Intensive therapy and remissions in rheumatoid arthritis: a systematic review.

BACKGROUND: We systematically reviewed the effectiveness of intensive treatment strategies in achieving remission in patients with both early and established Rheumatoid Arthritis (RA). METHODS: A systematic literature review and meta-analysis evaluated trials and comparative studies reporting remission in RA patients treated intensively with disease modifying anti-rheumatic drugs (DMARDs), biologics and Janus Kinase (JAK) inhibitors. Analysis used RevMan 5.3 to report relative risks (RR) in random effects models with 95% confidence intervals (CI). RESULTS: We identified 928 publications: 53 studies were included (48 superiority studies; 6 head-to-head trials). In the superiority studies 3013/11259 patients achieved remission with intensive treatment compared with 1211/8493 of controls. Analysis of the 53 comparisons showed a significant benefit for intensive treatment (RR 2.23; 95% CI 1.90, 2.61). Intensive treatment increased remissions in both early RA (23 comparisons; RR 1.56; 1.38, 1.76) and established RA (29 comparisons RR 4.21, 2.92, 6.07). All intensive strategies (combination DMARDs, biologics, JAK inhibitors) increased remissions. In the 6 head-to-head trials 317/787 patients achieved remission with biologics compared with 229/671 of patients receiving combination DMARD therapies and there was no difference between treatment strategies (RR 1.06; 0.93. 1.21). There were differences in the frequency of remissions between early and established RA. In early RA the frequency of remissions with active treatment was 49% compared with 34% in controls. In established RA the frequency of remissions with active treatment was 19% compared with 6% in controls. CONCLUSIONS: Intensive treatment with combination DMARDs, biologics or JAK inhibitors increases the frequency of remission compared to control non-intensive strategies. The benefits are seen in both early and established RA.CH is a South Thames Rheumatology Specialist Registrar working in Kings College Hospital. FI is supported by the Academic department of Rheumatology. DLS is supported by TITRATE study programme. The TITRATE study is funded by the National Institute for Health Research (NIHR) as one of its Programme Grants For Applied Research (Grant Reference Number: RP-PG-0610-10066; Programme Title: Treatment Intensities and Targets in Rheumatoid Arthritis Therapy: Integrating Patients’ And Clinicians’ Views – The TITRATE Programme

A systematic review of randomised controlled trials in rheumatoid arthritis: the reporting and handling of missing data in composite outcomes.

BACKGROUND: Most reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome. The aims of this review were to assess the range of missing data rates in primary composite outcomes and to document the current practice for handling and reporting missing data in published RA trials compared to the Consolidated Standards of Reporting Trials (CONSORT) recommendations. METHODS: A systematic search for randomised controlled trials was conducted for RA trials published between 2008 and 2013 in four rheumatology and four high impact general medical journals. RESULTS: A total of 51 trials with a composite primary outcome were identified, of which 38 (75 %) used the binary American College of Rheumatology responder index and 13 (25 %) used the Disease Activity Score for 28 joints (DAS28). Forty-four trials (86 %) reported on an intention-to-treat analysis population, while 7 trials (14 %) analysed according to a modified intention-to-treat population. Missing data rates for the primary composite outcome ranged from 2-53 % and were above 30 % in 9 trials, 20-30 % in 11 trials, 10-20 % in 18 trials and below 10 % in 13 trials. Thirty-eight trials (75 %) used non-responder imputation and 10 (20 %) used last observation carried forward to impute missing composite outcome data at the primary time point. The rate of dropout was on average 61 % times higher in the placebo group compared to the treatment group in the 34 placebo controlled trials (relative rate 1.61, 95 % CI: 1.29, 2.02). Thirty-seven trials (73 %) did not report the use of sensitivity analyses to assess the handling of missing data in the primary analysis as recommended by CONSORT guidelines. CONCLUSIONS: This review highlights an improvement in rheumatology trial practice since the revision of CONSORT guidelines, in terms of power calculation and participant's flow diagram. However, there is a need to improve the handling and reporting of missing composite outcome data and their components in RA trials. In particular, sensitivity analyses need to be more widely used in RA trials because imputation is widespread and generally uses single imputation methods, and in this area the missing data rates are commonly differentially higher in the placebo group

Sub-optimal CD4 reconstitution despite viral suppression in an urban cohort on Antiretroviral Therapy (ART) in sub-Saharan Africa: Frequency and clinical significance

<p>Abstract</p> <p>Background</p> <p>A proportion of individuals who start antiretroviral therapy (ART) fail to achieve adequate CD4 cell reconstitution despite sustained viral suppression. We determined the frequency and clinical significance of suboptimal CD4 reconstitution despite viral suppression (SO-CD4) in an urban HIV research cohort in Kampala, Uganda</p> <p>Methods</p> <p>We analyzed data from a prospective research cohort of 559 patients initiating ART between 04/04–04/05. We described the patterns of SO-CD4 both in terms of:- I) magnitude of CD4 cell increase (a CD4 count increase < 50 CD4 cells/μl at 6 months, <100 cells/μl at 12 months; and <200 cells/μl at 24 months of ART) and II) failure to achieve a CD4 cell count above 200 cells/μl at 6,12 and 24 months of ART. Using criteria I) we used logistic regression to determine the predictors of SO-CD4. We compared the cumulative risk of clinical events (death and/or recurrent or new AIDS-defining illnesses) among patients with and without SO-CD4.</p> <p>Results</p> <p>Of 559 patients initiating ART, 386 (69%) were female. Median (IQR) age and baseline CD4 counts were 38 yrs (33–44) and 98 cells/μl (21–163) respectively; 414 (74%) started a d4T-based regimen (D4T+3TC+NVP) and 145 (26%) a ZDV-based regimen (ZDV+3TC+EFV). After 6, 12 and 24 months of ART, 380 (68%), 339 (61%) and 309 (55%) had attained and sustained HIV-RNA viral suppression. Of these, 78 (21%), 151 (45%) and 166 (54%) respectively had SO-CD4 based on criteria I), and 165(43%), 143(42%) and 58(19%) respectively based on criteria II). With both criteria combined, 56 (15%) and 129 (38%) had SO-CD4 at 6 and 12 months respectively. A high proportion (82% and 58%) of those that had SO-CD4 at 6 months (using criteria I) maintained SO-CD4 at 12 and 24 months respectively. There were no statistically significant differences in the incidence of clinical events among patients with [19/100PYO (12–29)] and without SO-CD4 [23/100PYO (19–28)].</p> <p>Conclusion</p> <p>Using criteria I), the frequency of SO-CD4 was 21% at 6 months. Majority of patients with SO-CD4 at 6 months maintained SO-CD4 up to 2 years. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.</p

Baseline predictors of remission, pain and fatigue in rheumatoid arthritis: the TITRATE trial.

BACKGROUND: Clinical trials show intensive treatment to induce remission is effective in patients with highly active rheumatoid arthritis (RA). The TITRATE trial showed that the benefits of intensive treatment also extend to moderately active RA. However, many patients failed to achieve remission or show improvements in pain and fatigue. We investigated whether baseline predictors could identify treatment non-responders. METHODS: The impact of obesity, depression, anxiety and illness perception on RA outcomes, including disease activity, remission, pain and fatigue were determined using a pre-planned secondary analysis of the TITRATE trial data. RESULTS: Body mass index was associated with disease activity levels and remission: obese patients had a higher overall disease activity and fewer obese patients achieved remission. Intensive management was not associated with increased remission in these patients. Obesity was also associated with increased overall pain and fatigue. Anxiety, depression and health perceptions had no discernible impact on disease activity but were associated with high levels of pain and fatigue. There was a strong association between anxiety and high pain scores; and between depression and high fatigue scores; and health perception was strongly related to both. None of the predictors had an important impact on pain and fatigue reduction in cross-sectional analysis. CONCLUSIONS: Disease activity is higher in obese patients and they have fewer remissions over 12 months. Anxiety, depression and health perceptions were associated with higher pain and fatigue scores. Intensive management strategies need to account for these baseline features as they impact significantly on clinical and psychological outcomes. TRIAL REGISTRATION: ISRCTN 70160382 ; date registered 16 January 2014

The relationship between social support and health-related quality of life in patients with antiphospholipid (hughes) syndrome

Objective: Antiphospholipid (Hughes) syndrome (APS) is recognised as a systemic autoimmune disease defined by recurrent thromboembolic events and/or pregnancy morbidity. Little is known about the psychological burden of this long-term condition. This study aims to explore the relationship between social support and health-related quality of life (HRQoL) in patients with APS. Methods: A total of 270 patients with a clinical diagnosis of APS participated in a cross-sectional online questionnaire survey. Data included demographics, disease-related information, social support and HRQoL. Results: Both perceived and ideal social support were associated with HRQoL in APS. Patients reported receiving insufficient social support. Perceived emotional support was related to physical functioning (B = 7.77, p = .006, 95% CI: 2.25, 13.29); perceived instrumental support was associated with bodily pain (B = 17.52, p <  .001, 95% CI: 11.15, 23.90) and perceived informational support with physical and social functioning (B = −6.30, p = .05, 95% CI: −12.52, −0.08; B = 8.06, p = .02, 95% CI: 1.17, 14.94). Ideal emotional support was related to physical and social functioning (B = 5.80, p = .04, 95% CI: 0.26, 11.34; B = 7.53, p = .04, 95% CI: 0.55, 14.51); ideal instrumental support was associated with mental health (B = 4.73, p = .03, 95% CI: 0.38, 9.07) and ideal informational support with vitality (B = 5.85, p = .01, 95% CI: 1.23, 10.46). Conclusion: Social support was linked to HRQoL in patients with APS. Insufficient social support was associated with limitations in various HRQoL domains. Increasing social support especially through provision of disease-specific education might contribute to improving HRQoL in patients with APS. Patient-tailored interventions addressing psychosocial aspects of living with APS are needed to improve patients’ psychological and physical status

A randomized placebo-controlled trial of methotrexate in psoriatic arthritis.

OBJECTIVE: MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA. METHODS: A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores). RESULTS: Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events. CONCLUSIONS: This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA. Trial registration. Current Controlled Trials, www.controlled-trials.com, ISRCTN:54376151

Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study

Objectives: To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent. Methods: In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18. Results: 53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): –1.03 (–1.66 to –0.40) vs –0.58 (–1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement. Conclusions: Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA. Trial registration number: NCT04991753

High rate of loss to clinical follow up among African HIV-infected patients attending a London clinic: a retrospective analysis of a clinical cohort

<p>Abstract</p> <p>Background</p> <p>Long-term regular clinic follow up is an important component of HIV care. We determined the frequency and characteristics of HIV-infected patients lost to follow up from a London HIV clinic, and factors associated with loss to all HIV follow up in the UK.</p> <p>Methods</p> <p>We identified 1859 HIV-infected adults who had registered and attended a London clinic on one or more occasions between January 1997 and December 2005. Loss to follow up was defined as clinic non-attendance for one or more years. Through anonymized linkage with the Survey of Prevalent HIV Infections Diagnosed and Health Protection Scotland, national databases of all HIV patients in care in the UK up to December 2006, loss-to-follow-up patients were categorized as Transfers (subsequently received care at another UK HIV clinic) or UKLFU (no record of subsequent attendance at any HIV clinic in the UK). Logistic regression analysis was used to identify factors associated with UKLFU for those both on highly active antiretroviral therapy (HAART) and not on HAART.</p> <p>Results</p> <p>In total, 722 (38.8%) of 1859 patients were defined as lost to follow up. Of these, 347 (48.1%) were Transfers and 375 (51.9%), or 20.2% of all patients, were UKLFU. Overall, 11.9% of all patients receiving HAART, and 32.2% not receiving HAART were UKLFU. Among those on HAART, risk factors for UKLFU were: African heterosexual female (OR = 2.22, 95% CI: 1.11-4.56) versus white men who have sex with men; earlier year of HIV clinic registration (1997-1999 OR: 3.51, 95% CI: 1.97-6.26; 2000-02 OR: 2.49, 95% CI: 1.43-4.32 vs. 2003-2005); CD4 count of < 200 versus > 350 cells/mm³(OR = 1.99, 95% CI:1.05-3.74); and a detectable viral load of > 400 copies/ml (OR = 5.03, 95% CI: 2.95-8.57 vs. ≤ 400 copies/ml) at last clinic visit.</p> <p>Among those not receiving HAART, factors were: African heterosexual male (OR = 3.91, 95% CI: 1.77-8.64) versus white men who have sex with men; earlier HIV clinic registration (2000-2002 OR: 2.91, 95% CI: 1.77-4.78; 1997-1999: OR: 5.26, 95% CI: 2.71-10.19); and a CD4 count of < 200 cells/mm³(OR: 3.24, 95% CI: 1.49-7.04).</p> <p>Conclusions</p> <p>One in five HIV-infected patients (one in three not on HAART and one in nine on HAART) from a London clinic were lost to all clinical follow up in the UK. Black African ethnicity, earlier year of clinic registration and advanced immunological suppression were the most important predictors of UKLFU. There is a need for all HIV clinics to establish systems for monitoring and tracing loss-to-follow-up patients, and to implement strategies for improving retention in care.</p