Long-term mortality in treated-to-target RA and UA: results of the BeSt and IMPROVED cohort

Abstract

Objectives: To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA).

Methods: The BeSt (BehandelStrategieën) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)≤2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed.

Results: Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy.

Conclusions: After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor.

Keywords: Epidemiology; Outcome Assessment, Health Care; Rheumatoid Arthritis.

Figure 1

20-year survival of BeSt study participants (from baseline until end of 2021) compared with the age-matched and sex-matched reference population.

Figure 2

Standardised mortality ratios (SMRs; 20-year follow-up) per treatment strategy arm of BeSt. Arm 1: sequential monotherapy (n=126), SMR 1.46 (95% CI 1.10 to 1.95); arm 2: step-up combination therapy (n=121), SMR 1.34 (95% CI 0.99 to 1.82); arm 3: initial combination with methotrexate (MTX)+sulfasalazine + prednisone (n=133), SMR 1.36 (95% CI 1.02 to 1.81); arm 4: initial combination with MTX+infliximab (n=128), SMR 1.11 (95% CI 0.81 to 1.53). SMR is based on a sex-matched and age-matched reference population.

Figure 3

Survival curve of Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study participants compared with the reference population.

Figure 4

Standardised mortality ratios (SMRs; 13-year follow-up) per treatment strategy arm of Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED). Early remission: patients in remission after 4 months (n=387), SMR 1.19 (95% CI 0.93 to 1.53); arm 1: not remission at 4 months, escalating to methotrexate (MTX)+hydroxychloroquine + sulfasalazine (n=83), SMR 0.88, 95% CI 0.40 to 1.97); arm 2: not in remission at 4 months, escalating to MTX+adalimumab (n=78), SMR 2.00 (95% CI 1.23 to 3.27); out of protocol: not in remission at 4 months but not randomised (n=50), SMR 2.05 (95% CI 1.13 to 3.69).