Yuzaiful Md Yusof

Targeting Interleukin-6 in Rheumatoid Arthritis

Interleukin (IL)-6 is a potent pro-inflammatory agent that plays a crucial role in the pathogenesis of systemic inflammatory disease. Targeting this pathway in rheumatoid arthritis (RA) seems an attractive option as IL-6 is important for both joint destruction and systemic manifestations. Currently, tocilizumab, which binds the IL-6 receptor, is licensed for treatment in active, moderate to severe disease in RA and systemic juvenile idiopathic arthritis (JIA). Several other promising IL-6 blocking agents as well as a subcutaneous form of tocilizumab are currently undergoing phase III clinical trials. The aim of this article is to provide an up-to-date analysis of clinical efficacy and tolerability data concerning the use of IL-6 inhibitors. Data from clinical trials demonstrated that clinical efficacy for tocilizumab, which included improvement in physical function and halting radiographic progression, were comparable to other biologics licensed for use in RA. Patients who should gain most are RA patients with systemic features such as high inflammatory markers and anaemia. Perhaps, the strongest selling point lies in its effectiveness as a monotherapy. This is particularly useful in those who are not tolerating combination treatment with methotrexate. Tocilizumab is one of a few biologics that have been shown to be superior to methotrexate in head-to-head studies. The safety profile of tocilizumab also is comparable to other currently available biologics. There is a small but significant increase in adverse events including infections in patients treated with tocilizumab compared to placebo, particularly in patients who are elderly and those with multiple comorbidities. Elevated lipid profiles are frequent but have not been associated with major cardiovascular events. IL-6 blockade is a major advancement in the treatment of RA as it targets a unique molecule. Over the next few years, evidence will be available on the long-term cardiovascular safety and efficacy of subcutaneous IL-6 blocking agents.

Effect of rituximab on the progression of rheumatoid arthritis–related interstitial lung disease: 10 years’ experience at a single centre

Objective To evaluate the effect of rituximab (RTX) in patients with RA-related interstitial lung disease (RA-ILD) and identify factors associated with outcome after treatment. Methods An observational study of patients with RA-ILD was conducted from a cohort of RTX-treated RA patients in a single centre for >10 years. Progression was defined by any of the following: a decrease of pre-RTX forced vital capacity (FVC) >10% or diffusion capacity of carbon monoxide (DLCO) >15% predicted, worsening of the ILD score or death from progressive ILD. Results Of 700 RA patients treated with RTX, 56 had RA-ILD (prevalence = 8%). After RTX, new ILD was diagnosed in 3/700 patients (incidence = 0.4%). Data for lung assessment were available for 44/56 patients. The median relative change pre- and post-RTX for FVC were -2.4% and +1.2% ( P = 0.025) and for DLCO were -4.4% and -1.3% ( P = 0.045). Post-RTX, 23/44 (52%) were stable and 7/44 (16%) had improved. Of the 14 (32%) with ILD that progressed, 9/56 (16%) were deaths due to progressive ILD. Factors associated with ILD progression were radiologic pattern of usual interstitial pneumonia, a previous history of lung progression and pre-RTX DLCO <46% predicted. Of those whose ILD progressed, 11/14 (79%) had severe ILD before RTX [median DLCO 42% predicted (interquartile range 41-49)]. Conclusion In this cohort of patients where RTX was given for arthritis, most patients with ILD pre-RTX remained stable/improved after treatment over a prolonged follow-up period. Patients who deteriorated/died had the most severe ILD pre-RTX, suggesting the drug was not contributory. RTX appears to be an acceptable therapeutic choice for patients with RA-ILD and further studies are warranted.

Primary myocardial disease in scleroderma—a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group

Cardiac disease is prevalent in SSc and associated with a poor prognosis. Differentiating primary myocardial disease (SSc-cardiomyopathy) from ischaemic heart disease is difficult and the disease phenotype most at risk is unclear. A comprehensive literature review was performed to inform the UK Systemic Sclerosis Study Group for cardiac disease tasked with producing a best practice pathway for the management of cardiac disease in SSc. This review describes the prevalence of SSc-cardiomyopathy, its associated greater mortality and various manifestations (e.g. heart failure, arrhythmias and diastolic dysfunction). The limited evidence suggests SSc-cardiomyopathy is associated with other poor prognostic indicators, including diffuse cutaneous disease, positive SSc-specific serology, black ethnicity, older age at disease onset, tendon friction rubs, abnormal nail-fold capillaroscopy and worse quality-of-life scores. Differentiating SSc-cardiomyopathy from ischaemic heart disease requires well-planned studies. Non-invasive investigative techniques are improving the understanding of its pathophysiological basis.

B-cell-targeted therapies in systemic lupus erythematosus and ANCA-associated vasculitis: current progress

B cells play a central role in the pathogenesis of systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated vasculitis. There are various strategies for targeting B cells including depletion, inhibition of survival factors, activation and inhibition of co-stimulatory molecules. Controlled trials in systemic lupus erythematosus have shown positive results for belimumab, promising results for epratuzumab and negative results for rituximab. The failure of rituximab in controlled trials has been attributed to trial design, sample size and outcome measures rather than true inefficacy. In anti-neutrophil cytoplasmic antibody-associated vasculitis, rituximab is effective for remission induction and in relapsing disease. However, the optimal long-term re-treatment strategy remains to be determined. Over the next 5 years, evidence will be available regarding the clinical efficacy of these novel therapies, biomarkers and their long-term safety.

Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus

Objective To assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR). Methods 125 patients with SLE treated with rituximab over 12 years were studied prospectively. A major clinical response was defined as improvement of all active British Isles Lupus Assessment Group (BILAG)-2004 domains to grade C/better and no A/B flare. Partial responders were defined by one persistent BILAG B. B-cell subsets were measured using highly sensitive flow cytometry. Patients with 2NDNR, defined by infusion reaction and defective depletion, were treated with ocrelizumab or ofatumumab. Results 117 patients had evaluable data. In cycle 1 (C1), 96/117 (82%) achieved BILAG response (major=50%, partial=32%). In multivariable analysis, younger age (OR 0.97, 95% CI 0.94 to 1.00) and B-cell depletion at 6 weeks (OR 3.22, 95% CI 1.24 to 8.33) increased the odds of major response. Complete depletion was predicted by normal complement and lower pre-rituximab plasmablasts and was not associated with increased serious infection post-rituximab. Seventy-seven (with data on 72) C1 responders were retreated on clinical relapse. Of these, 61/72 (85%) responded in cycle 2 (C2). Of the 11 C2 non-responders, nine met 2NDNR criteria (incidence=12%) and tested positive for anti-rituximab antibodies. Lack of concomitant immunosuppressant and higher pre-rituximab plasmablasts predicted 2NDNR. Five were switched to ocrelizumab/ofatumumab, and all depleted and responded. Conclusion Treatment with anti-CD20 agents can be guided by B-cell monitoring and should aim to achieve complete depletion. 2NDNR is associated with anti-rituximab antibodies, and switching to humanised agents restores depletion and response. In SLE, alternative anti-CD20 antibodies may be more consistently effective.

Biologics in systemic lupus erythematosus: current options and future perspectives.

Data from clinical trials highlighted the potential and pitfalls of the use of biologics to treat systemic lupus erythematosus. With improved understanding of immunopathogenesis and lessons learned from controlled trials, there is a growing optimism for personalized treatment from an increasing range of targeted therapies.

Prediction of autoimmune connective tissue disease in an at-risk cohort: prognostic value of a novel two-score system for interferon status

Objective To evaluate clinical, interferon and imaging predictors of progression from ‘At Risk’ to autoimmune connective tissue diseases (AI-CTDs). Methods A prospective observational study was conducted in At-Risk of AI-CTD (defined as antinuclear antibody (ANA) positive; ≤1 clinical systemic lupus erythematosus (SLE) criterion; symptom duration <12 months and treatment-naïve). Bloods and skin biopsy (non-lesional) were analysed for two interferon-stimulated gene expression scores previously described (IFN-Score-A and IFN-Score-B). Forty-nine healthy controls (HCs) and 114 SLE were used as negative and positive controls. Musculoskeletal ultrasound was performed. Progression was defined by meeting classification criteria for AI-CTDs at 12 months. Results 118 individuals with 12-month follow-up were included. Of these, 19/118 (16%) progressed to AI-CTD (SLE=14, primary Sjogren’s=5). At baseline, both IFN scores differed among At-Risk, HCs and SLE groups (p<0.001) and both were elevated in At-Risk who progressed to AI-CTD at 12 months versus non-progressors, to a greater extent for IFN-Score-B (fold difference (95% CI) 3.22 (1.74 to 5.95), p<0.001) than IFN-Score-A (2.94 (1.14 to 7.54); p=0.018). Progressors did not have significantly greater baseline clinical characteristics or ultrasound findings. Fold difference between At-Risk and HCs for IFN-Score-A was markedly greater in skin than blood. In multivariable logistic regression, only family history of autoimmune rheumatic disease, OR 8.2 (95% CI 1.58 to 42.53) and IFN-Score-B, 3.79 (1.50–9.58) increased the odds of progression. Conclusion A two-factor interferon score and family history predict progression from ANA positivity to AI-CTD. These interferon scores may allow stratification of individuals At-Risk of AI-CTD permitting early intervention for disease prevention and avoid irreversible organ damage.

Defining inflammatory musculoskeletal manifestations in systemic lupus erythematosus

Objective To define the prevalence and clinical associations of clinical and imaging definitions of synovitis in unselected SLE patients with musculoskeletal (MSK) symptoms. Methods 112 patients with SLE (excluding RF and CCP positive patients); 88 consecutive with inflammatory MSK symptoms and 24 asymptomatic SLE controls were recruited. Patients had clinical assessment (BILAG, SLEDAI, joint counts, patient and physician visual analogue score), routine laboratory tests and US of two hands and wrists (synovitis and tenosynovitis, OMERACT definitions). Results Overall, 68% (60/88) of symptomatic patients had US inflammation (grey scale ⩾ 2 and/or PD ⩾ 1 or tenosynovitis) compared with 17% (4/23) of asymptomatic patients. In symptomatic patients, clinical inflammation was seen defined by BILAG A or B in 38% (34/88) or defined by the SLEDAI-MSK criterion in 32% (28/88). BILAG A/B had sensitivity (95% CI) of 56% (41, 69%) and specificity of 89% (72, 96%) for US-confirmed inflammation. SLEDAI-MSK criterion had sensitivity of 44% (31, 59%) and specificity of 89% (72, 96%). In patients with inflammatory symptoms, 27% (24/88) had subclinical inflammation (abnormal US but no clinically swollen joints) and 35% (31/88) had no clinical or US inflammation. Subclinical tenosynovitis and PD were associated with significantly higher IgG, physician visual analogue score, tender joint count. Conclusion In SLE patients with MSK symptoms, a large proportion of objective, clinically meaningful inflammation is only identifiable by US. The existing classification of MSK SLE using disease activity instruments based on joint swelling is inaccurate to guide patient selection for clinical trials, biologic therapy, or treat-to-target protocols.