Effectiveness and Safety of Tofacitinib in Canadian Patients With Rheumatoid Arthritis: Primary Results From a Prospective Observational Study

Abstract

Objective: The Canadian Tofacitinib for Rheumatoid Arthritis Observational (CANTORAL) is the first Canadian prospective, observational study assessing tofacitinib. The objective was to assess effectiveness and safety for moderate to severe rheumatoid arthritis (RA). Coprimary and secondary outcomes are reported from an interim analysis.

Methods: Patients initiating tofacitinib from October 2017 to July 2020 were enrolled from 45 Canadian sites. Coprimary outcomes (month 6) included the Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA) and remission. Secondary outcomes (to month 18) included the CDAI and the 4-variable Disease Activity Score in 28 joints (DAS28) using the erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level to define LDA and remission; the proportions of patients achieving mild pain (visual analog scale <20 mm), and moderate (≥30%) and substantial (≥50%) pain improvements; and the proportions of patients achieving a Health Assessment Questionnaire disability index (HAQ DI) score greater or equal to normative values (≤0.25) and a HAQ DI score greater or equal to minimum clinically important difference (MCID) (≥0.22). Safety was assessed to month 36.

Results: Of 504 patients initiating tofacitinib, 44.4% received concomitant methotrexate. At month 6, 52.9% and 15.4% of patients were in CDAI-defined LDA and remission, respectively; a similar proportion of patients achieved outcomes by month 3 (first post-baseline assessment). By month 3, 27.2% and 41.7% of patients, respectively, were in DAS28-ESR-defined LDA and DAS28-CRP <3.2; 14.7% and 25.8% achieved DAS28-ESR remission and DAS28-CRP <2.6. By month 3, mild pain and moderate and substantial pain improvements occurred in 29.6%, 55.6%, and 42.9% of patients, respectively; 19.9% and 53.7% of patients achieved a HAQ DI score greater than or equal to normative values and a HAQ DI score greater than or equal to MCID, respectively. Outcomes were generally maintained to month 18. Incidence rates (events per 100 patient-years) for treatment-emergent adverse events (AEs), serious AEs, and discontinuations due to AEs were 126.8, 11.9, and 14.5, respectively, and AEs of special interest were infrequent.

Conclusion: Tofacitinib was associated with early and sustained improvement in RA signs and symptoms in real-world patients. Effectiveness and safety were consistent with the established tofacitinib clinical profile.

Figure 1

Achievement of disease activity thresholds over time for patients receiving tofacitinib. A, CDAI‐, DAS28‐4(ESR)–, and DAS28‐4(CRP)–defined LDA and remission; B, ACR20/50/70 response rates. For A, the dotted line at month 6 indicates the time point for assessment of the coprimary end points (achievement of CDAI‐defined LDA and remission). Error bars correspond to the 95% confidence interval (95% CI) around the response rates. Remission and LDA values for DAS28‐4(CRP) (<2.6 and <3.2, respectively) have not been validated (ref. 24), but are commonly used in rheumatology (ref. 25). ACR20/50/70 = American College of Rheumatology criteria for 20%, 50%, or 70% improvement in disease activity; CDAI = Clinical Disease Activity Index; DAS28‐4(CRP) = 4‐variable Disease Activity Score in 28 joints using the C‐reactive protein level; DAS28‐4(ESR) = DAS28 using the erythrocyte sedimentation rate; LDA = low disease activity; n = number of patients meeting response criteria; N = number of patients with available data at each visit.

Figure 2

Achievement of patient‐reported response thresholds over time in patients receiving tofacitinib. A, Patient‐reported pain (visual analog scale [VAS]); B, Health Assessment Questionnaire disability index (HAQ‐DI); C, Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐F). MCID = minimum clinically important difference; n = number of patients meeting response criteria; N = number patients with available data at each visit; n/a = not applicable. Error bars indicate the 95% confidence interval (95% CI).

Figure 3

Kaplan‐Meier time to discontinuation in the overall study population (Canadian Tofacitinib for Rheumatoid Arthritis Observational [CANTORAL] study ongoing at data cut, July 16, 2021). Broken line shows the median survival rate. * = time from treatment initiation until premature study discontinuation or last available assessment date. † = mean (SE) survival time may have been underestimated because the estimation was restricted to the largest observation, which was censored. 95% CI = 95% confidence interval; FAS = full analysis set; NE = nonestimable.