Lancet Rheumatology最新文献

Takayasu arteritis, a granulomatosis vasculitis with a pathogenesis that is poorly defined but known to be associated with HLA-B*52, shares many features with other MHC-I-opathies. In addition to the shared clinical features of inflammatory bowel diseases, cutaneous inflammation, and HLA-B*52, is shared association of an IL12B single- nucleotide polymorphism encoding the common IL-12 and IL-23 p40 subunit, which might affect not only type 17 cytokine responses, but also IFNγ and TNF production-the cardinal type 1 cytokines in granuloma formation. Considering the translational context of responses to TNF inhibition in Takayasu arteritis, in this Personal View we propose Takayasu arteritis as a type 1 MHC-I-opathy. Additionally, type 1 and type 17 T-cell immune responses show immune plasticity, which connects the overlapping features of Takayasu arteritis and spondyloarthritis spectrum disorders, providing a basis for shared anti-TNF responses, and points to p40 and IFNγ cytokine antagonism and potential selective CD8 T-cell repertoire ablation.

New pathogenesis-based therapeutics and evidence-based consensus treatment recommendations, often with predefined treatment goals, have remarkably improved outcomes across many chronic diseases. However, a clinically significant subgroup of patients responds poorly to interventions and show a progressive decline in the disease trajectory, which poses an increasing health-care challenge. Difficult-to-treat approaches exist in several areas of medicine and the need for similar definitions has recently also emerged in rheumatology. The term difficult-to-treat refers not only to patients with pathology-driven, treatment-refractory disease, but also implicates multiple other factors that can contribute to patients being in this state, including having few treatment options, misdiagnosis, and coincident psychosocial factors. Therefore, the difficult-to-treat state requires a comprehensive, holistic, multidisciplinary approach that considers the specific characteristics of each disease and the personalised needs of the patient. In this Personal View, we provide an overview of the different aspects of the concept of difficult-to-treat disease, highlight its advantages, and propose the importance of incorporating this concept more widely in the design of rheumatological treatment strategies.

Background: Moderate doses of glucocorticoids result in improvements in nearly all patients with polymyalgia rheumatica, but related adverse events are common in older individuals. We aimed to evaluate whether treatment with baricitinib (a Janus kinase 1/2 inhibitor) results in disease control without the use of oral glucocorticoids in people with recent-onset polymyalgia rheumatica.

Methods: We conducted a randomised, double-blind, placebo-controlled, parallel-group trial at six expert centres in France. Participants with recent (<6 months) polymyalgia rheumatica naive to glucocorticoids and a C-reactive protein polymyalgia rheumatica activity score (CRP PMR-AS) of more than 17 were randomly assigned (1:1), with stratification by hospital, to receive either 4 mg baricitinib orally or placebo (with oral glucocorticoids as rescue treatment in the event of high disease activity) for 12 weeks, followed by 2 mg baricitinib or placebo for another 12 weeks. Subdeltoid glucocorticoid injections at week 1 and week 4 were permitted. Participants, investigators, outcome assessors, and sponsor personnel were masked to group assignments. The primary outcome was a CRP PMR-AS of 10 or less at week 12 without oral glucocorticoid use from week 1 to week 12, analysed in all randomly assigned participants who did not withdraw before first treatment administration. Participants were followed up for 36 weeks. An individual with lived experience of polymyalgia rheumatica was involved in the study design. The trial was registered on ClinicalTrials.gov, NCT04027101, and is complete.

Findings: We assessed 39 individuals for eligibility between Dec 1, 2020, and Aug 30, 2023. 34 participants (22 women and 12 men) were randomly assigned; 18 participants were assigned to the baricitinib group and 16 participants were assigned to the placebo group. One person allocated to placebo withdrew before the first infusion and was not included in analyses. The primary endpoint was reached at week 12 by 14 (78%) of 18 participants in the baricitinib group and two (13%) of 15 participants in the placebo group (relative risk 5·8, 95% CI 3·2-10·6; crude p=0·0004; adjusted p<0·0001). The most common adverse events were musculoskeletal and connective tissue disorders (13 [72%] of 18 participants in the baricitinib group and four [25%] of 16 in the placebo group. There were no deaths and no major adverse cardiovascular events in either study group.

Interpretation: This study suggests that, compared with placebo, individuals with polymyalgia rheumatica receiving 4 mg baricitinib are less likely to need oral glucocorticoids to have low disease activity at week 12 of treatment without any new safety signals.

Funding: CHU Brest and Eli Lilly.

Background: Uncertainty exists regarding patient outcomes when using TNF inhibitors versus other biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis-associated interstitial lung disease (ILD). We compared survival and respiratory hospitalisation outcomes following initiation of TNF-inhibitor or non-TNF inhibitor biological or targeted synthetic DMARDs for treatment of rheumatoid arthritis-associated ILD.

Methods: We did a retrospective, active-comparator, new-user, observational cohort study with propensity score matching following the target trial emulation framework using US Department of Veterans Affairs (VA) electronic and administrative health records. VA health-care enrollees with rheumatoid arthritis-associated ILD and no previous receipt of ILD-directed therapies (eg, antifibrotics) who initiated a TNF inhibitor or non-TNF inhibitor between Jan 1, 2006, and Dec 31, 2018, were included. Propensity score matching was performed using demographics, health-care use, health behaviours, comorbidity burden, rheumatoid arthritis-related severity factors, and ILD-related severity factors, including baseline forced vital capacity. Study outcomes were respiratory hospitalisation, all-cause mortality, and respiratory-related death over follow-up of up to 3 years, from VA, Medicare, and National Death Index data. People with lived experience of rheumatoid arthritis-associated ILD were not involved in the design or conduct of this study.

Findings: Of 1047 patients with rheumatoid arthritis-associated-ILD who initiated biological or targeted synthetic DMARDs, we matched 237 patients who had initiated TNF inhibitors and 237 who had initiated non-TNF inhibitors (mean age 68 years [SD 9]); 434 (92%) of 474 were male and 40 (8%) were female. Death and respiratory hospitalisation did not significantly differ between groups (adjusted hazard ratio 1·21 [95% CI 0·92-1·58]). Respiratory hospitalisation (1·27 [0·91-1·76]), all-cause mortality (1·15 [0·83-1·60]), and respiratory mortality (1·38 [0·79-2·42]) did not differ between groups. Secondary, sensitivity, and subgroup analyses supported the primary findings.

Interpretation: In US veterans with rheumatoid arthritis-associated ILD, no difference in outcomes were seen between those who started TNF inhibitors compared to those starting non-TNF biological or targeted synthetic DMARDs. These data do not support systematic avoidance of TNF inhibitors in all people with rheumatoid arthritis-associated ILD. Comparative efficacy trials in patients with rheumatoid arthritis-associated ILD are needed given the potential for residual confounding and selection bias in observational studies.

Funding: US Department of Veterans Affairs.