Granulomatosis with Polyangiitis: A Rare but Clinically Important Disease for the Otolaryngologist.

INTRODUCTION: Granulomatosis with polyangiitis (GPA) is rare but debilitating autoimmune disease and commonly presents with sinonasal as well as other head and neck symptoms. AIMS: To summarize the ear, nose, and throat-specific symptomatology and management of GPA. METHODS AND RESULTS: We performed a literature review by using the PubMed search engine to provide a summary of recent and important literature that is pertinent to an otolaryngologist's clinical practice. We provide a guide on the pathophysiology, epidemiology, clinical features, investigation, and management (operative and nonoperative) of this important disease. CONCLUSIONS: This review illustrates the important role that an otolaryngologist can play in the work up and symptom management of patients with GPA. Knowledge of the common presenting symptoms as well as more rare presentations of GPA is extremely important for otolaryngologists as prompt diagnosis and management is extremely important to avoid significant morbidity and mortality.

Association between weight gain and knee osteoarthritis: a systematic review.

OBJECTIVE: Although weight loss is recommended to manage knee osteoarthritis (KOA), adults tend to gain weight with age which may affect KOA symptoms and progression. We conducted a systematic review and data synthesis to investigate the association between weight gain and KOA, defined by clinical features, structural progression, and total knee replacement (TKR). DESIGN: MEDLINE and EMBASE were systematically searched for controlled trials and cohort studies of participants with (or at risk of) KOA examining the relationship between weight gain and KOA clinical features (pain, function, quality of life), structural progression, and TKR. Risk of bias was assessed using the ROBINS-I tool. Results were organised by outcome, with meta-analyses performed where appropriate. RESULTS: Twenty-three studies were included. Results showed significant detrimental effects of weight gain on pain (4 of 7 studies), stiffness (2 of 2 studies), function (5 of 6 studies), and the single studies examining quality of life, and clinical and radiographic KOA. Weight gain adversely affected cartilage (6 of 9 studies), bone marrow lesions (1 of 4 studies), meniscal damage (1 of 3 studies) and effusion/synovitis (1 of 1 study). Weight gain significantly increased TKR (3 of 6 studies): meta-analysis of 2 with available data demonstrated significant increases in TKR/5 kg weight gain in women, HR 1.34 (95% CI 1.18-1.51), and in men, HR 1.25 (95% CI 1.16-1.34). CONCLUSIONS: Weight gain in adults is associated with increased clinical and structural KOA and TKR. Prevention of weight gain should be considered to improve outcomes in KOA.

International Bullous Diseases Group: consensus on diagnostic criteria for epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a complex autoimmune bullous disease disease with variable clinical presentations and multiple possible diagnostic tests, making an international consensus on the diagnosis of EBA essential. OBJECTIVES: To obtain an international consensus on the clinical and diagnostic criteria for EBA. METHODS: The International Bullous Diseases Group (IBDG) met three times to discuss the clinical and diagnostic criteria for EBA. For the final voting exercise, 22 experts from 14 different countries voted on 50 different items. When > 30% disagreed with a proposal, a discussion was held and re-voting carried out. RESULTS: In total, 48 of 50 proposals achieved consensus after discussion. This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed. CONCLUSIONS: This first international consensus conference established generally agreed-upon clinical and laboratory criteria defining the clinical classification of and diagnostic testing for EBA. Holding these voting exercises in person with the possibility of discussion prior to voting has advantages in reaching consensus over Delphi exercises with remote voting.

Management options for femoroacetabular impingement: a systematic review of symptom and structural outcomes.

OBJECTIVE: The optimal therapy for femoroacetabular impingement (FAI) is unclear. The aim of this systematic review was to examine the evidence for surgical and non-surgical treatment of FAI on symptom and structural outcomes. DESIGN: MEDLINE and EMBASE were searched electronically. Surgical and non-surgical management strategies were searched with "FAI". Studies which included comparison groups and reported symptom or structural outcomes were included (Levels I-III evidence). A risk of bias assessment was performed. RESULTS: Eighteen studies comparing management strategies for FAI were identified. Most studies had high risk of bias. No study compared surgical and non-surgical treatment. When surgical approaches were compared there was evidence of superior symptom outcomes with arthroscopy compared to open surgery and with labral preservation. There was some evidence that surgical interventions are effective in reducing alpha angle (improved hip shape), but no data on whether this affects long-term outcomes. There was some weak evidence that surgery is associated with structural progression of hip osteoarthritis (OA). CONCLUSIONS: Although evidence supports improvement in symptoms after surgery in FAI, no studies have compared surgical and non-surgical treatment. Therefore no conclusion regarding the relative efficacy of one approach over the other can be made. Surgery improves alpha angle but whether this alters the risk of development or progression of hip OA is unknown. This review highlights the lack of evidence for use of surgery in FAI. Given that hip geometry may be modified by non-surgical factors, clarifying the role of non-surgical approaches vs surgery for the management of FAI is warranted.

A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone.

BACKGROUND: Pemphigus vulgaris (PV) is a blistering disease and tumour necrosis factor-α has a role in its pathogenesis. OBJECTIVES: To evaluate the safety of infliximab (IFX) with prednisone compared with prednisone alone in the treatment of PV. In addition, treatment response was assessed and mechanistic studies were performed. METHODS: Subjects with PV who had ongoing disease activity while being maintained on prednisone were randomized to receive either IFX or placebo in addition to prednisone. Response status and immunoglobulin (Ig) G anti-desmoglein (Dsg)1 and Dsg3 antibodies were assessed at 18 and 26 weeks. RESULTS: Ten subjects were randomized to each group. There were no safety signals during the course of the study. At week 18, one subject in each group had responded. At week 26, three IFX-treated subjects vs. none in the placebo group had responded (P = 0·21). At weeks 18 and 26, the median IgG anti-Dsg1 and anti-Dsg3 levels were lower in the IFX-treated patients [IgG anti-Dsg-1 (week 18, P = 0·035; week 26, P = 0·022); IgG anti-Dsg3 (week 18, P = 0·035; week, 26 P = 0·05)]. CONCLUSIONS: This study is limited by the relatively small sample size. There was no significant difference between study arms in the proportion of subjects with treatment-related adverse events > grade 3. IFX therapy was not shown to be effective for the treatment of patients with PV in this randomized, placebo-controlled trial, although IFX treatment may be associated with a decrease in anti-Dsg1 and Dsg3 antibodies.

Role of IgE in bullous pemphigoid: a review and rationale for IgE directed therapies.

Bullous pemphigoid (BP) is an autoimmune blistering disorder that is characterized by elevated total serum IgE and both IgG and IgE class autoantibodies directed against the hemidesmosomal proteins BP180 and BP230. In BP, IgE is found at the basement membrane zone and coating mast cells in lesional skin. IgE binding to immune cells is mediated through its high affinity receptor, FcεRI on the surface of mast cells, basophils and eosinophils. In BP lesions, IgE binding is thought to be a critical step in the activation of these cells. Models of the disease have demonstrated that BP IgE can replicate the early stages of BP lesion formation. These findings suggest that IgE inhibition may be a therapeutic approach for BP. Omalizumab is a humanized monoclonal antibody that inhibits IgE binding to FcεRI and is currently FDA-approved for the treatment of severe allergic asthma. To date, two case reports have each described the efficacy of omalizumab in a patient with severe recalcitrant BP. These studies are the first to provide clear evidence of the contribution of IgE autoantibodies in the pathogenesis of human BP and suggest that omalizumab may provide an additional therapeutic tool for treatment.

New and innovative interventions in the management of pemphigus.

Pemphigus is a rare autoimmune blistering disease usually treated with systemic glucocorticoids with adjuvant immunosuppressants or anti-inflammatories. However significant morbidity and mortality is associated with these treatments. This review discusses conventional therapeutic options, as well as new and emerging therapies that may be safer alternatives to broad-based immunosuppression.

Management of cutaneous manifestations of lupus erythematosus: A systematic review.

BACKGROUND: Cutaneous lupus erythematosus (CLE), occurring with or without systemic lupus erythematosus (SLE), is a group of inflammatory skin diseases that can be very debilitating, causing significant psychological distress, and sometimes scarring. OBJECTIVES: We sought to comprehensively present the evidence for different treatment modalities in patients with cutaneous manifestations of lupus erythematosus (LE). METHODS: Medline, Embase, Scopus and Cochrane CENTRAL were searched electronically from 1990 to March 2019, using keywords related to cutaneous lupus and synonyms and treatment. Articles retrieved were screened for relevance, including reference lists of retrieved reviews. We included clinical trials, observational studies or case series with ≥5 patients focussing on treatment of CLE, with or without SLE. RESULTS: The search identified 6637 studies, of which 107 were included. Each study commonly included a heterogeneous mixture of CLE subtypes, with or without SLE. The 107 included studies investigated 11 different categories of treatment in 7343 patients. Treatments included topical calcineurin inhibitors (13 studies), sun protection (5 studies), R-salbutamol cream (2 studies), antimalarials (22 studies), synthetic DMARDs (10 studies), retinoids (2 studies), thalidomide/lenalidomide (22 studies), biologic therapies (15 studies), intravenous immune globulin (3 studies), laser (6 studies) and other therapies (7 studies). General measures to be considered include smoking cessation, sun protection measures and optimisation of vitamin D levels. Moderate evidence exists for benefit with topical CNIs, particularly as a steroid sparing agent in areas at high risk of steroid complications (e.g. facial skin). There is moderate evidence for hydroxychloroquine, which is first-line in SLE patients, limited evidence to support other synthetic DMARDs, and moderate evidence supporting thalidomide but with significant risk of toxicity. Of biologic therapies, there are moderate data to support belimumab. Limited evidence exists for other therapies. CONCLUSION: Many management options are available for CLE, including topical, systemic and biologic therapies, with a variable balance of efficacy and toxicity. There is a paucity of high-quality clinical trial data. Further trials are required to better understand optimal management of CLE, particularly in specific subgroups.

Autoimmunity in bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering disease primarily of the elderly, characterized by the development of urticarial plaques surmounted by subepidermal blisters and the deposition of immunoglobulins and complement at the basement membrane zone (BMZ). Immunologically, it is characterized by the development of autoantibodies targeting two structural proteins of the hemidesmosomes, BP180 (collagen XVII) and BP230. BP230 is intracellular protein of the hemidesmosomal plaque, while BP180 is a transmembrane protein with a collagenous extracellular domain. The weight of experimental evidence indicates that BP180 is the primary target of the pathogenic autoantibodies. Autoantibodies are of both the IgG or IgE class, and their binding in the skin triggers complement activation, mast cell degranulation and the accumulation of inflammatory cells, including eosinophils, mast cells, and neutrophils. Release of proteases from these inflammatory cells results in cleavage of the BMZ and blister formation. While the initial triggers of autoantibody production remain obscure, a better understanding of the pathomechanisms of blister formation will lead to the development of new therapeutic strategies.

Superficial temporal vein graft in stapedotomy: a functional and aesthetic alternative.

The Causse technique of performing stapedotomy with vein graft interposition is widely-employed, with the vein graft harvested from the dorsum of the hand/wrist. Donor site scarring may be of cosmetic concern, especially in female patients. A prospective series of 19 patients undergoing stapedotomy with vein graft harvested from the superficial temporal vein is evaluated from aesthetic and functional perspectives. Results show that vein interposition from this donor site is not only aesthically acceptable but just as successful in improving hearing outcome after stapedotomy. We suggest the use of the superficial temporal vein and/or its branches as an alternative vein graft in stapedotomy.

Characterization of keratocalmin, a calmodulin-binding protein from human epidermis.

Using affinity-purified calmodulin-binding proteins from human epidermis we have developed a monoclonal IgM antibody, ROC 129.1, to a human desmosomal calcmodulin-binding protein. This antibody reacts with a submembranous 250-kD protein from human keratinocytes and stains human epidermis in a "cell-surface pattern". Permeability studies indicated that the epitope with which this monoclonal reacts is on the inner surface of the cell membrane. Immunoelectronmicroscopy localized the antigen to the desmosome. The epitope is restricted to stratified squamous epithelia and arises between 8-12 wk of fetal development. This desmosomal calmodulin-binding protein, which we have termed keratocalmin, may be involved in the calcium-regulated assembly of desmosomes.

A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180.

Subepidermal blistering associated with the human skin diseases bullous pemphigoid and herpes gestationis has been thought to be an IgG autoantibody-mediated process; however, previous attempts to demonstrate the pathogenicity of patient autoantibodies have been unsuccessful. An immunodominant and potentially pathogenic epitope associated with these blistering diseases has recently been mapped to the extracellular domain of a human epidermal antigen, BP180. Patient autoantibodies that react with this well-defined antigenic site failed to crossreact with the murine form of this autoantigen and thus could not be assayed for pathogenicity in a conventional passive transfer mouse model. As an alternative, rabbit polyclonal antibodies were generated against a segment of the murine BP180 protein homologous with the human BP180 autoantibody-reactive site and were passively transferred into neonatal BALB/c mice. The injected animals developed a subepidermal blistering disease that closely mimicked bullous pemphigoid and herpes gestationis at the clinical, histological, and immunological levels. Autoantibodies that recognize the human BP180 ectodomain are therefore likely to play an initiatory role in the pathogenesis of bullous pemphigoid and herpes gestationis.

Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris.

Pemphigus vulgaris (PV) is a cutaneous autoimmune disease characterized by blister formation in the suprabasilar layers of skin and mucosae and anti-desmoglein-3 (Dsg3) autoantibodies bound to the surface of lesional keratinocytes and circulating in the serum of patients. This disease can be reproduced in neonatal mice by passive transfer of patients' IgG, indicating that humoral immunity plays an important role in the pathogenesis of PV. Currently, the role of T lymphocytes in the development of PV is not clear. Here, we report that three immunoreactive segments of the ectodomain of Dsg3 specifically induced proliferation of T cells from PV patients. We found that T lymphocytes from 13 out of 14 patients responded to at least one of three Dsg3 peptides. T cells from controls and other patient groups did not respond to these Dsg3 peptides. The major T cell population stimulated by these Dsg3 peptides was CD4 positive. Dsg3-specific T cell lines and clones were developed and were shown to express a CD4 positive memory T cell phenotype. Upon stimulation, these cell lines and clones secreted a Th2-like cytokine profile. The Dsg3 responses of these T cells were restricted to HLA-DR, and not -DQ and -DP, of the major histocompatibility complex. This information will help to elucidate the cellular immune abnormalities leading to production of pathogenic IgG autoantibodies in patients with PV.

A major role for neutrophils in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein, BP180. Using a passive transfer mouse model, our group has shown previously that antibodies to the murine BP180 (mBP180) ectodomain are capable of triggering a blistering skin disease that closely mimics human BP. In this study, we investigated the role of neutrophils in the immunopathogenesis of this disease model. BALB/c mice depleted of circulating neutrophils by treatment with neutrophil-specific antibodies were no longer susceptible to the pathogenic effects of anti-mBP180 IgG. IgG and complement were deposited at the dermal-epidermal junction of these animals, but there was no evidence of inflammatory infiltration or blistering. C5-deficient mice, which are resistant to the pathogenic activity of anti-mBP180 IgG, could be made susceptible to this IgG-mediated blistering disease by intradermal administration of a neutrophil chemoattractant, IL-8 or C5a. Intraperitoneal injection of IL-8, which sequesters neutrophils in the peritoneal cavity, interferes with anti-mBP180-induced neutrophilic infiltration of the skin and prevented the development of BP disease in BALB/c mice. These findings provide the first direct evidence that neutrophils recruited to the skin via a C5-dependent pathway play an essential role in subepidermal blister formation in experimental BP, and suggest new directions for disease intervention.

A critical role for neutrophil elastase in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 and BP230. The immunopathologic features of BP can be reproduced in mice by passive transfer of anti-BP180 antibodies. Lesion formation in this animal model depends upon complement activation and neutrophil recruitment. In the present study, we investigated the role of neutrophil elastase (NE) in antibody-induced blister formation in experimental BP. Abnormally high levels of caseinolytic activity, consistent with NE, were detected in extracts of lesional skin and blister fluid of mice injected with anti-BP180 IgG. The pathogenic anti-BP180 IgG failed to induce subepidermal blistering in NE-null (NE(-/-)) mutant mice. NE(-/-) mice reconstituted with neutrophils from wild-type mice became susceptible to experimental BP. Wild-type mice given NE inhibitors (alpha1-proteinase inhibitor and Me-O-Suc-Ala-Ala-Pro-Val-CH(2)Cl), but not mice given cathepsin G/chymase inhibitors (alpha1-antichymotrypsin or Z-Gly-Leu-Phe-CH(2)Cl), were resistant to the pathogenic activity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, NE cleaved BP180 in vitro and in vivo. These results implicate NE directly in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the experimental BP model.

The role of complement in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is a blistering skin disease associated with an IgG autoimmune response directed against the ectodomain of the hemidesmosomal protein, BP180. An animal model of BP has recently been developed by our laboratory based on the passive transfer of rabbit antimurine BP180 antibodies into neonatal BALB/c mice. The experimental animals develop a blistering disease that reproduces all of the key immunopathological features of BP. In the present study we have investigated the role of complement in the pathogenesis of subepidermal blistering in the mouse model of BP. We demonstrate the following. (a) Rabbit anti-murine-BP180 IgG was effective in inducing cutaneous blisters in a C5-sufficient mouse strain, but failed to induce disease in the syngeneic C5-deficient strain; (b) neonatal BALB/c mice, pretreated with cobra venom factor to deplete complement, became resistant to the pathogenic effects of the anti-BP180 IgG; (c) F(ab')2 fragments generated from the anti-BP180 IgG exhibited no pathogenic activity in the mouse model; and (d) histologic evaluation of the skin of mice described in points b and c above showed minimal or no neutrophilic cell infiltration in the upper dermis. Thus, anti-BP180 antibodies trigger subepidermal blistering in this BP model via complement activation. This experimental model of BP should greatly facilitate future studies on the pathophysiology of autoantibody-mediated diseases of the dermal-epidermal junction.