Real-World Evaluation of the Effectiveness and Safety of Dupilumab in Bullous Pemphigoid: An Ambispective Multicenter Case Series.

BACKGROUND: Bullous pemphigoid affects elderly individuals with multiple comorbidities, making conventional treatments unsuitable. OBJECTIVE: Evaluate the effectiveness and safety of dupilumab in the treatment of bullous pemphigoid. METHODS: A multicenter ambispective cohort study was conducted in 34 hospitals. Patients with bullous pemphigoid treated with Dupilumab were included. Most of patients (97.1%) received an initial 600 mg dose followed by 300 mg every two weeks. OUTCOMES AND MEASURES: The primary outcome was the proportion of patients achieving complete remission within 4 weeks, defined as Investigator Global Assessment score of 0 or 1. Complete remission at weeks 16, 24, and 52, adverse events, reductions in peak pruritus numerical rating scale, and systemic glucocorticoid use were also assessed. RESULTS: The study included 103 patients with a median age of 77.3 years, 58.0% male. Complete remission was achieved by 53.4% within 4 weeks and 95.7% by week 52. Peak pruritus scale reduced by 70.0% by week 4 and was completely controlled by week 24. Thirteen patients presented adverse events, most of which were mild. Systemic glucocorticoid use reduced by 82.1% by week 52. Shorter disease duration and exclusive cutaneous involvement predicted better response at 16 weeks. No differences in response rates to dupilumab were observed between drug-associated bullous pemphigoid and idiopathic cases. No significant difference in response rates was observed between patients treated with dupilumab in monotherapy and those receiving dupilumab with concomitant treatments. CONCLUSIONS: Dupilumab is effective, rapid, and safe in managing bullous pemphigoid, reducing the need for corticosteroids and other treatments. Early initiation and exclusive skin involvement predict better outcomes.

Efficacy of omalizumab for the treatment of bullous pemphigoid: Spanish multicentre real-world experience.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. Most patients are older and have associated multiple comorbidities. Topical and systemic corticosteroids are considered the first-line treatment for BP, and immunosuppressants are used as steroid-sparing treatments. However, both have side-effects and contraindications, which are even more common in this older population. New treatments targeting interleukins and receptors related to BP pathogenesis have been proposed to decrease these side-effects while achieving equal or better effectiveness and response rates. Omalizumab is a monoclonal antibody that targets IgE and has been proposed for the treatment of BP due to the evidence that IgE autoantibodies play an essential role in BP pathogenesis. OBJECTIVES: To assess the efficacy and safety of omalizumab for the treatment of BP. METHODS: We carried out a multicentre, retrospective, observational study including patients diagnosed with BP who received omalizumab for ≥ 3 months from 15 tertiary hospitals in Spain. IgE levels prior to treatment were measured, and we evaluated the possible correlation with clinical response. We excluded patients treated with omalizumab for < 3 months, as we consider this duration to be insufficient for a comprehensive assessment of its efficacy. To evaluate the effectiveness of the treatment, we used the percentage of body surface area improvement. RESULTS: We included 36 patients. The vast majority had associated multiple comorbidities, and all patients had used other systemic therapies apart from corticosteroids before omalizumab. In total, 83% experienced some kind of treatment response and 42% of all patients treated achieved complete response. We did not find any correlation between higher IgE levels and a better response (P = 0.2). All patients tolerated omalizumab without reported side-effects. CONCLUSIONS: Omalizumab is a good therapeutic alternative for BP as it provided clinical response in most patients, and nearly one-half of the cases achieved complete response. It showed no side-effects, which is crucial in older patients with BP.

Sweet Syndrome: Clinical Presentation, Malignancy Association, Autoinflammatory Disorders and Treatment Response in a Cohort of 93 Patients with Long-term Follow-up.

Sweet syndrome is a neutrophilic dermatosis associated with multiple disorders. This retrospective case-series study of patients with Sweet syndrome in a tertiary hospital in Spain from 2001 to 2021, explores clinicopathological characteristics of Sweet syndrome and variables associated with malignancy, presence of autoinflammatory disorders and differences between histological subtypes. A total of 93 patients were identified: 30% idiopathic, 34% malignancy-associated, 29% reactive to infections or drug-associated, and 6% with an autoimmune/inflammatory condition. Acute myeloid leukaemia was the most common malignancy (16/93) followed by myelodysplastic syndrome (7/93). Patients with acute myeloid leukaemia presented isolated flares, marked cytopaenia and rapid response to treatment, whereas myelodysplastic syndrome followed a chronic-recurrent course. The most frequent associated medications and inflammatory  disorders were filgrastim and hydroxyurea (n = 2);  and inflammatory bowel disease (n = 4). In addition, 3 patients were diagnosed with VEXAS syndrome. Male sex (p = 0.006), fever (p = 0.034), increased erythrocyte sedimentation rate (p < 0.001), anaemia (p < 0.001), and thrombocytopaenia (p < 0.001) were associated with malignancy. Histologically, patients were classified as classic (60%), histiocytoid (22.5%) or subcutaneous (15%), with pain (p = 0.011) and nodules (p < 0.001) being associated with subcutaneous-Sweet syndrome. Sweet syndrome in the context of cytopaenia should alert the presence of malignancy. An  acquired autoinflammatory condition should be explored  in relapsing Sweet syndrome with myelodysplastic syndrome. A minimum follow-up of 6 months is recommended.

High-risk mucosal human papillomavirus-associated squamous cell carcinoma of the fingers presents distinctive clinicopathological characteristics and outcomes: a bicentric retrospective study.

BACKGROUND: High-risk mucosal human papillomavirus (HR-HPV) seems to play a role in cutaneous squamous cell carcinoma (cSCC), particularly in nail tumours, where genitodigital transmission has been suggested. The role of HR-HPV in nonungual cSCC of the finger needs to be clarified. AIM: To evaluate the prevalence, clinicopathological characteristics, surrogates and outcomes of HR-HPV in cSCC of the finger. METHODS: This was an observational bicentric study including patients with an excised in situ or invasive cSCC located on the finger. Differences in HR-HPV and non-HR-HPV tumours were evaluated. RESULTS: Forty-five patients (45 tumours) were included. HR-HPV was detected in 33% of cases (22% HPV type 16). The mean age was lower in patients with HR-HPV than in those with non-HR-HPV (62·4 vs. 81·1 years, P = 0·001). HR-HPV tumours were smaller (10 mm vs. 15 mm, P = 0·07) and more frequently intraepidermal (60% vs. 20%, P = 0·004). The absence of elastosis (P = 0·030) and inflammation (P = 0·026) and the presence of basaloid morphology (P = 0·003) were surrogates of HR-HPV detection. Mean p16 positivity was 61% in HR-HPV and 36% in non-HR-HPV tumours (P = 0·061). Recurrence after surgery was more common in HR-HPV tumours (58% vs. 34%), although this was not statistically significant. HR-HPV was detected in 27% of the nonungual tumours. CONCLUSION: HR-HPV-associated cSCC of the finger appears in younger patients, is smaller and is less infiltrative than non-HR-HPV tumours. The presence of a basaloid morphology and the absence of elastosis and inflammation could be used as markers for HR-HPV detection. The high prevalence of HR-HPV in nonungual cSCC suggests its aetiopathogenic role in these tumours.

Clinicopathological, Genetic and Survival Advantages of Naevus-associated Melanomas: A Cohort Study.

Several studies have suggested that naevus-associated melanomas differ from de novo melanomas, being thinner and with less ulceration; however, the prognostic implication is unclear. The objective of this study was to describe clinicopathological, genetic and survival characteristics of de novo and naevus-associated melanomas in a cohort of primary invasive cutaneous melanomas over a 20-year period. Of the 2,227 patients included in the study, 509 (22.86%) had naevus-associated melanomas. Compared with patients with de novo melanoma, they were younger, with a fairer phototype and a higher naevus count, tumours were predominantly the superficial spreading subtype, American Joint Committee on Cancer stage I, located on the trunk, and there were fewer signs of invasiveness (thinner Breslow index, less ulceration, lower mitotic index and less satellitosis). Germline mutation-al status did not show any significant association. As determined through univariate analysis, overall surviv-al was significantly better in patients with naevus- associated melanoma (hazard ratio 0.64; 95% confidence interval 0.51-0.80, p < 0.001), but multivariate analysis did not support this prognostic indication (hazard ratio 0.94; 95% confidence interval 0.75-1.18, p < 0.606). Despite this, we conclude that naevus- associated and de novo melanomas should be considered as different subtypes of melanoma.

Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches.

Chronic mucocutaneous candidiasis (CMC) is characterized by a chronic or recurrent non-invasive infection, mainly due to Candida albicans, in skin, nails, and mucous membranes, associated in some cases with autoimmune manifestations. The key immune defect is a disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of-function (GOF) mutations. The initial appropriate treatment for fungal infections is with azoles. However, the frequent occurrence of drug resistance is the main limitation. Therefore, identification of the underlying inborn error if immunity in CMC may allow to widen therapeutic options aimed at restoring immunological function. Type I and II Janus kinase-inhibitors have been shown to control CMC in cases associated with STAT1 GOF. In this review, we delve into the pathogenesis of CMC and the underlying immune mechanisms. We describe the reported genetic defects in which CMC is the main manifestation. Diagnostic and therapeutic approaches for these patients are also offered.

Diagnostic accuracy of imaging studies for initial staging of T2b to T4b melanoma patients: A cross-sectional study.

BACKGROUND: There is no consensus on the imaging tests that should be performed at the initial staging of melanoma patients. OBJECTIVE: To evaluate the diagnostic accuracy of 4 imaging studies for the initial staging of melanoma patients. METHODS: Cross-sectional study with prospectively collected data, from January 2011 to April 2017, including patients with clinical stage T2b to T4b according to 2009 American Joint Committee on Cancer, without evidence of metastasis. RESULTS: Initial staging of 308 patients detected 16.6% of metastases and 5.8% false-positive results, overall. Regional lymph node ultrasonography showed a metastasis detection rate (MDR) of 12.8%, false-positive rate of 0.8%, and accuracy of 96.0%. Computed tomography (CT) and positron emission tomography-CT had the highest detection rates at stage T4b: MDR, 13.3%; false-positive rate, 8.9%; accuracy, 91.1%; and MDR, 6.9%; false-positive rate, 0%; and accuracy, 93.1%, respectively. Brain magnetic resonance imaging showed a MDR of 2.0% in T4b. LIMITATIONS: Single-center study. CONCLUSION: Performing ultrasound scans for assessing lymph node metastasis in patients with American Joint Committee on Cancer T2b stage and above is advisable. In patients with stage T4b, CT or positron emission tomography-CT are suitable for the detection of metastasis. Brain magnetic resonance imaging at T4b deserves further discussion, considering the ultimate clinical benefit in management and therapeutic options for asymptomatic patients.

Case Report: Localized bullous pemphigoid induced by local triggers: a case series and a proposal for diagnostic criteria based on a literature review.

Introduction: Localized bullous pemphigoid (LBP) is an infrequent bullous pemphigoid (BP) variant restricted to a body region. According to the most compelling evidence, LBP occurs in patients with pre-existent serum antibodies against the basement membrane zone, which occasionally acquire the capacity to induce disease after the influence of different local factors acting as triggers. Methods: We hereby present a multicenter cohort of 7 patients with LBP developed after local triggers: radiotherapy, thermal burns, surgery, rosacea, edema and a paretic leg. In addition, we conducted a review of the literature, and we propose a set of diagnostic criteria for LBP, also based on our case series and the 2022 BP guidelines from the European Academy of Dermatology and Venereology. Results: During follow-up, three of the patients from our series evolved to a generalized BP, with only one requiring hospitalization. Our literature search retrieved 47 articles including a total of 108 patients with LBP, with a 63% with a potential local precipitating factor previous to their diagnosis. LBP mostly affected older females, and a subsequent generalized progression occurred in 16.7% of the cases. The most frequently involved areas were the lower limbs. Radiation therapy and surgery were responsible for the inducement of nearly 2 in 3 cases of LBP. We observed a significantly higher risk of generalization in cases where the trigger led to the developing of LBP earlier (p=0.016). Our statistical analysis did not detect any other prognosis factor for generalization when assessing direct immunofluorescence, histological and serological results, or other patient related factors. Conclusion: LBP should be suspected in patients with recurrent localized bullous eruptions. The presence of a trauma history in the same anatomic area is reported in most cases.

Anti-Desmocollin Autoantibodies in Autoimmune Blistering Diseases.

The presence of anti-desmocollin (Dsc) antibodies is rarely described in autoimmune blistering diseases patients. Moreover, several clinical phenotypes of pemphigus may be associated with these antibodies. In this review we analyze clinicopathological, immunologic and outcome features of anti-Dsc autoimmune blistering diseases patients, to improve their diagnosis and management. We conducted a systematic search of PubMed and Embase (1990-present) for studies reporting cases of autoimmune blistering diseases with anti-Dsc antibodies. We classified the selected patients as patients with exclusively anti-Dsc autoantibodies, and patients with anti-Dsc and other autoantibodies. Of 93 cases with anti-Dsc autoantibodies included, 38 (41%) had exclusively these antibodies. Only 18% of patients presented with the typical clinicopathological phenotype of pemphigus vulgaris or pemphigus foliaceous. Mucosal involvement was seen in approximately half of the patients. Up to 18% of cases were associated with neoplasms. Acantholysis was described in 54% of cases with histopathological information. Treatments and outcomes vary in the different clinical phenotypes. The presence of anti-Dsc antibodies must be suspected mainly in those patients with either atypical pemphigus, in special with clinical pustules, or in cases showing intraepithelial or dermal neutrophilic/eosinophilic infiltrate on histological examination and dual pattern by direct immunofluorescence examination.

Skin Manifestations in COVID-19: Prevalence and Relationship with Disease Severity.

BACKGROUND: Data on the clinical patterns and histopathology of SARS-CoV-2 related skin lesions, as well as on their relationship with the severity of COVID-19 are limited. METHODS AND MATERIALS: Retrospective analysis of a prospectively collected cohort of patients with SARS-CoV-2 infection in a teaching hospital in Barcelona, Spain, from 1 April to 1 May 2020. Clinical, microbiological and therapeutic characteristics, clinicopathological patterns of skin lesions, and direct immunofluorescence and immunohistochemical findings in skin biopsies were analyzed. RESULTS: Fifty-eight out of the 2761 patients (2.1%) either consulting to the emergency room or admitted to the hospital for COVID-19 suspicion during the study period presented COVID-19 related skin lesions. Cutaneous lesions could be categorized into six patterns represented by the acronym "GROUCH": Generalized maculo-papular (20.7%), Grover's disease and other papulo-vesicular eruptions (13.8%), livedo Reticularis (6.9%), Other eruptions (22.4%), Urticarial (6.9%), and CHilblain-like (29.3%). Skin biopsies were performed in 72.4%, including direct immunofluorescence in 71.4% and immunohistochemistry in 28.6%. Patients with chilblain-like lesions exhibited a characteristic histology and were significantly younger and presented lower rates of systemic symptoms, radiological lung infiltrates and analytical abnormalities, and hospital and ICU admission compared to the rest of patients. CONCLUSION: Cutaneous lesions in patients with COVID-19 appear to be relatively rare and varied. Patients with chilblain-like lesions have a characteristic clinicopathological pattern and a less severe presentation of COVID-19.