rgaret H. Ma

Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.

Summary Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While “tonic” intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.

Remission in early rheumatoid arthritis

Objective. We systematically reviewed remission as an outcome measure in observational studies and randomized controlled trials (RCT) in early rheumatoid arthritis (RA). Our objectives were to identify its frequency using different criteria, to determine the influence of different treatment strategies on remission, and to review the effects of remission on radiological outcomes. Methods. Pubmed, Medline and Embase were searched using the following terms: Early Rheumatoid Arthritis or Early RA combined with Remission, Treatment, anti-Tumor Necrosis Factor (TNF) or Disease-modifying Antirheumatic Drugs (DMARD). Remissions were reported using American College of Rheumatology (ACR) criteria and Disease Activity Score (DAS) criteria. Results. Seventeen observational studies (4762 patients) reported remission in 27% of patients, 17% by ACR criteria and 33% by DAS criteria. Twenty RCT (4 comparing DMARD monotherapies, 13 comparing monotherapy with combination therapies, 3 comparing combination therapies) enrolled 4290 patients. ACR remissions occurred in 16% receiving DMARD monotherapy and 24% combination therapies (random effects OR 1.69, 95% CI 1.12–2.36). DAS remissions occurred in 26% and 42%, respectively (OR 2.01, 95% CI 1.46–2.78). Observational studies showed continuing radiological progression despite remission. RCT showed less radiological progression in remission when treated with combination therapy compared to monotherapies. Conclusion. Remission is a realistic treatment goal in early RA. Combination therapies using DMARD with or without TNF inhibitors increase remissions. Radiological progression occurred in remission but is reduced by combination therapies. ACR and DAS remission criteria are not directly comparable and standardization is needed.

ACPA-positive and ACPA-negative rheumatoid arthritis differ in their requirements for combination DMARDs and corticosteroids: secondary analysis of a randomized controlled trial

IntroductionUK guidelines recommend that all early active rheumatoid arthritis (RA) patients are offered combination disease-modifying antirheumatic drugs (DMARDs) and short-term corticosteroids. Anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA may differ in their treatment responses. We used data from a randomized controlled trial - the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial - to examine whether responses to intensive combination treatments in early RA differ by ACPA status.MethodsThe CARDERA trial randomized 467 early active RA patients to receive: (1) methotrexate, (2) methotrexate/ciclosporin, (3) methotrexate/prednisolone or (4) methotrexate/ciclosporin/prednisolone in a factorial-design. Patients were assessed every six months for two years. In this analysis we evaluated 431 patients with available ACPA status. To minimize multiple testing we used a mixed-effects repeated measures ANOVA model to test for an interaction between ACPA and treatment on mean changes from baseline for each outcome (Larsen, disease activity scores on a 28-joint count (DAS28), Health Assessment Questionnaire (HAQ), EuroQol, SF-36 physical component summary (PCS) and mental component summary (MCS) scores). When a significant interaction was present, mean changes in outcomes were compared by treatment group at each time point using t-tests stratified by ACPA status. Odds ratios (ORs) for the onset of new erosions with treatment were calculated stratified by ACPA.ResultsACPA status influenced the need for combination treatments to reduce radiological progression. ACPA-positive patients had significant reductions in Larsen score progression with all treatments. ACPA-positive patients receiving triple therapy had the greatest benefits: two-year mean Larsen score increases comprised 3.66 (95% confidence interval (CI) 2.27 to 5.05) with triple therapy and 9.58 (95% CI 6.76 to 12.39) with monotherapy; OR for new erosions with triple therapy versus monotherapy was 0.32 (95% CI 0.14 to 0.72; P = 0.003). ACPA-negative patients had minimal radiological progression irrespective of treatment. Corticosteroid’s impact on improving DAS28/PCS scores was confined to ACPA-positive RA.ConclusionsACPA status influences the need for combination DMARDs and high-dose tapering corticosteroids in early RA. In CARDERA, combination therapy was only required to prevent radiological progression in ACPA-positive patients; corticosteroids only provided significant disease activity and physical health improvements in ACPA-positive disease. This suggests ACPA is an important biomarker for guiding treatment decisions in early RA.Trial registrationCurrent Controlled Trials ISRCTN32484878

Remission in Early Rheumatoid Arthritis: Predicting Treatment Response

Objective. Optimizing therapeutic strategies to induce remission requires an understanding of the initial features predicting remission. Currently no suitable model exists. We aim to develop a remission score using predictors of remission in early rheumatoid arthritis (RA). Methods. We used a dataset from a UK randomized controlled trial that evaluated intensive treatment with conventional combination therapy, to develop a predictive model for 24-month remission. We studied 378 patients in the trial who received 24 months’ treatment. Our model was validated using data from a UK observational cohort (Early RA Network, ERAN). A group of 194 patients was followed for 24 months. Remission was defined as 28-joint Disease Activity Score < 2.6. Logistic regression models were used to estimate the associations between remission and potential baseline predictors. Results. Multivariate logistic regression analyses showed age, sex, and tender joint count (TJC) were independently associated with 24-month remission. The multivariate remission score developed using the trial data correctly classified 80% of patients. These findings were replicated using ERAN. The remission score has high specificity (98%) but low sensitivity (13%). Combining data from the trial and ERAN, we also developed a simplified remission score that showed that younger men with a TJC of 5 or lower were most likely to achieve 24-month remission. Remission was least likely in older women with high TJC. Rheumatoid factor, rheumatoid nodules, and radiographic damage did not predict remission. Conclusion. Remission can be predicted using a score based on age, sex, and TJC. The score is relevant in clinical trial and routine practice settings.

Hypoxanthine impairs morphogenesis and enhances proliferation of a neuroblastoma model of Lesch Nyhan syndrome

Extracellular purines have essential roles in neuronal development; hence, disruptions in their metabolism as reported in Lesch Nyhan syndrome (LNS) could result in developmental abnormalities. The deficiency of hypoxanthine‐guanine phosphoribosyl transferase (HGPRT) in LNS leads to increased hypoxanthine and uric acid production. We have reported that HGPRT‐deficient B103‐4C neuroblastoma, a neuronal model of LNS, proliferated less and differentiated more than their HGPRT‐positive B103 counterparts. Here, we sought to determine whether differences in proliferation and differentiation would occur when these cells were cultured in the presence of hypoxanthine or in a hypoxanthine‐/serum‐free chemically defined media (NBMN2). In media with 1% serum, hypoxanthine (50 μM) significantly increased the proliferation of both cell lines with a greater effect on B103‐4C cells. In 1% serum media, hypoxanthine increased differentiation of B103 but decreased B103‐4C differentiation. In NBMN2, B103 proliferated far more than B103‐4C, but both cell types differentiated to the same extent. These results are interpreted to suggest that elevated levels of central nervous system (CNS) hypoxanthine as reported in LNS may affect neuronal development, and to implicate hypoxanthine and abnormal neuronal development as causative factors in the etiology of LNS. J. Neurosci. Res. 63:500–508, 2001.

Randomised controlled trial of Tumour necrosis factor inhibitors Against Combination Intensive Therapy with conventional disease-modifying antirheumatic drugs in established rheumatoid arthritis: the TACIT trial and associated systematic reviews

BACKGROUND Rheumatoid arthritis (RA) is initially treated with methotrexate and other disease-modifying antirheumatic drugs (DMARDs). Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors (TNFis), which are effective but expensive. OBJECTIVE We assessed whether or not combination DMARDs (cDMARDs) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis. DESIGN An open-label, 12-month, pragmatic, randomised, multicentre, two-arm trial [Tumour necrosis factor inhibitors Against Combination Intensive Therapy (TACIT)] compared these treatment strategies. We then systematically reviewed all comparable published trials. SETTING The TACIT trial involved 24 English rheumatology clinics. PARTICIPANTS Active RA patients eligible for TNFis. INTERVENTIONS The TACIT trial compared cDMARDs with TNFis plus methotrexate or another DMARD; 6-month non-responders received (a) TNFis if in the cDMARD group; and (b) a second TNFi if in the TNFi group. MAIN OUTCOME MEASURES The Heath Assessment Questionnaire (HAQ) was the primary outcome measure. The European Quality of Life-5 Dimensions (EQ-5D), joint damage, Disease Activity Score for 28 Joints (DAS28), withdrawals and adverse effects were secondary outcome measures. Economic evaluation linked costs, HAQ changes and quality-adjusted life-years (QALYs). RESULTS In total, 432 patients were screened; 104 started on cDMARDs and 101 started on TNFis. The initial demographic and disease assessments were similar between the groups. In total, 16 patients were lost to follow-up (nine in the cDMARD group, seven in the TNFi group) and 42 discontinued their intervention but were followed up (23 in the cDMARD group and 19 in the TNFi group). Intention-to-treat analysis with multiple imputation methods used for missing data showed greater 12-month HAQ score reductions with initial cDMARDs than with initial TNFis [adjusted linear regression coefficient 0.15, 95% confidence interval (CI) -0.003 to 0.31; p = 0.046]. Increases in 12-month EQ-5D scores were greater with initial cDMARDs (adjusted linear regression coefficient -0.11, 95% CI -0.18 to -0.03; p = 0.009) whereas 6-month changes in HAQ and EQ-5D scores and 6- and 12-month changes in joint damage were similar between the initial cDMARD group and the initial TNFi group. Longitudinal analyses (adjusted general estimating equations) showed that the DAS28 was lower in the initial TNFi group in the first 6 months (coefficient -0.63, 95% CI -0.93 to -0.34; p < 0.001) but there were no differences between the groups in months 6-12. In total, 36 patients in the initial cDMARD group and 44 in the initial TNFi group achieved DAS28 remission. The onset of remission did not differ between groups (p = 0.085 on log-rank test). In total, 10 patients in the initial cDMARD group and 18 in the initial TNFi group experienced serious adverse events; stopping therapy because of toxicity occurred in 10 and six patients respectively. Economic evaluation showed that the cDMARD group had similar or better QALY outcomes than TNFi with significantly lower costs at 6 and 12 months. In the systematic reviews we identified 32 trials (including 20-1049 patients) on early RA and 19 trials (including 40-982 patients) on established RA that compared (1) cDMARDs with DMARD monotherapy; (2) TNFis/methotrexate with methotrexate monotherapy; and (3) cDMARDs with TNFis/methotrexate. They showed that cDMARDs and TNFis had similar efficacies and toxicities. CONCLUSIONS Active RA patients who have failed methotrexate and another DMARD achieve equivalent clinical benefits at a lower cost from starting cDMARDs or from starting TNFis (reserving TNFis for non-responders). Only a minority of patients achieve sustained remission with cDMARDs or TNFis; new strategies are needed to maximise the frequency of remission. TRIAL REGISTRATION Current Control Trials ISRCTN37438295. FUNDING This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 66. See the NIHR Journals Library website for further project information.

Clinical and Serological Predictors of Remission in Rheumatoid Arthritis Are Dependent on Treatment Regimen

Objective. Early intensive treatment is now the cornerstone for the management of rheumatoid arthritis (RA). In the era of personalized medicine, when treatment is becoming more individualized, it is unclear from the current literature whether all patients with RA benefit equally from such intensive therapies. We investigated the benefit of different treatment regimens on remission rates when stratified to clinical and serological factors. Methods. The Combination Anti-rheumatic Drugs in Early Rheumatoid Arthritis (CARDERA) trial recruited patients with RA of less than 2 years’ duration who had active disease. The trial compared 4 treatment regimens: methotrexate monotherapy, 2 different double therapy regimens (methotrexate and cyclosporine or methotrexate and prednisolone) and 3-drug therapy. Clinical predictors included age, male sex, and tender joint count (TJC) and serological biomarkers included rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA). Results. Patients who were male, over 50 years, had ≥ 6 TJC, were RF-IgM–positive, or ACPA-positive were more likely to achieve remission at 24 months using 3-drug therapy compared to monotherapy (OR 2.99, 4.95, 2.71, 2.54, and 3.52, respectively). There were no differences in response to monotherapy and 3-drug therapy if patients were female, under 50 years, had < 6 TJC, or were seronegative. Conclusion. Early intensive regimens have become the gold standard in the treatment of early RA. Our study suggests that this intensive approach is only superior to monotherapy in certain subsets of patients. Although these are unlikely to be the only predictors of treatment response, our study brings us a step closer to achieving personalized medicine in RA.

Adding New Perspectives to the Kaleidoscope of Remission Criteria in Rheumatoid Arthritis

Remission has many meanings. In some medical contexts it indicates lessened disease severity. In other contexts it implies the disease has disappeared. Concepts of remission in rheumatoid arthritis (RA) reflect both models. Some definitions indicate only low disease activity states. Other definitions suggest the absence of disease, with undetectable symptoms, signs, and disease markers. Critically, remission differs from “cure,” which implies RA will never return. Current opinion favors restricting remission to patients with either no or minimal synovitis, without longterm structural or functional sequelae. The seminal report by Pinals, et al in 1981 concluded “complete” RA remission indicates the “total absence of articular and extraarticular inflammation and immunological activities”1. However, many years later, uncertainties remain on how to define genuine remission states. The introduction of new therapeutic options and strategies over the past decade has made remission an achievable goal. An immediate consequence of this perspective is the need for an accurate and uniform way to identify remission. Although there are many definitions, remission does not yet have an internationally accepted gold standard. Remission criteria differ between studies, and remission rates vary depending on the remission criteria used. We have previously noted these variations2. Some remission criteria use categorical descriptions; the original American College of Rheumatology (ACR) remission criteria are one important example1. However, these criteria are very stringent and too few patients achieve this goal to make the definition a useful outcome to discriminate between patients in clinical trial settings, or to make it a realistic outcome in the routine clinic setting. Consequently, many variants have been described. Continuous composite measures are often used to define remission; the most commonly used are the low scores using the Disease Activity Score (DAS3) or its modifications such as DAS28–erythrocyte sedimentation rate (DAS-ESR) … Address correspondence to Dr. H.Y. Ma, Department of Rheumatology, GKT School of Medicine, Weston Education Centre, Kings College London, 10 Cutcombe Road, London SE5 9RS, UK. E-mail: margaret.ma{at}nhs.net

Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders?

Abstract Objectives RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. Methods We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0–6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6–12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. Results Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0–6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6–12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). Conclusion Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states. Trail registration EudraCT, https://www.clinicaltrialsregister.eu, 2010-020738-24; ISRCTN registry, https://www.isrctn.com, 28955701

Flares in Rheumatoid Arthritis Patients with Low Disease Activity: Predictability and Association with Worse Clinical Outcomes

Objective. To investigate predictors of flare in rheumatoid arthritis (RA) patients with low disease activity (LDA) and to evaluate the effect of flare on 12-month clinical outcomes. Methods. Patients with RA who were taking disease-modifying antirheumatic drugs and had a stable 28-joint count Disease Activity Score (DAS28) < 3.2 were eligible for inclusion. At baseline and every 3 months, clinical (DAS28), functional [Health Assessment Questionnaire–Disability Index (HAQ-DI), EQ-5D, Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-F), Medical Outcomes Study Short Form-36 (SF-36)], serum biomarkers [multibiomarker disease activity (MBDA) score, calprotectin, CXCL10], and imaging data were collected. Flare was defined as an increase in DAS28 compared with baseline of > 1.2, or > 0.6 if concurrent DAS28 ≥ 3.2. Cox regression analyses were used to identify baseline predictors of flare. Biomarkers were cross-sectionally correlated at time of flare. Linear regressions were performed to compare clinical outcomes after 1 year. Results. Of 152 patients, 46 (30%) experienced a flare. Functional disability at baseline was associated with flare: HAQ-DI had an unadjusted HR 1.82 (95% CI 1.20–2.72) and EQ-5D had HR 0.20 (95% CI 0.07–0.57). In multivariate analyses, only HAQ-DI remained a significant independent predictor of flare (HR 1.76, 95% CI 1.05–2.93). At time of flare, DAS28 and its components significantly correlated with MBDA and calprotectin, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers. Patients who flared had significantly worse outcomes at 12 months (HAQ-DI, EQ-5D, FACIT-F, SF-36, and radiographic progression). Conclusion. Flares occur frequently in RA patients with LDA and are associated with worse disease activity, quality of life, and radiographic progression. Higher baseline HAQ-DI was modestly predictive of flare, while biomarker correlation at the time of flare suggests a noninflammatory component in a majority of events.