Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1-4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.

PRURITIC RASH IN AN ELDERLY PATIENT WITH UNCONTROLLED DIABETES MELLITUS.

OBJECTIVE: Acquired reactive perforating collagenosis is an uncommon skin disease that belongs to a group of dermatologic disorders characterized by transepidermal elimination of dermal material. It is highly associated with systemic disease, primarily diabetes mellitus and dialysis-dependent chronic renal failure. METHODS: A 70-year-old female with 20 years of poorly controlled type 2 diabetes mellitus presented with a 6-month history of multiple pruritic erythematous papules and nodules with central hyperkeratosis, involving her right dorsal arm. Histologic examination was consistent with acquired reactive perforating collagenosis. In addition to topical treatment of the disease, the patient was referred to endocrinology for appropriate management of her underlying diabetes mellitus. RESULTS: Ideal treatment should involve both the endocrinologist and dermatologist. Control of the underlying systemic disease, in this case diabetes, as well topical or systemic medications can both help to improve this condition. Our patient re-established care with her endocrinologist who adjusted her medication regimen, resulting in improved hemoglobin A1c values. Our patient additionally benefited from topical betamethasone cream, ammonium lactate, and pimecrolimus application. The combined therapy led to resolution of her pruritic rash. CONCLUSION: This case highlights the importance of the skin exam by the endocrinologist, as he or she plays a unique role in identifying this rare and difficult-to-treat dermatologic disease. Early detection and prompt referral to a dermatologist are crucial in preventing progression of disease, treating the disease, and improving the patient's quality of life.

Racial differences in cancer risk among relatives of patients with early onset lung cancer.

BACKGROUND: Relatives of patients with early onset lung cancer are at increased risk for lung cancer, and this risk varies by race. This study evaluates whether first-degree relatives of patients with early onset lung cancer are at increased risk for cancer at sites other than lung. METHODS: Family histories were ascertained from 673 lung cancer patients < 50 years of age identified from the Metropolitan Detroit Surveillance, Epidemiology and End Results program, and 773 age-, race-, and sex-matched control subjects were obtained via random-digit dialing. Data were collected for 3,556 case relatives (mothers, fathers, and siblings) and 3,943 control relatives, and unconditional logistic regression models using generalized estimating equations were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among case relatives, African Americans were 2.44-fold more likely to have head and neck cancers and 1.86-fold more likely to have any tobacco-related cancer compared to white case relatives (95% CI, 1.04 to 5.69% and 95% CI, 1.25 to 2.76, respectively). African-American case relatives were at increased risk for head and neck cancers (OR, 13.42; 95% CI, 1.65 to 109.01), all tobacco-related cancers (OR, 3.77; 95% CI, 2.16 to 6.55), tobacco-related cancers other than lung (OR, 4.10; 95% CI, 1.56 to 10.79), and cancer at any site (OR, 1.45, 95% CI, 1.04 to 2.02) compared to African-American control relatives. CONCLUSIONS: These results can be used to counsel family members of patients with early onset lung cancer, and suggest target populations for preventive strategies, including smoking cessation and appropriate screening.