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.

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).

Successful Treatment of Keloids and Hypertrophic Scars With Systemic and Intralesional Dupilumab.

Keloids and hypertrophic scars negatively impact the quality of life for millions of people in the world. Unfortunately, though many thera-peutic approaches are used to treat scars, they are often limited in efficacy with high rates of recurrence. Lately, a better understanding of the immune dysregulation of several dermatologic conditions has led to the emergence of multiple cytokine-targeted therapies for numerous conditions. Several studies have implicated T helper 2 (Th2) immune dysregulation in the development of scars and keloids, with interleukins (IL)-4 and -13 identified as pro-fibrotic mediators. Dupilumab is an IL-4 receptor alpha antagonist that inhibits the ex-pression of both IL-4 and -13. Herein, we describe a 44-year-old woman who developed numerous disfiguring hypertrophic scars and keloids after suffering from a severe herpes zoster infection. Given the number of scars, intralesional corticosteroid injections were not feasible. Therefore, treatment with systemic dupilumab was initiated. Many scars flattened, several even developing a cigarette-paper-like texture due to rapid involution. The largest and most recalcitrant keloid was further treated with intralesional dupliumab injec-tions every 2 weeks with an even more dramatic improvement noted in 2 months. To our knowledge, this is the first report of treating multiple keloids and hypertrophic scars with both systemic and intralesional dupilumab. Dermatologists may want to consider treating keloids that cover a large area with systemic dupilumab, a therapy with an established, reassuring safety profile. The most recalcitrant areas may further benefit from concentrating dupilumab by intralesional delivery. J Drugs Dermatol. 2023;22(12):1220-1222.  doi:10.36849/JDD.6385.

Botulinum toxin for refractory Raynaud's phenomenon: A "how to" guide for pediatric patients.

Raynaud's phenomenon describes symptoms caused by digital vascular spasm and is classically induced by cold exposure. Severe cases can result in ulceration, necrosis, and digital autoamputation. When standard and adjunctive medical therapies fail or are contraindicated, botulinum toxin A (BTX-A) is an effective treatment option that can be added to existing regimens and should be considered before utilizing rescue therapies associated with higher risk and often higher cost. This report describes our technique, highlights considerations relevant to pediatric patients, and provides photos and videos of the procedure performed on a 16-year-old girl.

Methotrexate for inflammatory skin disease in pediatric patients: Consensus treatment guidelines.

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.

Dental Anomalies in Parry-Romberg Syndrome: A 40-Year Retrospective Review.

OBJECTIVE: This study investigates crown and root anomalies in patients with Parry-Romberg Syndrome. DESIGN: This is a retrospective review of patients with Parry-Romberg Syndrome who were evaluated at a tertiary care center from 1980-2020. SETTING: Patients seen in the dental unit from 1980-2020. PATIENTS, PARTICIPANTS: Seventeen patients with documented Parry-Romberg Syndrome were referred for dental evaluation. MAIN OUTCOME MEASURES: All dental anomalies were documented. Root anomalies were assessed using panoramic radiographs and cone beam CT (CBCT) scans to evaluate buccal-lingual, mesio-distal, and axial measurements of hypoplastic teeth, which were compared to those of contralateral teeth. RESULTS: Findings included agenesis (29%, n = 5), hypoplastic teeth (29%, n = 5), delayed canine eruption (24%, n = 4), and mulberry molars (12%, n = 2). Of the five patients with tooth hypoplasia, four had CBCT records and the fifth had panoramic radiographs available for assessment. Axial length was always shorter in hypoplastic teeth relative to contralateral teeth, with differences ranging from 1.2-9.2 mm. Differences in crown size of hypoplastic versus contralateral teeth were unpredictable but always present. CONCLUSIONS: Patients with Parry-Romberg Syndrome can have hypoplastic roots with atypical crown morphology. A patient's specific dental anomaly will influence planning and treatment.

Crowdsourcing as a means of fundraising for juvenile dermatomyositis.

This study used the crowdsourcing platform GoFundMe to analyze the financial hardships associated with treatment of juvenile dermatomyositis. Uncovered medical expenses, travel costs, and loss of income were all commonly cited reasons for fundraising, demonstrating high out-of-pocket costs and significant economic hardship associated with this disease, even among families with health insurance.

A systematic review and meta-analysis to inform cancer screening guidelines in idiopathic inflammatory myopathies.

OBJECTIVES: To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening. METHODS: A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review. RESULTS: Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud's phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD -1189.96) or lactate dehydrogenase (WMD -336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers. CONCLUSION: Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.

Augmented reality in dermatology: Are we ready for AR?

Augmented reality (AR) refers to a group of technologies that capture, analyze, and superimpose digital information onto the real world. This information gives health care providers unique and useful perspectives that can enhance patient care. AR has been utilized in selected scenarios in health care for several decades, notably laparoscopic surgery and vein finding. In recent years, improved wireless technologies, computing power, and analytics are leading to rapid growth in the AR industry. Novel health care-specific use cases are rapidly being introduced with the potential to widely affect clinical care, particularly in dermatology because of the visual nature of the field. In this article, we define AR, profile clinical and educational uses of AR in dermatology, and discuss key policy considerations for the safe and appropriate use of this emerging technology.

Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: A concise review with an emphasis on distinctive clinical features.

Melanoma differentiation-associated gene 5 (MDA5) is a recently described autoantigen target in a subset of patients with dermatomyositis. Anti-MDA5 dermatomyositis is characterized by a unique mucocutaneous and systemic phenotype that includes cutaneous and oral ulceration, painful palmar papules, alopecia, panniculitis, arthritis, a lower incidence of myositis, and, importantly, an elevated risk of interstitial lung disease with a potentially fatal course. Because the clinical features can differ substantially from those typically observed in cutaneous dermatomyositis, the diagnosis is often overlooked, which might negatively affect patient outcomes. This review aims to familiarize the clinician with the distinctive clinical features of anti-MDA5 dermatomyositis in order to enhance its recognition and to facilitate an appropriate screening and management strategy.