A JAK Inhibitor for Treatment of Rheumatoid Arthritis: The Baricitinib Experience

Abstract

Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved as monotherapy or in combination with methotrexate for treating adults with moderate-to-severe active rheumatoid arthritis (RA) and provides improvements in clinical signs, symptoms and patient-reported outcomes. Currently, baricitinib is approved for treating RA in more than 75 countries. In several pivotal Phase II and III RA trials (RA-BALANCE, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BEYOND), up to seven years of baricitinib treatment was well tolerated and provided rapid and sustained efficacy, which was confirmed in real-world settings. Safety signals for another JAK inhibitor, tofacitinib, have emerged, as observed in the post-marketing Phase IIIb/IV trial Oral Rheumatoid Arthritis Trial (ORAL) Surveillance; safety signals were subsequently highlighted in a retrospective study of baricitinib and consequently new recommendations and warnings and precautions for all JAK inhibitors have been issued. Ongoing studies to further characterise and clarify the benefit:risk of JAK inhibitors include registries and controlled trials. This capstone review summarises clinical and real-world data outlining the benefit:risk profile of baricitinib, confirming that the improved disease activity and physical function of patients with RA treated with this JAK inhibitor observed in clinical trials is translated into effectiveness in clinical practice, with a low rate of discontinuations.

Keywords: baricitinib; randomised controlled trial; real-world evidence; rheumatoid arthritis.

Figure 1

Long-term efficacy of baricitinib in RA-BEYOND according to originating study (RA-BEAM or RA-BUILD) ^a: (a) CDAI remission (≥2.8); (b) CDAI LDA (≥10). Adapted from a presentation by Caporali and colleagues [37]. ^a Data were also collected in RA-BEYOND from patients randomised to placebo or adalimumab in the originating studies; the data shown here are from patients in the baricitinib treatment groups for the entire study duration. ^b Year three corresponds to 156 weeks of the originating study RA-BUILD and 160 weeks of the originating study RA-BEAM. ^c Year seven corresponds to 360 weeks of the originating study RA-BUILD and 364 weeks of the originating study RA-BEAM. ^d Entry to RA-BEYOND was at 24 weeks of the originating study RA-BUILD and 52 weeks of the originating study RA-BEAM. ^e Patients were analysed by treatment assigned at randomisation in the originating study, regardless of rescue. CDAI, Clinical Disease Activity Index; LDA, low disease activity; W, week.

Figure 2

Treat-to-target goals of remission/LDA with BARI at six months of treatment in real-world studies and in RCTs in patients with RA. The included studies are: BEAM [6], BEACON [8], BSRBR-RA [29], ORBIT-RA [60], IPS [64], TBCR-RA [74], Iwamoto et al. [75], JPMS [76], RA-BE-REAL [77], Sapienza University study [78], LTHT [81]. ^a LDA was defined as DAS28-CRP ≤3.2, DAS28-ESR ≤3.2, CDAI ≤10. ^b Remission was defined as DAS28-CRP <2.6, DAS28-ESR <2.6, CDAI ≤2.8. ^c Blue bars indicate RWE reporting a pooled BARI dose group and red bars indicate RCT data from patients on BARI 4 mg. ^d REM value extrapolated from a graph [60]. ^e LDA was defined as DAS28-CRP ≤3.1. ^f LDA was defined as CDAI ≤11.0; remission was defined as CDAI ≤3.3. BARI, baricitinib; BSRBR-RA, British Society for Rheumatology Biologics Register for Rheumatoid Arthritis; CDAI, Clinical Disease Activity Index; DAS28-CRP, Disease Activity Score in 28 joints—C-reactive protein; DAS28-ESR, Disease Activity Score in 28 joints—erythrocyte sedimentation rate; IPS, Italian prospective study; JPMS, Japan post-marketing surveillance; LDA, low disease activity; LTHT, Leeds Teaching Hospitals NHS Trust database; n = number of patients in the study-specific baricitinib group; RA, rheumatoid arthritis; RCT, randomised controlled trial; RWE, real-world evidence; TBCR, Tsurumai Biologics Communication Registry.

Figure 3

Rates of AEs of special interest with baricitinib in RCTs, a PMS study in Japan and in the general RA population [76,117,118,119,120]. ^a Herpes zoster incidence is higher in Asia compared to North America and Europe [121]. AEs, adverse events; BARI, baricitinib; excl., excluding; IR, incidence rate; MACE, major adverse cardiovascular events; NMSC, non-melanoma skin cancer; PMS, post-marketing surveillance; PY, patient-years; RA, rheumatoid arthritis; RCT, randomised controlled trial; VTE, venous thromboembolism; YFU, years follow-up.

Figure 4

Differences in the reported risk of: (a) MACE; (b) VTE for baricitinib versus TNFis ^a in patients with RA according to different real-world analyses [33,79,80,97]. ^b Note that the reported data are from different analyses (weighted HR, adjusted HR and IRR) and therefore cannot be considered directly comparative. The side-by-side presentation is for illustrative purposes only. ^a All data are for baricitinib versus TNFis, with the exception of the ARTIS MACE analyses for which the comparator was the TNFi etanercept. ^b Table 4 shows the designs of the reported analyses. ^c Weighted using inverse probability of treatment weighting method and concomitant administration of MTX as a time-varying variable. Propensity score included age, sex, use of ≥1 csDMARD and use of bDMARD (within two years before index date and at index date), comorbidities (obesity, diabetes, COPD, severe chronic renal disease, dyslipidaemia, hypertension, atherosclerosis of extremities and history of CV or thromboembolic events within 10 years), use of systemic corticosteroids and NSAIDs within two years before index date and at index date, antiplatelet agents, anticoagulants. ^d Calculated after nearest-neighbour propensity score matching of treatment groups (baricitinib:TNFi) to balance baseline risk factors. Variables considered for inclusion in the propensity score models were risk factors specific to each outcome, including patient demographics, medical history (including comorbidities) and treatments for RA, where available from the original sources. ^e Weighted using baseline patient characteristics (age, sex, immigrant status, highest achieved education, rheumatoid factor/anti-citrullinated protein antibodies, RA duration, previous b/tsDMARD use, co-medication with conventional synthetic DMARDs and glucocorticosteroids, the 28-joint disease activity score, the Health Assessment Questionnaire-Disability Index, history of malignancy, infections, joint surgery, chronic pulmonary disease, diabetes, cardiovascular disease, depression and the sum of days hospitalized in last five years) from Cox regression adjusted with stabilised inverse probability of treatment weights constructed as the inverse of the predicted probability to have received the treatment actually received, multiplied by the sample proportion with the same treatment. ^f Estimated using Cox proportional hazards regression, adjusted for age, sex, line of therapy, comorbidities, socioeconomic variables, RA disease variables, civil status and smoking, using an indicator for missing variables. ARTIS, Anti-Rheumatic Therapy in Sweden; bDMARD, biologic disease-modifying antirheumatic drug; COPD, chronic obstructive pulmonary disease; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CV, cardiovascular; HR, hazard ratio; IRR, incidence rate ratio; MACE, major adverse cardiovascular events; MTX, methotrexate; NSAIDs, non-steroidal anti-inflammatory drugs; RA, rheumatoid arthritis; SNDS, Système National des Données de Santé (French national health data system); TNFi, tumour necrosis factor inhibitor; tsDMARD, targeted-synthetic disease-modifying antirheumatic drug; VTE, venous thromboembolism.