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Ocular predominant mucous membrane pemphigoid (oMMP) is a severe subtype of MMP that can lead to scarring and blindness. While conjunctival biopsy for direct immunofluorescence (DIF) is considered the gold standard for diagnosis, limited sensitivity results in a false-negative rate upwards of 40%. Likewise, it remains unclear to what extent a negative biopsy, whether false-negative or true-negative, results in a different prognosis, with patients previously termed "pseudopemphigoid" demonstrating comparable disease progression. Serologic testing allows for a less invasive means to demonstrate circulating autoantibodies against known autoantigens in pemphigoid diseases. Patients with MMP, particularly oMMP, however, typically demonstrate low titers of circulating autoantibodies, limiting the diagnostic utility of these tests. The autoantigen integrin ß4 has been previously reported to be a specific marker of pure ocular MMP, while in the majority of patients with oMMP, the identified target antigens are BP180 (type XVII collagen) and laminin 332. Recent studies have, however, demonstrated inconsistent reactivity and specificity for integrin ß4 as an ocular-specific marker in MMP. Herein, we review the role of serologic testing in the diagnosis and prognosis of oMMP, as well as the current understanding of autoantigens in oMMP.Abbreviations: BMZ - basement membrane zone, DIF - direct immunofluorescence, IIF - indirect immunofluorescence, MMP - mucous membrane pemphigoid, oMMP - ocular predominant mucous membrane pemphigoid.
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Penfigoide Ampolloso , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/tratamiento farmacológico , Humanos , Administración Oral , Estudios Retrospectivos , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Administración Cutánea , Administración TópicaRESUMEN
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.
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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.
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Epidermólisis Ampollosa Adquirida , Humanos , Animales , Ratones , Neutrófilos , Autoanticuerpos , Piel , VesículaRESUMEN
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.
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COVID-19 , Podocitos , Animales , Ratones , Chlorocebus aethiops , Humanos , Vacunas contra la COVID-19 , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , SARS-CoV-2 , Integrinas , ProteinuriaRESUMEN
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.
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Penfigoide Ampolloso , Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Penfigoide Ampolloso/complicaciones , Penfigoide Ampolloso/tratamiento farmacológico , Psoriasis/complicaciones , Psoriasis/tratamiento farmacológico , Enfermedades Cutáneas Vesiculoampollosas/complicaciones , Interleucina-23RESUMEN
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 12â 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 ≥ 12â 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 12â 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 1â year following therapy. There is no signal for elevated risk of tuberculosis, hepatitis B virus reactivation, Pneumocystis jiroveci pneumonia and progressive multifocal leukoencephalopathy.
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COVID-19 , Infecciones por Citomegalovirus , Pénfigo , Humanos , Azatioprina/uso terapéutico , Rituximab/efectos adversos , Ácido Micofenólico , Inmunosupresores/efectos adversos , Pénfigo/tratamiento farmacológico , Pénfigo/epidemiología , Estudios de Cohortes , Infecciones por Citomegalovirus/inducido químicamenteRESUMEN
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.
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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.