Faculty Bibliography

Background/Purpose: Previous studies on the association of dermatomyositis (DM) with cardiovascular (CV) disease have used combined idiopathic inflammatory myositis cohorts, included only non-United States (US) cohorts, included only inpatients, or have not included matched controls. We aimed to describe the burden and timing of CV disease in a demographically and geographically diverse sample of inpatients and outpatients with DM in the US. Table 1. All of Us Database Diagnosis Search Terms.
Method(s): We performed a nested, matched, case-control analysis based on diagnostic coding in the All of Us Registered Tier Dataset v5 (Table 1). We used nearest neighbor propensity score matching to select for age-, sex-, race-, and ethnicity-matched controls for each DM case. We compared CV comorbidities and their dates of diagnosis between cases and controls using Pearson's chi-squared test or Fisher's exact test for categorical variables and the unpaired t-test for continuous variables. A multivariable conditional logistic regression model was built by including comorbidities with significance of P < 0.1 in univariable analysis, followed by backward elimination of comorbidities with a significance of P > 0.1 or with evidence of collinearity. A sensitivity analysis was performed that excluded DM cases with comorbid systemic lupus Table 2. Demographic and clinical characteristics of DM cases versus age-, sex-, race-, and ethnicity-matched controls in All of Us. erythematosus (SLE), rheumatoid arthritis, psoriasis, or systemic sclerosis.
Result(s): Of the 214,206 All of Us participants with electronic health record data, we identified 248 DM cases and 992 controls (Table 2). The mean follow-up time for DM cases was 7.1 +/- 4.8 years. Compared to controls, DM cases were significantly associated with 14 of 14 tested CV comorbidities in univariable analysis: atrial fibrillation (AF), cerebrovascular disease (CVD), chronic kidney disease (CKD), chronic obstructive pulmonary disease, coronary artery disease, deep vein thrombosis, heart failure, hyperlipidemia, hypertensive disorder (HTN), myocardial infarction, peripheral artery disease, pulmonary embolism, type 2 diabetes (T2D), and valvular heart disease (VHD). Aside from HTN, which was diagnosed on average 3.6 years earlier in the DM cohort, comorbidities were diagnosed at similar ages between cases and controls. In multivariable analysis, CKD, CVD, T2D, and VHD remained significantly associated with DM (Table 3). In the sensitivity analysis, 154 cases and 616 controls were identified. Univariable analysis results were similar except AF was not a significant association. In multivariable analysis, CKD, T2D, and VHD remained significantly associated; the odds ratio for CVD was 2.11 (p = 0.086).
Conclusion(s): This study found an association between DM and T2D, which has been previously reported. Unique to this study is the strong association of DM with CKD and with VHD, which remained significant in multiple multivariable models. Elevated risk of CV disease has been established in chronic inflammatory states such as SLE. This study shows a similar association between CV disease and DM. It is necessary to establish if treatment of DM decreases risk of CV disease, as is the case in the treatment of other rheumatologic diseases. Our study is limited by ascertainment of diagnoses using electronic health records and a lack of data on clinical features of DM

Dermatomyositis (DM) is an autoimmune connective tissue disease that most commonly affects skin and muscles. Clinical manifestations can be protean, with some patients experiencing skin-limited disease while others develop serious systemic complications including interstitial lung disease (ILD). While both T cell-mediated and humoral immune dysregulation have been purported to play a role in manifesting said end-organ damage, our understanding of immunophenotypic prognostic factors associated with the development of ILD in DM patients remains limited. Thus, we sought to identify potential biomarkers that might be differentially expressed in lesional skin obtained from DM patients with versus without ILD. Utilizing NanoString technology, we assessed differential mRNA expression of 800 immune-related genes in formalin-fixed, paraffin-embedded lesional skin samples obtained from five DM patients with ILD compared to five DM patients without ILD. Among 42 highly regulated genes, 10 were significantly (p<0.05) upregulated in DM patients with ILD: CD44, NFKBIZ, CD24, EGR1, DEFB103B, CCL18, CCL22, CXCL2, S100A8 and S100A9. Notably, serum levels of S100A8/A9 heterodimer (an endogenous ligand of Toll-like receptor 4) are known to correlate with clinical severity in patients with DM-associated ILD, thereby supporting NanoString's utility in identifying salient genes associated with end-organ damage in DM. We also identified several novel genes downregulated in patients with DM-associated ILD that play a role in autophagy and adaptive immune activation: CLEC7, LEF1, KLRC2, BTLA, MUC1, and TCF7. Taken together, our results begin to characterize an immune-related gene expression signature in lesional DM skin that may be associated with comorbid ILD. While validation experiments are ongoing, the identification of biomarkers of systemic disease in lesional DM skin not only has the potential for risk stratifying DM patients at the time of tissue diagnosis but may provide novel targets for early intervention against DM-associated ILD.
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Importance/UNASSIGNED:Acute generalized exanthematous pustulosis (AGEP) is a rare, severe cutaneous adverse reaction associated with systemic complications. Currently available data are largely limited to small retrospective case series. Objective/UNASSIGNED:To describe the clinical characteristics, disease course, and outcomes of a heterogeneous group of patients with AGEP across the US. Design, Setting, and Participants/UNASSIGNED:A retrospective review of a case series of patients was conducted from January 1, 2000, through July 31, 2020. All 340 included cases throughout 10 academic health systems in the US were scored retrospectively using the EuroSCAR scoring system, and patients with a score corresponding to probable or definite AGEP and aged 18 years or older were included. Main Outcomes and Measures/UNASSIGNED:Patient demographic characteristics, clinical course, suspected causative agent, treatment, and short- and long-term outcomes. Results/UNASSIGNED:Most of the 340 included patients were women (214 [62.9%]), White (206 [60.6%]), and non-Hispanic (239 [70.3%]); mean (SD) age was 57.8 (17.4) years. A total of 154 of 310 patients (49.7%) had a temperature greater than or equal to 38.0 °C that lasted for a median of 2 (IQR, 1-4) days. Of 309 patients, 263 (85.1%) developed absolute neutrophilia and 161 patients (52.1%) developed either absolute or relative eosinophilia. Suspected causes of AGEP were medications (291 [85.6%]), intravenous contrast agents (7 [2.1%]), infection (3 [0.9%]), or unknown (39 [11.5%]). In 151 cases in which a single medication was identified, 63 (41.7%) were β-lactam antimicrobials, 51 (33.8%) were non-β-lactam antimicrobials, 9 (6.0%) were anticonvulsants, and 5 (3.3%) were calcium channel blockers. The median time from medication initiation to AGEP start date was 3 (IQR, 1-9) days. Twenty-five of 298 patients (8.4%) had an acute elevation of aspartate aminotransferase and alanine aminotransferase levels, with a peak at 6 (IQR, 3-9) days. Twenty-five of 319 patients (7.8%) experienced acute kidney insufficiency, with the median time to peak creatinine level being 4 (IQR, 2-5) days after the AGEP start date. Treatments included topical corticosteroids (277 [81.5%], either alone or in combination), systemic corticosteroids (109 [32.1%]), cyclosporine (10 [2.9%]), or supportive care only (36 [10.6%]). All-cause mortality within 30 days was 3.5% (n = 12), none of which was suspected to be due to AGEP. Conclusions and Relevance/UNASSIGNED:This retrospective case series evaluation of 340 patients, the largest known study cohort to date, suggests that AGEP onset is acute, is usually triggered by recent exposure to an antimicrobial, may be associated with liver or kidney complications in a minority of patients, and that discontinuation of the triggering treatment may lead to improvement or resolution.

Importance/UNASSIGNED:Generalized pustular psoriasis (GPP) is a chronic, orphan disease with limited epidemiological data. Objective/UNASSIGNED:To describe the clinical characteristics, treatments, longitudinal disease course, and disease-specific health care utilization among patients with GPP across the United States. Design, Setting, and Participants/UNASSIGNED:A retrospective longitudinal case series involving 95 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for GPP and were treated at 20 US academic dermatology practices between January 1, 2007, and December 31, 2018. Main Outcomes and Measures/UNASSIGNED:The primary outcome is to describe the patient characteristics, associated medical comorbidities, treatment patterns complications, and GPP-specific health care utilization. Results/UNASSIGNED:Sixty-seven of 95 patients (70.5%) were women (mean age, 50.3 years [SD, 16.1 years]). In the initial encounter, 35 patients (36.8%) were hospitalized and 64 (67.4%) were treated with systemic therapies. In total, more than 20 different systemic therapies were tried. During the follow-up period, 19 patients (35.8%) reported hospitalizations at a median rate of 0.5 hospitalizations per year (IQR, 0.4-1.6). Women had a decreased risk of an emergency department or hospital encounter (odds ratio, 0.19; 95% CI, 0.04-0.83). Conclusions and Relevance/UNASSIGNED:Generalized pustular psoriasis is a rare, chronic disease without standard treatment and is associated with continued health care utilization over time.

Importance/UNASSIGNED:Palmoplantar pustulosis (PPP) is a is a chronic, orphan disease with limited epidemiological data. Objective/UNASSIGNED:To describe the clinical characteristics, treatments, longitudinal disease course, and health care utilization in adults with PPP across the US. Design, Setting, and Participants/UNASSIGNED:This retrospective, longitudinal case series from 20 academic dermatology practices in the US included a consecutive sample of 197 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for PPP between January 1, 2007, and December 31, 2018. Data analysis was performed June 2020 to December 2020. Main Outcomes and Measures/UNASSIGNED:The primary outcome was to describe the patient characteristics, associated medical comorbidities, treatment patterns, complications, and PPP-specific health care utilization. Results/UNASSIGNED:Of 197 patients, 145 (73.6%) were female, and the mean (SD) age at presentation was 53.0 (12.6) years, with a mean (SD) follow-up time of 22.1 (28.0) months. On initial presentation, 95 (48.2%) patients reported skin pain, and 39 (19.8%) reported difficulty using hands and/or feet. Seventy patients (35.5%) were treated with systemic treatments, and use of more than 20 different systemic therapies was reported. In patients with at least 6 months of follow-up (n = 128), a median (IQR) of 3.7 (4-10) dermatology visits per year were reported; 24 (18.8%) patients had 5 or more visits during the study period. Conclusions and Relevance/UNASSIGNED:In this case series, PPP was associated with persistent symptoms, continued health care utilization, and a lack of consensus regarding effective treatments, emphasizing the unmet medical need in this population. Additional research is necessary to understand treatment response in these patients.