ObjectiveTo investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.MethodsA total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.ResultsAmong patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.ConclusionPharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.
Tocilizumab, a humanized monoclonal antibody directed against the interleukin (IL)-6 receptor, is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis (JIA). We describe a case of multiple halo naevi occurring in a patient with a history of JIA treated with tocilizumab. IL-6 is a key cytokine in the setting of cancer through its effects on angiogenesis and inhibition of adaptive anti-tumour immunity. IL-6 also plays a role in melanocyte function, and increased levels have been noted in vitiligo skin, where it is a paracrine inhibitor of melanocytes. Tocilizumab may therefore lead to the development of halo naevi secondary to subsequent activation of adaptive immunity. Alternatively, as tocilizumab results in increased serum IL-6 levels, the epidermal cytokine profile is altered. Increased levels of IL-6 may therefore have a direct inhibitory effect on melanocytes, where access by tocilizumab may be limited due to differential size difference.
Established RA risk markers at 6q23 are associated also with radiographic severity in autoantibody-positive RA; as for susceptibility, the association for these markers in combination is stronger than that for markers alone.
BackgroundInterstitial lung disease (ILD) is a common cause of morbidity and mortality in connective tissue disease (CTD) (1), particularly in systemic sclerosis, where it is the most common cause of death (2). Despite several immunosuppressive regimes, including intravenous cyclophosphamide, a significant proportion of patients have progressive ILD. Recent evidence has shown that rituximab is an effective treatment in antisynthetase syndrome associated ILD (3) and in treatment refractory connective tissue disease associated interstitial lung disease (CTD-ILD) as rescue therapy (4).ObjectivesThe objective of this study was to investigate patient outcomes when using rituximab for CTD-ILD refractory to standard immunosuppression, in our specialist centre in Sheffield, UK.MethodsA retrospective case review was performed on 12 patients who had received rituximab for CTD-ILD. Details of previous treatment, pulmonary function tests, imaging, autoimmune profiles and basic demographic data were collected. Exercise tolerance, symptoms of dyspnoea and percent predicted forced vital capacity (FVC) and percent predicted diffusion capacity of carbon monoxide (DLco) were compared from baseline and six to nine months after receiving rituximab, to assess response to treatment.ResultsAfter six months treatment four patients had significant increases in FVC or DLco defined as an increase of ≥10% or ≥15% from baseline respectively, and three patients had stable disease. Five patients showed progressive disease including one patient with diffuse systemic sclerosis who died and one patient with polymyositis who required lung transplantation. A steroid sparing effect was observed, with a median reduction in prednisolone dose of 5mg daily at six months.ConclusionsWe found that rituximab can be an effective treatment in some patients with progressive CTD-ILD, even in disease refractory to standard treatment with IV cyclophosphamide. Patients with Jo-1 polymyositis were more likely to have a significant response to treatment. Further randomized controlled studies are needed to aid treatment decisions in this patient group to enable clinicians to identify likely responders, to determine if rituximab is as effective as cyclophosphamide and if use in early CTD-ILD will improve patient outcomes.ReferencesCastelino FV et al. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Research and Therapy. 2010;12(4):213.Tyndall AJ et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Annals of the rheumatic diseases. 2010 Oct;69(10):1809-15.Sem M et al. Rituximab treatment of the anti-synthetase syndrome: a retrospective case series. Rheumatology. 2009 Aug;48(8):968-71.Keir GJ et al. Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy. The European respiratory journal. 2012 Sep; 40(3):641-8.Disclosure of InterestNone declared
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