IgG4 autoantibodies are inhibitory in the autoimmune disease bullous pemphigoid.

The IgG4 subclass of antibodies exhibits unique characteristics that suggest it may function in an immunoregulatory capacity. The inhibitory function of IgG4 has been well documented in allergic disease by the demonstration of IgG4 blocking antibodies, but similar functions have not been explored in autoimmune disease. Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease characterized by autoantibodies directed against BP180 and an inflammatory infiltrate including eosinophils and neutrophils. Animal models have revealed that the NC16A region within BP180 harbors the critical epitopes necessary for autoantibody mediated disease induction. BP180 NC16A-specific IgG belong to the IgG1, IgG3, and IgG4 subclasses. The purpose of this study was to determine effector functions of different IgG subclasses of NC16A-specific autoantibodies in BP. We find that IgG4 anti-NC16A autoantibodies inhibit the binding of IgG1 and IgG3 autoantibodies to the NC16A region. Moreover, IgG4 anti-NC16A blocks IgG1 and IgG3 induced complement fixation, neutrophil infiltration, and blister formation clinically and histologically in a dose-dependent manner following passive transfer to humanized BP180-NC16A mice. These findings highlight the inhibitory role of IgG4 in autoimmune disease and have important implications for the treatment of BP as well as other antibody mediated inflammatory and autoimmune diseases.

Toll-like receptor 9 promoter polymorphism as a predictive factor of narrow-band UVB phototherapy response in patients with psoriasis.

BACKGROUND: Prediction of response to ultraviolet B (UVB) phototherapy in psoriatic patients mainly relies on clinical criteria, although some genetic predictors have been identified. Toll-like receptors (TLRs) have been involved in psoriasis pathogenesis through activation of the innate immune system. Their polymorphisms may condition not only the clinical profile of psoriasis but also the response to therapy. METHODS: We analyzed the role of functional single-nucleotide polymorphisms (SNPs) of TLR2, 5, 4, and 9 in clinical response to a standard narrow-band UVB (NBUVB) therapy in 39 patients with moderate to severe psoriasis. RESULTS: We found a significant relationship between TLR9-1486T/C SNP variants and a better response to NBUVB phototherapy. Patients with TC and CC genotype showed a higher improvement of Psoriasis Area and Severity Index (PASI) than patients with TT genotype. Results of multivariate analysis indicate that the differences in PASI improvement at the end of phototherapy attributed to TRL9 SNP genotype were not dependent on the patients' phototype, age, gender, body mass index, basal PASI, or disease evolution. CONCLUSIONS: We describe a functional genetic variant in TLR9 gene that might affect the susceptibility to antipsoriatic treatment. The search of genetic predictive factors may be helpful in therapy selection and optimization of therapeutic regimes in psoriatic 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.

Allergen sensitization stratifies IL-31 production by memory T cells in atopic dermatitis patients.

Background: The role of allergen sensitization in IL-31 production by T cells and specifically in the clinical context of atopic dermatitis (AD) has not been characterized. Methods: The response to house dust mite (HDM) in purified memory T cells cocultured with epidermal cells from AD patients (n=58) and control subjects (n=11) was evaluated. AD-associated cytokines from culture supernatants, plasma proteins and mRNA expression from cutaneous lesions were assessed and related with the clinical features of the patients. Results: HDM-induced IL-31 production by memory T cells defined two subsets of AD patients according to the presence or absence of IL-31 response. Patients in the IL-31 producing group showed a more inflammatory profile, and increased HDM-specific (sp) and total IgE levels compared to the IL-31 non-producing group. A correlation between IL-31 production and patient's pruritus intensity, plasma CCL27 and periostin was detected. When the same patients were analyzed based on sp IgE and total IgE levels, an increased IL-31 in vitro response, as well as type 2 markers in plasma and cutaneous lesions, was found in patients with sp IgE levels > 100 kUA/L and total IgE levels > 1000 kU/L. The IL-31 response by memory T cells was restricted to the cutaneous lymphocyte-associated antigen (CLA)+ T-cell subset. Conclusion: IgE sensitization to HDM allows stratifying IL-31 production by memory T cells in AD patients and relating it to particular clinical phenotypes of the disease.

Apremilast improves quality of life and ultrasonography parameters in patients with nail psoriasis: A prospective cohort study.

Specific studies on apremilast for nail psoriasis are lacking. Our objective was to evaluate the nail-specific patient-reported outcomes, clinical efficacy, ultrasound (US) parameters, and safety of apremilast for nail psoriasis. We conducted a prospective cohort study including adult patients with plaque and nail psoriasis with a fingernail Nail Psoriasis Severity Index (NAPSI) score of 12 or more. Patients were treated with apremilast 30 mg b.i.d. for 52 weeks. Forty-five patients were included. At week 52, the Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA) Patient Benefit Index global weighted score was 2 or more in 52% of patients and NAPPA Quality of Life and fingernail NAPSI improved by 57% and 53%, respectively. US parameters improved from week 16 onwards. Target nail NAPSI improvements were higher for nail matrix scores (60%) than for nail bed scores (38%, p < 0.001). Baseline target nail bed NAPSI was associated with not achieving a target nail 50% reduction in NAPSI score at week 52 in the bivariate analysis (p = 0.024). Safety was consistent with the known apremilast profile. Results from apremilast therapy for 52 weeks in patients with psoriasis and predominant nail disease show significant improvements in nail-specific quality of life, clinical signs, and structural restoration on US, suggesting that apremilast may be considered in the treatment of nail psoriasis.

Rituximab in childhood pemphigus vulgaris: a long-term follow-up case and review of the literature.

Pemphigus vulgaris is an infrequent but life-threatening autoimmune blistering disease that is rare in the pediatric age. Although the mainstay of therapy for childhood pemphigus vulgaris (CPV) is steroids, adjuvant immunosuppressive drugs are often needed to control the disease. Thus, an important part of CPV morbidity can be related to treatment. We report the youngest CPV patient described in the English literature, an 18-month-old boy, who has been followed up for 16 years. During this period, the patient has received several immunosuppressive therapies with variable response. He has finally achieved a long-lasting and complete remission with rituximab. Successful treatment with rituximab has previously been reported in 6 cases of CPV, in whom rituximab presented a good side effect profile. Our patient has experienced a chronic and severe clinical course with multiple flares eventually developing vegetative lesions. Since he presented refractoriness to multiple therapies, we administered rituximab. The introduction of this drug led to a dramatic clinical response and a long-term clinical remission. Based on the experience of this case and the data reported in the literature, we believe that rituximab may be a safe and efficacious agent for the treatment of severe CPV.

The Role of Teledermatology and Teledermoscopy in the Diagnosis of Actinic Keratosis and Field Cancerization.

Actinic keratosis (AK) and field cancerization are increasing health problems insufficiently diagnosed by primary care physicians. The objective of this study was to assess the validity and reliability of teledermatology (TD) and teledermoscopy in the diagnosis of AK and field cancerization in a gatekeeper healthcare model. A prospective diagnostic test evaluation was done to assess the diagnostic concordance, accuracy, and performance parameters and the interobserver and intraobserver concordances of TD and teledermoscopy compared with dermatologists' face-to-face evaluation or histopathology. A total of 636 patients with 1,000 keratotic skin lesions were included. TD diagnostic concordance for AK and field cancerization evaluation was very high and superior to primary care physicians' diagnosis (92.4% vs. 62.4% and 96.7% vs. 51.8%, P < 0.001). TD sensitivity, specificity, and positive and negative predictive values for AK diagnosis and field cancerization were high (range = 82.2-95.0) and better than primary care physicians' diagnosis. Teledermoscopy yielded better results in diagnostic concordance, performance parameters, and AK subtypes. Intraobserver and interobserver agreement was >0.83. TD and, to a greater extent, teledermoscopy may be valid and reliable tools for the diagnosis of AK and field cancerization and may improve diagnosis and correct allocation and management in gatekeeper healthcare systems. It can be an alternative tool to training primary care physicians in direct diagnosis of these lesions.

Prevalence study of nevi in children from Barcelona. Dermoscopy, constitutional and environmental factors.

BACKGROUND: Malignant melanoma is becoming an increasingly important problem in public health as incidence rates have been increasing continuously in Caucasian populations. Childhood and adolescence is an important time of life for the formation and evolution of nevi, and the presence of a higher number of nevi in early life could predict a major risk of developing melanoma. OBJECTIVES: (1) To determine the number of nevi and the dermoscopic pattern predominance in children of our population. (2) To relate it to constitutional and environmental factors. METHODS: Clinical and dermoscopic examinations were performed in 180 children aged 1-15 years. A questionnaire including topics such as past history of sunburns, tanning ability, tendency to sunburn, history of sunlight exposure, use of sunscreens, tendency to freckle and family history of cancer was completed in a face-to-face interview with the parents. On clinical examination, we evaluated hair color, eye color, number of nevi and the presence of nevi in specific locations. All melanocytic lesions were examined dermoscopically, and all patterns were registered as present or absent. We also registered the predominant dermoscopic pattern of the child, defined as being present in more than 40% of all of the individual's nevi. RESULTS: The mean number of moles was 17.5. Male gender, past history of sunburns, facial freckling and family history of breast cancer were independent risk factors for having a higher number of nevi. We found that 61.1% of children had nevi on the face and neck, 17.2% on the buttocks, 11.7% on the scalp, 19.4% had acral nevi and 31.7% had congenital nevi. We found the presence of nevi in some of these locations to be a risk factor for having a higher number of nevi. The most frequent dominant dermoscopic pattern found in our population was the globular type. Interestingly, we found that the homogeneous pattern predominates in the youngest children, the reticular pattern predominates in adolescents and the dominant globular pattern is constant among all ages evaluated. CONCLUSION: This is the first study clinically and dermoscopically characterizing nevi in children from our population, and evaluating constitutional and environmental risk factors.

Sclerodermiform linear lupus erythematosus: A distinct entity or coexistence of two autoimmune diseases?

The coexistence of features of chronic cutaneous lupus erythematosus and scleroderma in the same skin lesions is very infrequent and has only been reported in 3 patients. This exceedingly rare condition has been named "sclerodermiform linear lupus erythematosus." We describe a new case of this dermatosis. Although the cause remains obscure, possible explanations include mosaicism following Blaschko's lines or the transfer of microchimerisms that mount a chronic graft-versus-host-like reaction. We suggest that these features may be a distinct clinicopathologic disorder characterized by an initial lichenoid reaction followed by the production of excessive, abnormal connective tissue.

Genetic and experimental evidence for the involvement of the CD6 lymphocyte receptor in psoriasis.

Psoriasis is a chronic inflammatory skin disease with a strong genetic background and is triggered by environmental factors. Available evidence supports CD6, a lymphocyte surface receptor mostly expressed by T cells, as a putative target in autoimmunity. Accordingly, a humanized anti-CD6 antibody has been assayed for the treatment of certain autoimmune disorders, including psoriasis. Here, we present novel evidence in mice and humans for a direct involvement of CD6 in psoriasis pathophysiology. First, an attenuated form of imiquimod-induced psoriasis-like skin inflammation was demonstrated in CD6-deficient mice, as deduced from lower epidermal thickness and local reduced production of pro-inflammatory cytokines, namely, interleukin-17A. Thus, isolated CD4+CD62L+ T cells from CD6-deficient mice displayed decreased in vitro T-helper type 17 polarization. Second, a statistically significant association between CD6 single-nucleotide polymorphisms (rs17824933, rs11230563 and rs12360861) and more severe forms of psoriasis was demonstrated in a cohort of 304 patients at three public hospitals from the metropolitan area of Barcelona. Taken together, these results provide new supportive evidence of the contribution of the CD6 lymphocyte receptor in psoriasis at both experimental and clinical levels.

Antineutrophil cytoplasmic antibodies.

Much like other autoantibodies (eg, anti-double stranded DNA in systemic lupus erythematosus or antiglomerular basement membrane antibodies in Goodpasture's syndrome), antineutrophil cytoplasmic antibodies (ANCA) have provided doctors with a useful serological test to assist in diagnosis of small-vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and their localised forms (eg, pauci-immune necrotising and crescentic glomerulonephritis). 85-95% of patients with Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune necrotising and crescentic glomerulonephritis have serum ANCA. ANCA directed to either proteinase 3 or myeloperoxidase are clinically relevant, yet the relevance of other ANCA remains unknown. Besides their diagnostic potential, ANCA might be valuable in disease monitoring. In addition, data seem to confirm the long-disputed pathogenic role of these antibodies. Present treatments for ANCA-associated vasculitis are not free from side-effects and as many as 50% of patients relapse within 5 years. Accurate understanding of the key pathogenic points of ANCA-associated vasculitis can undoubtedly provide a more rational therapeutic approach.

Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review.

CONTEXT: Immunosuppressive therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have greatly advanced patient survival but have turned ANCA-associated vasculitis (AAV) into chronic, relapsing disorders. Long-term treatment and disease-related morbidity are major threats. The last decade has seen a collaborative international effort to determine effective treatment. OBJECTIVE: To analyze the reported evidence on AAV therapy in order to provide physicians with a rational approach for dealing with various clinical scenarios. DATA SOURCES: We searched English-language articles on the medical treatment of AAV published between 1966 and March 2007 using MEDLINE. Articles from the reference lists of the most relevant articles retrieved were also analyzed. STUDY SELECTION: Studies of current available drug treatments or medical interventions for patients with AAV were included. Duplicate publications, case reports, and uncontrolled trials and series including fewer than 10 patients were excluded. DATA SYNTHESIS: We included 2 meta-analyses, 20 randomized controlled prospective trials, and 62 uncontrolled trials with more than 10 patients or observational studies. Outcome measures and treatment protocols were heterogeneous across trials. Cotrimoxazole can be used alone or in combination with corticosteroids to induce and maintain remission in cases of isolated upper respiratory tract involvement. To induce remission, methotrexate plus corticosteroids can be used instead of cyclophosphamide for patients with generalized, non-organ-threatening disease. When methotrexate is used as maintenance therapy, the likelihood of relapse is high and rigorous monitoring is mandatory. Pulse cyclophosphamide with corticosteroids can be used to induce remission in patients with generalized organ-threatening disease. The combination of azathioprine and daily prednisone is effective in maintaining remission. Plasma exchange is at present the best complement to immunosuppressants in advanced renal disease. In Churg-Strauss syndrome, treatment can be started with high doses of corticosteroids, tapering them when the clinical situation improves. In patients with a high risk of death, cyclophosphamide should be introduced. CONCLUSIONS: Although AAV therapies should be tailored to the patient's specific clinical situation, evidence for treatment of several disease states is lacking. There is a need for safer and more effective drugs.