Luca Fania

IgE recognition of bullous pemphigoid (BP)180 and BP230 in BP patients and elderly individuals with pruritic dermatoses.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease of the elderly and is associated with IgG and IgE autoantibodies against the hemidesmosomal proteins, BP180 and BP230. The purpose of this study was to characterize the epitope specificity of IgE against defined regions of BP180 and BP230 in 32 BP patients and 21 elderly patients with pruritic disorders who did not yet fulfill all the criteria of BP by immunoblot (IB), ELISA and indirect immunofluorescence microscopy. Our findings show that IgE from BP sera preferentially targets the COOH-terminus of BP230 (IB: 16/32, ELISA: 12/32) and, to a lesser extent, the BP180-NC16A domain (IB: 11/32, ELISA: 9/32). Noteworthy, a subgroup of elderly patients with pruritic dermatoses also showed IgE recognition of BP180-NC16A (IB: 1/21, ELISA: 4/21) and less frequently of BP230 (IB: 2/21, ELISA: 2/21). Thus, IgE recognition of the BP autoantigens is presumably an early pathogenetic event in BP.

Alteration of Cholinergic System in Keratinocytes Cells Produces Acantholysis: A Possible Use of Cholinergic Drugs in Pemphigus Vulgaris

Human epidermis shows a non-neuronal cholinergic system including keratinocyte (kc) acetylcholine (Ach) axis which is composed by enzymes and two families of Ach receptors (muscarinic and nicotinic receptors). The activity of these two receptors can regulate the interkeratinocytes and kcs-extracellular matrix adhesion modifying the regulation of intercellular adhesion molecules like cadherins and integrins. Some authors demonstrate that acantholysis in pemphigus depends not only on anti desmogleins antibodies (abs) (mostly IgG) but even on other abs directed against kc membrane antigens (e.g. anti Ach receptors Abs). In the early phase of pemphigus pathogenesis, anti Ach receptors Abs block Ach signaling essential for cell shape and intercellular adhesion and increase the phosphorylation of adhesion molecules. Combined with the action of abs antidesmogleins, anti Ach receptors Abs cause the acantholytic phenomenon. In vitro experiments show that high doses of Ach in acantholytic kcs can rapidly reverse this pathologic event. In vivo experiments using neonatal mice model of Pemphigus have demonstrated that cholinergic agonists reduce these lesions. Therapy with pyridostigmine bromide and Nicotinamide per os or pilocarpine used topically, drugs that present cholinomimetic effects, has lead to encouraging results in patients affected by Pemphigus disease. Cholinergic agents could have a strategic role in the therapy of pemphigus since they could be responsible for the early stage of acantholytic diseases.

Ocular Mucous Membrane Pemphigoid after Lyell Syndrome: Occasional Finding or Predisposing Event?

PURPOSE Ocular mucous membrane pemphigoid (OMMP) is an autoimmune disease involving the eye and characterized by subepithelial detachment resulting from an immunologic reaction against conjunctival basal membrane zone (BMZ) antigens. Lyell syndrome (LS) is a drug-induced, T cell-mediated, cytotoxic reaction involving the mucocutaneous areas. Two patients with LS are presented in whom OMMP developed. DESIGN Report of 2 cases. PARTICIPANTS Two male patients, 80 and 60 years old, with persistent corneal ulcerations, corneal melting, and inflammation some months after an LS episode. METHODS Conjunctival biopsy samples were obtained to perform direct immunofluorescence (DIF) and histologic analyses. Indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) also were performed. MAIN OUTCOME MEASURES Immunodeposit findings on the conjunctival BMZ obtained by DIF and IIF, inflammatory infiltration of the corneoconjunctival samples studied by histologic analysis, and autoantibodies of patient sera directed against BMZ antigens tested by ELISA. RESULTS Direct immunofluorescence analyses showed immunoglobulin G and complement 3 component deposits along the BMZ in a linear pattern. Histologic analysis revealed the presence of eosinophils, neutrophils, and mast cells with fibrin deposition in the substantia propria of both patients; the data confirmed the clinical suspicion of OMMP. The IIF and ELISA results were negative. CONCLUSIONS Chronic eye surface injury associated with LS may promote autoimmunization against ocular epithelial BMZ antigens, playing a strategic role in the subsequent onset of OMMP. The occurrence of OMMP after LS could be an occasional finding, or conversely, LS could be an underestimated predisposing factor in the development of OMMP.

Increased prevalence of diabetes mellitus in bullous pemphigoid patients during the last decade

Editor Bullous pemphigoid (BP) is a rare autoimmune blistering disease. The association between BP and diabetes mellitus (DM) has been previously reported with inconsistent results. Dipeptidyl peptidase (DPP)-IV inhibitors, approved in Europe by EMA in 2007 to treat type-2 DM, are antihyperglycemic drugs that could induce BP disease. To investigate the possible association between BP and DM, we collected administrative data from our Institute during the years 2001–2016 and we studied the prevalence of diabetes in patients with pemphigus and pemphigoid. We have analysed all the hospital discharge records from January 2001 to December 2016 for patients with a principal diagnosis of pemphigus (ICD-9-CM 694.4) or BP (ICD-9-CM 694.5). Then, we considered the ICD-9-CM code 250.00/.02/.03/ .20/.72/.92, that is, type-1 or 2 DM with or without complications. Complicated DM is characterized by blood sugar level above 250 mg/dL or a value of glycated haemoglobin test >7% or DM with hyperosmolarity. Also, for each year, and for three different time periods (i.e. 2001–6, 2007–11 and 2012–16), we have computed the relative risk (RR) and the 95% confidence interval (95% C.I.) for the prevalence of DM in patients with BP vs patients with pemphigus. We have produced three logistic regression models – separately for the three time periods specified above – to assess the role of BP to the risk of diabetes, when accounting for age and gender. While until 2006, the proportion of diabetes is 13.2% in BP and 14.4% in pemphigus (for comparison, the prevalence of DM in Italian population is 4.9%), starting in 2007, the proportion of diabetes is significantly higher in patients with BP than in patients with pemphigus (e.g. 25.2% vs 10.1% in 2012–2016, P < 0.001) (Table 1). We observe in fact a RR of 0.92 for the years 2001–2006, of 2.19 for the years 2007–2011 and of 2.49 for 2012–2016 – and for these last two periods, the P-value is <0.001. The three multiple logistic regression models show that, while, in the 2001–2006 years, the risk of diabetes is significantly lower in patients with BP compared to pemphigus (RRadj = 0.52, 95% C.I. 0.35 to 0.78), starting in the following period, the direction of the association is inverted (RRadj = 1.21, 95% C.I. 0.84 to 1.75); in the last period of observation, the RRadj increases to 1.68 and reaches statistical significance (95% C.I. 1.22 to 2.31) (Table 2).

Ustekinumab treatment of pityriasis rubra pilaris: A report of five cases

Pityriasis rubra pilaris (PRP) is a rare, chronic, inflammatory skin disease of unknown etiology. Patients refractory to conventional therapies have been treated successfully with biologic drugs such as anti‐tumor necrosis factor agents. Recently, a role of the interleukin‐23/T‐helper 17 axis in PRP has been described. Our objective was to assess the effectiveness of ustekinumab in five patients with adult‐onset PRP refractory to conventional therapies. In the present study, four patients had type I and one patient type II adult‐onset PRP. They were treated with three s.c. doses of ustekinumab at weeks 0, 4 and 16. Clinical response was evaluated monthly during treatment up to a 15‐month follow‐up period. All patients promptly showed a decrease in erythema, follicular hyperkeratosis and scaling. After three injections, complete remission of skin lesions was achieved in four out of five cases and a significant clinical improvement was shown in one case. To the best of our knowledge, this is the largest case series reported on ustekinumab treatment in PRP. Our results, in addition to previous studies from other groups, suggest that ustekinumab may be a possible first‐line treatment for PRP patients refractory to conventional therapies.

Detection and characterization of IgG, IgE, and IgA autoantibodies in patients with bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors

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A Possible Role for CD8+ T Lymphocytes in the Cell-Mediated Pathogenesis of Pemphigus Vulgaris

Pemphigus vulgaris (PV) is an autoimmune blistering disease whose pathogenesis involves both humoral and cell-mediated immune response. Though the pathogenetic role of autoantibodies directed against desmoglein 3 is certain, a number of other factors have been suggested to determine acantholysis in PV. In this study we examined the possible role of CD8+ T cells in the development of acantholysis by a passive transfer of PV autoantibodies using CD8 deficient mice, and we also studied the inflammatory infiltrate of PV skin lesions by immunohistochemical staining. The results of the immunohistochemical staining to study the expression of CD3, CD4, and CD8 in PV skin lesions showed that CD4+ are more expressed than CD8+ in the inflammatory infiltrate of PV lesions, confirming the data of the previous literature. The passive transfer study showed a lower incidence of pemphigus in the group of CD8 deficient mice compared to the control one of wild-type mice. These results suggest that CD8+ T cells may play a role in the pathogenesis of PV, perhaps through the Fas/FasL pathway.

Real-life efficacy and safety of ingenol mebutate for the treatment of actinic keratosis of the face and scalp: A single arm retrospective study

Abstract Background: The efficacy and safety of ingenol mebutate versus placebo have been proven in four randomized controlled trials (RCTs), although there is a lack of real-life studies corroborating such promises in routine clinical practices. In our study, we sought to describe real-life effectiveness, safety and regimen adherence among patients with multiple AKs on the face treated with ingenol mebutate and evaluate correlates of clinical outcomes in this population. Methods: We reviewed the clinical charts of adult patients with multiple (≥3) AK grade I and II of the face and scalp, treated with ingenol mebutate from April 2014 to April 2015. All subjects received the medication according to ingenol mebutate standard of care. Results: We enrolled 88 patients during the study period and carried out 122 treatment cycles. The unadjusted lesion clearance rate per treated field was 81.3% and the average local skin reactions score at day 4 was 6.0 ± 2.8 (range: 0–18). Conclusions: We observed an excellent rate (>99%) of adherence to ingenol mebutate. This was mirrored by the fact that our clinical outcomes broadly confirmed results obtained in RTCs. Our study showed that the efficacy and safety of ingenol mebutate observed in RCTs can be reliably translated in real-world practice.

Dermoscopy of Melanocytic Lesions in Patients Affected by Oculocutaneous Albinism: A Case Series

Background: Although the majority of skin cancers in albino patients consists of squamous and basal cell carcinomas, malignant melanomas have also been described, albeit less frequently. Objective: The aim of our study was to evaluate melanocytic lesions in albino patients to look for any recurrent dermoscopic pattern. Methods: We enrolled 12 consecutive albino patients presenting to our department and examined each patient for the presence of melanocytic nevi with the unaided eye and then with dermoscopy. Melanocytic lesions with suspicious clinical or dermoscopic features were excised and histopathologically evaluated. Results: Analysis of the recorded images permitted us to find two main dermoscopic patterns in this group of patients. The first one was represented by a homogeneous light-brown yellowish pattern associated with comma-like and dotted vessels; the second one consisted of a classical brown reticular pattern frequently associated with central depigmentation and with comma-like vessels. Moreover, based on some atypical dermoscopic features, in 2 patients we excised 3 melanomas in situ (in the same patient) and a thick melanoma (3.2 mm). Conclusions: Dermoscopy may represent a useful tool for the evaluation of melanocytic lesions in albino patients, permitting an early diagnosis of melanoma.

Simvastatin‐associated dermatomyositis

A 72-year-old Caucasian woman was referred to our department for evaluation of heliotrope rash and muscular weakness, mainly on the proximal part of the thighs. She had been taking simvastatin (HMGCoA reductase inhibitor, 20 mg daily) for 3 months for dyslipidemia. The erythema was localized on the periorbital area, cheeks, frontal region of the face and, in a “V” presentation, on the upper chest. Gottron’s papules were found on the extensor surface of the hands. Her eruption involved firstly the periorbital area but quickly spread to the other parts of the face (Figure 1), upper chest, and the dorsum of the hands. The patient reported intense fatigue and dyspnea. The onset of these clinical features was not associated with fever, lymphadenopathy, calcinosis, Raynaud’s phenomenon, nor sclerodactyly. Her family medical history was negative for any relevant dermatoses. Laboratory examinations showed raised levels of creatine kinase (285 U/I) and LDH (425 U/I). Antinuclear antibody test (ANA) was positive at 1/320, with a clumpy pattern. Other autoantibodies and lupus anticoagulant test were negative. Serum cryoglobulins and complement levels were normal. A malignancy workup did not find any underlying tumor. A biopsy specimen from the cheek showed an interface dermatitis characterized by vacuolar degeneration of basal keratinocytes, epidermal atrophy and interstitial mucin deposits in the dermis (Figure 2). Direct immunofluorescence was negative. The electromyogram showed decreased amplitude and duration of motor unit potentials, and fibrillations on muscle contraction in proximal muscle. A muscular biopsy was not performed. Considering diagnosis of simvastatin induced dermatomyositis (DM), treatment with this statin was promptly stopped, and steroid treatment with prednisone (0.75 mg/kg/day) was instituted, with a marked improvement of the skin lesions and of the muscle weakness. After 8 months from the diagnosis the patient had no signs and symptoms of DM. Statins are competitive inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA), with a reductase activity that can spark the onset of myopathy and rhabdomyolysis caused by noninflammatory toxic or metabolic processes (Hamilton-Craig, 2001; Sailler et al., 2008). It’s reported that myopathy occurs in 0.1–0.2% of patients treated with statins (Thompson, Clarkson, & Karas, 2003). This therapy can increase up to three times the risk of myopathy in patients after 50 years of age (Sailler et al., 2008). Fourteen cases of DM induced by statins have been reported. DM can occur from 2 months up to 5 years after starting treatment with statins. The drugs implicated in the induction of DM belong to the first generation (simvastatin, lovastatin, and pravastatin), second generation (atorvastatin and fluvastatin), and third generation (cerivastatin). Six case reports have described the association between simvastatin and DM (Hill, Zeitz, & Kirkham, 1995; Inhoff et al., 2009; Khattak, Morris, & Branford, 1994; Rasch, Schimmer, & Sander, 2009; Vasconcelos & Campbell, 2004; Zaraa et al., 2011). Inhoff et al. reported the unique case of amyopathic DM (Inhoff et al., 2009). Hill et al. reported a DM case complicated by a lung fibrosis that caused the death of the patient (Hill et al., 1995). Muscle involvement has been described in 3 of 4 patients (two cases not reported) while females seem to be more often involved (3 of 5 patients, two cases not found) (Table 1). The pathogenesis of simvastatin-induced DM is not well known. It has been hypothesized that statins in rare cases may promote cellular apoptosis that could cause the release of nuclear antigens and favour an autoimmune process. Case reports showed that statins may trigger autoimmune diseases like systemic or subacute cutaneous lupus erythematosus and systemic sclerosis (No€ el, 2007). Other hypotheses suggest that statins may increase HLA class I expression by myocytes, favour exposure of hidden antigens by damaged myocytes, or promote FIGURE 1 Heliotrope rash characterized by erythema localized on periorbital area, cheeks, and frontal region of the face