Autoimmune bullous dermatoses in cancer patients treated by immunotherapy: a literature review and Italian multicentric experience.

Cutaneous immune-related adverse events are frequently associated with immune checkpoint inhibitors (ICIs) administration in cancer patients. In fact, these monoclonal antibodies bind the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1/ligand 1 leading to a non-specific activation of the immune system against both tumoral cells and self-antigens. The skin is the most frequently affected organ system appearing involved especially by inflammatory manifestations such as maculopapular, lichenoid, psoriatic, and eczematous eruptions. Although less common, ICI-induced autoimmune blistering diseases have also been reported, with an estimated overall incidence of less than 5%. Bullous pemphigoid-like eruption is the predominant phenotype, while lichen planus pemphigoides, pemphigus vulgaris, and mucous membrane pemphigoid have been described anecdotally. Overall, they have a wide range of clinical presentations and often overlap with each other leading to a delayed diagnosis. Achieving adequate control of skin toxicity in these cases often requires immunosuppressive systemic therapies and/or interruption of ICI treatment, presenting a therapeutic challenge in the context of cancer management. In this study, we present a case series from Italy based on a multicenter, retrospective, observational study, which included 45 patients treated with ICIs who developed ICI-induced bullous pemphigoid. In addition, we performed a comprehensive review to identify the cases reported in the literature on ICI-induced autoimmune bullous diseases. Several theories seeking their underlying pathogenesis have been reported and this work aims to better understand what is known so far on this issue.

Eosinophilic dermatosis of hematologic malignancy in patients with chronic lymphocytic leukemia/non-Hodgkin's B lymphoma: a single center prospective clinico-pathological study.

Background: The pathogenesis of eosinophilic dermatosis of hematologic malignancy (EDHM) is poorly understood. Previously thought to be a hypersensitivity reaction to insect bites, immune dysregulation and cytokine imbalance are now thought to be responsible. Its prognostic significance is unclear. Objective: To describe the clinical, pathological and immunological findings in a series of oncohematological patients with EDHM. Methods: An observational prospective cohort study of oncohematological patients receiving a diagnosis of EDHM between April 2017 and December 2018. Results: A total of 15 patients with EDHM (10 females and 5 males) were identified among 422 oncohematological patients. Disease presentation varied from firm erythematous papules to more polymorphic presentations. The lesions were most prevalent on the exposed sites, 8/15 patients recalled an insect bite. Lesion seasonality was reported in 13/15 patients. IgE levels were elevated in six patients, circulating IL-4 and IL-5 were within a normal range. Twelve out of 15 patients developed skin manifestations after chemotherapy. The infiltrate could be eosinophil-rich or lymphocytic-rich. Interestingly, the histopathologic findings were in accordance with arthropod bites. Conclusion: A role for insect bites in EDHM is supported by our findings. EDHM may be related to aggressive hematologic disease.

A monolateral pigmented lesion of the nipple.

Pigmented mammary Paget's disease is a very rare variant of mammary Paget's disease linked to an underlying carcinoma in almost all cases. We present the case of a 62-year-old female patient who came to our attention for the evaluation of a monolateral asymptomatic pigmented lesion of the right nipple, which turned out to be a pigmented mammary Paget's disease unassociated to an underlying malignancy - an extremely rare entity only anecdotally reported in literature. The two main peculiarities of our patient's lesion, the importance of immunohistochemistry in the differential diagnosis and the theories on its pathogenesis are discussed. Further studies are necessary to establish the best treatment options. Click here for the corresponding questions to this CME article.

Anti-laminin 332 antibody detection using biochip immunofluorescence microscopy in a real-life cohort of Italian patients with mucous membrane pemphigoid

Background: Mucous membrane pemphigoid (MMP) with anti-laminin 332 autoantibodies may be associated with malignancies, however, current serological assays have considerable limitations. At present, no commercial test for anti-laminin 332 antibodies is available, restricting the diagnosis to specialized laboratories worldwide. Biochip immunofluorescence microscopy has shown promising results in selected cohorts of laminin 332-MMP patients. Objectives: To detect anti-laminin 332 antibodies by biochip immunofluorescence microscopy in a real-life cohort of MMP patients and compare the results with those from traditional immunoblotting. Materials & Methods: Sera were obtained from 31 patients with MMP, 28 with bullous pemphigoid, five with pemphigus vulgaris, five with paraneoplastic pemphigus, five with linear IgA bullous dermatosis, and 10 controls, and analysed by biochip immunofluorescence using human cells expressing laminin 332. Immunoblotting was performed using purified laminin 332. Results: MMP involved the oral mucosa in 65%, ocular mucosa in 9%, oral and ocular mucosae extensively in 13% as well as other mucosae in 13% of patients. Concomitant cutaneous involvement was reported in 35% of patients. Three MMP patients had an underlying malignancy. Anti-laminin 332 antibodies were detected in 2/31 (6%) cases by both methods. Based on immunoblotting, both laminin 332-positive sera reacted with α3 chain (in one case also with ß3 chain). Both patients with anti-laminin 332 antibodies had extensive mucosal involvement and only one had cancer. Anti-laminin 332 antibodies were not detected in control groups. Conclusion: Biochip immunofluorescence is an appropriate technique to detect anti-laminin 332 antibodies which should be tested in patients with MMP.

Autoantibody Profile of a Cohort of 54 Italian Patients with Linear IgA Bullous Dermatosis: LAD-1 Denoted as a Major Auto-antigen of the Lamina Lucida Subtype.

Linear IgA bullous dermatosis (LABD) is characterized by presence of multiple IgA autoantibodies, and a comparatively lesser number of IgG antibodies, directed against different hemidesmosomal antigens. The main autoantigens are LAD-1, LABD-97, BP180 and BP230, type VII collagen and laminin 332. We retrospectively studied the serology of 54 Italian patients with LABD using enzyme-linked immunosorbent assay (ELISA), immunoblotting assay, and indirect immunofluorescence on monkey oesophagus and salt-split skin. Among these, indirect immunofluorescence of salt-split skin elicits the greatest sensitivity. Sixty-three percent of the sera were observed to be positive, with a lamina lucida pattern observed in 48%, a sub-lamina densa pattern in 2% and a mixed pattern in 13% of the cases. IgA reactivity to LAD-1 on immunoblotting was found in 52% of sera, to BP180-NC16A by ELISA in 32% and to BP230 in 26%. Only 17% of patients possessed circulating IgG autoantibodies. LAD-1 was determined to be a major autoantigen of the lamina lucida subtype. Combined serological assays demonstrated a high sensitivity (82%), suggesting that this approach could support diagnosis when a biopsy is not feasible or direct immunofluorescence results are negative.

Rituximab as a dual therapeutic option for pemphigus and primary cutaneous B-cell lymphomas: Two case reports.

It is known that individuals with immune dysregulation have an increased risk of non-Hodgkin lymphoma. This association has been proven for pemphigus as well as for other autoimmune disease. We describe the development of cutaneous B-cell lymphoma in two patients affected by long-standing pemphigus vulgaris and pemphigus foliaceus (i.e., characterized by histological and immunopathological features different from those of paraneoplastic pemphigus). In both cases, a therapy with rituximab allowed to achieve the complete remission for the lymphoproliferative disease (never recurred at follow up) and a substantial long-term improvement of the clinical manifestations of pemphigus, although persistent to serological disease and occasional recurrences. We suggest that clinicians should consider that patients with long-standing pemphigus, both vulgaris and foliaceus, may develop primary cutaneous B-cell lymphomas, as shown in our report, and in these cases the treatment with rituximab is elective, providing a therapeutic option for both low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphomas and pemphigus. Nevertheless, as shown in our cases, a constant surveillance for pemphigus is necessary.

Female Patients with Dermatitis Herpetiformis Show a Reduced Diagnostic Delay and Have Higher Sensitivity Rates at Autoantibody Testing for Celiac Disease.

OBJECTIVE: Our objective was to characterize the demographic information, clinical features, and laboratory data of patients with dermatitis herpetiformis (DH). METHODS: In this multicentre cross-sectional study, consecutive patients with a new diagnosis of DH that referred to nine different Italian centers between 2011 and 2016 were characterized assessing demographic, clinical and laboratory findings, and evaluating gender and age differences across selected variables. RESULTS: A total of 151 patients were included. Among them, 81 (53.6%) were males and 70 (46.4%) were females, with a male to female ratio of 1.2 : 1. The median age at the time of diagnosis was 41 years (range 0-85). Males had a significant longer diagnostic delay if compared to females (9 vs. 3 months, respectively; p = 0.01). Direct immunofluorescence was positive in 94.7% of the patients, while duodenal biopsy showed partial to total villous atrophy in 70.1% of patients. All the females resulted positive to at least one of the antibodies tested, while a total of 12 male patients (10.5%) tested negative to celiac-specific antibodies. Female patients had a high rate (14.1%) of autoimmune thyroiditis. CONCLUSIONS: Our study confirmed some of the most relevant data regarding DH that have been previously reported in the literature. In addition, we found a reduced diagnostic delay in females with respect to males, possibly related to the higher sensitivity of serologic testing in females with DH compared to males. Finally, we demonstrated that intestinal involvement could be severe in patients with DH and that females should be tested for thyroiditis.

Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics.

BACKGROUND: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated.

Intralesional vinblastine injections for treatment of classic Kaposi sarcoma in diabetic patients.

Classic Kaposi sarcoma (KS) usually is a localized and slowly progressing disease that mainly affects elderly patients; therefore, local treatment generally is recommended. In this study, we evaluated the clinical efficacy of intralesional vinblastine (VNB) for the treatment of classic KS in 6 participants with type 2 diabetes mellitus. Results indicated that intralesional VNB injections may be an effective alternative treatment of classic KS in diabetic patients.

Pseudoepitheliomatous changes in a case of vegetating Darier­White disease: a unique histopathological finding.

Darier­White disease (DWD) is a rare autosomal dominant genodermatosis, characterized by constant and typical histopathological findings, such as hyperkeratosis, dyskeratosis with corps ronds and grains and papillary microvilli formation with suprabasal clefting. Despite its nearly constant histopathological presentation, unusual clinical variants are reported, such as the vegetating and cornifying ones. These variants share the same histopathological features of the classic type, except for the striking hyperkeratosis and acanthosis. Here, unreported pseudoepitheliomatous features are described in an elderly male patient with a long history of vegetating and verrucous papules and nodules of DWD, associated with typical nail involvement. These unique histolopathological changes were closely in conjunction with the characteristic microscopic features of DWD. Differential diagnosis with other pseudoepitheliomatous and acantholytic conditions such as reticulated seborrheic keratosis, inverted follicular keratosis, and acantholytic squamous cell carcinoma is also considered. Pseudoepitheliomatous features, in this case of vegetating DWD, could be regarded as a reactive epidermal phenomenon because of different stimuli, i.e. maceration, bacterial superinfection, and chronic scratching.

Photoinduced dermatitis and oral lichenoid reaction in a chronic myeloid leukemia patient treated with imatinib mesylate.

BACKGROUND: Imatinib mesylate (IM) is a phenylaminopyrimidine that represents the first-line treatment for chronic myeloid leukemia (CML), Philadelphia chromosome-positive. It acts as a potent and selective inhibitor of the bcr-abl fusion protein by a competitive inhibition at the adenosine triphosphate-binding site of the enzyme, which leads to the inhibition of tyrosine phosphorylation of the proteins involved in bcr-abl signal transduction. IM is generally well tolerated and usually provokes only mild side effects consisting of nausea, myalgia, edema and muscle cramps. OBSERVATION: This is a report of a patient affected by CML, who developed a photoinduced dermatitis and an oral lichenoid reaction associated with IM treatment. The lesions were resolved, thanks to the withdrawal of the therapy, and they relapsed after the reintroduction of IM, confirming the drug-induced pathogenesis. CONCLUSION: Skin changes are the most common non-hematologic side effects to IM treatment and are usually dose dependent. In particular, patients with IM therapy reported a lightening and depigmentation of the skin, that may alter the skin protection against ultraviolet exposure, with a possible subsequent intolerance to sun exposure, as reported in our patient, and higher risk of skin cancer. They are frequently self-limited or easily managed; nevertheless, in some cases, the therapy needs to be discontinued or may only be continued with concomitant oral steroid.