Improvement Thresholds for Morning Stiffness Duration in Patients Receiving Delayed- Versus Immediate-Release...

Morning stiffness, a common patient reported symptom in rheumatoid arthritis, is associated with an increase in early morning inflammatory cytokines and significant disability. Little is known about categorical morning stiffness responses to glucocorticoid use in rheumatoid arthritis patients. Chronic pain threshold models have indicated previously that response rates of 15% to 30% indicate minimally important relief, 40% to 50% indicate substantial pain relief, and greater than 70% represents extensive pain relief. The objective of the present analysis was to assess differences in the percentages of patients achieving 25%(minimally important change), 50% (substantial change), and 75% (extensive change) reduction in the duration of patient-reported morning stiffness between patients receiving DR- and IR-prednisone in the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) trial.

The CAPRA-1 trial was a 12-week, double-blind study followed by an additional 9-month open-label extension. Patients in the CAPRA-1 trial were randomized to IR-prednisone in the morning or DR-prednisone at bedtime in addition to stable disease modifying antirheumatic drug therapy. After the double-blind phase, patients randomized to IR-prednisone (N =110) were switched to DR-prednisone and followed at 3, 6, and 9 months in an open-label extension phase. Patients originally randomized to DR-prednisone (N = 97) continued that therapy in the open-label extension. Patient morning stiffness diary entries from 4 weeks before and 4 weeks after each scheduled visit were analyzed over 1 year for threshold response. The number of patients reaching threshold response (25%, 50%, and 75% improvement) and time to morning stiffness response were examined.

The DR-prednisone arm had significantly more responders in all three morning stiffness threshold response categories at the end of the double-blind period compared with IR-prednisone (p ≤ 0.05). Patients who switched from IR- to DR-prednisone in the open-label extension had comparable responses in all categories within 3 months and significantly shorter time to response versus patients already receiving DR-prednisone.

DR-prednisone produced significantly higher morning stiffness response rates compared with IR prednisone, as defined by 25%, 50%, and 75% improvement thresholds, at week 12. The time to reach these thresholds was quicker with DR-prednisone, and patients who switched to DR-prednisone from IR-prednisone achieved responses comparable to the continuous DR-prednisone group over 9 months of therapy. This analysis is the first to assess time-to-event and percentage threshold morning stiffness responses to differently timed glucocorticoid therapy and propose clinically meaningful response rates in RA patients.