Histopathology of autoimmune bullous dermatoses: what's new?

Autoimmune bullous dermatoses are characterized by the presence of tissue-bound and often circulating pathogenic autoantibodies targeting structural components of the skin and/or mucous membranes. The diagnostic workup for this heterogeneous group of disorders consists of a multi-step process, of which the light microscopic examination is a crucial component. This review is organized following a classification scheme that is based on two main histopathologic features, namely level of intraepithelial split and composition of the inflammatory infiltrate. Overall, we aim to place emphasis on the histopathologic clues that can assist pathologists in differential diagnosis and review the updates in the literature.

Impact of adding an IgG4 conjugate to routine direct immunofluorescence testing for subepithelial and intraepithelial autoimmune blistering disorders.

BACKGROUND: Certain autoimmune bullous dermatoses are mediated by autoantibodies of the IgG4 subclass. We determined the diagnostic impact of adding IgG4 to our conventional direct immunofluorescence (DIF) panel. METHODS: For all cases submitted to our referral laboratory for DIF over 1 month (n = 630), we performed IgG4 testing and collected consecutive biopsy specimens showing definite or indeterminate linear or cell-surface deposition of IgG, IgG4, and/or C3. On retrospective blinded review, we classified the pattern and whether the findings were definite, indeterminate, or negative. When present, substantial background staining was recorded. RESULTS: Seventy DIF specimens met the inclusion criteria. Of 22 (31.4%) specimens equivocal for linear or cell-surface deposition, 9 (40.9%) had definitive IgG4 findings, either linear (3 of 14 equivocal linear cases; 21.4%) or cell-surface (6 of 8 equivocal cell-surface cases; 75.0%). Background deposition was substantial in 14 cases (20.0%) for IgG but in none for C3 or IgG4. CONCLUSION: IgG4 allowed the classification of over 40% of DIF cases that were otherwise equivocal by IgG and C3. IgG4 staining showed lower levels of non-specific background staining than IgG or C3. IgG4 appears to contribute most value in cases with cell-surface deposition or with equivocal linear IgG deposition and negative C3 results.

Radiation-induced pemphigus or pemphigoid disease in 3 patients with distinct underlying malignancies.

The cutaneous lesions of radiation-induced pemphigus or pemphigoid disease may resemble other skin diseases, including recurrent underlying cancer. We performed a computerized search of Mayo Clinic (Rochester, Minnesota) archives and identified 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for breast, cervical, and metastatic malignancies, respectively. In 2 of these patients, the disease was initially confined to the irradiated field but subsequently disseminated to other parts of the patients' bodies, including mucosal surfaces. In all 3 patients, the blistering disease occurred 5 to 14 months after the onset of radiation therapy. All 3 were treated with corticosteroids and demonstrated complete recovery of the skin eruption after radiotherapy was discontinued. Although the precise mechanism of this cutaneous eruption is unknown, clinicians should be alert for this potentially serious complication and evaluate all cutaneous eruptions developing during and after radiotherapy.

Pneumocystis jiroveci pneumonia in patients treated with systemic immunosuppressive agents for dermatologic conditions: a systematic review with recommendations for prophylaxis.

Pneumocystis jiroveci pneumonia is an opportunistic infection associated with substantial rates of mortality in immunosuppressed patients. Prophylaxis recommendations are mostly targeted toward patients with non-dermatologic diagnoses. This study was conducted to determine when dermatology patients treated with immunosuppressive medications should be offered P. jiroveci pneumonia prophylaxis. We searched the literature from January 1, 1993, to December 31, 2013, using terms relating to P. jiroveci pneumonia and dermatologic diagnoses to analyze the clinical characteristics of previously affected patients. Guidelines for P. jiroveci pneumonia prophylaxis from other medical fields were also analyzed. Of 17 dermatology patients reported to have contracted P. jiroveci pneumonia, eight (47.1%) died of the pneumonia. Risk factors included lack of prophylaxis, systemic corticosteroid therapy, lymphopenia, hypoalbuminemia, low serum CD4 counts, comorbid pulmonary or renal disease, malignancy, and prior organ transplantation. The present conclusions are limited by heterogeneity among the selected studies and limitations in their identification and selection. However, P. jiroveci pneumonia in dermatology patients is associated with a high mortality rate. Based on our analysis, we propose that prophylaxis be considered in dermatology patients in whom treatment with systemic corticosteroids at doses exceeding 20 mg/day or treatment with corticosteroid-sparing immunosuppressive agents is anticipated for at least 4 weeks, and in patients with additional risk factors for P. jiroveci pneumonia.

Frequency of cutis laxa-like clinical features and elastolysis in scleromyxedema: a retrospective clinicopathologic study of 19 patients with scleromyxedema.

BACKGROUND: Cutis laxa-like features were observed in a subset of patients with scleromyxedema. Given this observation, clinical and histopathologic features of scleromyxedema were reviewed in correlation with elastic tissue staining. METHODS: We retrospectively reviewed clinical records and histopathologic features from patients with scleromyxedema seen at our institution from 1992 through 2013. We also evaluated available skin biopsies with an elastin stain and assessed whether dermal elastin fibers were diminished in density or were fragmented (or both). RESULTS: Nineteen patients with scleromyxedema and 34 skin biopsies were identified. Alcian blue (mucin) stain was used to grade mucin deposition as weakly positive (24%), positive (44%) and markedly positive (32%). Eight patients (42%) had clinical findings of cutis laxa, which were often observed in conjunction with areas of papular eruption or induration. Elastic tissue fibers were normal in 9 of 34 skin specimens (26%), 18 of 34 specimens (53%) had diminished elastic fiber density and 7 of 34 (21%) had markedly decreased density. The elastic tissue was fragmented in 25 specimens (74%). CONCLUSIONS: A cutis laxa-like clinical presentation and decreased elastic tissue density on skin biopsy were consistent findings. Dermatologists and dermatopathologists should be aware of these previously unreported clinical and histopathologic findings.

CAM use in dermatology. Is there a potential role for honey, green tea, and vitamin C?

Complementary and alternative medicine (CAM) is a group of non-traditional medical practices that includes natural products, manipulations, and mind and body medicine. CAM use has grown and become popular among patients. In dermatology, honey, green tea, and vitamin C have been used as topical treatments for a variety of diseases. We performed a systematic review to explore the cutaneous effects of each of these three products. Honey's unique antibacterial, anti-inflammatory, and antioxidant properties were shown to contribute to wound healing, especially in ulcers and burns. Green tea, among many health benefits, demonstrated protection from ultraviolet-induced events, such as photoimmunosuppression and skin cancer growth. Vitamin C, known for its antioxidant properties and key role in collagen production, has been shown to produce positive effects on skin hyperpigmentation and aging. Future large well-designed clinical trials are needed in order to further investigate the potential of these agents as dermatological therapies.

A randomized controlled clinical study to evaluate the effectiveness of an active moisturizing lotion with colloidal oatmeal skin protectant versus its vehicle for the relief of xerosis.

Xerosis is a common skin condition, occurring most often in the winter and in low relative humidity, which results in loss of moisture, cracking, and desquamation. Many emollient creams and lotions are available for use as preventive moisturizers. However, few controlled experiments have been published comparing the efficacy of active moisturizing products versus the vehicle used to deliver the products to the skin. Therefore, we conducted this randomized, double-blind, controlled clinical study to objectively compare a commercially available moisturizing product against its own vehicle. The active colloidal oatmeal moisturizer used in this study showed significant benefits versus its vehicle control in several dermatological parameters used to measure skin dryness.

Use of complementary and alternative medicine by patients seen at the dermatology department of a tertiary care center.

The use of complementary and alternative medicine (CAM) among patients with dermatologic conditions has not been well studied. The aim of this study was to evaluate the frequency and pattern of CAM use in patients referred to the dermatology department of a tertiary care center. Patients referred to the dermatology department of an academic tertiary referral center between February 2, 2010, and February 10, 2010, were invited to participate in an 86-question survey regarding CAM use during the previous year. A total of 300 patients completed the survey, of whom 154 (51%) were women. Eighty-two percent (n = 247) of the respondents had used some type of CAM during the previous year. The most frequently used treatment and technique was massage therapy (33%), and the most commonly used vitamin was vitamin C (31%). Herbs or other dietary supplements were used by 58% (n = 173) of patients. Seventy-eight percent (n = 235) of patients stated that physicians should consider incorporating CAM approaches into their treatment recommendations, and 89% of patients (n = 267) stated that our dermatology department should study CAM approaches in research studies. CAM utilization is high among patients at a large academic dermatology department. Patients indicated a strong preference for having CAM approaches incorporated into their treatment recommendations and believed in the value of clinical studies to further refine the role of CAM.

Infection and infection prevention in patients treated with immunosuppressive medications for autoimmune bullous disorders.

Infection contributes to considerable morbidity and mortality in patients treated for autoimmune bullous disorders because of the impaired cutaneous barrier, alteration of the protective normal flora, and host immunosuppression (inherent and iatrogenic). Prevention of cutaneous impetiginization and infection starts with excellent wound care. In patients to be started on immunosuppressive medications, consideration should be given to vaccination status and possible need for pneumocystis pneumonia prevention. Patients should be educated on the signs and symptoms of early infection and the need to seek early medical intervention as needed.

Pemphigoid nodularis: a case report.

Several variants of bullous pemphigoid have been reported including pemphigoid nodularis. Patients with pemphigoid nodularis have clinical features of prurigo nodularis in combination with clinical or immunologic characteristics of bullous pemphigoid. We report the case of a 71-year-old woman with pemphigoid nodularis. The diagnosis was suspected clinically and established by positive indirect immunofluorescence (IIF) findings characteristic of pemphigoid. Results of direct immunofluorescence (DIF) testing were negative, which emphasizes the importance of conducting both DIF and IIF when pemphigoid nodularis is suspected.

Role of primary prophylaxis for pneumocystis pneumonia in patients treated with systemic corticosteroids or other immunosuppressive agents for immune-mediated dermatologic conditions.

BACKGROUND: The incidence of pneumocystis pneumonia (PCP), an opportunistic infection caused by Pneumocystis jiroveci, in patients taking immunosuppressive medications for dermatologic indications is unknown. OBJECTIVE: We sought to define the incidence of PCP in patients with dermatologic conditions, to characterize risk factors for PCP development in these patients, to examine PCP prophylaxis practices among dermatologists, and to document adverse effects of PCP prophylaxis medications. METHODS: We reviewed the medical records of patients taking immunosuppressive medications for longer than 1 month who were treated for dermatologic conditions between 1998 and 2007 at Mayo Clinic, Rochester, MN. RESULTS: Of 198 patients meeting inclusion criteria (150 [75.8%] of whom received no PCP prophylaxis), one patient (0.5% and 0.7%, respectively) had PCP that developed during the follow-up period. In this patient, a 94-year-old woman with bullous pemphigoid, severe interstitial pulmonary fibrosis, aortic stenosis, and hypoalbuminemia, PCP developed within 7 months of diagnosis and was treated with methotrexate and prednisone. She had not received PCP prophylaxis. Only 6 patients (3%) with dermatology as their primary service received PCP prophylaxis. Overall, rates of adverse effects with PCP prophylaxis were low. LIMITATIONS: The study design was retrospective. Low rates of PCP precluded our development of concrete PCP prophylaxis guidelines. CONCLUSIONS: Results did not support routine administration of PCP prophylaxis in all patients taking immunosuppressive medications. When prescribing immunosuppressive medications for dermatologic indications, physicians should consider PCP prophylaxis on a case-by-case basis.

The management of mucous membrane pemphigoid and pemphigus.

Mucous membrane pemphigoid and pemphigus vulgaris are autoimmune blistering disorders in which many similar drugs and therapeutic strategies are utilized. In general, localized disease can be treated with topical agents. In contrast, patients with more severe and progressive disease usually require a combination of systemic corticosteroids and immunosuppressive medications. Oral corticosteroids, adjuvant immunosuppressive agents, antibiotics such as dapsone and immunomodulatory procedures like intravenous immunoglobulin are the main therapeutic agents used in treating these two disorders. Much of the morbidity and mortality associated with these disorders are related to the sites involved and to the drugs used for therapy. Treatment should be individualized based on severity, extent, and rate of progression of disease, comorbidities, and age of the patient. Serum levels of specific autoantibodies and indirect immunofluorescence titers, in certain cases, can be used to monitor response to therapy.

Combination cytokine therapy inhibits tumor growth by generation of tumor-specific T-cell responses in a murine melanoma model.

Various cytokines, including interferon alpha (IFNalpha), tumor necrosis factor alpha (TNFalpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been used as adjuvant therapy for advanced-stage melanoma with some success but with marked toxicity, which appears to be related to higher doses. We investigated the efficacy of IFNalpha, GM-CSF, and TNFalpha in various combinations to induce antitumor and immune responses in a B16F10 murine melanoma model. These studies showed that GM-CSF, IFNalpha, and TNFalpha, when injected together intratumorally, mediated significant inhibition of tumor growth. Tumor regression correlated with local tumor necrosis and significant infiltration of T cells. In addition, this injected intralesional cytokine cocktail also induced lymphadenopathy, with an increase in both CD4(+) and CD8(+) T cells in the draining lymph nodes. Furthermore, tumor-specific CD8(+) T cells were identified from draining lymph nodes. These investigations identify the combined effects of IFNalpha, GM-CSF, and TNFalpha in induction of the adaptive immune response and generation of antigen-specific T-cell reactivity. These results support potential clinical trials of the low-dose cytokine combination as adjuvant therapy for melanoma.

Development of Pneumocystis carinii pneumonia in patients with immunobullous and connective tissue disease receiving immunosuppressive medications.

BACKGROUND: Pneumocystis carinii pneumonia (PCP) causes morbidity and mortality in immunocompromised hosts. Data describing use of PCP prophylaxis in immunosuppressed dermatologic patients are lacking. OBJECTIVE: We sought to describe the frequency of PCP among dermatologic patients receiving immunosuppression for immunobullous disease or connective tissue disease. METHODS: We retrospectively reviewed the cases of patients with immunobullous and connective tissue disease at our department of dermatology between 1980 and 2006 who received immunosuppression and had subsequent development of pneumonia. We recorded patient characteristics, use of PCP prophylaxis, whether PCP developed, and if so, their morbidity and mortality. RESULTS: Of 334 patients identified, 7 (2.1%) were given the diagnosis of PCP during immunosuppressive treatment. Of these 7 patients, 3 (43%) died within 1 month of diagnosis, and none received PCP prophylaxis. LIMITATIONS: Retrospective study design and limited patient group are limitations. CONCLUSIONS: PCP prophylaxis may improve outcomes for some patients with immunobullous or connective tissue disease receiving immunosuppressive therapy.

Glucocorticoid-induced osteoporosis in dermatologic practice: a review.

Systemic glucocorticoids are widely used in dermatologic practice for various conditions including connective tissue and immunobullous diseases, vasculitis, dermatitis, neutrophilic and other dermatoses, and androgen excess syndromes. Long-term use of systemic glucocorticoids has been associated with substantial and rapid bone loss, which places patients at increased risk for bone fractures. Therefore, bone density measurements and the timely initiation of lifestyle modifications and pharmacotherapy are essential for future bone health. The use of several Food and Drug Administration-approved agents to prevent and treat corticosteroid-induced bone loss has been inconsistent among many specialties. In this review, the authors summarize guidelines on the prevention and treatment of corticosteroid-induced bone loss published by the American College of Rheumatology and supplement these guidelines with descriptions of the latest approved pharmacologic therapies and user-friendly flow algorithms. This summary should aid dermatologists in providing education and recommendations regarding bone health for their patients on systemic glucocorticoids.

Pruritic rash on the buttocks after a beach vacation: a case report.

A 56-year-old man sought treatment after a vacation for an intensely pruritic skin eruption involving the buttocks. On physical examination, annular plaques were noted. Workup revealed dermatitis herpetiformis (DH) and subclinical celiac disease.

Cytokine therapy in advanced melanoma.

Patients with melanoma considered at high risk for recurrence or regional metastases often have to choose between adjuvant interferon therapy or enrolling in a clinical trial. High-dose interleukin-2 therapy has had limited success in producing durable responses in stage IV melanoma; this success has been offset by marked toxicity. High-dose interferon alpha therapy has consistently shown disease-free survival benefit in clinical trials but has marked toxicity. The overall survival benefit has been inconsistent and controversial. Treatment with granulocyte macrophage colony-stimulating factor has shown promise in early studies. Various cytokines have had some success in treating advanced stage melanoma but with marked toxicity. Cytokine therapy that is well-tolerated and consistently provides an overall survival benefit for high-risk melanoma patients has not been achieved. Cytokines will continue to have a role in therapy for advanced-stage melanoma, most likely in combination with other immunomodulatory therapy. The challenge is finding the right doses, frequency, combinations, and duration of treatment.