Spring 2025 Press Review – Lancet Rheumatology

December 2024 to March 2025

Author: Antony Psarras and Rositsa Dacheva

Cenerimod, a sphingosine-1-phosphate receptor modulator, versus placebo in patients with moderate-to-severe systemic lupus erythematosus (CARE): an international, double-blind, randomised, placebo-controlled, phase 2 trial

Askanase A, et al. (doi:10.1016/S2665-9913(24)00246-7) aimed to determine the efficacy, safety and tolerability of four doses of cenerimod, a selective sphingosine-1-phosphate (S1P₁) receptor modulator, in adults with moderate-to-severe SLE receiving standard of care background therapy. CARE was a double-blind, randomised, placebo-controlled, phase 2 trial in adults (aged 18–75 years) with moderate-to-severe SLE. The primary endpoint was change from baseline to month six in mSLEDAI-2K score, assessed in all participants randomly assigned to treatment. 810 patients were screened and 427 were randomly assigned to 0.5 mg (n=85), 1 mg (n=85), 2 mg (n=86), and 4 mg (n=85) cenerimod or placebo (n=86). At month six, the least squares mean change from baseline in mSLEDAI-2K score was not statistically significant between the placebo group and the treatment groups. Treatment-emergent adverse events up to 12 months had no clear treatment-related or dose-related pattern across the groups. The primary endpoint was not met. Cenerimod was well tolerated over 12 months. Cenerimod 4 mg is being investigated for the treatment of SLE in two ongoing phase 3 trials (NCT05648500, NCT05672576).

CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series

Auth J, et al. (doi:10.1016/S2665-9913(24)00282-0) presented a detailed analysis of the effects of CD19-targeting CAR T-cell therapy in patients with systemic sclerosis. Six patients with severe diffuse systemic sclerosis with an insufficient response to at least two treatments were consecutively recruited to receive CD19-targeting CAR T-cell treatment (1 × 10⁶ CAR T cells per kg bodyweight). Events were pre-defined as: progression of interstitial lung disease, onset of congestive heart failure, onset of renal failure, onset of arterial hypertension or initiation of new immunosuppressive or antifibrotic therapy. The median follow-up time was 487 days (IQR 342–585). No events occurred within the observational period. The probability of improvement in the ACR-CRISS score increased to a median of 100% (IQR 100–100) at 6 months. Median mRSS decreased by 31% (IQR 29–38), corresponding to a median of 8 points (IQR 7–13) within 100 days. The extent of disease on CT scan decreased by a median of 4% (IQR 3–4) due to reduction of ground-glass opacities, while the reticular pattern remained stable. Forced vital capacity improved by a median of 195 mL (IQR 18–275) at the latest observational timepoint. This study provided evidence that CD19-targeting CAR T-cell therapy might intercept with the progression of fibrotic organ manifestations in patients with systemic sclerosis.

Cardiovascular events in patients with gout initiating urate-lowering therapy with or without colchicine for flare prophylaxis: a retrospective new-user cohort study using linked primary care, hospitalisation, and mortality data

Cipolletta E, et al. (doi: 10.1016/S2665-9913(24)00248-0) aimed to estimate the risk of cardiovascular events in patients with gout initiating urate-lowering therapy and colchicine as flare prophylaxis compared with no prophylaxis.The authors used a retrospective new-user cohort study using data from the Clinical Practice Research Datalink Aurum, an English primary-care database linked to hospitalisation and mortality records. Of the 111,460 patients eligible for the study, 99,800 patients with gout initiating urate-lowering therapy were included. 4,063 (4.1%) patients had previous cardiovascular events and 16,028 (16.1%) patients were prescribed colchicine prophylaxis. Patients with colchicine prophylaxis had significantly lower risk of cardiovascular events compared with those without prophylaxis. The weighted rates of cardiovascular events were 28.8 per 1000 person-years (95% CI 25.2 to 33.2) in patients with colchicine prophylaxis and 35.3 per 1000 person-years (33.0 to 37.9) in those without prophylaxis. Findings were similar across analytical approaches, stratified analyses and for secondary outcomes. In patients with gout initiating urate-lowering therapy, the risk of cardiovascular events was reduced in those prescribed colchicine prophylaxis compared with no prophylaxis. These findings provide an additional argument for using colchicine for gout flare prophylaxis.

Development of rheumatoid arthritis after methotrexate in anti-citrullinated protein antibody-negative people with clinically suspect arthralgia at risk of rheumatoid arthritis: 4-year data from the TREAT EARLIER trial

Dumoulin Q, et al (doi:10.1016/S2665-9913(24)00196-6) investigated the risk of developing rheumatoid arthritis (RA) in ACPA-negative people with clinically suspected arthralgia at risk of developing RA. They used 4-year data from the TREAT EARLIER trial, a randomised, double-blind, placebo-controlled, proof-of-concept trial conducted in the southwest region of the Netherlands. 901 people with clinically suspect arthralgia were assessed for eligibility and 236 were enrolled in TREAT EARLIER. After 4 years, 52 (22%) of 236 participants had developed the primary outcome of RA (25 [21%] of 119 in the treatment group and 27 [23%] of 117 in the placebo group). After risk stratification, a 1-year course of methotrexate was associated with a reduced rate of development of ACPA-negative RA in participants with predicted increased risk of developing the disease. Subclinical joint inflammation, physical functioning, and grip strength persistently improved upon treatment in ACPA-negative participants with increased risk of developing RA, but not in those with low risk.