Andrew J. K. Östör

The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review

OBJECTIVES Patients with RA have an increased prevalence of cardiovascular disease (CVD). This is due to traditional risk factors and the effects of chronic inflammation. MTX is the first-choice DMARD in RA. We performed a systematic literature review to determine whether MTX affects the risk of CVD in patients with RA. METHODS We searched Medline, Embase, Cochrane database, database of abstracts of reviews of effects, health technology assessment and Science Citation Index from 1980 to 2008. Conference proceedings (British Society of Rheumatology, ACR and EULAR) were searched from 2005 to 2008. Papers were included if they assessed the relationship between MTX use and CVD in patients with RA. Two reviewers independently assessed each title and abstract for relevance and quality. RESULTS A total of 2420 abstracts were identified, of which 18 fulfilled the inclusion criteria. Two studies assessed the relationship between MTX use and CVD mortality, one demonstrated a significant reduction in CVD mortality and the second a trend towards reduction. Five studies considered all-cause CVD morbidity. Four demonstrated a significant reduction in CVD morbidity and the fifth a trend towards reduction. MTX use in the year prior to the development of RA decreased the risk of CVD for 3-4 years. Four studies considered myocardial infarction, one demonstrated a decreased risk and three a trend towards decreased risk with MTX use. CONCLUSION The current evidence suggests that MTX use is associated with a reduced risk of CVD events in patients with RA. This suggests that reducing the inflammation in RA using MTX not only improves disease-specific outcomes but may also reduce collateral damage such as atherosclerosis.

Tumour necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review

OBJECTIVES RA is associated with early ischaemic heart disease. This appears to be driven largely by the presence of chronic inflammation. Studies suggest that treatment with disease-modifying drugs such as MTX may reduce the incidence of cardiovascular events in RA. Anti-TNF therapies significantly reduce inflammation in RA. However, the extent to which these agents also reduce cardiovascular disease (CVD) is uncertain. The purpose of this study was to explore the effect of anti-TNF agents on CVD in RA using a systematic literature review. METHODS We searched for studies of adults with RA treated with TNF antagonists where cardiovascular outcomes were recorded using MEDLINE, EMBASE, Cochrane Database, Database of Abstracts and Reviews of Effects, Health Technology Appraisal, Science Citation Index and Clinical Evidence from 1989 to 2010. Conference proceedings for the British Society of Rheumatology, ACR and EULAR between 2005 and 2009 were hand searched. Two reviewers assessed abstracts for inclusion and then quality of selected papers was assessed. RESULTS A total of 1840 abstracts were identified and 20 articles were suitable for inclusion. Information was obtained on the effect of TNF antagonists on overall CVD events, myocardial infarction, strokes and heart failure. CONCLUSION In many studies, TNF antagonists appear to reduce the likelihood of CVD in individuals with RA. Reassuringly, there does not appear to be an increased risk of cardiac failure. However, the reduction in CVD is not as consistently seen as with studies of MTX.

Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study

Objectives To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. Methods SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patients global health component (DAS28-3)–erythrocyte sedimentation rate (ESR) over 6 months. Results 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3–ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3–ESR at 6 months was significantly greater in rituximab than TNFi patients: −1.5 (0.2) vs −1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (−1.7 vs −1.3; p=0.017) but not intolerance (−0.7 vs −0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3–ESR with rituximab than with TNFi (−1.6 (0.3) vs −1.2 (0.3); p=0.011), particularly those switching because of inefficacy (−1.9 (0.3) vs −1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. Conclusions These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

Abatacept: a T-cell co-stimulation modulator for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a debilitating autoimmune disease that has traditionally been treated with disease-modifying anti-rheumatic drugs (DMARDs). In the European Union (EU), patients who fail to respond to traditional DMARDs may receive tumor necrosis factor-alpha (TNF-alpha) antagonists. However, approximately one-third of patients fail TNF-alpha antagonists due to adverse effects or lack of efficacy, and there are limited treatment options available to these patients. As knowledge of the underlying immunopathology of RA evolves, new strategies for inhibiting the inflammatory process have emerged. It is well known that activated T cells play a key role in orchestrating the immunopathological mechanisms of RA. Inhibiting the full activation of T cells is a rational strategy in the treatment of RA and represents a novel method of inhibiting disease activity, distinct from inflammatory cytokine blockade. Here, the safety and efficacy of abatacept, a selective T-cell co-stimulation modulator recently approved in the EU, is reviewed in patients with RA who have shown an inadequate response to TNF-alpha antagonists. In a randomized, placebo-controlled, double-blind, phase III trial of patients with an inadequate response to TNF-alpha antagonism, abatacept was effective in improving the signs and symptoms of RA, as well as patient-centered outcomes, such as fatigue, disability, and other mental and physical aspects of health-related quality of life. These improvements were sustained through 2 years during the open-label, long-term extension period. In this trial, abatacept demonstrated a safety and tolerability profile similar to placebo. Taken together, these data suggest that selective co-stimulation modulation with abatacept may be a viable option for patients who are refractory to both traditional therapies and TNF-alpha antagonists.

Biologic agents for rheumatoid arthritis—negotiating the NICE technology appraisals

In England and Wales, the National Institute for Health and Clinical Excellence (NICE) has provided guidance [technology appraisals (TAs) 130, 186, 195, 198 and 225] on the use of biologic drugs for the treatment of RA. This is based on an analysis of efficacy, safety and cost-effectiveness, and has resulted in a complex management pathway that restricts freedom to prescribe biologics according to their licensed indications. Specifically, TNF antagonists are the only class of biologics that can be used first line in DMARD-inadequate responders, and only in patients with a persistent 28-joint DAS score of ≥5.1. Alternative biologic agents are denied to those with contraindications to anti-TNF drugs and are also not supported following intolerance to TNF antagonists. Rituximab is the only class of biologic permitted after TNF antagonist inefficacy, in the absence of a contraindication to its use, whereas abatacept and tocilizumab are licensed and may be a more efficacious choice at this stage in some patient groups. Furthermore, for patients who demonstrate sequential inadequate responses, treatment is restricted to one TNF antagonist, rituximab and tocilizumab, whereas abatacept is only a permitted choice when rituximab is contraindicated or has been withdrawn because of an adverse event. In this review, we discuss the treatment algorithm published by NICE, and suggest alternatives where perceived deficiencies exist.

Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials

Objectives. To investigate changes in neutrophil count and occurrences of infection in RA patients treated with the IL‐6 receptor‐&agr; inhibitor tocilizumab (TCZ). Methods. Data were pooled from patients who received i.v. TCZ (4 mg/kg + MTX, 8 mg/kg ± DMARDs, 10 mg/kg) or placebo + DMARDs in phase 3/4 clinical trials, long‐term extensions or a pharmacology study. Neutrophil counts were measured routinely according to the Common Toxicity Criteria for Adverse Events grades; TCZ dosing was adjusted if necessary. Covariates associated with decreased neutrophil counts were assessed with multivariate regression analysis. Infection rates within 30 days of neutrophil count changes were calculated per 100 patient‐years of TCZ exposure. Results. In placebo‐controlled parts of trials, more TCZ‐treated than placebo‐treated patients had grade 1/2 or 3/4 neutrophil counts (TCZ: 28.2%/3.1%; placebo: 8.9%/0.2%). In placebo‐controlled trials + long‐term extensions, 4171 patients provided 16204.8 patient‐years of TCZ exposure. Neutrophil counts decreased through week 6 from baseline [mean (s.d.) change, ‐2.17 (2.16) × 109/l) and remained stable thereafter. Rates (95% CI) of serious infections within 30 days of normal [4.66 (4.31, 5.03)], grade 1/2 [2.48 (1.79, 3.34)] and 3/4 [2.77 (0.34, 10.01)] neutrophil counts were similar. Baseline neutrophil count <2 × 109/l and female gender were associated with grade 3/4 neutrophil counts [odds ratio (OR) (95% CI): 19.02 (6.76, 53.52), 2.55 (1.40, 4.66)]. Patients who stopped TCZ in response to decreased neutrophil count returned more quickly to normal levels than patients who reduced or continued their dose. Conclusion. Decreases in neutrophil counts in patients taking TCZ do not appear to be associated with serious infections and are normalized by current risk mitigation guidelines.

The 2013 BSR and BHPR guideline for the use of intravenous tocilizumab in the treatment of adult patients with rheumatoid arthritis

RA is a chronic multisystem inflammatory disorder with a prevalence of 0.5 1% in the general population. The management of RA has evolved considerably in the last few decades and newer therapies continue to be developed. Tocilizumab (TCZ) [1] is a humanized anti-IL-6 receptor (anti-IL-6R) antibody licensed for use in combination with MTX for the treatment of moderate to severe RA in adult patients who have either responded inadequately to or who were intolerant to previous therapy with one or more DMARDs or TNF antagonists. In such patients, TCZ can be administered as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. Several large randomized controlled trials (RCTs) have demonstrated the efficacy and tolerability of TCZ in the treatment of RA.

Cost Effectiveness of Etoricoxib versus Celecoxib and Non-Selective NSAIDS in the Treatment of Ankylosing Spondylitis

AbstractObjective: To evaluate the cost effectiveness of etoricoxib (90mg/day) relative to celecoxib (200 or 400mg/day), and the non-selective NSAIDs naproxen (1000mg/day) and diclofenac (150 mg/day) in the initial treatment of ankylosing spondylitis (AS) from the UK NHS perspective. Methods: A Bayesian cost-effectiveness model was developed to estimate the costs and benefits associated with initiating AS treatment with etoricoxib, celecoxib, diclofenac or naproxen. Efficacy, safety and medical resource and cost data were obtained from the literature. The obtained efficacy estimates were synthesized with a mixed treatment comparison meta-analysis. Treatment benefit and degree of disease activity, as reflected with Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, were related to QALYs and AS-specific costs (related to BASDAI). Other cost outcomes related to drug acquisition, and gastrointestinal and cardiovascular safety. Uncertainty in the source data was translated into uncertainty in cost-effectiveness estimates and therefore decision uncertainty. Costs and outcomes were discounted at 3.5% per annum. Results: There was a >98% probability that treatment with etoricoxib results in greater QALYs than the other interventions. Over a 30-year time horizon, starting AS treatment with etoricoxib was associated with about 0.4 more QALYs than the other interventions. At 2 years there was a 77% probability that etoricoxib had the lowest cost. This increased to >99% at 30 years. Etoricoxib is expected to save £13 620 (year 2007 values) relative to celecoxib (200/400 mg), £9957 relative to diclofenac and d9863 relative to naproxen. For a willingness-to-pay ceiling ratio of £20 000 per QALY, there was a >97% probability that etoricoxib was the most cost-effective treatment. Additional analysis with different assumptions, including celecoxib 200 mg, and ignoring cost-offsets associated with improvements in disease activity, supported these findings. Conclusions: This economic evaluation suggests that, from the UK NHS perspective, etoricoxib is the most cost-effective initial NSAID treatment for AS patients.

Will treatment of rheumatoid arthritis with an IL-6R inhibitor help facilitate the ‘age of remission’?

Background: Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic disease, which negatively influences patients’ quality of life, work productivity and longevity. Current therapies include traditional and biologic disease-modifying antirheumatic drugs (DMARDs). Although these are effective for many, a substantial proportion of patients fail to respond to these agents, suffer from loss of efficacy and/or experience unpleasant side effects, highlighting the need for alternatives. Objectives/methods: To address how a greater proportion of RA patients may potentially achieve disease remission, we reviewed data on IL-6 as a therapeutic target. Results/conclusions: IL-6 is an important driver of RA pathogenesis, mediating both articular and systemic effects of the disease. Tocilizumab, an inhibitor of the IL-6 receptor (IL-6R), is beneficial in treating RA in a variety of clinical contexts. Evidence to date supports the use of tocilizumab, as monotherapy or combination therapy, as an effective approach to the treatment of RA. Here, we discuss key efficacy and safety data from the recently published Phase III trials.

Access to the next wave of biologic therapies (Abatacept and Tocilizumab) for the treatment of rheumatoid arthritis in England and Wales: Addressing treatment outside the current NICE guidance

Patients in England and Wales with rheumatoid arthritis (RA) receive treatment from the National Health Service (NHS) with therapies approved by the European Medicines Agency (EMA), under guidance from the National Institute for Health and Clinical Excellence (NICE). This document overviews the current NICE guidelines for the treatment of RA and identifies scenarios when such guidance may not represent the optimum management strategy for individual patients. Specifically, we consider the use of tocilizumab or abatacept as the most appropriate treatments for some patients. In such scenarios, it may be possible for the clinician to secure access to the required therapy through an application procedure known as an ‘individual funding request’, the process of which is described in detail here. At present, it is unclear the extent to which the proposed reform of the NHS will affect the role of NICE in providing guidance and setting standards of care. Until the full impact of the proposed changes are realized, individual funding requests will remain a valuable way of securing the optimal treatment for all patients suffering from RA.