The concept of difficult-to-treat disease in rheumatology: where next?

Lancet Rheumatol. 2025;7:e274–89 doi: 10.1016/S2665-9913(24)00340-0

Nagy et al. propose a unifying and holistic framework for understanding and addressing the concept of difficult-to-treat (D2T) disease across rheumatology, integrating cross-disciplinary evidence and recommending its incorporation into future disease management strategies. The D2T state requires a comprehensive, holistic, multidisciplinary approach that considers the specific characteristics of each disease and the personalised needs of the patient.

Mariette et al. investigated the long-term safety of filgotinib with regard to MACE, VTE and malignancy across RA and UC clinical trial populations. Rates of these events remained low overall, with some increases observed in patients aged 65 years and older.

March 2025

Floris et al. conducted a monocentric cohort study to assess the impact of biologic treatment on the development of PsA in patients with PsO. Treatment with biologics significantly reduced the likelihood of PsA development, with lower prevalence observed across different biologic classes and patterns of joint involvement.

Zavoriti and Miossec explored the impact of tofacitinib on inflammation and coagulation in RA. Tofacitinib reduced synovial and vascular inflammation by inhibiting IFNɣ, IL-17A, and IL-6 production but failed to prevent the prothrombotic effects of inflammatory cytokines on endothelial cells. These findings suggest that while tofacitinib reduces inflammation, it does not mitigate associated thrombotic risk.

February 2025

Sands et al. evaluated tamuzimod, a selective sphingosine 1-phosphate receptor 1 modulator, in patients with moderately-to-severely active UC. At Week 13, clinical remission (defined as an MMS stool frequency subscore of ≤1, rectal bleeding subscore of 0, and endoscopic subscore ≤1, excluding friability) was achieved by 28% and 24% of patients receiving tamuzimod 60 mg and 30 mg, respectively, compared with 11% in the placebo group. The treatment was well tolerated; most AEs were mild or moderate.

Gladman et al. assessed the impact of bimekizumab over 1 year on patient-reported symptoms, HRQoL, and work productivity in patients with PsA who were bDMARD-naïve or TNF-IR. The study showed that bimekizumab treatment resulted in sustained improvements across multiple domains, including pain, fatigue, physical function, and work impairment.

January 2025

Ferrante et al. conducted a phase 3 trial evaluating the efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn’s disease. The study demonstrated that mirikizumab significantly improved clinical and endoscopic outcomes compared with placebo at week 52, with a favourable safety profile and tolerable adverse events.

Poddubnyy et al. analysed five clinical trials to evaluate extra-musculoskeletal manifestations (EMMs) like uveitis, IBD, and psoriasis in patients treated with UPA. They observed low incidences across PsA, r-axSpA, and nr-axSpA. Numerically, uveitis rates were lower in
UPA-treated patients than in those receiving placebo, particularly in r-axSpA.

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McInnes et al. assessed the efficacy of guselkumab over 48 weeks in patients with psoriatic arthritis who had an inadequate response to TNF inhibitors. The results demonstrated consistent improvements in joint, skin, and patient-reported outcomes across all baseline-defined subgroups. Guselkumab showed greater efficacy compared with placebo at Week 24, with responses maintained or improved through Week 48.

December 2024

Buch et al. demonstrated that filgotinib sustained its efficacy in rheumatoid arthritis patients through Wk156 in the FINCH 4 long-term extension study, showing stable safety profiles. The study reported high ACR response rates and remission based on Boolean criteria, underlining filgotinib's potential for extended clinical benefits.