From traditional to targeted: the changing trajectory of therapies in dermatomyositis.

PURPOSE OF REVIEW: New breakthroughs in our understanding of dermatomyositis (DM) have spawned the recent development of novel agents that specifically target key drivers in DM immunopathogenesis. This review aims to provide a comprehensive overview of new and forthcoming therapies for DM and to highlight their mechanisms of action, best evidence to date, and potential impact on disease management. RECENT FINDINGS: Strategies that either counteract dysregulated interferon signaling [via the inhibition of interferon ß, the type I interferon receptor subunit 1 (IFNAR1), or janus kinase (JAK)-signal transducer and activator of transcription (STAT) transduction] or induce durable autoreactive B cell depletion through chimeric antigen receptor (CAR) T-cell therapy appear to hold the most promise for sustained remission in DM. SUMMARY: The trajectory of DM treatments is rapidly evolving, fueled by the unparalleled insights provided by multiomic studies and big data analysis pipelines. Targeted therapies that maximize both efficacy and safety have the potential to complement or replace traditional immunosuppressives and revolutionize the approach to the management of DM.

Brepocitinib, a potent and selective TYK2/JAK1 inhibitor: scientific and clinical rationale for dermatomyositis.

Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/ß, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).

Area Deprivation and Disease Severity in Adult Patients With Discoid Lupus Erythematosus.

Importance: The association of area deprivation with outcomes in discoid lupus erythematosus (DLE) remains poorly understood. Objective: To determine the association between US Census block measures of deprivation and disease severity in adult patients with DLE. Design, Setting, and Participants: This cross-sectional study included 154 patients with DLE seen between January 1, 2007, and January 1, 2024, at a single-center referral-based specialty rheumatologic-dermatology clinic in Philadelphia, Pennsylvania. Patients were aged 18 to 73 years and were enrolled in the University of Pennsylvania's Cutaneous Lupus Erythematosus Database study. Data were analyzed between January 1, 2024, and May 8, 2024. Exposures: Residence in a highly disadvantaged area as geocoded by a state area deprivation index (ADI). Main Outcomes and Measures: The main outcome was DLE disease severity as codified by the validated Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) damage and activity scores. Results: A total of 154 adult patients with DLE (128 women [83%] and 26 men [17%]; mean [SD] age, 43 [13] years; 6 [4%] Asian individuals, 98 [64%] Black individuals, 2 [1%] Hispanic individuals, 46 [30%] White individuals, and 2 individuals [1%] with other race or ethnicity; 78 [51%] with an ADI >5; 43 who currently smoked [28%];and 56 [36%] with concurrent systemic lupus erythematosus) were included in the analysis. By multivariable logistic regression, residence within communities with an ADI greater than 5 was associated with nearly 4-fold greater odds of moderate to severe damage (odds ratio [OR], 3.90; 95% CI, 1.27-12.69] and activity (OR, 3.31; 95% CI, 1.27-9.44). Concurrent cigarette smoking was similarly associated with greater odds of moderate to severe damage (OR, 3.15; 95% CI, 1.09-10.29). After controlling for ADI and other confounders, race was not significantly associated with DLE disease severity. Conclusions and Relevance: The results of this cross-sectional study suggest that geospatial disadvantage is associated with DLE disease severity independent of race. This invites a paradigm shift that considers the social context within which racial disparities are observed, highlighting the potential for geographically targeted interventions and policy changes to improve patient outcomes in DLE.

Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus.

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.