDs. Although patients given early DMARD therapy show short-term benefits, longer-term results show no prolonged clinical advantages from early DMARDs. By 5 years patients receiving early DMARDs had similar disease activity and comparable health assessment questionnaire scores to patients who received DMARDs later in their disease course. X-ray progression was persistent and virtually identical in both groups. These negative findings do not invalidate the case for early DMARD therapy, as it is gives sustained reductions in disease activity in the early years of treatment without excessive risks from adverse effects. However, early DMARDs alone do not adequately control RA in the longer term. This may require starting with very aggressive therapy or treating patients more aggressively after early DMARD therapy has been initiated.     

Effect of Combination Therapy on Joint Destruction in Rheumatoid Arthritis: A Network Meta-Analysis of Randomized Controlled Trials

Background

Despite significant cost differences, the comparative effect of combination treatments of disease modifying anti-rheumatic drugs (DMARDs) with and without biologic agents has rarely been examined. Thus we performed a network meta-analysis on the effect of combination therapies on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA).

Methods and Findings

The following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine, azathioprin, penicillamin) or 1 DMARD plus low dose glucocorticoid (LDGC); triple DMARD: 3 DMARDs or 2 DMARDs plus LDGC; biologic combination: 1 DMARD plus biologic agent (tumor necrosis factor α inhibitor (TNFi) or abatacept or tocilizumab or CD20 inhibitor (CD20i)). Randomized controlled trials were identified in a search of electronic archives of biomedical literature and included in a star-shaped network meta-analysis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. Effects are reported as standardized mean differences (SMD). The effects of data from 39 trials published in the period 1989–2012 were as follows: Double DMARD: −0.32 SMD (CI: −0.42, −0.22); triple DMARD: −0.46 SMD (CI: −0.60, −0.31); 1 DMARD plus TNFi: −0.30 SMD (CI: −0.36, −0.25); 1 DMARD plus abatacept: −0.20 SMD (CI: −0.33, −0.07); 1 DMARD plus tocilizumab: −0.34 SMD (CI: −0.48, −0.20); 1 DMARD plus CD20i: −0.32 SMD (CI: −0.40, −0.24). The indirect comparisons showed similar effects between combination treatments apart from triple DMARD being significantly better than abatacept plus methotrexate (−0.26 SMD (CI: −0.45, −0.07)) and TNFi plus methotrexate (−0.16 SMD (CI: −0.31, −0.01)).

Conclusion

Combination treatment of a biologic agent with 1 DMARD is not superior to 2–3 DMARDs including or excluding LDGC in preventing structural joint damage. Future randomized studies of biologic agents should be compared versus a combination of DMARDs.     

The supplementary therapeutic DMARD role of low-dose glucocorticoids in rheumatoid arthritis

The management of rheumatoid arthritis (RA) is primarily based on the use of disease-modifying antirheumatic drugs (DMARDs), mainly comprising synthetic chemical compounds (that is, methotrexate or leflunomide) and biological agents (tumor necrosis factor inhibitors or abatacept). On the other hand, glucocorticoids (GCs), used for decades in the treatment of RA, are effective in relieving signs and symptoms of the disease, but also interfere with radiographic progression, either as monotherapy or in combination with conventional synthetic DMARDs. GCs exert most of their biological effects through a genomic action, using the cytosolic GC receptor and then interacting with the target genes within target cells that can result in increased expression of regulatory - including anti-inflammatory - proteins (transactivation) or decreased production of proinflammatory proteins (transrepression). An inadequate secretion of GCs from the adrenal gland, in relation to stress and inflammation, seems to play an important role in the pathogenesis and disease progression of RA. At present there is clear evidence that GC therapy, especially long-term low-dose treatment, slows radiographic progression by at least 50% when given to patients with early RA, hence satisfying the conventional definition of a DMARD. In addition, long-term follow-up studies suggest that RA treatment strategies which include GC therapy may favorably alter the disease course even after their discontinuation. Finally, a low-dose, modified night-release formulation of prednisone, although administered in the evening (replacement therapy), has been developed to counteract the circadian (night) rise in proinflammatory cytokine levels that contributes to disease activity, and might represent the way to further optimize the DMARD activity exerted by GCs in RA.     

Effective use of TNF antagonists

Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment, combined with the availability of the anti-TNF agents, has contributed to a shift in treatment paradigms favoring the early and timely use of DMARDs with biologic therapies. Improvement in symptom control does not always equate to a reduction in disease progression or disability. With the emergence of structure-related outcome measures as the primary means for assessing the effectiveness of antirheumatic agents, the regular use of X-rays is recommended for the continued monitoring and evaluation of patients. In addition to the control of symptoms and improvement in physical function, a reduction in erosions and joint-space narrowing should be considered among the goals of therapy, leading to a better quality of life. Adherence to therapy is an important element in optimizing outcomes. Durability of therapy with anti-TNF agents as reported from clinical trials can also be achieved in the clinical setting. Concomitant methotrexate therapy might be important in maintaining TNF antagonist therapy in the long term. Overall, the TNF antagonists have led to improvements in clinical and radiographic outcomes in patients with RA, especially those who have failed to show a complete response to methotrexate.     

A new paradigm of quality of care in rheumatoid arthritis: how our new therapeutics have changed the game

Demonstrating the effectiveness of expensive new rheumatoid arthritis (RA) therapeutics is imperative to determine whether the quality of care has improved with the introduction of these agents. Our current RA quality measures are primarily process based, but they must become outcomes based to better demonstrate quality. New RA quality measures must be multidimensional, accounting for all of the important outcomes in RA: radiographic, functional status, and disease activity. To fully understand the potential benefits of new therapeutics in RA, outcome measures must be integrated with routine practice.New medications for rheumatoid arthritis (RA), combined with early, aggressive treatment strategies, have improved care. New biologic and small molecule therapies come with a hefty price tag, and demonstrating effectiveness is increasingly important: is the quality of care actually better for RA patients with newer therapies?To answer this question, we must first define quality. As described by the Institute of Medicine, quality of care is ''the degree to which healthcare services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge’ [1]. Quality of care can be evaluated using quality measures, which are tools that provide the ability to quantify an aspect of healthcare relative to an established criterion [2]. Other facets of quality include patient satisfaction and access to care. Quality of care in RA is currently largely based on the use of process-based quality measures. For example: the frequency of disease-modifying anti-rheumatic drug (DMARD) prescribing in RA; the use of disease activity and functional status measures in routine practice; and laboratory monitoring frequency according to established recommendations. These RA quality measures are primarily derived from the Arthritis Foundation Starter Set and the Physician Quality Reporting Database RA measure set, but the American College of Rheumatology is actively developing a new RA measure set [3]. Although the current RA quality measures provide a reasonable starting point, they do not fully capture the spectrum of care quality for patients with RA in the United States.Measures of quality of care are evolving to include concepts such as clinical outcomes. Some even argue that our primary goal should be to provide value: the health outcomes achieved per dollar spent [4]. This newer model incorporates the total cost of providing care to patients for a specific condition over a defined time period, relative to the health outcome achieved. For example, in RA the total cost of care would include nonbiologic and biologic DMARDs, office visits, physical therapy and inpatient hospitalizations. But the real question is how to best define outcomes in a chronic, complex condition such as RA? Outcomes can be multidimensional, accounting for all facets of care for a RA patient: radiographic progression, improvement in functional status score, or a decrease in disease activity score. Radiographic progression is often discussed as an important outcome in randomized controlled trials of RA therapeutics, but it is not a routine part of clinical practice. Measurement of functional status using a standardized, validated instrument is an important patient-reported outcome, capturing key information about how RA impacts activities of daily living. Patient-reported outcomes are not used regularly in many busy, office practices despite the correlation with disease outcomes and mortality [5,6].While professional groups such as the American College of Rheumatology have made recommendations on the measurement of disease activity through the use of tools such as the Disease Activity Score-28, the Clinical Disease Activity Index, or the Routine Assessment of Patient Disease Activity 3, documenting sustained low disease activity or remission requires multiple measurements [7]. Encouraging rheumatologists to treat to target and moving patients from high disease activity to remission is just one dimension of RA outcomes. Each potential clinical outcome has strengths and limitations and probably cannot serve as a standalone measure, but taken together they provide a more nuanced portrait of RA quality of care.Moving from thinking about quality measures as process based to outcomes based is a significant challenge. To achieve good outcomes in RA using the new therapeutics in RA, one needs to consider the timing of therapy, the duration of treatment, and the co-existence of other medical conditions. Some patients may delay initiation of DMARD therapy due to fear of toxicity or lack of understanding of the risk/benefit profile; other patients may not be fully adherent to the treatment plan due to financial issues, socioeconomic factors or language barriers; and still others may not have access to rheumatology care until after they have sustained radiographic or functional damage from their RA. Since quality is often measured at the level of the rheumatologist, how do we risk adjust for these complex patient-related factors when evaluating outcomes in RA? Some rheumatologists see tertiary-care referral patients with longer disease duration, more treatment failures, and multiple co-morbidities. Developing appropriate case-mix adjustment tools to allow for meaningful comparison across providers is a huge task. We have learned that even for a simple quality measure such as whether RA patients receive a DMARD, this case-mix adjustment matters. When evaluating the quality measure on receipt of DMARDs for patients with RA, case-mix adjustment identified age, race and socioeconomic status as negative predictors of DMARD receipt [8].Even though the road will be tough, we must determine how to best measure outcomes in RA to assess quality of care. The expenditures associated with biologic treatments raise important questions for how to demonstrate the effectiveness of medications for RA. However, there are emerging data on RA patients remaining in remission with fewer doses or even cessation of biologic drugs, raising the possibility that we can improve value for patients by simultaneously achieving good health outcomes and decreasing the overall cost of care [9]. An important first step to showing that new therapeutics are translating into better quality of care is incorporating the use of quantitative measurement of disease activity and functional status into routine clinical practice. By regularly measuring possible RA outcome measures, such as disease activity and functional status, we can identify patients who are achieving poor outcomes and create strategies to re-design care delivery for those patients. For example, the use of intensive nurse outreach between regularly scheduled rheumatologist visits to document medication adherence, side effects and education may improve outcomes faster and facilitate treating to target. Developing clinical risk-adjustment tools for RA can help offset differences in patient case mix among rheumatologists.However, measuring outcomes presents major challenges for the healthcare system in general. Collecting structured data to allow quality assessment is not routine in many practices and would place new burdens on the already stressed healthcare system, adding costs and frustration. Furthermore, accurately assessing quality of care requires adjusting for case-mix severity. This is especially true if outcomes become the focus of quality assessment. Collecting the dataset required for case-mix adjustment further taxes the healthcare provider. In addition, there are unanswered questions that remain: what is the current natural history of RA if diagnosed early and treated aggressively with combination nonbiologic and biologic DMARDs? To fully achieve the potential benefits of new therapeutics in RA, we first need RA quality measures that incorporate outcomes and these need to be easily integrated into typical practice.     

Early combination disease-modifying antirheumatic drug therapy and tight disease control improve long-term radiologic outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish Rheumatoid Arthritis Combination Therapy trial

Introduction  

Early treatment of rheumatoid arthritis (RA) has been shown to retard the development of joint damage for a period of up to 5 years. The aim of this study was to evaluate the radiologic progression beyond that time in patients with early RA initially treated with a combination of three disease-modifying antirheumatic drugs (DMARDs) or a single DMARD.     

Derivation and preliminary validation of an administrative claims-based algorithm for the effectiveness of medications for rheumatoid arthritis

Introduction

Administrative claims data have not commonly been used to study the clinical effectiveness of medications for rheumatoid arthritis (RA) because of the lack of a validated algorithm for this outcome. We created and tested a claims-based algorithm to serve as a proxy for the clinical effectiveness of RA medications.

Methods

We linked Veterans Health Administration (VHA) medical and pharmacy claims for RA patients participating in the longitudinal Department of Veterans Affairs (VA) RA registry (VARA). Among individuals for whom treatment with a new biologic agent or nonbiologic disease-modifying agent in rheumatic disease (DMARD) was being initiated and with registry follow-up at 1 year, VARA and administrative data were used to create a gold standard for the claims-based effectiveness algorithm. The gold standard outcome was low disease activity (LDA) (Disease Activity Score using 28 joint counts (DAS28) ≤ 3.2) or improvement in DAS28 by > 1.2 units at 12 ± 2 months, with high adherence to therapy. The claims-based effectiveness algorithm incorporated biologic dose escalation or switching, addition of new disease-modifying agents, increase in oral glucocorticoid use and dose as well as parenteral glucocorticoid injections.

Results

Among 1,397 patients, we identified 305 eligible biologic or DMARD treatment episodes in 269 unique individuals. The patients were primarily men (94%) with a mean (± SD) age of 62 ± 10 years. At 1 year, 27% of treatment episodes achieved the effectiveness gold standard. The performance characteristics of the effectiveness algorithm were as follows: positive predictive value, 76% (95% confidence interval (95% CI) = 71% to 81%); negative predictive value, 90% (95% CI = 88% to 92%); sensitivity, 72% (95% CI = 67% to 77%); and specificity, 91% (95% CI = 89% to 93%).

Conclusions

Administrative claims data may be useful in evaluating the effectiveness of medications for RA. Further validation of this effectiveness algorithm will be useful in assessing its generalizability and performance in other populations.     

Safety of biologic and nonbiologic disease-modifying antirheumatic drug therapy in veterans with rheumatoid arthritis and hepatitis B virus infection: a retrospective cohort study

IntroductionWe evaluated the safety of current treatment regimens for patients with RA and HBV in a large US cohort.MethodsWe identified biologic and nonbiologic treatment episodes of RA patients using 1997 to 2011 national data from the US Veterans Health Administration. Eligible episodes had evidence of HBV infection (HBV surface antigen, HBV core antibody, HBV e-antibody and/or HBV DNA) and had a baseline alanine aminotransferase (ALT) <1.5 times the upper limit of laboratory normal within 90 days prior to initiation of a new biologic or nonbiologic DMARD. The main outcome of interest was hepatotoxicity, defined as ALT elevation >100 IU/mL. Results were reported as the cumulative incidence of treatment episodes achieving hepatotoxicity at 3, 6 and 12 months post biologic exposure.ResultsFive hundred sixty-six unique RA patients with HBV contributed 959 treatment episodes. Mean age was 62.1 ± 10.3 years; 91.8% were male. Hepatotoxicity was uncommon, with 26 events identified among 959 episodes (2.7%) within 12 months. Hepatotoxicity was comparable between biologic and nonbiologic DMARDs (2.6% vs. 2.8%, P = 0.87). The median time between HBV screening and starting a new RA drug was 504 days (IQR 144, 1,163). Follow-up HBV testing occurred among 14 hepatotoxicity episodes (53.8%) at a median of 202 days (IQR 82, 716) from the date of ALT elevation. A total of 146 (15.2%) treatment episodes received at least one test for HBV DNA at any point in the observation period.ConclusionsAmong US veterans with RA and HBV the risk of hepatotoxicity is low (2.7%), and comparable between biologic and nonbiologic DMARDS (2.8% vs. 2.6%, P = 0.87). HBV testing associated with DMARD initiation or hepatotoxicity was infrequent.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0628-z) contains supplementary material, which is available to authorized users.     

B淋巴细胞表面分子靶向治疗类风湿关节炎的研究进展

类风湿关节炎(rheumatoid arthritis,RA)是一种慢性、系统性的自身免疫性疾病,迄今病因尚不明确,且缺乏针对其安全有效的治疗药物.由于B淋巴细胞在RA致病机制中的重要作用,近年来不断有针对B淋巴细胞上不同靶点的治疗药物推出.这些B淋巴细胞靶向生物制剂包括针对CD20分子的抗CD20单克隆抗体,如rituximab、ocrelizumab和ofatumumab等;针对B淋巴细胞刺激因子(B lymphocyte stimulator,BLyS)及其受体的belimumab和atacicept等以及处于初期研究阶段的抗CD22单克隆抗体和B、T淋巴细胞之间CD40/CD40L共刺激反应阻断剂等.上述靶向制剂的疗效在对RA及其动物模型的治疗中得到了证实,提示将B淋巴细胞作为RA治疗靶点是一项非常有前景的治疗策略.     

Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months

Introduction  

Rheumatoid arthritis (RA) is associated with changes in body composition and bone mineral density (BMD). The purpose of the present study was to evaluate whether anti-TNF treatment in early RA has an impact on body composition and BMD besides that which could be achieved by intensive disease-modifying anti-rheumatic drug (DMARD) combination therapy.     

A longitudinal study of rheumatoid arthritis in South Africans

Little is known about the functional outcome of rheumatoid arthritis (RA) in Africans treated with disease-modifying antirheumatic drugs (DMARDs). We describe our experience with 182 RA patients seen at a tertiary hospital in South Africa. During the median follow-up period of 3.3 years, the proportion of patients with severe functional disability (American College of Rheumatology [ACR] functional classes [FCs] 3 and 4) declined significantly from 48.9% at presentation to 30.8% at last visit (P =.0006). There was a significant fall in the median Westergren erythrocyte sedimentation rate (ESR) (46-28 mm/hour, P <.00001) and C-reactive protein (CRP) (19-15.5 mg/L, P =.006) over this period. Logistic regression analysis showed that the factors that negatively affected functional outcome at last visit were severe functional disability at presentation (odds ratio [OR] = 4.1, P =.0004), delay in referral for specialist care > 2 years (OR = 3.1, P =.02), and ESR at last visit > 28 mm/hour (OR = 3.2, P =.002). DMARDs and oral corticosteroids were prescribed in 93.1% of patients at presentation and 60.4% of patients at last visit. Life-table analysis showed that the survival time with methotrexate (MTX) use was significantly longer compared with the other DMARDs (P =.0002). A total of only 37 surgical procedures were performed on 21 patients. This retrospective study shows that despite the late presentation and severe disease, patients do improve on DMARD therapy in the medium term. The study highlights the need for prospective studies to assess the efficacy and safety of DMARDs, particularly in early disease, in the developing countries where biologics are unlikely to be affordable in the foreseeable future.     

Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study

Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.     

Plasma Levels of IL-37 and Correlation with TNF-α, IL-17A,and Disease Activity during DMARD Treatment of Rheumatoid Arthritis

The aim of this study was to assess the change of IL-37 concentrations in rheumatoid arthritis (RA) patients under Disease-modifying anti-rheumatic drug (DMARD) therapy, and to establish a correlation between Interleukin-37 and pro-inflammatory cytokines in plasma and disease activity. The plasma level of IL-37 was determined using ELISA in 50 newly diagnosed RA patients and 30 healthy controls (HC). Plasma levels of IL-17A, IL-6 and TNF-α were measured using flow a cytometric bead array assay. We found that the concentrations of IL-37, as well as IL-17A, IL-6 and TNF-α, were higher in plasma of RA patients compared to HCs. Compared to patients who did not respond to DMARD treatment, treatment of patients responsive to DMARDs resulted in down-regulation of IL-17A, IL-6 and TNF-α expression. The plasma level of the anti-inflammatory cytokine IL-37 was also decreased in drug responders after DMARD treatment. The plasma level of IL-37 in RA patients was positively correlated with pro-inflammatory cytokines (IL-17A, TNF-α) and disease activity (CRP, DAS28) in RA patients. IL-37 expression in RA and during DMARD treatment appears to be controlled by the level of pro-inflammatory cytokines. This results in a strong correlation between plasma levels of IL-37 and disease activity in RA patients.     

Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low--results from RABBIT, the German biologics register

We investigated the frequency of remission according to the disease activity score (DAS28) definition, modified American Rheumatology Association (ARA) criteria, and the frequency of an achievement of a functional status above defined thresholds ('functional remission', 'physical independence') in rheumatoid arthritis (RA) patients treated with either biologics or conventional DMARDs. We used the data of a prospective cohort study, the German biologics register RABBIT (German acronym for Rheumatoid Arthritis--Observation of Biologic Therapy) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics (BIOL; n = 818) or a conventional DMARD (n = 265). Logistic regression analysis was applied to adjust for differences in baseline risks. Taking risk indicators such as previous DMARD failures or baseline clinical status into account, we found that biologics doubled the chance of remission compared to conventional DMARD therapies (DAS28 remission, adjusted odds ratio (OR) 1.95 (95% confidenece interval (CI) 1.2-3.2)); ARA remission, OR 2.05 (95% CI 1.2-3.5)). High remission rates (DAS28 remission, 30.6%; ARA remission, 16.9%) were observed in BIOL patients with a moderate disease activity (DAS28, 3.2 to 5.1) at the start of treatment. These rates decreased to 8.5% in patients with DAS28 > 6. Sustained remission at 6 and 12 months was achieved in <10% of the patients. Severely disabled patients (< or = 50% of full function) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence (> or = 67% of full function) than controls (OR 3.88 (95% CI 1.7-8.8)). 'Functional remission' (> or = 83% of full function) was more often achieved in BIOL than in controls (OR 2.18 (95% CI 1.04-4.6)). In conclusion, our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence. However, temporary or even sustained remission remain ambitious aims, which are achieved in a minority of patients only.     

Do anti-TNF agents have equal efficacy in patients with rheumatoid arthritis?

Tumor necrosis factor (TNF) antagonists have dramatically improved the outcomes of rheumatoid arthritis (RA). Three agents currently available in the USA--infliximab, etanercept, and adalimumab--have been designed to modify the biologic effects of TNF. Infliximab and adalimumab are monoclonal antibodies, and etanercept is a soluble protein. The pharmacokinetic and pharmacodynamic properties of each differs significantly from those of the others. All three agents are effective and safe, and can improve the quality of life in patients with RA. Although no direct comparisons are available, clinical trials provide evidence that can be used to evaluate the comparative efficacy of these agents. Infliximab, in combination with methotrexate, has been shown to relieve the signs and symptoms of RA, decrease total joint score progression, prevent joint erosions and joint-space narrowing, and improve physical function for up to 2 years. Etanercept has been shown to relieve the signs and symptoms of RA, decrease total joint score progression, and slow the rate of joint destruction, and might improve physical function. Etanercept is approved with and without methotrexate for patients who have demonstrated an incomplete response to therapy with methotrexate and other disease-modifying anti-rheumatic drugs (DMARDs), as well as for first-line therapy in early RA, psoriatic arthritis, and juvenile RA. Adalimumab relieves the signs and symptoms of RA with and without methotrexate and other DMARDs, decreases total joint score progression, prevents joint erosions and joint-space narrowing in combination with methotrexate, and might improve physical function. When selecting a TNF antagonist, rheumatologists should weigh evidence and experience with specific agents before a decision is made for use in therapy.     

Approaches to the therapy of rheumatoid arthritis

The treatment of RA is generally empirical. While there are many effective agents available, there are no agents that are curative. Progressive disease is frequently seen even in patients who are responsive to current therapies. Newer, more effective therapies are needed. The most promising area for new treatments appears to be specific biologic approaches with monoclonal antibodies or stimulants or inhibitors of lymphocytokines.     

Aspects of early arthritis. Traditional DMARD therapy: is it sufficient?

There is increasing evidence for beneficial effects of early DMARD (disease-modifying antirheumatic drug) therapy over delayed treatment in patients who present with arthritis of recent onset. However, no universal consensus exists concerning the choice of initial drug or whether single drugs or combinations should be given as initial treatments. Recent studies have focused on the benefits of various strategies in which treatments were tailored to achieve low levels of disease activity, as assessed using validated response criteria. These studies demonstrated superiority of 'aggressive' over 'conventional' approaches. Whether the inclusion of tumour necrosis factor antagonists or other biologic targeted therapies in such strategies confers additional benefits in terms of improved long-term outcomes must be clarified by further studies. Assessment of risks in the individual patient, allowing individual 'tailoring' of the initial treatment, would be desirable.