Concomitant nivolumab-associated Grover disease and bullous pemphigoid in a patient with metastatic renal cell carcinoma.

Immune checkpoint inhibitor (ICI)-induced bullous pemphigoid (BP) and Grover disease (GD) are uncommon, and concomitant GD and BP is rarer still. We report a third case of concomitant BP and GD associated with nivolumab with emphasis on the clinical, histopathologic and immunofluorescence findings as well as differential diagnoses. A 73-year-old male with metastatic renal cell carcinoma on nivolumab developed erythematous scaly papules on the trunk with biopsy showing suprabasal acantholysis with dyskeratosis, consistent with GD. Subsequently, he developed widespread lesions on arms, legs, trunk, and scrotum with new vesiculobullae and urticarial lesions. Biopsy of a vesicle showed subepidermal blister with numerous eosinophils and neutrophils, and immunofluorescence and serological studies were supportive of BP. He continued to have clinically apparent GD that was confirmed on repeat biopsy. The patient was diagnosed with concomitant GD and BP induced by nivolumab and successfully treated with dupilumab. The relationship between ICI-induced GD and BP is not well understood; it has been suggested that T-cell activation against the BP180 antigen expressed on surface of tumor cells may predispose susceptible individuals to BP. Subsequent ICI-induced GD may create keratinocyte injury needed to expose additional proteins to reactivated and autoreactive T-cells, leading to autoimmunity. An important differential diagnosis is bullous GD, which can be distinguished by negative immunofluorescence and serological studies.

Cutaneous Immune-Related Adverse Events (irAEs) to Immune Checkpoint Inhibitors: A Dermatology Perspective on Management [Formula: see text].

Immune checkpoint inhibitors have proven to be efficacious for a broad spectrum of solid organ malignancies. These monoclonal antibodies lead to cytotoxic T-cell activation and subsequent elimination of cancer cells. However, they can also lead to immune intolerance and immune-related adverse event (irAEs) that are new and specific to these therapies. Cutaneous irAEs are the most common, arising in up to 34% of patients on PD-1 inhibitors and 43% to 45% on CTLA-4 inhibitors. The most common skin manifestations include maculopapular eruption, pruritus, and vitiligo-like lesions. A grading system has been proposed, which guides management of cutaneous manifestations based on the percent body surface area (BSA) involved. Cutaneous irAEs may prompt clinicians to reduce drug doses, add systemic steroids to the regiment, and/or discontinue lifesaving immunotherapy. Thus, the goal is for early identification and concurrent management to minimize treatment interruptions. We emphasize here that the severity of the reaction should not be graded based on BSA involvement alone, but rather on the nature of the primary cutaneous pathology. For instance, maculopapular eruptions rarely affect <30% BSA and can often be managed conservatively with skin-directed therapies, while Stevens-Johnson syndrome (SJS) affecting even 5% BSA should be managed aggressively and the immunotherapy should be discontinued at once. There is limited literature available on the management of the cutaneous irAEs and most studies present anecdotal evidence. We review the management strategies and provide recommendations for psoriatic, immunobullous, maculopapular, lichenoid, acantholytic eruptions, vitiligo, alopecias, vasculitides, SJS/toxic epidermal necrolysis, and other related skin toxicities.

Distinguishing histopathologic features of acantholytic dermatoses and the pattern of acantholytic hypergranulosis.

BACKGROUND: Acantholysis can be seen in multiple skin diseases. Adnexal acantholysis has been regarded as a feature distinguishing pemphigus vulgaris (PV) from acantholytic conditions. METHODS: A retrospective review of the histopathologic features of diseases with acantholysis including PV, pemphigus foliaceus (PF), Hailey-Hailey disease (HHD), Darier disease (DD), Grover disease, and pityriasis rubra pilaris (PRP) was performed. RESULTS: Biopsies of PV (n = 49), HHD (n = 27), DD (n = 25), Grover disease (n = 65), and PRP (n = 33) showed suprabasilar acantholysis. Acantholysis was limited to the lower epidermis in PV and PRP, and involved all epidermal layers in HHD, DD, and Grover disease. Acantholysis in PF (n = 38) mainly involved the upper epidermis. Follicular acantholysis occurred more frequently in PV and PF (P < 0.0001). Eccrine acantholysis was found in PV (42%), HHD (18%), PF (13%), and DD (4%). Grover disease, DD, and HHD had greater dyskeratosis (P < 0.0001). Neutrophils were more common in PV, PF, and HHD, while eosinophils were more common in Grover disease and DD. A pattern termed acantholytic hypergranulosis occurred predominantly in PF. CONCLUSION: Adnexal acantholysis does not reliably distinguish PV from PF. The level of acantholysis, degree of dyskeratosis, and acantholytic hypergranulosis are distinguishing features between the two types of pemphigus and other acantholytic disorders.

Atypical features and systemic associations in extensive cases of Grover disease: A systematic review.

BACKGROUND: Grover disease is an acantholytic disorder that typically occurs on the trunk of older individuals, primarily white men, in association with heat and xerosis. Cases with extensive and/or atypical distributions have been reported. OBJECTIVE: To review the literature characterizing the population, morphology, associations, and disease course of extensive or atypical eruptions of Grover disease. METHODS: A systematic literature review identified 50 articles with 69 cases. RESULTS: Patient age ranged from 14 to 83 years (mean age, 56 ± 15), with 71% of patients being male and 29% female. Areas of involvement included the trunk (90%), upper and lower extremities (63% and 61%, respectively), face/scalp (28%), neck (21%), groin (11%), buttocks (8%), and axillae (6%). The most common associations included a history of malignancy (61%), recent chemotherapy (38%), and recent transplant (20%). LIMITATIONS: Extensive cases with typical clinical morphology may not have been examined by biopsy or reported; thus, this review may have publication bias toward more severe or atypical presentations. CONCLUSIONS: Greater variability exists among patients affected by extensive or atypical Grover disease than among those with typical disease. Malignancy is a common association, and there may be a role for immunosuppression in the pathogenesis of extensive or atypical Grover disease.

Bullous, pseudobullous, & pustular dermatoses.

Several dermatoses are typified by the formation of spaces (blisters; bullae) within or beneath the epidermis. These may be acellular or filled with particular species of inflammatory cells. Etiological categories include infectious, immune-mediated, genetic, drug-related, and idiopathic lesions. Examples of such disorders include impetigo, Herpes virus infections, pemphigus, bullous pemphigoid and pemphigoid gestationis, epidermolysis bullosa acquisita, IgA-related dermatoses, inherited epidermolysis bullosa variants, Hailey-Hailey disease, and porphyria cutanea tarda. Other conditions manifest microscopic acantholysis within the surface epithelium but are not associated with clinical bullae, such as Darier disease and Grover disease. Finally, both infectious and non-infectious causes exist for the development of neutrophilic pustules in the epidermis, as seen in pustular psoriasis, Sneddon-Wilkinson disease (subcorneal pustular dermatosis), and acute generalized exanthematous pustulosis. This review considers the clinical and histological features of all of these diseases.

Transient acantholytic dyskeratosis (Grover's disease) after bone marrow transplantation.

Cutaneous eruptions in recipients of allogeneic haematopoietic stem cell transplantation (AHSCT) are frequent, and common aetiologies include graft-versus-host disease (GVHD), drug reactions, viral infections and engraftment syndrome. Transient acantholytic dermatosis or Grover's disease has been described in oncology patients and it is rarely reported after AHSCT. However, this benign and self-limiting condition should be histologically distinguished from other, more serious entities, mainly stage IV GVHD, in order to avoid inappropriate treatment with corticosteroids and intensive immunosuppression.

Retinoids for the Treatment of Refractory Grover's Disease: A Case Series and Review of the Literature.

Grover's disease, also known as transient acantholytic dermatosis (TAD), currently has no published randomized control trials regarding the treatment of the disease; thus, evidence for treatment is largely derived from case studies and case reports. In this case series, we summarize the current treatment options for Grover's disease and discuss two cases of refractory Grover's disease treated with low-dose oral isotretinoin in patients who previously failed to reach clearance with multiple treatment options. Our aim is to highlight the efficacy of low-dose systemic retinoid therapy in Grover's disease when other treatment options prove unsatisfactory.

A Grover-Like Skin Rash: A Potential Indicator of Underlying Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

Transient acantholytic dermatosis, also known as Grover's disease, is an acquired dermatological condition characterised by the sudden emergence of pruritic, erythematous papules, or vesicles, primarily affecting the trunk. It is observed most commonly in men older than 50 years. Histology typically demonstrates a pattern of focal acantholysis within the epidermis, dyskeratotic cells including corps ronds and grains, and a variable perivascular lymphocytic infiltrate in the upper dermis. While its aetiology is not well understood, recognised triggers include excessive heat, sweating, sun exposure, and certain drugs, such as chemotherapy agents. More recently, isolated reports of Grover's disease and Grover-like skin eruptions have been described in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and following COVID-19 vaccination. We report the case of a 65-year-old man who presented to secondary care with a nine-day history of an intensely pruritic rash over his chest and back. On internal medical workup, he was found to have SARS-CoV-2 infection and rapidly deteriorated due to coronavirus disease 2019 (COVID-19)-associated pneumonia, necessitating a 10-day hospital admission for supportive care. Diagnostic workup of his skin lesions confirmed transient acantholytic dermatosis (Grover's disease), which resolved following a course of oral corticosteroids. This case underscores the rare but significant association between Grover's disease and COVID-19, contributing valuable insights to the evolving body of literature on cutaneous lesions associated with SARS-CoV-2 infection, and highlighting the importance of considering SARS-CoV-2 screening as part of the diagnostic workup for patients presenting with Grover-like skin eruptions.

Is Grover's disease an autoimmune dermatosis?

Grover's disease (GD) is a transient or persistent, monomorphous, papulovesicular, asymptomatic or pruritic eruption classified as non-familial acantholytic disorder. Contribution of autoimmune mechanisms to GD pathogenesis remains controversial. The purpose of this study was to investigate antibody-mediated autoimmunity in 11 patients with GD, 4 of which were positive for IgA and/or IgG antikeratinocyte antibodies by indirect immunofluorescence. We used the most sensitive proteomic technique for an unbiased analysis of IgA- and IgG-autoantibody reactivities. Multiplex analysis of autoantibody responses revealed autoreactivity of all 11 GD patients with cellular proteins involved in the signal transduction events regulating cell development, activation, growth, death, adhesion and motility. Semiquantitative fluorescence analysis of cultured keratinocytes pretreated with sera from each patient demonstrated decreased intensity of staining for desmoglein 1 and/or 3 and PCNA, whereas 4 of 10 GD sera induced BAD expression, indicating that binding of autoantibodies to keratinocytes alters expression/function of their adhesion molecules and activates apoptosis. We also tested the ability of GD sera to induce visible alterations of keratinocyte shape and motility in vitro but found no specific changes. Thus, our results demonstrated that humoral autoimmunity in GD can be mediated by both IgA and IgG autoantibodies. At this point, however, it is impossible to conclude whether these autoantibodies cause or are caused by the disease. Antidesmoglein antibodies may be triggered by exposure to immune system of sequestered antigens due to disintegration of desmosomes during primary acantholysis. Clarifying aetiology of GD will help improve treatment, which currently is symptomatic and of marginal effectiveness.

Grover's disease secondarily infected with herpes simplex virus and Staphylococcus aureus: case report and review.

The case of a 73-year old man with herpes simplex and staphylococcus aureus infection complicating established Grover's disease is presented. This was treated successfully with valaciclovir. While reports of bacterial and herpetic infections complicating other acantholytic diseases, such as Darier's disease, have been published previously, only one publication to date shows herpes simplex infection in Grover's disease.

An Unusual Trigger of Grover's Disease (GD).

Grover's disease (GD) is a rare skin condition that presents as a pruritic, erythematous papular, or papulovesicular rash. We report a unique case of GD triggered by honeybee stings. An 80-year-old Caucasian male presented with a pruritic papulovesicular rash on his trunk and arms after being stung by honeybees. He had a history of honeybee venom allergy and developed immediate erythema at the sting sites, which progressed over two days. His laboratory tests were unremarkable, including a complete blood count and comprehensive metabolic profile. Despite using oral antihistamines, emollients, and topical steroids, his rash continued to progress onto his neck, face, scalp, and back. A skin biopsy of the rash revealed suprabasilar and intraspinous acantholysis with focal corps ronds and upper dermis lymphocytic infiltrate -- the histopathologic finding of GD. He had failed first-line treatment for GD. However, after five months and significant morbidity, he was successfully treated with systemic steroids, high-potency topical steroids, emollients, and antihistamines for extensive and prolonged GD. This case report highlights honeybee venom as a possible trigger of GD and discusses a potential immune-mediated etiopathogenesis, which can be used to guide further research and management of this rare disease.

Bullous Grover's Disease in a Chinese Tibetan Adolescent: A Case Report.

Grover's disease (GD), also known as Transient acantholytic dermatosis, has no typical clinical rash features. It usually occurs in elderly white men but very rarely in China. This is a disease of acantholysis and dyskeratosis, which is usually considered to be spontaneous remission. The skin lesions of the disease are diverse, and the main symptom is severe itching. We have reported a case of GD in a 14-year-old Chinese Tibetan male whose clinical manifestations were pruritic red papule, generalized red papules, papulo vesicles and blisters ranging from millet rice to soybean size. Skin lesions change rapidly and variously. In order to confirm the diagnosis, we have done skin biopsies, immunofluorescence, dermoscopy, microscopy and other examinations. Pathological skin biopsy showed acantholysis. Intraepidermal blisters and the presence of blisters on the basal cells as well as under the stratum corneum can be observed on the same pathological section. Type IV collagen immunohistochemistry showed blisters in the epidermis. The diagnosis of GD depended on the exclusion of other diseases. After we performed whole exon sequencing (WES) on DNA from the patient's blood, pathogenic gene mutations were not found. Pustular psoriasis, Subcorneal pustular dermatosis, Herpesvirus infections, Dermatitis herpetiformis, Pemphigus vulgaris, Norwegian scabies, Darier's disease, and Hailey-Hailey disease were all excluded. We successfully treated adolescent GD with minocycline combined with methotrexate. The patient was followed up for 19 months without recurrence.

Management and Treatment of Grover's Disease: A Case Report and Review of Literature.

This case report details a rare case of Grover's disease in an 80-year-old Caucasian male complaining of a rash across his chest over the last three to four months. The patient has a past medical history of essential hypertension, hyperlipidemia, osteoarthritis of the knee, chronic gastroesophageal reflux disease (GERD), supraventricular tachycardia, status post prostate cancer, and restless legs syndrome. During his initial evaluation, he was found to have a pruritic, erythematous, papular rash most notably along his upper trunk and chest. The patient utilized multiple lotions, emollients, and anti-itch creams with minimal relief of his symptoms and presentation. Following a referral to Dermatology, a biopsy of the rash was conducted, which revealed intraepidermal acantholysis, the hallmark finding for a diagnosis of Grover's disease. Subsequently, he was treated with a topical triamcinolone acetonide 0.1% cream for 14 days. This study details a case of Grover's disease along with potential comorbidities and contributing factors in order to further understand the pathogenesis and etiology of this relatively rare condition.

A Rare Case of Transient Acantholytic Dermatosis (AKA. Grover's Disease) with Concomitant Pediculosis Pubis: An Atypical Presentation and First Documented Case Report.

A 66-year-old male presented with a one-month history of persistent pruritic eruptions distributed mainly on the trunk. A punch biopsy from the left upper abdomen revealed focal acantholytic dyskeratosis with mixed inflammatory infiltrate in the dermis composed of numerous eosinophils. Grover's disease was diagnosed based on the clinical and histopathological findings. Appropriate treatment was initiated but failed to relieve symptoms of itchiness. A further investigation of the hair follicles under mineral oil preparation revealed an infestation of pediculosis pubis. Subsequent treatment with Ivermectin and permethrin cream led to the complete resolution of his symptoms. This case report highlights an unusual and first documented case of Grover's disease with a concomitant infestation of pediculosis pubis. To date, no reported cases in the literature have associated Grover's disease with pubic lice infestation. However, there are three reported cases of concurrent scabies and Grover's disease in the literature. This rare case underscores the clinical value in further investigating treatable underlying conditions in patients with suspected transient acantholytic dermatosis.

A Case of Extensive Grover's Disease in a Patient with a History of Multiple Non-Melanoma Skin Cancers.

We report on a 69-year-old man who presented with itching and erythematous papules on his torso and extremities, which were resistant to topical therapy with antibiotics and steroids. Physical examination revealed multiple erythematous papules on his back, neckline, and lower extremities. The lesions had appeared 4 years earlier and usually worsened with heat or extensive sweating. Histopathology of previous skin biopsies had shown multiple cutaneous squamous cell carcinomas or was non-conclusive. Thus, a re-biopsy was performed, revealing acanthosis and focal acantholytic dyskeratosis. These clinical and anamnestic findings lead to the diagnosis of extensive Grover's disease (GD). Oral therapy with isotretinoin 30-mg QD led to the regression of the skin lesions. Topical adapalene, as well as topical corticosteroids, were later prescribed for maintenance therapy.

Case for diagnosis. Atypical Grover's disease.

A 55-year-old male presented with an eight-month history of erythematous papules and plaques with demarcated areas of spared skin on his trunk, upper extremities, neck, and face. Grover's disease is a rare, acquired disorder of unknown origin, which is classically characterized by the appearance of erythematous papules on the upper trunk that are usually transient. As in the present case, there are reports of atypical disease, with facial involvement, pityriasis rubra pilaris-like lesions, and a more chronic course.