OP0182 Prevention of Rheumatoid Arthritis by B Cell Directed Therapy in The Earliest Phase of The Disease: The Prairi Study

Abstract

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...

A Prospective Study of the Development of Inflammatory Arthritis in the Family Members of Indigenous North American People With Rheumatoid Arthritis

“…Double seropositivity for ACPAs and RF was associated with the highest rates of inflammatory arthritis development and the shortest latency period, consistent with findings in other cohorts. Some practitioners treat ACPA/RF double‐seropositive individuals with hydroxychloroquine, and several ongoing clinical trials are targeting this patient population using other strategies . Surprisingly, the multistate modeling indicated that the likelihood of ACPA/RF double seropositivity reverting to seronegativity after 5 years was >30%.…”

Patients' Perceptions of Their Relatives' Risk of Developing Rheumatoid Arthritis and of the Potential for Risk Communication, Prediction, and Modulation

“…Research efforts are therefore being directed toward the earliest stages of RA and toward the identification of biomarkers predictive of future RA development, to facilitate early treatment and preventive interventions for those at risk . Clinical trials are underway to evaluate therapeutic intervention for individuals with arthralgia but without clinically manifest arthritis , and promising early results may herald a paradigm shift from treatment toward prevention of RA .…”

The 2016 Eular Guidelines for the Diagnosis and Treatment of Early Arthritis

“…Новые перспективы кардинального улучшения исхо-дов РА связаны с возможностью профилактики развития заболевания в «преартритической» фазе, проявляющейся так называемыми «клинически подозрительной артралги-ей» (clinically suspect arthralgia) или АЦЦП-позитивной артралгией, при которых годовой риск развития РА соста-вляет 32-35%, а трехлетний риск достигает 50% [138,139]. Предварительные результаты исследования PRAIRI (Prevention of RA by RItuximab) свидетельствуют о замедле-нии прогрессирования заболевания у пациентов с РФ/АЦБ-позитивными артралгиями и субклиническими признаками синовита, получивших инфузию анти-В-кле-точного препарата ритуксимаба [133]. В настоящее время запланирована серия исследований, касающихся оценки эффективности ГХ (исследование SropRA -Strategy to prevent the onset of clinically Apparent Rheumatoid Arthritis), МТ (TREAT EARLIER -Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis), блокатора костимуляции Т-лимфоцитов АБЦ (APIPPRA -Arthritis Prevention In the Preclinical Phase of Rheumatoid Arthritis with Abatacept и ARIAA -Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACCP Positive Arthralgia), аторвастатина (STAPRA -STAtins to Prevent Rheumatoid Arthritis) в отношении предотвращения РА у пациентов с артралгиями, имеющими риск развития РА.…”