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Apart from autopsy, tissue correlates of coronavirus disease 2019 (COVID-19) clinical stage are lacking. In the current study, cutaneous punch biopsy specimens of 15 individuals with severe/critical COVID-19 and six with mild/moderate COVID-19 were examined. Evidence for arterial and venous microthrombi, deposition of C5b-9 and MASP2 (representative of alternative and lectin complement pathways, respectively), and differential expression of interferon type I-driven antiviral protein MxA (myxovirus resistance A) versus SIN3A, a promoter of interferon type I-based proinflammatory signaling, were assessed. Control subjects included nine patients with sepsis-related acute respiratory distress syndrome (ARDS) and/or acute kidney injury (AKI) pre-COVID-19. Microthrombi were detected in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P 0.001) and none of the nine patients with pre-COVID-19 ARDS/AKI (P 0.001). Cells lining the microvasculature staining for spike protein of severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID-19, also expressed tissue factor. C5b-9 deposition occurred in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P 0.001) and none of the nine patients with pre-COVID-19 ARDS/AKI (P 0.001). MASP2 deposition was also restricted to severe/critical COVID-19 cases. MxA expression occurred in all six mild/moderate versus two (15%) of 13 severe/critical cases (P 0.001) of COVID-19. In contrast, SIN3A was restricted to severe/critical COVID-19 cases co-localizing with severe acute respiratory syndrome coronavirus 2 spike protein. SIN3A was also elevated in plasma of patients with severe/critical COVID-19 versus control subjects (P ≤ 0.02). In conclusion, the study identified premortem tissue correlates of COVID-19 clinical stage using skin. If validated in a longitudinal cohort, this approach could identify individuals at risk for disease progression and enable targeted interventions.

Supplementary Figure from Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma

Supplementary Table from Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma

Kohlmeier-Degos Disease is a unique thrombotic microvascular and arteriopathic vasculopathy that is highly selective in the organs it targets. It invariably involves the skin and can be a purely cutaneous process. It affects both the microvasculature and the arterial system ranging from a thrombogenic microangiopathy to a fibrointimal obliterative arteriopathy with an accompanying background of extravascular fibrosis. A potentially lethal complication of Kohlmeier-Degos disease is constrictive pericarditis and pleuritis. We present three male patients, ages 26 years, 46 years and 58 years of age with established cutaneous and gastrointestinal Kohlmeier-Degos disease who developed progressive pericarditis which in two necessitated a pericardiectomy. There are 6 other reported cases, 5 in men, with restrictive symptoms developing on average 6 years following the onset of skin disease and all with gastrointestinal involvement. Half of the patients died within one year following the diagnosis of cardiopulmonary restrictive disease. The restrictive symptoms developed within 12 months, 2 years and 11 years following the initial skin presentation. In one patient this complication developed despite receiving eculizumab, indicative that this extravascular fibrosing reaction was not complement mediated as opposed to the thrombotic microvascular component of the disease which is C5b-9 mediated. Two of the three patients had evidence of right ventricular dysfunction. Two of our patients died within 1 year of developing constrictive pericarditis due to progressive cardiopulmonary failure. A profibrogenic process resembling scleroderma was seen given the degree of smooth muscle actin staining along with a mirror image reduction in CD34 expression within the fibrotic pleura and pericardium. There was significant upregulation in type I interferon signaling in cases tested as revealed by the degree of staining for MXA, the surrogate type I interferon marker. We propose that excessive type I interferon signaling results in the influx of monocyte derived dendritic cells with subsequent transdifferentiation into potent collagen producing myofibroblasts. We believe that targeting and suppressing type I interferon signaling should be a cornerstone of early therapy in patients with Kohlmeier- Degos disease to prevent pleural and pericardial fibrosis.

Fil: Cayrol, María Florencia. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina Fil: Cayrol, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Revuelta, Maria V. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos Fil: Debernardi, Maria Mercedes. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina Fil: Debernardi, Maria Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Paulazo, Maria Alejandra. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina Fil: Paulazo, Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Phillip, Jude M. Johns Hopkins University. Institute for Nanobiotechnology. Chemical and Biomolecular Engineering, Oncology. Departments of Biomedical Engineering; Estados Unidos Fil: Zamponi, Nahuel. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina Fil: Sterle, Helena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina Fil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Magro, Cynthia. Weill Cornell Medicine, Department of Pathology and Laboratory Medicine; Estados Unidos Fil: Marullo, Rossella. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos Fil: Mulvey, Erin. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos Fil: Ruan, Jia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos Fil: Cremaschi, Graciela A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cremaschi, Graciela A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina Fil: Cerchietti, Leandro. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos Abstract: Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the aVb3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an aVb3-dependent manner, the antineoplastic effect of bexarotene, levothyroxine supplementation in preclinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin aVb3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin aVb3 inhibitors as part of CTCL regimens based on bexarotene administration.

Psoriasis is a common autoimmune dermatosis representing an interplay between certain genetic predisposing factors along with clonally restricted Th1 T cells responding to epidermal keratinocyte derived antigen. A unique IL17/IL23 cytokine-rich milieu is pathogenetically significant and conducive to its salient histomorphologic features, such as epidermal hyperplasia and intraepidermal influx of neutrophils. The classic cutaneous manifestation is that of plaque psoriasis also referred to as psoriasis vulgaris with characteristic well-circumscribed erythematous plaques covered by silvery scales. Follicular psoriasis is an uncommon variant manifesting as a scaly folliculocentric hyperkeratotic eruption of the trunk and extremities, irrespective of the presence or absence of conventional lesions of psoriasis vulgaris. In this study we present 5 cases of follicular psoriasis, review the literature, and provide a proposal regarding relevant pathologic findings and potential pathogenetic mechanisms. The incidence of follicular psoriasis is unknown, emphasizing its rarity given the overall incidence of conventional psoriasis in the general population. Owing to the lack of awareness, this clinical presentation is often mistaken for other follicular dermatoses, including bacterial folliculitis, pityriasis rubra pilaris, keratosis pilaris, or follicular eczema.

Pustular psoriasis occurs rarely in children but can present with acute toxicity requiring inpatient admission. For the best approach, medical providers should have an evidence based and systematic treatment algorithm in their armamentarium. Toillustrate this point, we describe a 13-year-old girl who was admitted with generalized pustular psoriasis and who responded dramatically to "wet wrap" therapy and cyclosporine bridged to etanercept. Using this case example, we highlight the three most important considerations in any patient with new onset pustularpsoriasis: avoidance of disease complications, acute "rescue" therapy, and maintenance therapy.

Lymphomatoid drug reactions can mimic endogenous T and B cell lymphoproliferative diseases.We present a novel form of cutaneous drug reaction with features of pityriasis lichenoides (PL), a recognized form of T cell dyscrasia.Ten cases were studied where a cutaneous eruption exhibiting semblance to PL within a few weeks to months after starting a particular drug.The patient cohort comprised 7 females and 3 males with the mean age of 60 years. Widely distributederythematous cutaneous lesions were present in 6 cases whereas a more localized distribution was seen in three cases. The most frequently implicated drugsassociated with the eruption were antidepressants and statins. Histologic examination showed a morphologic picture identical to PL including marked epitheliotropism of mildly atypical lymphocytes, psoriasiform epidermal hyperplasia, dyskeratosis, hemorrhage, and a thick parakeratotic scale. Therewas a significant reduction in the expression of CD7 and CD62L amid the T cells. Regression of the eruption occurred in all cases excluding one.Thefindings conform the categorization of this process as a form of T-cell dyscrasia albeit one that is reversible, dependent on the drug withdrawal. The limitationof our study includes the retrospective design of the study.

Metastatic Crohn disease is a rare cutaneous manifestation of Crohn disease characterized by granulomatous lesions discontinuous with the diseased areas of the gastrointestinal tract. We report a case of a 32-year-old woman with history of Crohn disease who was admitted for treatment of cellulitis after presenting with a tender erythematous plaque of the left calf. Microbiological tests including tissue cultures were negative. A skin biopsy revealed granulomatous dermatitis consistent with metastatic cutaneous Crohn disease. Owing to concomitant perianal fistulas and abscesses and prior infusion reaction to infliximab, the patient was treated with certolizumab, a pegylated tumor necrosis factor (TNF) inhibitor combined with methotrexate resulting in complete resolution of the skin lesion. This case emphasizes the importance of recognizing this rare skin manifestation of Crohn disease and adds certolizumab as one of TNF inhibitors useful in the treatment of metastatic cutaneous Crohn disease.

Reed syndrome, also known as Multiple Uterine and Cutaneous Leiomyomas (MCUL), is an autosomal dominant defect in the fumurate hydrase gene, leading to a predisposition of leiomyomas of the skin and uterus. Patients with Reed syndrome may present with cutaneous leiomyomas, uterine leiomyomas and/or leiomyosarcomas. A 37-year-old woman presented to the dermatology clinic with several subcutaneous nodules. Punch biopsy was performed and the diagnosis of angioleiomyosarcoma with supervening degenerative changes was made. Medical history was positive for uterine leiomyomas. These concomitant findings led to the diagnosis of Reed syndrome. At the present time, genetic counseling is a suggested screening parameter for patients with multiple cutaneous leiomyomas. The superficial nature of these lesions and the low staging made surgical excision the preferred and actual treatment method. Adjunct radiation and chemotherapy have not been shown to provide clear benefit of survival. Owing to an association with renal cell carcinoma, a referral for nephrology consultation is also recommended.