Herpes Zoster and Tofacitinib Therapy in Patients With Rheumatoid Arthritis

Objective.To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353).Methods.After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose.Results.In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128.Conclusion.In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.

Objective.To describe the longterm safety and efficacy profile of tofacitinib in patients with moderate to severe active rheumatoid arthritis (RA).Methods.Data were pooled from 2 open-label studies (NCT00413699, NCT00661661) involving patients who had participated in qualifying phase I, II, or III index studies of tofacitinib. Safety data included over 60 months of observation; efficacy data are reported up to Month 48. Treatment was initiated with tofacitinib 5 or 10 mg twice daily. Primary endpoints were adverse events (AE) and laboratory safety data. Secondary endpoints included American College of Rheumatology (ACR) response rates, and Disease Activity Score (28 joints) (DAS28)-4[erythrocyte sedimentation rate (ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) assessments.Results.Overall, 4102 patients were treated for 5963 patient-years; mean (maximum) treatment duration was 531 (1844) days; 20.8% of patients discontinued treatment over 60 months. The most common AE were nasopharyngitis (12.7%) and upper respiratory tract infection (10.5%). Serious AE were reported in 15.4% of patients with an exposure-estimated incidence rate of 11.1 events/100 patient-years. Serious infections were reported in 4.5% of patients with an exposure-estimated incidence rate of 3.1 events/100 patient-years (95% CI: 2.66–3.55). Mean values for laboratory variables were stable over time and consistent with phase II and III studies. Persistent efficacy was demonstrated through Month 48, as measured by ACR response rate (ACR20/50/70) DAS28-4-ESR, and HAQ-DI. Safety and efficacy were similar for patients receiving tofacitinib as monotherapy or with background nonbiologic disease-modifying antirheumatic drugs.Conclusion.Tofacitinib demonstrated consistent safety and persistent efficacy over 48 months in patients with RA.

SummaryIn this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease.