Viruses and pemphigus: an intriguing never-ending story.

Virus infections and autoimmunity have long been linked. As to pemphigus, many studies have been directed to prove or rule out the possibility of viral induction. Herpesviruses have often been related to the onset or reactivation of pemphigus. The association may be (i) casual, (ii) due to the iatrogenic immunosuppression facilitating opportunistic viral infections or (iii) based on a pathogenic link between the viral presence and the host's dysregulated immune response leading to autoimmunity. Japanese researchers, using real-time polymerase chain reaction, lately detected herpes simplex virus DNA in the saliva from pemphigus patients at the earliest stage of the disease and with no signs or history of herpetic infection, thus confirming the possible existence of cases of pemphigus induced by herpesviruses. These selected cases could be included into the innovative concept of 'paraviral eruptions', where an inciting role for induction may be played by the concomitant intake of certain drugs.

Discoid lupus erythematosus at a site of previous injury.

A 71-year-old man with three patches of discoid lupus erythematosus (DLE) confined to the right preauricular region drew our attention because of the unusual linear arrangement of the lesions. Twenty-five years previously, the patient had suffered a trauma in the same area from falling off his motorcycle. We believe that, despite the great lapse in time, this injury may have facilitated the onset of DLE in the very same area, through long-term destabilization of the local neuroimmune network. The case fits the recently coined concept of the immunocompromised district, a cutaneous region with altered immune control, more susceptible to harbouring opportunistic infections, tumours, and immune disorders.

A Multivariate Analysis of Depression Prevalence in Psoriasis Patients: A Cohort Study.

The literature reported higher depression rates in psoriasis patients compared to the general population. Our study aimed to verify whether variability in depression prevalence was due to using different diagnostic tools. We also aimed to determine whether dysfunctional coping strategies might increase the depression burden. We assessed psoriasis severity by the Psoriasis Area Severity Index (PASI) and PSOdisk. We analyzed mental alterations of 120 outpatients by Hamilton Depression and Anxiety Rating Scales (HAM-D and HAM-A), Symptom Checklist-90-Revised (SCL-90-R), plus coping strategies and quality of life by Coping Orientation to Problems Experienced (COPE) Inventory and 36-Item Short Form Health Survey (SF-36). We divided our cohort into five subgroups from minimal to severe psoriasis using the PSOdisk total score. Depression prevalence varied according to the assessment criteria for specificity, frequency, and severity. Different mood disorders other than major depression emerged when we used DSM-IV-TR criteria. Correlation analysis of the criteria we used to diagnose depression or depressed mood indicated that a dysfunctional coping strategy was highly and positively correlated only in patients of the severe subgroup. Differently, a negative correlation emerged between the SF-36 Mental Summary Component (MSC) and behavioral disengagement, thus suggesting that psychopathological distress might induce patients with a marked/severe psoriasis to adopt dysfunctional coping strategies. Dermatologists are fundamental in detecting comorbid depression, referring psoriasis patients to mental health specialists to achieve adequate treatments, and preventing suicide risk.

Guselkumab: an anti-IL-23 antibody for the treatment of moderate-to-severe plaque psoriasis.

Guselkumab, a subcutaneously administered fully human IgG1λ monoclonal antibody that selectively inhibits the p19 subunit of interleukin 23, is approved in both the USA and the EU for the treatment of adult patients with moderate-to-severe plaque psoriasis. The efficacy and safety of guselkumab were demonstrated in four randomized, double-blind, Phase III trials (VOYAGE 1 and 2, NAVIGATE, and ECLIPSE), which demonstrated high levels of clinical response over three years of continuous treatment, regardless of sex, age, body weight, and race, maintaining a favourable safety profile and long-term tolerability. Guselkumab was shown to be efficacious in patients with prior failure of other biologics, including adalimumab and ustekinumab, and was superior to both adalimumab and secukinumab in head-to-head trials. Guselkumab efficacy was also observed in the treatment of psoriasis localized in difficult-to-treat body regions including the scalp, palms and/or soles, and fingernails. Treatment with guselkumab improved health-related quality of life and patient-reported signs and symptoms. Guselkumab has a consistently favourable safety profile and is well tolerated over the long-term. Clinical development of guselkumab as a treatment is ongoing for other immune-mediated inflammatory diseases, including psoriatic arthritis, Crohn's disease, and ulcerative colitis. In the overall management of patients with plaque psoriasis, guselkumab is a robust treatment option with durable maintenance of response over time.

Treat-to-Target Approach for the Management of Patients with Moderate-to-Severe Plaque Psoriasis: Consensus Recommendations.

INTRODUCTION: Treat-to-target strategies are used in several chronic diseases to improve outcomes. Treatment goals have also been suggested for psoriasis, but there is currently no consensus on targets, and guidance is needed to implement this strategy in clinical practice. The project 'Treat to Target Italia' was launched by a scientific board (SB) of 10 psoriasis experts to generate expert consensus recommendations. METHODS: On the basis of the published literature, their clinical experience, and the results of a survey among Italian dermatologists, the SB identified four relevant topics: (1) clinical remission; (2) quality of life; (3) abrogation of systemic inflammation; (4) safety. They drafted 20 statements addressing these four topics and submitted them to a panel of 28 dermatologists, in a Delphi process, to achieve consensus (greater than 80% agreement). RESULTS: Consensus was reached on all statements. Treatment goals defining clinical remission should include a 90% improvement from baseline in the Psoriasis Area and Severity Index (PASI90 response) or an absolute PASI score of less than or equal to 3. Patient's quality of life and satisfaction are important targets. If PASI targets are achieved, there should be no or very low impact of psoriasis on quality of life [Dermatology Life Quality Index (DLQI) score less than or equal to 3]. If PASI or DLQI goals are not achieved within 3-4 months, treatment should be changed. Abrogation of systemic inflammation may be crucial for preventing or delaying inflammatory comorbidities. Safety is an equally important target as efficacy. CONCLUSION: These 20 consensus statements define the parameters of a treat-to-target strategy for psoriasis in Italy. It is hoped that use of these in the management of patients with psoriasis will improve treatment outcomes and patient health-related quality of life.

WITHDRAWN: Efficacy and local tolerability of different spray products in the treatment of mild to moderate acne of the back and chest. A controlled, 3-arm, assessor-blinded prospective trial.

AHEAD OF PRINT ARTICLE WITHDRAWN BY PUBLISHER.

Psychiatric morbidity and pemphigus: a review of theories and literature on pathogenesis.

Skin diseases are very common in the community and a large number of general practice visits are due to dermatological problems. Most dermatologists believe that psychiatric problems are frequent among subjects coming to their attention and several studies on dermatological patients have revealed that they prevalently suffered from psychiatric disorders. However, there are only few articles in the literature dealing with stress-induced pemphigus or psychiatric troubles associated with pemphigus. The relationship between pemphigus and psychiatric disorders is still a matter of debate. The first question is whether the association is circumstantial or causal. Subsequently, it should be clarified if psychogenic factors can be considered an inducing factor for pemphigus onset, or a possible complication of this skin disease, or a comorbidity of it, or, in the end, an adverse reaction to conventional therapy for pemphigus. In any case, further studies are needed to investigate the underlying mechanism linking psychiatric diseases and pemphigus.

Pemphigus vegetans of the folds (intertriginous areas).

Pemphigus vegetans (P Veg), the rarest form of pemphigus, is thought to be a variant of pemphigus vulgaris (PV). Classically, two subtypes of P Veg are recognized: (1) Neumann P Veg, which usually begins as PV with vesicles and bullae that rupture to form hypertrophic granulating erosions, then evolving into vegetating exuding masses; (2) Hallopeau P Veg, initially characterized by pustular lesions that, after rupturing, merge and gradually evolve into vegetating erosions with a centrifugal expansion. The disease typically affects the big folds (axillary, inframammary, inguinocrural, intergluteal), where semiocclusion, maceration, and mixed infections continuously incite exudation and granulation tissue formation (wet P Veg). In nonintertriginous locations, the vegetating buttons can dry out to change into warty, fissured, painful, seborrheic keratosis-like lesions (dry P Veg). Histologic examination indicates hyperplastic epidermis with intramalpighian leukocyte microabscesses and indistinct traits of suprabasal acantholysis. Immunofluorescence findings are similar to those of PV. Diagnosis is straightforward when PV lesions coexist. Difficulties can arise in cases with nonflexural location. Cytology (Tzanck test), histology, immunofluorescence, and ELISA search for anti-desmoglein antibodies are the diagnostic laboratory tools. Systemic treatment is similar to that for PV, high-dose steroids being the first choice therapy. Immunosuppressive agents and etretinate may allow a steroid-sparing effect. Topical treatment is aimed at countering the granulation tissue formation by means of several strategies (sublesional steroid injection, application of medicated gauzes in the involved flexures, chemical cautery or surgical excision of vegetating lesions).

Cutaneous sarcoidosis: an intriguing model of immune dysregulation.

Sarcoidosis is a systemic granulomatous disease characterized by the presence of non-caseating granulomas. Its etiology remains obscure. A plausible hypothesis suggests that a complex interplay of host factors, infectious processes, and non-infectious environmental factors, matched with a susceptible genetic background, results in a pathway that leads to systemic granulomatous inflammation. Although presentations of sarcoidosis vary enormously, multi-organ involvement is a common feature. Cutaneous involvement occurs in about 25% of patients with protean manifestations and variable prognoses. Skin manifestations are divided into specific lesions with histopathologically evident non-caseating granulomas and nonspecific lesions arising from a reactive process that does not form granulomas. A peculiar form of cutaneous sarcoidosis is represented by sarcoidal lesions at sites of trauma that has caused scarring. The pathogenesis of scar sarcoidosis remains unknown. Scar sarcoidosis is also associated with herpes zoster infection, surgery, and tattooing. Such heterogeneous events, along with those at the sites of chronic lymphedema, thermal burns, radiation dermatitis, and vaccinations, occur on areas of vulnerable skin labeled "immunocompromised districts". Numerous options are available for the treatment of cutaneous sarcoidosis. Although corticosteroids remain the treatment of choice for initial systemic therapy, other nonsteroidal agents have proven effective and therefore useful for long-term management. Tumor necrosis factor-α antagonists such as infliximab may have a role in the treatment of cutaneous sarcoidosis, especially in refractory cases that are resistant to standard regimens. Elucidation of the relationship of sarcoidal granulomas with malignancy and immunity may facilitate a better understanding of some pathomechanisms operating in neoplastic and immunity-related disorders.

Foods, diet, and skin diseases.

Human skin is continuously exposed to internal and external influences that may alter its condition and functioning. As a consequence, the skin may undergo alterations leading to immune dysfunction, imbalanced epidermal homeostasis, or other skin disorders. New theories are developing that link food intake and health. The objective of this review is to evaluate current knowledge about the interrelation of food and skin, particularly the effect of nutrients on some cutaneous immune disorders and therapeutic actions of nutrients in skin disorders.

Pemphigus erythematosus relapse associated with atorvastatin intake.

Statins, also known as 3-hydroxy-3-methylglutaril-CoA reductase inhibitors, are well-tolerated drugs used for prevention of atherosclerosis and cardiovascular events. Although they are generally considered safe, some serious adverse effects, such as myositis, myopathy, and rhabdomyolysis can rarely occur. Furthermore, recent data from long-term follow-up on patients who have been taking statins for a long period of time suggest that prolonged exposure to statins may trigger autoimmune reactions. The exact mechanism of statin-induced autoimmune reactions is unclear. Statins, as proapoptotic agents, release nuclear antigen into the circulation and may induce the production of pathogenic autoantibodies. Herein we report the case of a 70 year-old man who developed a relapse of pemphigus erythematosus, a syndrome with features of both lupus erythematosus and pemphigus, after atorvastatin intake.

Locus minoris resistentiae: An old but still valid way of thinking in medicine.

Locus minoris resistentiae (lmr) refers to a body region more vulnerable than others. This ancient concept, which is also present in Achilles' and Siegfried's old epic myths, weaves through many fields of medicine. In any internal organ or external body region with a congenital or acquired altered defense capacity, a disease process may occur more easily than elsewhere. Illustrative instances are the appearance of hepatocarcinoma on a cirrhotic liver, the onset of lung carcinoma in a tuberculosis scar, cases of osteosarcoma arising in chronic osteomyelitis, and carcinoma complicating chronic cholelithiasis, just to name a few. In dermatology there are countless reports of privileged localization of cutaneous lesions on injured skin which, therefore, represents a typical condition of lmr. The Köbner phenomenon itself features the oldest, simplest, and most common example of lmr, because it denotes the appearance of new lesions pertaining to a previously present skin disorder at the sites of trauma or other insult. The modern transposition of this old but still valid way of thinking in medicine is the reading key of this issue, devoted to lmr in dermatology.

Granulomatous dysimmune reactions (sarcoidosis, granuloma annulare, and others) on differently injured skin areas.

Granulomatous disorders are chronic cell-mediated immune responses histologically characterized by collections of macrophages, epithelioid cells, and multinucleated giant cells. This disease spectrum often has an infectious origin, but sometimes neither an infective agent nor an inciting antigenic stimulus can be identified. The skin may be a preferential target for these disorders, especially in the areas that have been damaged by various forms of skin injury (eg, herpetic infections, trauma, thermal or solar burns, vaccinations, tattoos). These damaged skin sites frame the new concept of an immunocompromised cutaneous district (ICD), which defines a skin area with acquired immune dysregulation that can pave the way for the local onset of opportunistic disorders, such as infections, tumors, and granulomatous disorders. Sarcoidosis, granuloma annulare (GA), and forms of granulomatous vasculitis, such as Churg-Strauss syndrome (CSS) and Wegener's granulomatosis (WG), are the most common granulomatous disorders that occur in an ICD and may share common pathogenic mechanisms. Recent studies have found clinical and pathologic overlapping features across noninfectious granulomas. Although no unifying etiology exists, the development of granulomatous processes in the ICD has often been reported and the literature contains various hypotheses to explain it: (1) overactive immune response in a previously injured region with or without loss of immune tolerance; (2) overall reduced immune response; (3) retention of an exogeneous antigen or foreign body; (4) altered neural signaling; and (5) a combination of all the aforementioned processes. T helper cells, T regulatory cells, and macrophages, as well as a number of antigenic proteins, have been identified as potential contributing factors. In addition, a genetic predisposition and an intact systemic immune system are both instrumental for the persistence of local granuloma formation in the ICD.

Radiation dermatitis, burns, and recall phenomena: Meaningful instances of immunocompromised district.

Ionizing and ultraviolet radiations, as well as burns, can selectively damage and immunologically mark the cutaneous area they act on through direct and indirect mechanisms. After the causal event has disappeared, the affected skin district may appear clinically normal, but its immune behavior is often compromised forever. In fact, irradiated or burned skin areas undergo a destabilization of the immune control, which can lead to either a reduction of immunity (as suggested by the facilitated local occurrence of tumors and infections) or an excess of it (as suggested by the possible local onset of disorders with exaggerated immune response). In other words, these areas become typical immunocompromised districts (ICD). Also, in recall phenomena the damaged skin area usually behaves as an ICD with an exaggerated immune response toward a wide range of drugs (especially chemotherapeutic agents) that prove to be harmless on the undamaged skin surface. The occurrence of any skin disorder on an irradiated, photoexposed, or burned skin area can be defined as an isoradiotopic, isophototopic, or isocaumatopic response, respectively; however, the opposite may also occur when elsewhere generalized cutaneous diseases or eruptions selectively spare irradiated, photoexposed, or burned skin sites (isoradiotopic, isophototopic, and isocaumatopic nonresponse, respectively). The pathomechanisms involved in any secondary disorder occurring on irradiated or burned skin areas may be linked to locally decreased or altered lymph flow (with dysfunction of lymph drainage) on the one hand, and to fibrotic throttling or reduction of peptidergic nerve fibers (with dysfunction of neuroimmune signaling) on the other hand, resulting in a significant dysregulation of the local immune response. Future clinical observations and experimental investigations on radiation dermatitis, sunburns, and thermal or chemical skin injuries should shed new light on the mechanisms regulating regional resistance to infectious agents, local oncogenesis, and district propensity to dysimmune reactions.

Pemphigus: associations and management guidelines: facts and controversies.

Pemphigus, a prototypical organ-specific human autoimmune disease, may be associated with other immunity-related disorders, viral infections, and different types of tumors. Coexistence with immune diseases is fairly frequent and, for some of them (eg, myasthenia gravis, Basedow's disease, rheumatoid arthritis, or lupus erythematosus), common pathogenic mechanisms can be considered. The association with viral infections (mainly herpesvirus infections) raises the question of whether the virus triggers the outbreak of the disease or simply complicates its clinical course. Neoplastic proliferations coexisting with pemphigus have a different histogenesis and the pathogenic link may vary according to the associated tumor (thymoma, lymphoma, carcinoma, or sarcoma). A subset of pemphigus-neoplasia association is represented by Anhalt's paraneoplastic pemphigus, with peculiar clinical, histologic, and immunologic features characterizing it. Coexistence of pemphigus with Kaposi's sarcoma, albeit not frequent, offers an intriguing speculative interest. The cornerstone of management in pemphigus is the combination of systemic corticosteroids and immunosuppressants. The conventional treatment used in most cases is based on oral administration of deflazacort and azathioprine. In selected cases, mycophenolate mofetil is preferred to azathioprine. Severe forms of pemphigus require intravenous pulse therapy with dexamethasone (or methylprednisolone) and cyclophosphamide. In the recent years, the use of high-dose intravenous immunoglobulin therapy has gained several consents. Rituximab, a monoclonal anti-CD 20 antibody, which affects both the humoral and cell-mediated responses, has proved to give a good clinical response, often paralleled by decrease of pathogenic autoantibodies. The combination with intravenous immunoglobulin offers the double advantage of better clinical results and a reduced incidence of infection. Interventional treatments, such as plasmapheresis and extracorporeal immunoadsorption, are aimed at patients with life-threatening forms of pemphigus and high levels of circulating autoantibodies, a circumstance where the medical therapy alone risks failing. Second-line treatments include gold salts (which we do not favor because of the acantholytic potential inherent in thiol structure) and the association of oral tetracyclines with nicotinamide, which is rather safe. Local treatments, supplementary to the systemic therapy, are aimed at preventing infections and stimulating reepithelialization of eroded areas. Innovative topical treatments are epidermal growth factor, nicotinamide gel, pimecrolimus, and a proteomics-derived desmoglein peptide. Pemphigus patients should be warned against over-indulging in unnecessary drug intake, prolonged exposure to ultraviolet rays, intense emotional stress, and too spiced or too hot foods. Cigarette smoking is not contraindicated in pemphigus patients because of the nicotine anti-acantholytic properties.

Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies.

Pemphigus includes a group of autoimmune bullous diseases with intraepithelial lesions involving the skin and Malpighian mucous membranes. Pemphigus vulgaris (PV), the most frequent and representative form of the group, is a prototypical organ-specific human autoimmune disorder with a poor prognosis in the absence of medical treatment. The pathomechanism of PV hinges on autoantibodies damaging cell-cell cohesion and leading to cell-cell detachment (acantholysis) of the epidermis and Malpighian mucosae (mainly oral mucosa). A controversy exists about which subset of autoantibodies is primarily pathogenic: the desmoglein-reactive antibodies or those directed against the acetylcholine receptors of the keratinocyte membrane. The onset and course of PV depend on a variable interaction between predisposing and inducing factors. Genetic predisposition has a complex polygenic basis, involving multiple genetic loci; however, the genetic background alone ("the soil"), although essential, is not by itself sufficient to initiate the autoimmune mechanism, as proven by the reports of PV in only one of two monozygotic twins and in only two of three siblings with an identical PV-prone haplotype. The intervention of inducing or triggering environmental factors ("the seed") seems to be crucial to set off the disease. The precipitating factors are many and various, most of them directly originating from the environment (eg, drug intake, viral infections, physical agents, contact allergens, diet), others being endogenous (eg, emotional stress, hormonal disorders) but somehow linked with the subject's lifestyle. As to certain drugs, their potential of provoking acantholysis may be implemented by their interfering with the keratinocyte membrane biochemistry (biochemical acantholysis) and/or with the immune balance (immunologic acantholysis). Viral infections, especially the herpetic ones, may trigger the outbreak of PV or simply complicate its clinical course. The precipitating effect might be due to interferons and other cytokines released by the host as a consequence of the viral attack, which overactivate the immune response. Inductions of PV by physical agents (ultraviolet or ionizing radiation, thermal or electrical burns, surgery and cosmetic procedures), contact allergens (in particular, organophosphate pesticides), dietary factors (eg, garlic, leek, onion, black pepper, red chili pepper, red wine, tea), and emotional stress are rare, but well-documented events. The possible intervention of the environment in the outbreak of PV has been overlooked in the past, but nowadays clinicians perceive it more frequently. The assumption that genetic factors alone are not sufficient to cause the outbreak of the disease, inevitably instills the idea that PV may not occur spontaneously, but always results from an interaction between an individual predisposing genetic background and environmental precipitating factors, often concealed or apparently harmless.