ObjectivesWe explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development.MethodsIndividuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo.ResultsEighty-one individuals received treatment and were followed up for a mean of 29.0 (0–54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development.ConclusionsA single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.

We would like to thank Dr Arnaud et al 1 for their comment on our article discussing the prognostic value of salivary gland assessments in primary Sjögren's syndrome ( pSS). 2 One of our findings was that having a lymphocytic focus score (LFS) ≥3 (number of foci/4 mm 2 ) at the time of diagnosis contributes significantly to the risk of lymphoma development during pSS disease course. We agree that the follow-up time after biopsy is important to take into account because differences observed could merely be a result of the time that patients have been followed. As displayed in our article, we therefore analysed the incidence rate of non-Hodgkin's lymphoma (NHL) per 1000 person-years and showed that the incidence rate was higher for patients with an LFS ≥3 than those with an LFS of either 1 or 2 (NHL incidence rate of 3.7 for LFS=1, 2.4 for LFS=2 and 12.8 for LFS ≥3, respectively, with a total of 1169 person-years at risk).As suggested, we have additionally performed Kaplan-Meier survival analysis and Cox's proportional hazard regression analysis. The Kaplan-Meier curve showed reduced survival for the patient group with an LFS ≥3 (Log-rank test: p=0.009). Using Cox's proportional hazard regression analysis, we observed that an LFS ≥3 was significantly associated with the development of NHL both in a univariate analysis (HR 6.2; 95% CI 1.3 to 29.3; p=0.021) and when adjusting for anti-SSA, anti-SSB, ≤40% immunoglobulin (Ig)A plasma cells and ≥25% IgM plasma cells in salivary gland specimens (HR 9.9; 95% CI 1.2 to 82.4; p=0.034).In addition, in the original manuscript, we had performed multivariable linear regression analysis to assess the association between LFS ≥3 and development of NHL. The results of multivariable logistic regression analysis, which is indeed more appropriate (variables in the equation: anti-SSA, anti-SSB, LFS ≥3, ≤40% IgA plasma cells and ≥25% IgM plasma cells in salivary gland specimens), are comparative to our previously reported findings and show independent and significant prediction for lymphoma development of LFS ≥3 (OR 14.72; 95% CI 1.6 to 136.4; p=0.018).Together, these results confirm our previous analyses that an LFS ≥3 might help to identify pSS patients with an increased risk for development of NHL.

BackgroundSystemic autoimmunity may precede the development of clinical signs and symptoms of seropositive rheumatoid arthritis (RA), which offers a window of opportunity to delay or prevent clinically manifest arthritis by targeted intervention. This could represent a paradigm shift from treatment to prevention1.ObjectivesTo explore if a single infusion of rituximab (anti-CD20 antibody) can prevent or delay the onset of clinically manifest arthritis in individuals at risk of developing autoantibody positive RA.MethodsEighty-two subjects with arthralgia who had never had clinically manifest arthritis and never used disease-modifying antirheumatic drugs were included in a multicentre, randomised, double-blind, placebo-controlled clinical trial. They were positive for both anti-citrullinated protein antibodies (ACPA) and rheumatoid factor and they had CRP levels ≥3 mg/l and/or subclinical synovitis on ultrasound or MRI of the hands. Subjects were randomized to receive a single iv infusion of either 1000 mg rituximab or placebo after 100 mg methylprednisolone premedication in each group. Subjects were prospectively followed to assess development of clinically manifest arthritis. We performed Kaplan-Meier survival analysis, Cox regression analysis and determined Treatment*Time Cox proportional hazards.ResultsEighty-one individuals (52 females; mean age 53 (IQR 13.5) years) received treatment, which was generally well tolerated. One patient withdrew before treatment. The median follow up was 27.0 months (IQR 25.0), during which 30 subjects developed arthritis: 16/40 (40%) in the placebo group and 14/41 (34%) in the rituximab group, after a median period of 11.5 (interquartile range [IQR] 12.5) months in the placebo group versus 16.5 (IQR 19.0) months in the rituximab group. Whereas the risk for development of arthritis in the placebo group was 40%, we found a reduction of 53% of this risk in the rituximab group at 18 months follow up (HR (95%CI)=0.475 (0.190–1.191)). At the 25% quartile (75% free of arthritis) of the cumulative arthritis-free survival, there was a delay in the development of arthritis of 12.0 months (12 months in the placebo group versus 24 months in the rituximab group. As expected, this effect attenuated over time. Treatment*Time Cox proportional hazard analysis showed that the beneficial effect of rituximab was statistically significant (P<0.0001)ConclusionsA single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA. This is the first study evaluating the effects of a biopharmaceutical in this population, and the results strongly support the rationale for future clinical trials aimed at prevention of RA by a targeted intervention.ReferencesGerlag DM, Norris JM, Tak PP. RA: from risk factors and pathogenesis to prevention: Towards prevention of autoantibody-positive rheumatoid arthritis: from lifestyle modification to preventive treatment. Rheumatology (Oxford). 2015 Sep 15. ReviewAcknowledgementN de Vries, DJ van Schaardenburg, E Brou...

Background:For rheumatoid arthritis (RA) patients included in clinical trials, background treatment with glucocorticoids (GCs) is quite common (40–60%), but their potential contribution to efficacy and safety of the disease modifying anti-rheumatic drug (DMARD) tested in that trial has rarely been evaluated.Objectives:To establish whether a stable GC dose at baseline and during the study contributed to the efficacy and safety of TCZ monotherapy initiated in RA patients in 4 TCZ RCTs. In addition, to investigate the same issue in the comparator arms of these trials, in which adalimumab (ADA) or methotrexate (MTX) was initiated.Methods:Data from 4 randomized controlled double-blind trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with TCZ monotherapy arms was analysed in this post hoc analysis [1–4]. Study participants were MTX-naïve, intolerant or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Because of differences between the studies in region, and baseline RA duration and disease severity, analyses were done separately for each study. Stable GC dose at baseline was allowed and was to be continued unchanged during the first 24 weeks. Analyses of covariance (ANCOVA) of change from baseline to Week 24 in CDAI and DAS28 and logistic regression analyses at Week 24 for CDAI remission and ACR50 were performed. Repeated measures analyses using all visits up to week 24 were also done. Incidence rates of serious adverse events (SAEs) were assessed by GC use.Table 1Disease Activities at week 24 of GC Users versus non-GC Users per Treatment per StudyResults:Baseline characteristics were mostly comparable between GC users and non-GC users in each treatment arm for each study. The adjusted differences (95% CIs) of CDAI change at week 24 between GC and non-GC users in TCZ arms of AMBITION, FUNCTION, ACT-RAY and ADACTA were -1.4 (-4.8, 2.1), 0.8 (-2.5, 4.1), 1.2 (-4.0, 6.3) and -4.2 (-9.7, 1.4), respectively (table 1). CDAI remission rates, ACR50 response rates and DAS28 score changes at 24 weeks neither were significantly different between GC users and non-GC users in the TCZ arms, nor in the MTX and ADA arms (table 1). Repeated measures analyses to week 24 showed no significant differences in DAS28 or CDAI. Statistically significant predictors for the various clinical outcomes included baseline CDAI, baseline DAS28, age, sex, RA duration and region. A numerically higher but not significantly different SAE rate was seen in the GC-arms of all four trials, compared to the non-GC-arms.Conclusions:No evidence was found that GC treatment at baseline and continued at a stable dose affects either clinical efficacy or safety over 24 weeks of TCZ, MTX, or ADA monotherapy initiated at baseline in RA clinical trials.References[1]Jones G, et al. Ann Rheum Dis2010;69:88–96.[2]Dougados M, et al. Ann Rheum Dis2013;72:43–50.[3]Gabay C, et al. Lancet2013;381:1541–50[4]Burmester GR, et al. Ann Rheum Dis2017;76:1279–84.Disclosure of Interest:M. Safy Grant/research support from: Research grant from AZ, J. Jacobs: None de...