Background/Purpose: Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor for the treatment of RA. The importance of “treat to target” in RA to attain remission and subsequently prevent structural damage is established.

Objectives: To examine the relationship between attainment of clinical remission at Months (Mo) 3 or 6 with inhibition of radiographic progression at Mo 12 in methotrexate (MTX)-naïve patients (pts) in the Phase 3, 24-mo ORAL Start trial (NCT01039688). Pre-planned interim 1-year analyses, including primary efficacy endpoints, were reported previously.¹

Methods: 952 pts were randomized 2:2:1 to tofacitinib 5 mg BID, 10 mg BID or MTX. Endpoints included remission defined by DAS28-4(ESR) <2.6, SDAI ≤3.3, CDAI ≤2.8 and ACR-EULAR Boolean-based criteria by observed data and van der Heijde modified Total Sharp Score (mTSS) linear extrapolation; the definition of non-progression was change from baseline in mTSS ≤0.5. Rates were calculated for radiographic non-progression at Mo 12 by remission at Mo 3 or 6.

Results: Across all definitions of remission, rates at Mo 3 and 6 were lower with MTX (3-8% and 11-14%; N=186) than tofacitinib 5 (29-46% and 37-49%; N=371) and 10 mg BID (39-64% and 73-84%; N=395). The positive predictive values of remission by various criteria at Mo 3 or 6 for radiographic non-progression at Mo 12 are presented in the table. Across all definitions of remission, a high proportion of pts receiving tofacitinib 10 mg BID in remission at Mo 3 and 6, respectively, had no radiographic progression at Mo 12 (94-95% and 89-92%). For pts receiving tofacitinib 5 mg BID, 69-80% were in remission at Mo 3 and had no radiographic progression at Mo 12, according to the stringency of the definition utilized, which increased to 78-85% for Mo 6 remission. 83-100% of the few patients on MTX in remission at Mo 3 or 6 had no radiographic progression at Mo 12. The proportion of pts who failed to achieve radiographic non-progression at Mo 12 following remission at Mo 3 and 6 (not shown in table) were: tofacitinib 5 mg BID, 18-31% and 15-22%; tofacitinib 10 mg  BID, 5-15% and 7-14%; MTX, 0-36% and 7-38%, respectively. Among the patients who did not achieve remission at Mo 3 and 6 (not shown in table), more pts receiving tofacitinib still achieved radiologic non-progression than with MTX (tofacitinib 5 mg BID, 80-83% and 82-84%; tofacitinib 10 mg  BID, 85-94% and 85-92%; MTX, 63-100% and 60-93%).

Conclusion: These results indicate that clinical remission within 3 or 6 months of treatment initiation has limited value in predicting radiological non-progression at Mo 12 in MTX-naïve RA pts treated with tofacitinib. This may be due to the high proportion of pts achieving radiological non-progression with tofacitinib treatment overall, in that pts who do not achieve remission criteria at Mo 3 or 6 may still benefit from structure preservation through Mo 12.

References:1. Lee EB et al. Arthritis Rheum 2012; 64(10 [supplement]):S1049

 

	Tofacitinib 5 mg BID (N=371) (n/N) % [95% CI]	Tofacitinib 10 mg BID (N=395) (n/N) % [95% CI]	Methotrexate (N=186) (n/N) % [95% CI]
Remission Criteria^ at Month 3 to Positively Predict Nonprogression@ in mTSS at Month 12
DAS28-4(ESR)	(36/46) 78.3% [63.6, 89.1]	(60/64) 93.8% [84.8, 98.3]	(8/8) 100.0% [63.1, 100.0]
SDAI	(28/35) 80.0% [63.1, 91.6]	(51/54) 94.4% [84.6, 98.8]	(4/4) 100.0% [39.7, 100.0]
CDAI	(26/33) 78.8% [61.1, 91.0]	(42/44) 95.5% [84.5, 99.4]	(5/6) 83.3% [35.9, 99.6]
ACR-EULAR Boolean	(20/29) 69.0% [49.2, 84.7]	(37/39) 94.9% [82.7, 99.4]	(3/3) 100.0% [29.2, 100.0]
Remission Criteria^ at Month 6 to Positively Predict Nonprogression@ in mTSS at Month 12
DAS28-4(ESR)	(41/49) 83.7% [70.3, 92.7]	(70/78) 89.7% [80.8, 95.5]	(12/13) 92.3% [64.0, 99.8]
SDAI	(37/44) 84.1% [69.9, 93.4]	(77/84) 91.7% [83.6, 96.6]	(13/14) 92.9% [66.1, 99.8]
CDAI	(35/41) 85.4% [70.8, 94.4]	(72/78) 92.3% [84.0, 97.1]	(12/13) 92.3% [64.0, 99.8]
ACR-EULAR Boolean	(29/37) 78.4% [61.8, 90.2]	(68/73) 93.2% [84.7, 97.7]	(10/11) 90.9% [58.7, 99.8]
^Remission definitions: DAS28-4(ESR), Disease Activity Score for 28-joint counts and erythrocyte sedimentation rate <2.6; SDAI, simplified disease activity index ≤3.3; CDAI, clinical disease activity index ≤2.8; ACR-EULAR Boolean requires ≤1 swollen and ≤1 tender joint, Patient Global (0-10) ≤1, C-Reactive Protein (mg/dL) ≤1. @Nonprogression in modified Total Sharp Score (mTSS) (change ≤0.5) at Month 12, imputed using linear extrapolation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/remission-at-3-or-6-months-and-radiographic-non-progression-at-12-months-in-methotrexate-naive-rheumatoid-arthritis-patients-treated-with-tofacitinib-or-methotrexate-a-post-hoc-analysis-of-the-oral-s/