A case of anti-laminin γ1 (p200) pemphigoid developed after dipeptidyl peptidase-4 inhibitor administration.

A 73-year-old man with diabetes mellitus was referred to our department for ultraviolet treatment for erythematous skin lesions with itching. On dipeptidyl peptidase-4 inhibitor (DPP-4i) sitagliptin (Januvia®) for diabetes mellitus, the erythematous skin lesions appeared and spread to the whole body. At the initial visit, erythema multiforme-like skin lesions with crusts were observed on the trunk and extremities, and the patient was suspected to have drug eruption. Histopathology demonstrated eosinophilic infiltration in the superficial dermis and inflammatory cell infiltration in the epidermis. Sitagliptin was discontinued, and erythematous lesions improved with oral prednisolone. Thereafter the patient was treated with phototherapy and  betamethasone sodium phosphate infusion for residual prurigo. However, blistering skin lesions appeared 5 months later. Histopathological findings were subepidermal blisters with eosinophilic abscess, and bullous pemphigoid was suspected. CLEIAs for autoantibodies to desmoglein 1 (Dsg1), Dsg3 and BP180 were negative. Direct immunofluorescence showed linear depositions of immunoglobulin G (IgG) and C3 at the epidermal basement membrane zone, and indirect immunofluorescence detected IgG anti-epidermal basement membrane zone antibodies, reacting with the dermal side of 1M NaCl-split normal human skin. IgG antibodies reacted with 200 kDa laminin γ1 (p200) by immunoblotting using dermal extracts. These results indicated that this patient was diagnosed with anti-laminin γ1 (p200) pemphigoid developed after DPP-4i administration. Although reports of DPP-4i-related bullous pemphigoid have accumulated, cases of anti-laminin γ1 (p200) pemphigoid developed after DPP-4i administration are rarely reported.

Dietary habits in Japanese patients with bullous pemphigoid: low intake of retinol.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Dietary habits may modulate the pathogenesis of BP. OBJECTIVES: We evaluated dietary habits in Japanese patients with BP and compared their results to those of age- and sex-matched healthy controls. We also examined the relationship between dietary habits versus IgG anti-BP180NC16A antibody or parameters of BP disease area index (BPDAI); cutaneous blisters/erosions, cutaneous urticaria/erythema, and mucosal blisters/erosions. MATERIALS & METHODS: Dietary habits were assessed by the validated, Brief-type self-administered Diet History Questionnaire. Severity of disease was assessed with BPDAI. RESULTS: Patients with BP showed a lower intake of retinol (vitamin A1) and beverages, and a higher intake of seasoning/spices, compared to controls. The bivariate and multivariable logistic regression analysis showed that BP was associated with a low intake of retinol and beverages. There were no significant correlations between IgG anti-BP180NC16A antibody levels and intake of nutrients/foods. The BPDAI score for cutaneous blisters/erosions significantly positively correlated with intake of carbohydrate and negatively with intake of retinol, vitamin A, animal fat, cholesterol, phosphorus, and vitamin B2. The BPDAI score for cutaneous urticaria/erythema significantly negatively correlated with intake of vitamin A. BP patients with mucosal blisters/erosions had a higher intake of cholesterol, n-6 polyunsaturated fatty acid, and eggs, and lower intake of seasoning/spices, compared to patients without BP. CONCLUSION: The supplementation of vitamin A might have prophylactic and/or therapeutic effects on BP.

Use of Complementary and Alternative Medicine in Patients with Autoimmune Bullous Dermatoses: A Cohort Study Analysis of a Rare Disease Group.

INTRODUCTION: Autoimmune bullous diseases (AIBD) are a heterogeneous group of rare autoantibody-mediated blistering dermatoses of the skin and/or mucous membranes. Their incidence is around 20 new cases per million inhabitants per year in Germany. Patients with chronic, oncological, or rare diseases often urge for a holistic therapeutic approach that includes complementary and alternative medicine (CAM). So far, only few contradictory reports on CAM in pemphigoid or pemphigus disease exist. The purpose of this study was to determine the frequency, motives, and satisfaction with the use of alternative treatments in patients with AIBD and to provide a basis for further investigation. METHODS: We used a structured online questionnaire, consisting of 20 questions to survey patients with AIBD and their relatives. The German pemphigus and pemphigoid self-help groups were responsible for distributing anonymized questionnaires. In total, we recovered 97 questionnaires, 63 of which met full inclusion criteria (24 males and 39 females). RESULTS: Of the included participants, more than half had a currently active disease. Of all patients, 58.7% stated that they had used CAM at least once. Women were more likely to use CAM, whereas age and education showed no association to CAM use. The main motives for using CAM were "doing something for oneself" and "opportunity to contribute to treatment" (38.1% each). The internet (23.8%) was the most common source of information, and vitamins were the most frequently used therapy (49.2%). CONCLUSION: Our results provide new insights into the demand for CAM within this rare disease patient group. Physicians should be aware of these methods to meet patient needs but also be able to identify potential barriers such as risks and interactions.

Drug-aggravated Bullous Pemphigoid in a 47-year-old Asian Woman - A Case Report.

INTRODUCTION: Bullous pemphigoid is the most common chronic recurrent autoimmune subepidermal blistering disorder most prevalent in the geriatric population. It varies widely in clinical presentation ranging from tense bullae to intense generalized pruritus. It is immunologic in origin with the presence of IgG antibodies. CASE REPORT: A 47-year-old female presented to the hospital with complaints of blisters in the lower limbs, which she self managed with neem oil, after which the blisters occurred over the body. The patient also experienced blisters over both upper and lower limbs, gluteal region, painful generalized ulcers, necrotic patches, multiple erythematous blisters, ulcer erosions over bilateral legs and upper limbs with few lesions, which were foul-smelling and oozing. On the second day of admission, the patient's CRP and ESR levels were tested and the levels were 33.5 and 35 mm/hr, respectively. The patient was treated with an injection of meropenem 1 g three times daily, dexamethasone 4 mg once daily, and ofloxacin 400 mg once daily. On the third day of admission, the patient complained of leg swelling, and subsequently, D-Dimer levels were checked, which showed a value of 5,740 and was treated with an injection of enoxaparin 40 mg for the same throughout the course of the hospital stay A skin biopsy confirmed the diagnosis of bullous pemphigoid. The culture test showed the growth of Klebsiella pneumonia and Acinetobacter baumani, which were resistant to most of the antibiotics. The patient was managed appropriately with modalities including antibiotics, anti-inflammatory agents, immunosuppressants, multivitamins, fluids, and albumin. The patient responded well to the treatment without new lesions or fever spikes. There was the presence of necrotic patches of old lesions alone at the time of discharge. CONCLUSION: This case report was done with the purpose of presenting an exemplary case of bullous pemphigoid aggravated by the application of neem oil and emphasizing the inappropriate use of folk medicine in an autoimmune disease like bullous pemphigoid.

Case Report: Pemphigoid Nodularis-Five Patients With Many Years of Follow-Up and Review of the Literature.

Pemphigoid nodularis is a rare form of pemphigoid that joins the clinical picture of prurigo nodularis and the immunological features of bullous pemphigoid, which is therapeutically challenging. Here, we analyze five female patients with a long-lasting course of nodular pemphigoid in terms of clinical and immunological characteristics and therapy. All the patients fulfilled clinical and immunological criteria of nodular pemphigoid. We applied numerous techniques allowing the proper diagnosis: direct and indirect immunofluorescence, salt split skin, ELISA, BIOCHIP, and fluorescence overlay antigen mapping using laser scanning confocal microscopy. Our study showed that 4 of 5 patients fulfilled the clinical and immunological criteria of nodular bullous pemphigoid. Two out of 4 patients presented exclusively nodular lesions; in the other two patients, blisters and erythematous lesions preceded prurigo-like lesions by a few years. The remaining patient had clinical and immunological criteria of nodular mucous membrane pemphigoid, presenting oral erosions, scarring conjunctivitis, and numerous disseminated nodules on the skin. All the patients were treated with multiple medicines; however, it was observed that the use of clobetasol propionate on the entire body plus antidepressants best controlled the disease. Pemphigoid nodularis mainly occurs in elderly women. In cases with coexisting psychological problems, antidepressants should be considered as an important complementary therapy to the basic one with clobetasol propionate.

A case report of steroid-refractory bullous pemphigoid induced by immune checkpoint inhibitor therapy.

The widespread use of immune checkpoint inhibitors in several malignancies has revealed new immune-related adverse events. Bullous pemphigoid (BP) is an antibody-driven autoimmune disease characterized by skin inflammation and fluid-filled bullae. Herein, a 69-year-old man with lung squamous cell carcinoma developed multiple vesicles and tense bullae 3 weeks after the initiation of a programmed death-1 (PD-1) inhibitor, pembrolizumab, and chemotherapy. Biopsy revealed a subepidermal bulla with lymphocytic and eosinophil infiltration, and immunohistochemical studies predominantly showed CD4+ cells, a few CD8+ cells, and the occasional CD20+ lymphocyte. The serum anti-BP180 antibody level, as well as the interleukin-6 and interleukin-10 levels, were elevated compared to the lower levels of tumor necrosis factor-α. Eosinophil levels were high and consistent with the development of blisters. A diagnosis of BP associated with PD-1 inhibitor therapy was made, and the Common Terminology Criteria for Adverse Events classification was grade 3. Immunotherapy was permanently discontinued, and the patient's bullous lesions failed to react to high-dose systemic corticosteroids combined with minocycline and niacinamide. Intermittent blister recurrence occurred in 2 months, eventually improving with the administration of two courses of intravenous immunoglobulin. At 5 weeks of follow-up, the patient's tumor was reduced on a computed tomographic scan. Despite stable BP treatment, however, he repeatedly developed complications due to the complexity of his underlying disease and could not be treated with anti-tumor therapy. Early recognition and management of serious immune-related bullous dermatologic toxicity are essential for patient safety.

Pemphigus Vulgaris and Bullous Pemphigoid of the Upper Aerodigestive Tract: A Review Article and Novel Approaches to Management.

BACKGROUND: Autoimmune bullous diseases are rare conditions characterized by blistering of the skin and mucous membranes. The 2 commonest forms are pemphigus vulgaris and bullous pemphigoid. The oral cavity or oropharynx may be the initial site of presentation or often the only site involved. SUMMARY: These conditions are often misdiagnosed or overlooked leading to poorer patient outcomes. Due to the chronic nature of these conditions and the systemic effects of treatment, there is a significant associated morbidity and mortality. As such, an understanding of the fundamentals of autoimmune bullous diseases is vital to those working in otolaryngology. The mainstay of management in both conditions is topical and systemic corticosteroids. There is also a role for immunomodulating and non-steroidal anti-inflammatory drugs as adjunct or alternative therapies. Surgical intervention may be required to protect the airway. Often multimodality treatment is required involving multidisciplinary input from otolaryngologists, oral surgeons, dermatologists, and rheumatologists. This review article will highlight the aetiology, pathology, clinical features, investigations, and management of both pemphigus vulgaris and bullous pemphigoid including recent advances in management.

Treatment options for autoimmune bullous dermatoses other than systemic steroids: A systematic review and network meta-analysis.

Autoimmune blistering diseases can eventually cause life-threatening complications if left untreated. Although there is no cure for these bullous diseases; their therapy is based on suppressing the immune system to cease the de novo formation of the generated antibodies. The current study aimed to assess the safety and efficacy of using standing alone alternative therapies beyond systemic steroids for management of autoimmune bullous diseases. We searched six literature databases for both randomized and quasi-randomized clinical trials that assessed the efficacy of drugs other than systemic steroids in autoimmune bullous diseases. Outcomes were calculated as odds ratios with 95% confidence-interval. We used the R software to perform conventional and network meta-analyses with a frequentist approach. The network ranking order for 629 bullous pemphigoid patients, from the best to the worst was, clobetasol propionate cream (40 mg; (P-score = .87), clobetasol propionate cream (10-30 mg; P-score = .77), nicotinamide plus tetracycline (P-score = .56), steroids (P-score = .29) and doxycycline (P-score = .01). Limitations of this study are the small sample of the included studies except for blister trial and lack of randomization in most trials. To conclude, Combined doxycycline and nicotinamides are safer and more effective option for extensive bullous pemphigoid patients than the usual use of systemic steroids. For limited disease, topical corticosteroid (40 mg/d) use provides a safer and better response modality than the other proposed treatments.

Treatment of bullous pemphigoid in Chinese patients with Tripterygium wilfordii Hook F.

Tripterygium wilfordii Hook F (TwHF) is a traditional Chinese herb used in many medicinal applications, but the treatment of bullous pemphigoid (BP) with TwHF has never been reported. The aim of this study was to evaluate the efficacy and safety of TwHF in BP patients. A retrospective study was performed from January 2015 to September 2019 in the Department of Dermatology, Peking Union Medical College Hospital. A total of 10 patients with mild to moderate BP and treated with TwHF were enrolled in the study with 10 mild or moderate BP patients treated with systemic glucocorticoid randomly selected as controls. In the TwHF group, a major response was seen in seven patients, a minor response in one and no response was seen in two patients. In the glucocorticoid group, a major response was seen in nine patients and a minor response in one patient. Two patients experienced treatment failure. The time to disease control in the TwHF group (34 ± 11 days) was longer as compared to the glucocorticoid group (18 ± 8 days, P < .05). Ten patients relapsed during the follow-up period. The adverse events in the TwHF group were lower than those in the glucocorticoid group (13 vs 19). Low-dose TwHF may be effective and safe for treating mild and moderate BP.

Psoriasis is associated with increased risk of bullous pemphigoid: A nationwide population-based cohort study in Taiwan.

Psoriasis may coexist with bullous pemphigoid (BP); however, no cohort studies have investigated the relationship between psoriasis and the risk of BP. This study aims to investigate the relationship between psoriasis and the risk of BP in Taiwan. This cohort study consists of 109 777 psoriatic patients and 109 777 matched non-exposed controls. Psoriatic patients diagnosed between 2002 and 2012 were identified from the Taiwan National Health Insurance Research Database. The age-, sex- and index date-matched non-exposed group was selected from the same database. The relationship between psoriasis and the risk of BP was investigated using Cox proportional hazards analyses. Psoriasis was significantly associated with an increased risk of BP (hazard ratio, 3.05; 95% confidence interval, 2.10-4.43; P < 0.001). The mean interval between the diagnoses of psoriasis and BP was 2.86 years, with the highest occurrence in the first year after psoriasis diagnosis, and gradually decreasing with each year of observation. Psoriatic patients with BP were significantly younger than BP patients in the non-exposed group (71.6 ± 13.9 vs 76.6 ± 7.7 years, respectively; P = 0.030). A higher proportion of patients with coexisting psoriasis and BP received phototherapy (20%). In conclusion, psoriasis was independently associated with a 3.05-fold increased risk of BP, and psoriatic patients with BP were younger, with over one-third of BP cases diagnosed in the first year after incident psoriasis. Therefore, clinicians treating patients with psoriasis may be aware of the possibility of the development of BP.

Omalizumab as an alternative therapeutic tool in the treatment of bullous pemphigoid: A case report.

Bullous pemphigoid (BP) is an acquired autoimmune bullous disease characterized by autoantibodies against the hemidesmosomal proteins found in the basal keratinocytes of the basement membrane zone (BMZ): a 180 kDa protein (type XVII collagen) mainly and the 230 kDa antigen. There is such evidence that the antibodies against the BMZ components are not only of IgG type, but also this bullous disease may have IgE antibodies directed to the BMZ that contribute to the pathogenesis of the disorder. IgE is not only thought to contribute to the pathogenesis of BP, it has also been suggested that eosinophils play a role in the development of the first signs associated with BP. A humanized monoclonal antibody directed to IgE, omalizumab, is approved for the treatment of severe asthma and chronic spontaneous urticaria, and it may be useful in the treatment of BP in the first stages of the disease.

Biological therapy of autoimmune blistering diseases.

INTRODUCTION: Autoimmune blistering skin diseases are a group of disorders subdivided according to the location of blister formation: intraepidermal blistering in the pemphigus group and subepidermal in the pemphigoid group. These conditions are clinically heterogeneous and are treated with systemic corticosteroids and/or other forms of immunosuppression on the basis of clinical subtype and disease severity. These approaches may not be effective for the induction and maintenance of clinical response or need to be stopped because of intolerable side effects. AREAS COVERED: Biological therapies can represent a valid alternative strategy in various autoimmune blistering disorders and this review article will address this issue with a special focus on pemphigus vulgaris and bullous pemphigoid. These biological approaches are designed to target B cells, autoantibodies, complement proteins, and several cytokines. EXPERT OPINION: Innovative strategies for the treatment of autoimmune blistering conditions primarily depend on the use of drugs with a high degree of specificity targeting crucial steps in the immunopathology of these disorders. Novel biological agents offer treatment alternatives to patients with autoimmune blistering conditions by targeting B cells, pathogenic autoantibodies, complement and cytokines.

Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases.

ω3-polyunsaturated free fatty acids (ω3-PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3-[2-chloro-5-(trifluoromethoxy)phenyl]-3-azaspiro[5.5]undecane-9-acetic acid ("compound A"; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than ω3-PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of Aldara™-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease-like dermatitis was scrutinized. Cpd A did not alter the course of Aldara-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease-like dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than ω3-PUFAs, this also suggests that GPR120/FFA4 activation by ω3-PUFAs does not significantly contribute to the health-promoting effects of ω3-PUFAs in autoimmune diseases.

Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies to COL17. Currently, systemic corticosteroids are used as first-line treatments for BP; alternatively, intravenous administration of high-dose IgG (IVIG) has been shown to be effective for patients with steroid-resistant BP in clinical practice. However, the effect of IVIG on BP has not fully been investigated. To examine the effects and mechanisms of action of IVIG against BP, we performed IVIG experiments using two experimental BP mouse models. One is a passive-transfer BP model that reproduces subepidermal separation in neonatal mice by the passive transfer of IgGs against COL17, such as polyclonal or monoclonal mouse IgG or IgG from BP patients. The other is an active BP model that continuously develops a disease phenotype in adult mice. IVIG decreased pathogenic IgG and the disease scores in both models. Injected IVIG distributed throughout the dermis and the intercellular space of the lower epidermis. Notably, IVIG inhibited the increase of IL-6 in both models, possibly by suppressing the production of IL-6 by keratinocytes. These results suggest that the inhibitory effects of IVIG on BP are associated with the reduction of pathogenic IgG and the modulation of cytokine production.

Blisters Induced by PUVA: A Report of 5 Cases. / Ampollas inducidas por PUVA. Presentación de 5 casos.

Blisters associated with PUVA treatments are an adverse effect of photochemotherapy that has been reported in the literature. Asymptomatic blisters appear spontaneously mainly on the lower limbs and resolve without treatment. The differential diagnoses to consider include a phototoxic reaction, pseudoporphyria, and PUVA-induced bullous pemphigoid. We describe the clinical and histologic features in 5 cases of blistering secondary to PUVA treatment. If this adverse effect is accurately diagnosed, photochemotherapy need not be interrupted, and unnecessary diagnostic procedures and additional treatments can be avoided.

Penfigoide buloso nodular tratado exitosamente con fototerapia UVB banda angosta / Pemphigoid nodularis successfully treated with narrow band UVB phototherapy

El Penfigoide nodular es una variante clínica poco frecuente de penfigoide buloso. Corresponde a una dermatosis ampollar subepidérmica, crónica, autoinmune, caracterizada por auto anticuerpos contra antígenos específicos de hemidesmosomas en la unión dermo-epidérmica. Su incidencia es desconocida. La etiopatogenia aún no es entendida del todo. Se presenta clínicamente como una superposición de características de pénfigo buloso y prurigo nodular. El diagnóstico se basa en hallazgos clínicos e inmunopatológicos. La histopatología con inmunofluorescencia directa es el gold standard para el diagnóstico. El manejo es difícil, tiene mala respuesta a corticoides potentes locales, siendo necesario el uso de corticoides sistémicos y diferentes inmunosupresores solos o combinados junto a antihistamínicos para el manejo de prurito intenso. Se presenta un caso de pénfigo nodular, donde destaca su buena respuesta a terapia combinada con metotrexato y luz UVB de banda angosta.

Pemphigoid Nodularis is a rare clinical variant of bullous pemphigoid. It is considered an autoimmune, chronic, subepidermal blistering dermatosis, characterized by antibodies against hemidesmosome-specific antigens at the dermo-epidermal junction. Its incidence is unknown and its etiopathogenetic not fully understood. Clinically, it presents with overlapping features of bullous pemphigoid and prurigo nodularis. The diagnosis is based on clinical and immunopathological findings, being the histopathological study with immunofluorescence the gold standard. The management is difficult; since it has a poor response to local potent corticosteroids, requiring the use of systemic corticosteroids and different immunosuppressants alone or combined with antihistamines for the intense pruritus. We present a case of nodularis pemphigoid, highlighting the good response to the combination of methotrexate and phototherapy with narrow band UVB.