Annette Czernik

Paraneoplastic autoimmune multiorgan syndrome: 20 years after.

The purpose of this review is to provide insight and clarification in the quandary of classification and delineate clinical and histological features and pathophysiology of paraneoplastic pemphigus. This is a paraneoplastic disease of epithelial autoimmunity and adhesion originally described by Dr. Anhalt in 1990. Paraneoplastic pemphigus represents only one manifestation of the heterogeneous autoimmune syndrome in which patients, in addition to small airways occlusion, may display a spectrum of at least five clinical variants of the mucocutaneous disease [i.e. pemphigus‐like, pemphigoid‐like, erythema multiforme‐like, graft‐versus‐host disease‐like, and lichen planus‐like, termed paraneoplastic autoimmune multiorgan syndrome (PAMS)]. There is a need for the expanded, inclusive classification of diverse mucocutaneous and respiratory presentations of PAMS. Multiple specific effectors of humoral and cellular autoimmunity mediating epithelial damage have been identified. An update of advances in clinical and basic research on PAMS and in management and overall prognosis of PAMS is provided.

Alopecia areata profiling shows TH1, TH2, and IL-23 cytokine activation without parallel TH17/TH22 skewing

BACKGROUND Alopecia areata (AA) is a common T cell-mediated disorder with limited therapeutics. A molecular profile of cytokine pathways in AA tissues is lacking. Although studies have focused on TH1/IFN-γ responses, several observations support a shared genetic background between AA and atopy. OBJECTIVE We sought to define the AA scalp transcriptome and associated biomarkers with comparisons with atopic dermatitis (AD) and psoriasis. METHODS We performed microarray and RT-PCR profiling of 27 lesional and 17 nonlesional scalp samples from patients with AA for comparison with normal scalp samples (n = 6). AA gene expression was also compared with samples from patients with lesional or nonlesional AD and those with psoriasis. A fold change of greater than 1.5 and a false discovery rate of less than 0.05 were used for differentially expressed genes (DEGs). RESULTS We established the AA transcriptomes (lesional vs nonlesional: 734 DEGs [297 upregulated and 437 downregulated]; lesional vs normal: 4230 DEGs [1980 upregulated and 2250 downregulated]), including many upregulated immune and downregulated hair keratin genes. Equally impressive as upregulation in TH1/interferon markers (IFNG and CXCL10/CXCL9) were those noted in TH2 (IL13, CCL18, CCL26, thymic stromal lymphopoietin, and periostin), TH9/IL-9, IL-23 (p40 and p19), and IL-16 mediators (all P < .05). There were no increases in TH17/TH22 markers. Hair keratin (KRT) expressions (ie, KRT86 and KRT85) were significantly suppressed in lesional skin. Greater scalp involvement (>25%) was associated with greater immune and keratin dysregulation and larger abnormalities in nonlesional scalp samples (ie, CXCL10 and KRT85). CONCLUSIONS Our data associate the AA signature with TH2, TH1, IL-23, and IL-9/TH9 cytokine activation, suggesting consideration of anti-TH2, anti-TH1, and anti-IL-23 targeting strategies. Similar to psoriasis and AD, clinical trials with selective antagonists are required to dissect key pathogenic pathways.

Intravenous immunoglobulin in the treatment of autoimmune bullous dermatoses: An update

High-dose intravenous immunoglobulin (IVIg) is being increasingly utilized as an off-label therapy for a variety of autoimmune and inflammatory conditions across various specialties. Numerous reports have shown that it is an effective treatment for autoimmune skin blistering disorders. Unlike most therapies for blistering disorders, IVIg is not immunosuppressive and has a favorable side effect profile. This has allowed its use to expand dramatically over the last decade. However, due to the rarity and severity of autoimmune skin blistering diseases, well-designed prospective trials are generally lacking. This work highlights major research developments and the best evidence to date regarding the treatment of autoimmune pemphigus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, pemphigoid gestationis, and linear IgA dermatosis with IVIg, providing an update on its efficacy, proposed mechanisms of action, side effect profile, and indications for use.

Improvement of Intravenous Immunoglobulin Therapy for Bullous Pemphigoid by Adding Immunosuppressive Agents: Marked Improvement in Depletion of Circulating Autoantibodies

BACKGROUND Various antibody-mediated autoimmune disorders are treated with intravenous immunoglobulin (IVIg). While the exact action of IVIg is unknown, it likely acts to rapidly and selectively lower the level of pathogenic antibodies. The most effective use of IVIg, an expensive and potentially toxic treatment of autoimmune disorders, remains undetermined. We propose that the addition of immunosuppressive agents to the IVIg regimen may increase the ability of IVIg to lower the level of pathogenic antibodies. OBSERVATIONS For 16 months, we observed a 78-year-old patient with autoantibody-mediated bullous pemphigoid who was treated with IVIg and an adjuvant therapy on 2 separate occasions as well as IVIg alone on 2 other occasions. We observed the greatest depression of bullous pemphigoid antibodies when IVIg was combined with an immunosuppressive agent. CONCLUSION These results support the hypothesis that agents that suppress antibody synthesis can offset the rebound in the level of individual antibody that follows their depletion and thus can improve the effectiveness of IVIg treatment while reducing the cost and the potential toxic effects of therapy.

Paraneoplastic pemphigus: a short review

Paraneoplastic pemphigus (PNP) is a fatal autoimmune blistering disease associated with an underlying malignancy. It is a newly recognized blistering disease, which was first recognized in 1990 by Dr Anhalt who described an atypical pemphigus with associated neoplasia. In 2001, Nguyen proposed the term paraneoplastic autoimmune multiorgan syndrome because of the recognition that the condition affects multiple organ systems. PNP presents most frequently between 45 and 70 years old, but it also occurs in children and adolescents. A wide variety of lesions (florid oral mucosal lesions, a generalized polymorphous cutaneous eruption, and pulmonary involvement) may occur in patients with PNP. The earliest and most consistent finding is severe stomatitis. There is a spectrum of at least five clinical variants with different morphology. Similarly, the histological findings are very variable. Investigations to diagnose PNP should include checking for systemic complications (to identify tumor), skin biopsies (for histopathological and immunofluorescence studies), and serum immunological studies. PNP is characterized by the presence of autoantibodies against antigens such as desmoplakin I (250 kD), bullous pemphigoid aniygen I (230 kD), desmoplakin II (210 kD), envoplakin (210 kD), periplakin (190 kD), plectin (500 kD), and a 170 kD protein. Unlike other forms of pemphigus, PNP can affect other types of epithelia, such as gastrointestinal and respiratory tract. Treatment of PNP is difficult, and the best outcomes have been reported with benign neoplasms that have been surgically excised. The first-line treatment is high-dose corticosteroids with the addition of steroid-sparing agents. Treatment failures are often managed with rituximab with or without concomitant intravenous immunoglobulin. In general, the prognosis is poor, not only because of eventual progression of malignant tumors but also because treatment with aggressive immunosuppression therapy often results in infectious complications, which is unfortunately at this time the most common cause of death in PNP.

Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts

BACKGROUND Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management, OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of recommendations. METHODS A preliminary survey, based on the European Dermatology Forum (EDF) and the European Academy of Dermatology and Venereology (EADV) guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology (AAD) conference. A second survey was sent following the meeting to more experts to achieve greater international consensus. RESULTS The 39 experts participated in the first round of the Delphi-survey while 54 from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II based on Delphi results and meeting discussion. LIMITATIONS Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first line therapy option for moderate to severe pemphigus.

Kinetics of Response to Conventional Treatment in Patients With Pemphigus Vulgaris

I t is difficult to evaluate the effectiveness of new therapies for pemphigus vulgaris (PV) because controlled trials are rarely performed. Comparison to historical trials is also problematic because little is known about the frequency and time it takes for active pemphigus to respond to conventional treatment. To address this problem, we evaluated the kinetics of response in PV to conventional treatment with prednisone.

Palmoplantar Psoriasis: A Review of Current Therapy

Palmoplantar psoriasis is a variant form of psoriasis that characteristically affects the skin of the palms and soles. It is chronic and inflammatory in nature and presents with hyperkeratotic, pustular, or mixed morphologies. Painful fissuring and bleeding may occur, which produces significant physical, functional, and social disability. Palmoplantar psoriasis is a therapeutically challenging condition and notoriously difficult to treat with topical therapy alone. Furthermore, limited data exist on treatment given that patients are typically excluded from clinical trials, which often require at least 10% body surface area (BSA) involved as an inclusion criterion. This article reviews the topical and systemic agents including biologics that have been investigated in the treatment of palmoplantar psoriasis. Combination therapy, comprising topical, systemic, and/or light treatments, with a particular focus on improvement in function and pain reduction, appears to be the most effective approach in treating these patients.

Paraneoplastic Autoimmune Multiorgan Syndrome: Paraneoplastic Pemphigus Revisited

This chapter summarizes current diagnostic criteria and expands on the unique clinical, histological features and pathophysiology of the mucocutaneous disease known as paraneoplastic pemphigus or, by the more encompassing term, paraneoplastic autoimmune multiorgan syndrome (PAMS). PAMS is an autoimmune mucocutaneous eruption that occurs in association with benign or malignant neoplasms. We provide insight and clarification that PAMS represents only one manifestation of the heterogeneous autoimmune syndrome in which patients, in addition to small-airway occlusion, may display a spectrum of at least five clinical variants, i.e., pemphigus-like, pemphigoid-like, erythema multiforme-like, graft-versus-host disease-like, and lichen planus-like. Multiple specific effectors of humoral and cellular autoimmunity mediating epithelial damage have been identified. Mucocutaneous lesions in patients with PAMS occur as a result of both humoral and cell-mediated immune mechanisms. Treatment is difficult and PAMS often does not respond to treatment of the underlying malignancy. An update of the advances in management and overall prognosis of PAMS is provided.

Controversies in the Treatment of Psoriasis: Is There a Role for Tonsillectomy?

Treatment of psoriasis traditionally has been directed at epidermal symptoms. Recent findings from a prospective study have implicated a circulating cross-reactive T-cell population in psoriasis etiology. These T cells appear to originate from streptococcal infection in the tonsils, and the study showed that tonsillectomy may lead to stable clinical improvement in psoriasis. Here, we review previous case reports and retrospective studies of tonsillectomy in the treatment of psoriasis and discuss findings in relation to the prospective study.