E. Delaporte

Risk factors for bullous pemphigoid in the elderly: a prospective case-control study.

A rise in the incidence of bullous pemphigoid (BP) was documented recently in Europe, and the main risk factors for BP remain unknown. We conducted a multicenter case-control study to evaluate risk factors for BP. We identified 201 incident BP cases and 345 controls individually matched for age, gender, center, and place of residence (home, nursing home, or extended-care facility). We used univariate and multivariate logistic regression analyses to compare drugs used for over 3 months, comorbidities, and physical and cognitive impairments between cases and controls. Mean age of BP patients was 84.2 (±8.7) years. Factors independently associated with BP by multivariate analysis were major cognitive impairment (odds ratio (OR), 2.19; 95% confidence interval (95% CI), 1.24-3.87), bedridden condition (OR, 2.19; 95% CI, 1.23-3.89), Parkinsons disease (OR, 2.16; 95% CI, 1.09-4.27), unipolar or bipolar disorder (OR, 5.25; 95% CI, 1.21-22.86), and chronic use of spironolactone (OR, 2.30; 95% CI, 1.20-4.46) or phenothiazines with aliphatic side chains (OR, 3.70; 95% CI, 1.21-11.34). Chronic analgesic use was associated with a lower risk of BP (OR, 0.49; 95% CI, 0.30-0.81). Thus, risk factors for BP include neurological disorders, particularly dementia and Parkinsons disease, psychiatric disorders (unipolar and bipolar disorders), bedridden condition, and chronic use of several drugs.

Severe Skin Lesions Cause Patients with Inflammatory Bowel Disease to Discontinue Anti-Tumor Necrosis Factor Therapy.

BACKGROUND & AIMS Psoriasiform and eczematiform lesions are associated with anti-tumor necrosis factor (TNF)-α therapies. We assessed clinical characteristics, risk factors, and outcomes of skin disease in patients with inflammatory bowel diseases that presented with psoriasiform and eczematiform lesions induced by anti-TNF-α agents. METHODS We studied 85 patients (69 with Crohns disease, 15 with ulcerative colitis, and 1 with indeterminate colitis; 62 women) with inflammatory skin lesions (62 psoriasiform and 23 eczematiform lesions). RESULTS Twenty-four patients had a history of inflammatory skin lesions and 15 had a familial history of inflammatory skin disease. Locations of eczematiform lesions varied whereas scalp and flexural varieties were mostly psoriasiform. Skin lesions emerged but inflammatory bowel disease was quiescent in 69 patients following treatment with any type of anti-TNF-α agent (60 with infliximab, 20 with adalimumab, and 5 with certolizumab). Topical therapy resulted in partial or total remission in 41 patients. Patients with psoriasiform lesions that were resistant to topical therapy and that changed anti-TNF-α therapies once or twice developed recurring lesions. Overall, uncontrolled skin lesions caused 29 patients to stop taking TNF-α inhibitors. CONCLUSIONS Inflammatory skin lesions following therapy with TNF-α inhibitors occurred most frequently among women and patients with a personal or familial history of inflammatory skin disease; lesions did not correlate with intestinal disease activity. Recurring and intense skin lesions caused 34% of patients in this study to discontinue use of anti-TNF-α agents.

Progression of actinic keratosis to squamous cell carcinoma of the skin correlates with deletion of the 9p21 region encoding the p16INK4a tumor suppressor

Actinic keratoses (AKs) are pre-neoplastic lesions that can develop into squamous cell carcinomas (SCCs) of the skin. Often AK and SCC have commonly altered p53. A status of another tumor suppressor, the p16(INK4a), was reported for SCC but not for AK. A comparative study of SCC and AK human samples by loss of heterozygosity (LOH) analysis determined that the p16(INK4a/ARF) locus is less frequently altered in AKs than in SCCs. These LOH data highly correlated with immunohistochemical findings demonstrating the presence of p16(INK4a) in the AK skin samples but its absence in SCC lesions. Our results imply that progression of AK into SCC may involve inactivation of p16(INK4a).

Long-Term Remissions of Severe Pemphigus After Rituximab Therapy Are Associated with Prolonged Failure of Desmoglein B Cell Response

Changes in the B cell repertoire mediate long-lasting therapeutic effects of rituximab in pemphigus patients. A Blistering Attack on Autoimmunity The devastating effects of autoimmune diseases like type 1 diabetes and multiple sclerosis are front-page news. However, rare autoimmune diseases may be even more distressing in their relative anonymity. One such condition is pemphigus, which is a severe blistering condition caused by autoantibodies to adhesion proteins in the skin and mucus. The B cell–depleting antibody rituximab has been shown to treat pemphigus short term in early clinical trials. Now, Colliou et al. find that rituximab therapy can help pemphigus patients even after 6 years, in part by reshaping the B cell repertoire during reconstitution. The authors followed pemphigus patients from their early trial out at least 6 years after rituximab therapy. They found that nearly two-thirds of patients achieved a long-term complete response—either completely off of therapy or when treated with low levels of supplementary prednisone. They then compared patients with complete response to those with incomplete response to look at differences in reconstitution of the B cell compartment. Patients with complete response had a greater proportion of naïve and transitional B cells than those with incomplete response, which suggests a barrier to B cell maturation. Indeed, many of these transitional B cells secreted the regulatory cytokine interleukin-10. Moreover, complete responders had a specific loss of anti–desmoglein-specific B cells, which are pathogenic in pemphigus patients, but not B cells that respond to infectious agents. Together, these data suggest that B cell repertoire is reshaped after rituximab therapy, allowing for long-term effects in addition to the short-term loss of pathogenic B cells. If these observations are confirmed in large studies, these data could form the basis for a new frontline therapy for recalcitrant pemphigus. Pemphigus is a severe blistering condition of the skin and mucosa caused by autoantibodies directed against desmogleins, which are a type of keratinocyte adhesion protein. B cell depletion by rituximab has short-term efficacy against pemphigus. We aimed to assess the long-term course of pemphigus patients after B cell depletion and to understand the immunological mechanisms that mediate long-lasting remissions. We evaluated the clinical course of 22 pemphigus patients treated with rituximab after a 79-month median follow-up and compared the anti-desmoglein B cell response and B and T lymphocyte subpopulations and repertoire between patients who achieved complete remission (CR) and those who had incomplete remission (IR). Thirteen patients (59%) experienced CR during the study, including 10 patients off treatment and 3 patients with prednisone doses <10 mg/day; 9 patients had IR. A marked increase was observed in the ratio of CD19+CD27− naïve B cells to CD19+CD27+ memory B cells. Indeed, patients in CR had a fourfold higher number of transitional B cells and interleukin-10–secreting regulatory B cells than those in IR. Furthermore, CR was associated with modification of the initial B cell repertoire and the disappearance of desmoglein-specific circulating immunoglobulin G–positive (IgG+) B lymphocytes, whereas a skewed B cell repertoire was observed in patients in IR. Thus, a blockage of B cell maturation, a prolonged repopulation with naïve B cells, and a delayed reappearance of memory B cells, which resulted in the disappearance of circulating desmoglein-specific IgG+ B lymphocytes, contribute to the long-lasting effectiveness of rituximab for treating pemphigus.

Synthesis of Type 1 (IFNyγ) and Type 2 (IL‐4, IL‐5, and IL‐10) Cytokines by Human Eosinophils

Eosinophils are not only the source of cytotoxic and proinflammatory mediators but they can also generate cytokines and growth factors, including their own factors of differentiation, namely IL-3, GM-CSF, and IL-5. Synthesis of IL-5 by eosinophils was demonstrated by in situ hybridization and immunostaining in a variety of diseases, such as coeliac disease, asthma, hypereosinophilic syndrome, or skin diseases. However, IL-5 synthesis by eosinophils was not shown in Crohns disease, whereas in other diseases, it was restricted to a subpopulation of eosinophils, suggesting some heterogeneity in cytokine-producing eosinophils. Here, we report that human eosinophils, in addition to the synthesis of IL-5, and Th2 cytokine, can synthesize IFN gamma, a Th1 cytokine, as well as IL-10 and IL-4, known to be mainly produced by Th2 cells. Double immunostaining procedures reveal the coexpression of IL-5, IL-4, and IL-10 by the same eosinophil populations, different from IFN gamma-producing eosinophils. We propose that distinct subpopulations of human eosinophils express Th2 or Th1 cytokines. These results point to the importance of cytokines derived from non T cells in the regulation of the immune response.

Neurological disorders in patients with bullous pemphigoid.

Background: Unexpected cases of bullous pemphigoid (BP) have been reported in adult patients with various neurological disorders suggesting a possible relationship between these diseases. Objectives: (1) To determine the prevalence and types of neurological disorders in patients with BP, (2) to assess patients’ functional impairment, and (3) to compare the clinical and biological findings as well as prognosis of BP patients presenting with or without neurological disorders. Methods: BP patients with neurological disorders were selected in a series of 341 consecutive BP patients treated in 20 French Dermatology Departments. Functional impairment was prospectively assessed using the Karnofsky score which is a measure of patients’ general condition. Results: At least one neurological disorder was present in 123 of the 341 BP patients (36%). They primarily consisted of dementia (n = 68; 20%; 95% CI: 16–25%), cerebral stroke (n = 52; 15%; 95% CI: 4–19%), and/or Parkinson’s disease or parkinsonism (n = 32; 9%; 95% CI: 7–13%). BP patients with neurological disease were older than patients without neurological disease (83.8 ± 7.5 years vs. 79.3 ± 10.3 years, p < 10–4). They also had a lower Karnofsky score (47 ± 19% vs. 74 ± 20%, p < 10–4). One-year overall survival rates of the two groups were 50.8% (95% CI: 41.8–59.7) and 78.7% (95% CI: 73.0–84.2), respectively (p < 10–4). In contrast, the number of bullae and main biological features at baseline were not different between the two groups of patients. Conclusion: This study demonstrated a high frequency of neurological disorders, particularly dementia, in BP patients. Most of these patients had a severe functional impairment and a poor prognosis.

Peroxisome proliferator-activated receptor α regulates skin inflammation and humoral response in atopic dermatitis

BACKGROUND The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma are ligand-activated transcription factors belonging to the nuclear receptor superfamily. In addition to their regulatory role on lipid and glucose metabolism, they exert anti-inflammatory properties. In skin both PPAR-alpha and PPAR-beta/delta regulate keratinocyte proliferation/differentiation and contribute to wound healing. The 3 PPAR isoforms are expressed by several cell types recruited into the dermis during inflammation. OBJECTIVE We have investigated the role of PPAR-alpha in the regulation of atopic dermatitis (AD), a common skin inflammatory disease. METHODS We chose a mouse model of inflammatory dermatosis with immunologic features of AD and used epicutaneous sensitization with ovalbumin in the absence of adjuvant, which mimics the human pathology. RESULTS On antigen sensitization, PPAR-alpha-deficient mice display increased epidermal thickening, dermal recruitment of inflammatory cells, lung inflammation, airway hyperresponsiveness, and IgE and IgG2a production compared with their wild-type counterparts. Increased inflammation was correlated to an enhancement of TH2 and, to a greater extent, TH1 responses and to increased skin expression of nuclear factor kappaB. Interestingly, PPAR-alpha expression was decreased in eczematous skin from patients with AD compared with skin from nonatopic donors, suggesting that defective PPAR-alpha expression might contribute to the pathology. Topical application of WY14643, a specific PPAR-alpha agonist, significantly decreased antigen-induced skin inflammation in the AD model. CONCLUSION PPAR-alpha acts as a negative regulator of skin inflammation in AD.

INTERFERON-ALPHA IN COMBINATION WITH CORTICOSTEROIDS IMPROVES SYSTEMIC MAST-CELL DISEASE

SIR. Systemic mast cell disease (SMCD) is characterized by abnormal proliferation of mast cells which inflltrate the bone marrow, spleen, liver, lymph nodes and skin. Histamine and other mediators are responsible for symptoms of varying severity, including itching, flushing, headaches, gastrointestinal attacks and vascular collapse. Anti-Hl and -H2 blocking agents, oral sodium cromoglycate. PUVA. and corticosteroids are the principal treatment modalities for mastocytosis. Interferon has been shown to be effective in a few cases of SMCD (Table 1). Recently, we successfully treated a patient with SMCD. who had cutaneous, gastrointestinal {Gl) and bone marrow involvement, using a combination of interferon-o (IFN-a) and corticosteroids.

First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial

BACKGROUND High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. METHODS We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harmans criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589. FINDINGS Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4-71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71-3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39-2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]). INTERPRETATION Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. FUNDING French Ministry of Health, French Society of Dermatology, Roche.

Clinicopathological Study of 13 Cases of Squamous Cell Carcinoma Complicating Hidradenitis Suppurativa

Background: To the best of our knowledge, only 52 cases of squamous cell carcinoma (SCC) complicating hidradenitis suppurativa (HS) have been reported since 1958. We describe 13 new cases. Methods: We propose a clinical and histological analysis of our cases. We include these results in a review of previously reported cases to analyze a total of 65 patients. In our series of 13 cases, we also investigate the presence of human papillomavirus (HPV) in tumor samples, by polymerase chain reaction (PCR) on paraffin-embedded material. Results: Malignant transformation affects mainly men with a long-term history of genitoanal HS. Although our cases were 7 well-differentiated carcinomas and 6 verrucous carcinomas, lymphatic and visceral metastasis occurred in 2 and 3 cases, respectively. With PCR, we demonstrated presence of HPV in genitoanal tumoral lesions, principally HPV-16. Conclusion: SCC complicating HS evolves poorly, despite a good histological prognosis. Our results sustain the implication of HPV in the malignant transformation of HS.