Drug-survival profiling of second-line biologic therapy in rheumatoid arthritis: Choice of another tumour necrosis factor inhibitor or a biologic of different mode of action?

OBJECTIVES: To assess the best choice of second-line therapy between tumour necrosis factor-inhibitor (TNFi) and biologics of different-mode-of-action (BDMA-rituximab/tocilizumab/abatacept) in rheumatoid arthritis (RA) by evaluating drug-survival following discontinuation of the first-line TNFi. METHODS: This retrospective drug-survival study was performed across two different hospitals by conventional-statistics and machine-learning approach. RESULTS: From a total of 435 patients, 213 (48.9%; TNFi = 122, BDMA = 91) discontinued their second-line biologic {median drug-survival: TNFi, 27 months [95% confidence interval (95%CI) 22-32] vs BDMA, 37 months (95%CI 32-52)}. As a second-line biologic, BDMA was likely to reduce the risk of treatment-discontinuation [hazard-ratio (HR) 0.63, 95%CI 0.48-0.83] compared to TNFi, but only in seropositive-patients (HR 0.52, 95%CI 0.38-0.73), not in seronegative-RA. Drug-survival benefit of BDMA over TNFi was not observed if the seropositive-patients were previously exposed to monoclonal-TNFi (HR 0.77, 95%CI 0.49-1.22) versus soluble-TNFi (etanercept/biosimilars) or if the first-line TNFi was terminated within 23.9 months of initiation (HR 0.97, 95%CI 0.56-1.68). CONCLUSIONS: BDMA, as a second-line biologic, is more likely to be sustained in seropositive-patients, particularly without prior exposure to monoclonal-TNFi. The drug-survival benefit of BDMA was not observed in seronegative-patients or if the first-line TNFi was stopped within 2 years.

The synergistic efficacy of hydroxychloroquine with methotrexate is accompanied by increased erythrocyte mean corpuscular volume.

OBJECTIVES: To determine whether concomitant HCQ modulates the increase in erythrocyte mean corpuscular volume (MCV) caused by MTX therapy, and whether this is associated with improved clinical response in RA. METHODS: A retrospective observational analysis was conducted on two independent hospital datasets of biologic-naïve, early-RA patients who started oral MTX. Baseline characteristics, DAS28-ESR and monthly MCV after starting MTX were obtained. Conventional and machine-learning statistical approaches were applied to the discovery cohort (Cohort 1, 655 patients) and results validated using Cohort 2 (225 patients). RESULTS: HCQ therapy with MTX was associated with a 2-fold increase in the likelihood of response defined in this study as clinical remission or low disease activity at 6 months (P <0.001). The improved clinical outcome of combination HCQ and MTX therapy was associated with an accelerated rise in MCV from 2 months after commencing therapy. The increase in MCV at 3 months was equivalent to the contemporaneous reduction in the DAS (DAS28-ESR) in predicting clinical response at 6 months. Using latent class mixed modelling, five trajectories of MCV change over 6 months from baseline were identified. The odds ratio of response to treatment was 16.2 (95% CI 5.7, 46.4, P <0.001) in those receiving combination therapy classified within the MCV elevation >5 fl class, which contained the most patients, compared with MTX alone. CONCLUSION: Our data provide mechanistic insight into the synergistic clinical benefit of concomitant HCQ with MTX, boosting the rise in MCV, which could serve as a companion biomarker of treatment response.

Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus : A Randomized Controlled Trial.

BACKGROUND: B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness. OBJECTIVE: To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE. DESIGN: Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003). SETTING: England. PARTICIPANTS: Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019. INTERVENTION: Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks. MEASUREMENTS: The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events. RESULTS: At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data. LIMITATIONS: Small sample size; biomarker primary end point. CONCLUSION: Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy. PRIMARY FUNDING SOURCE: Versus Arthritis.

SLE is not a one-size-fits-all disease.

In this Viewpoint we discuss how experimental medicine applied in the setting of clinical trials can address unmet need in the prototypic autoimmune disease systemic lupus erythematosus (SLE) to improve outcomes for patients.

Identification of biomarkers to stratify response to B-cell-targeted therapies in systemic lupus erythematosus: an exploratory analysis of a randomised controlled trial.

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with widespread immune dysregulation and diverse clinical features. Immune abnormalities might be differentially associated with specific organ involvement or response to targeted therapies. We aimed to identify biomarkers of response to belimumab after rituximab to facilitate a personalised approach to therapy. Methods: In this exploratory analysis of a randomised controlled trial (BEAT-LUPUS), we investigated immune profiles of patients with SLE recruited to the 52-week clinical trial, which tested the combination of rituximab plus belimumab versus rituximab plus placebo. We used machine learning and conventional statistics to investigate relevant laboratory and clinical biomarkers associated with major clinical response. BEAT LUPUS is registered at ISRCTN, 47873003, and is now complete. Findings: Between Feb 2, 2017, and March 28, 2019, 52 patients were recruited to BEAT-LUPUS, of whom 44 provided clinical data at week 52 and were included in this analysis. 21 (48%) of 44 participants were in the belimumab group (mean age 39·5 years [SD 12·1]; 17 [81%] were female, four [19%] were male, 13 [62%] were White) and 23 (52%) were in the placebo group (mean age 42·1 years [SD 10·5]; 21 [91%] were female, two [9%] were male, 16 [70%] were White). Ten (48%) of 21 participants who received belimumab after rituximab and eight (35%) of 23 who received placebo after rituximab had a major clinical response at 52 weeks (between-group difference of 13% [95% CI -15 to 38]). We found a predictive association between baseline serum IgA2 anti-double stranded DNA (dsDNA) antibody concentrations and clinical response to belimumab after rituximab, with a between-group difference in major clinical response of 48% (95% CI 10 to 70) in patients with elevated baseline serum IgA2 anti-dsDNA antibody concentrations. Moreover, among those who had a major clinical response, serum IgA2 anti-dsDNA antibody concentrations significantly decreased from baseline only in the belimumab group. Increased circulating IgA2 (but not total) plasmablast numbers, and T follicular helper cell numbers predicted clinical response and were both reduced only in patients who responded to belimumab after rituximab. Serum IgA2 anti-dsDNA antibody concentrations were also associated with active renal disease, whereas serum IgA1 anti-dsDNA antibody and IFN-α concentrations were associated with mucocutaneous disease activity but did not predict response to B-cell targeted therapy. Patients with a high baseline serum interleukin-6 concentration were less likely to have a major clinical response, irrespective of therapy. Interpretation: This exploratory study revealed the presence of distinct molecular networks associated with renal and mucocutaneous involvement, and response to B-cell-targeted therapies, which, if confirmed, could guide precision targeting of advanced therapies for this heterogenous disease. Funding: Versus Arthritis, UCLH Biomedical Research Centre, LUPUS UK, and GSK.

Adalimumab or etanercept as first line biologic therapy in enthesitis related arthritis (ERA) - a drug-survival single centre study spanning 10 years.

OBJECTIVES: To analyse and compare drug-survival of adalimumab and etanercept (and their biosimilars) in biologic-naïve patients with ERA (Enthesitis-Related Arthritis). METHODS: In this retrospective observational study, conventional statistics and machine-learning were applied to compare drug-survival (adalimumab, etanercept and their biosimilars initiated: 2009-2019) in ERA and identify determinants. The primary outcome was discontinuation of treatment due to primary- or secondary-failure and adverse drug-reactions. RESULTS: During the observation period, 99 of 188 patients with ERA on first-line TNF inhibitors (etanercept-n=108, adalimumab-n=80) discontinued their treatment (median survival-time 3.9years, 95%CI 2.6-4.9years). Adalimumab was associated with longer drug-survival compared to etanercept especially after an initial positive response, with the median time to treatment discontinuation 4.9years (95% CI 3.9-5.7) for adalimumab, compared to 2years (95%CI 1.4-4.0) for etanercept (HR of treatment-discontinuation-0.49, 95%CI 0.32--0.75, p=0.001). Adjusted by propensity-score, adalimumab-methotrexate combination was associated with longer drug survival, compared to adalimumab-monotherapy (HR-0.41, 95%CI 0.20-0.85), etanercept-monotherapy (HR-0.28, 95%CI 0.15-0.53), and etanercept-methotrexate combination (HR-0.39, 95%CI 0.21-0.73). The presence of HLA-B27 was associated with longer drug-survival (HR-0.50, 95%CI 0.29-0.87) following an initial positive response. Higher-CRP at baseline was associated with higher rate of primary-failure (HR-1.68, 95%CI 1.08-2.62). Axial-ERA (sacroiliitis±spinal-involvement) was associated with poorer drug-survival for both primary- and secondary-failure (overall HR-2.03, 95%CI 1.22-3.40). Adjusted by propensity-score, shorter drug-survival was observed in patients with baseline-CRP≥12.15 mg/L, but only in the context of axial-ERA, not in peripheral-ERA (no sacroiliitis/spinal-involvement) (HR-2.28, 95%CI 1.13--3.64). CONCLUSION: Following an initial positive primary response, continuing methotrexate with adalimumab was associated with the longest drug-survival compared to adalimumab-monotherapy or etanercept-based regimens. Axial-ERA was associated with a poorer drug-survival. A CRP >12.15 in patients with axial-ERA was associated with a higher rate of primary-failure. Further prospective studies are required to confirm these findings.

CNS Vasculitis in Anti-Synthetase Syndrome.

A 52-year-old woman known to have anti-synthetase syndrome (ASS) with positive anti-alanyl-tRNA synthetase antibody (anti-PL 12) for 4 years presented with headache and progressive deterioration of cognitive functions manifested predominantly by episodes of confusion and dyslexia. Clinical, laboratory and radiological evaluation as well as response to treatment was indicative of vasculitis of the central nervous system (CNS). CNS vasculitis is one of the rare manifestations of inflammatory myositis and no case has been reported to suggest CNS vasculitis in ASS.