Polymorphous Cutaneous Sarcoidosis With Excellent Response to Minocycline.

Sarcoidosis is notorious for producing a wide variety of skin lesions, which are categorized as either specific or nonspecific. The specific lesions include primary morphologies ranging from micropapules to subcutaneous nodules. Nonspecific skin lesions include associated conditions like erythema nodosum, calcinosis cutis, and prurigo. It is not uncommon for a patient to have a combination of specific and nonspecific lesions. In contrast, it is exceedingly rare for one patient to have multiple specific sarcoidal lesions. When present, the term "polymorphous cutaneous sarcoidosis" has been used. We present the case of a patient who presented with three specific cutaneous morphologies of sarcoidosis: papular sarcoid, Darier-Roussy subcutaneous sarcoidosis, and lupus pernio. After only two months of oral minocycline, our patient demonstrated remarkable improvement with near-complete resolution of the cutaneous lesions. In addition to describing the rare polymorphous presentation, this case also highlights the challenge of relating lesion type to overall prognosis when multiple morphologies are present.

C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita.

Introduction: Inflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype. Methods: To better understand the changes induced in neutrophils upon recruitment from peripheral blood into lesional skin in EBA, we performed single-cell RNA-sequencing of whole blood and skin dissociate to capture minimally perturbed neutrophils and characterize their transcriptome. Results: Through this approach, we identified clear distinctions between circulating activated neutrophils and intradermal neutrophils. Most strikingly, the gene expression of multiple C-type lectin receptors, which have previously been reported to orchestrate host defense against fungi and select bacteria, were markedly dysregulated. After confirming the upregulation of Clec4n, Clec4d, and Clec4e in experimental EBA as well as in lesional skin from patients with inflammatory EBA, we performed functional studies in globally deficient Clec4e-/- and Clec4d-/- mice as well as in neutrophil-specific Clec4n-/- mice. Deficiency in these genes did not reduce disease in the EBA model. Discussion: Collectively, our results suggest that while the upregulation of Clec4n, Clec4d, and Clec4e is a hallmark of activated dermal neutrophil populations, their individual contribution to the pathogenesis of EBA is dispensable.

Cutaneous Crohn's disease after proctocolectomy for medically refractory colonic Crohn's disease: a case series and review of the literature.

Background: Cutaneous Crohn's disease (CCD), also known as metastatic Crohn's disease (CD), is one of the rarest and most challenging cutaneous manifestations of CD. It is characterized by non-caseating granulomatous inflammation of the skin at sites that are non-contiguous with the gastrointestinal (GI) tract. Diagnosis of CCD needs a high clinical suspicion since morphological presentation varies widely and lacks an apparent correlation to the activity of the luminal CD. The onset of CCD in patients without active GI CD is a particularly understudied phenomenon. Methods: We present a case series of a unique patient group who developed CCD while in remission from a luminal CD perspective, mainly after a proctocolectomy for Crohn's colitis. We also provide a literature review and summary of case reports of CCD after proctocolectomy. Results: Our 4 adult patients diagnosed with CCD after proctocolectomy presented herein, were successfully treated with high-dose corticosteroids, followed by biologic therapy. Furthermore, a comprehensive review of CCD is provided regarding its pathogenesis, clinical presentation, differential diagnosis, and the evidence behind the available treatments. Conclusions: CCD should be considered in any CD patient presenting with skin lesions regardless of their disease activity status and history of proctocolectomy. The treatment remains challenging; biologics remain the cornerstone and a multidisciplinary approach is recommended. Larger randomized clinical trials are essential to determine the optimal treatment protocol and to improve outcomes.

SuPAR mediates viral response proteinuria by rapidly changing podocyte function.

Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.

Risk of infections in patients with pemphigus treated with rituximab vs. azathioprine or mycophenolate mofetil: a large-scale global cohort study.

BACKGROUND: The risk of infectious complications among patients with pemphigus managed by rituximab is yet to be precisely elucidated. OBJECTIVES: To evaluate the risk of infections in patients with pemphigus managed by rituximab vs. first-line corticosteroid-sparing agents [azathioprine and mycophenolate mofetil (MMF)]. METHODS: A global population-based cohort study compared patients with pemphigus initiating rituximab (n = 963) vs. azathioprine or MMF (n = 963) regarding the risk of 26 different infections. Propensity score matching was conducted to optimize comparability. RESULTS: During the initial 12 months following treatment, patients under rituximab experienced elevated risk of COVID-19 [hazard ratio (HR) 1.82, 95% confidence interval (CI) 1.06-3.14; P = 0.028], parasitic diseases (HR 3.22, 95% CI 1.04-9.97; P = 0.032) and cytomegalovirus (CMV) infection (HR 1.63, 95% CI 1.04-2.58; P = 0.033). When evaluating infections developing ≥ 12 months after drug initiation, rituximab was associated with greater risk of pneumonia (HR 1.45, 95% CI 1.00-2.10; P = 0.047), COVID-19 (HR 1.87, 95% CI 1.49-2.33; P < 0.001), osteomyelitis (HR 2.42, 95% CI 1.11-5.31; P = 0.023), herpes simplex virus (HR 2.06, 95% CI 1.03-4.11; P = 0.037) and CMV (HR 1.63, 95% CI 1.07-2.49; P = 0.023) infections. CONCLUSIONS: Within the first 12 months after treatment, patients under rituximab experience an elevated risk of COVID-19, parasitic and CMV infections. Rituximab is associated with pneumonia, osteomyelitis and viral diseases even beyond the first year after therapy. Pneumococcal vaccine and suppressive antiviral therapy should be considered even 1 year following therapy. There is no signal for elevated risk of tuberculosis, hepatitis B virus reactivation, Pneumocystis jiroveci pneumonia and progressive multifocal leukoencephalopathy.

Off-Label Uses of Rituximab in Dermatology.

Purpose of Review: Rituximab has transformed the treatment of B-cell malignancies and rheumatoid arthritis in the past 2 decades. More recently, this anti-CD20 monoclonal antibody has seen increasing usage in the field of dermatology. This review highlights the evidence supporting its use in several important dermatologic conditions. Recent Findings: Key recent findings include the 2018 FDA approval of rituximab for the treatment of moderate-to-severe pemphigus. Summary: Data from randomized controlled trials have demonstrated the efficacy of rituximab in pemphigus, ANCA-associated vasculitis, and cryoglobulinemic vasculitis. More limited data suggests its use in recalcitrant cases of diseases such as pemphigoid, epidermolysis bullosa acquisita, and dermatomyositis. There is scarce evidence and mixed results for rituximab when studied in cutaneous polyarteritis nodosa and cutaneous lupus erythematosus.

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms.

Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies targeting BP180 and BP230. While deposits of IgG and/or complement along the epidermal basement membrane are typically seen suggesting complement -mediated pathogenesis, several recent lines of evidence point towards complement-independent pathways contributing to tissue damage and subepidermal blister formation. Notable pathways include macropinocytosis of IgG-BP180 complexes resulting in depletion of cellular BP180, direct induction of pro-inflammatory cytokines from keratinocytes, as well as IgE autoantibody- and eosinophil-mediated effects. We review these mechanisms which open new perspectives on novel targeted treatment modalities.

Deciphering the Contribution of BP230 Autoantibodies in Bullous Pemphigoid.

Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease predominantly affecting elderly patients and carries significant morbidity and mortality. Patients typically suffer from severe itch with eczematous lesions, urticarial plaques, and/or tense blisters. BP is characterized by the presence of circulating autoantibodies against two components of the hemidesmosome, BP180 and BP230. The transmembrane BP180, also known as type XVII collagen or BPAG2, represents the primary pathogenic autoantigen in BP, whereas the intracellular BP230 autoantigen is thought to play a minor role in disease pathogenesis. Although experimental data exist suggesting that anti-BP230 antibodies are secondarily formed following initial tissue damage mediated by antibodies targeting extracellular antigenic regions of BP180, there is emerging evidence that anti-BP230 IgG autoantibodies alone directly contribute to tissue damage. It has been further claimed that a subset of patients has a milder variant of BP driven solely by anti-BP230 autoantibodies. Furthermore, the presence of anti-BP230 autoantibodies might correlate with distinct clinical features. This review summarizes the current understanding of the role of BP230 and anti-BP230 antibodies in BP pathogenesis.

Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases.

An estimated 20-25% of the population is affected by chronic, non-communicable inflammatory skin diseases. Chronic skin inflammation has many causes. Among the most frequent chronic inflammatory skin diseases are atopic dermatitis, psoriasis, urticaria, lichen planus, and hidradenitis suppurativa, driven by a complex interplay of genetics and environmental factors. Autoimmunity is another important cause of chronic skin inflammation. The autoimmune response may be mainly T cell driven, such as in alopecia areata or vitiligo, or B cell driven in chronic spontaneous urticaria, pemphigus and pemphigoid diseases. Rare causes of chronic skin inflammation are autoinflammatory diseases, or rheumatic diseases, such as cutaneous lupus erythematosus or dermatomyositis. Whilst we have seen a significant improvement in diagnosis and treatment, several challenges remain. Especially for rarer causes of chronic skin inflammation, early diagnosis is often missed because of low awareness and lack of diagnostics. Systemic immunosuppression is the treatment of choice for almost all of these diseases. Adverse events due to immunosuppression, insufficient therapeutic responses and relapses remain a challenge. For atopic dermatitis and psoriasis, a broad spectrum of innovative treatments has been developed. However, treatment responses cannot be predicted so far. Hence, development of (bio)markers allowing selection of specific medications for individual patients is needed. Given the encouraging developments during the past years, we envision that many of these challenges in the diagnosis and treatment of chronic inflammatory skin diseases will be thoroughly addressed in the future.

The Immunogenetics of Autoimmune Blistering Diseases.

Dermatological conditions constituting the group of autoimmune blistering diseases (AIBD) are characterized by loss of immunotolerance and humoral, as well as cellular, autoimmune responses that result in the development of bullae and erosions on the skin and mucous membranes. AIBDs are broadly categorized into pemphigus and pemphigoid classes with several distinct subtypes amongst them. Advances in genetics have allowed for the study and identification of alleles, and even single nucleotide polymorphisms, that harbor increased susceptibility or confer protection for the development of these conditions. The focus of this chapter pertains to a comprehensive review of the known genetic associations with AIBDs, including HLA class I-III, as well as non-HLA genes and non-coding sequences that influence cellular processes and signaling pathways.