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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 3–4months, 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.

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.

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.

Bullous pemphigoid (BP) is an organ-specific human autoimmune disease typical of the elderly, which may be associated with many different disorders (immune, neurologic, psychiatric, hematologic, pulmonary, and cardiovascular), as well as with different types of tumors. The crucial question is whether these associations are casual or causal. In particular, the relationship between BP and malignancy is still a matter of debate. Although this association often has been emphasized, it is not clear whether the coexistent malignancy and BP are pathogenically connected or if their association is merely linked to aging. In our survey, the BP/neoplasm association ratios have not increased with age. Instead, significantly higher ratios have been found in younger patients; therefore, a meticulous investigation for a malignant neoplasm should always be pursued in young or middle-aged patients with BP, in particular regarding the severe forms of the disorder or those refractory to conventional treatment. The management of BP strictly depends on the multifactorial pathogenesis of this disorder. In fact, inflammation in BP seems to be more crucial for blister formation than in other autoimmune bullous disorders, such as pemphigus. Even if first-line treatments are typically immunosuppressants, newer therapeutic agents targeting specific pathogenic steps that are linked with inflammation have been proposed. Treatments selectively suppressing autoantibody formation, inflammation cascade, or both are available. Grouping therapies according to their mechanism of action may be useful to test new drug associations or to evaluate efficacy and tolerability of drugs with the same target.

Etanercept is a competitive inhibitor of tumor necrosis factor-alpha (TNF-α) a polypeptide hormone, involved in the development of the immune system, in host defense and immune surveillance. Even if the etanercept mechanism of action is not completely understood, it is supposed that it negatively modulates biological responses mediated by molecules (cytokines, adhesion molecules, or proteinases) induced or regulated by TNF. For this reason, it is widely used in the treatment of immunologicals diseases, such as rheumatoid and psoriatic arthritis, polyarticular juvenile idiopathic active, ankylosing spondylitis, and plaque psoriasis. Etanercept has a good tolerability profile. Adverse events related to skin are rare, arising usually in about 5% of patients treated with anti-TNF α. In this scenario, we describe a case of figurate urticaria arose after the re-administration of etanercept in a patient affected by psoriasis and hepatitis B. A 65-year-old man, affected by psoriasis, was hospitalized in September 2014 to the Regional Center for the treatment of psoriasis and Biological Drugs of Second University of Naples for progressive extension of psoriatic skin lesions. The laboratory analysis detected positivity for hepatitis B virus (HBV) antigens. For this reason, it was administered to him lamivudine 100 mg/die about 30 days before to start etanercept treatment. The etanercept therapy has resulted in a progressive improving of skin manifestations, and the patient decided individually to stop the therapy. Afterwards, for worsening of the psoriatic lesions, he was again hospitalized and treated with the same therapeutic schedule (lamivudine followed by etanercept). Ten days after the start of therapy, the patient showed the onset of urticarial rash. Due to this, the treatment with lamivudine and etanercept was suspended and the patient's clinical conditions improved. It is probably that immunological disorders due to etanercept therapy and HBV infection could explain the onset of figurate urticaria in our patient. In this contest, the post-marketing surveillance confirms its important role in the monitoring of drugs tolerability and effectiveness.

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.

During the last decades, the conventional therapy for autoimmune blistering diseases has been high-dose, long-term systemic corticosteroid and immunosuppressive agents or adjuvant drugs. Long-term, high-dose steroid therapy can result in serious adverse effects. The rationale for using adjuvant drugs is that concerns reducing the need for corticosteroids, and hence, their side effects, or it may result in better control of the disease, or both. Immunosuppressive agents are not free of adverse effects, however. Prolonged immune suppression may account for high rates of morbidity, disability, and possible death. There is no consensus about the first-choice adjuvant drug for the management of blistering autoimmune diseases. This contribution evaluates six adjuvant drugs — cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, intravenous immunoglobulin, and rituximab — and discusses the choice of a “winning drug” that is effective and safe

Recurrent lymphangitis, deep trauma, malignancy, and related treatments (ie surgery and radiotherapy) are usually considered the commonest causes of lymphedema. The role of chronic venous disease in this context is often overlooked; yet, all patients with advanced venous disease (stasis dermatitis) have some degree of lymph circulation impairment.1 Venous edema is assumed to be the sole consequence of increased capillary filtration from venous hypertension. Because lymph drainage is the main buffer against the formation of edema, a compensation for the increased lymph load does occur at the beginning. In the long run, however, when the transport capacity is exceeded, the lymphatics fail to keep their buffer function, and interstitial fluid accumulates. This leads to a clinical condition of mixed venous and lymphatic insufficiency that causes a progressive swelling of soft tissues, which is termed phlebolymphedema.2 There is clinical and laboratory evidence confirming the presence of microangiopathy of the lymphatic network in patients with chronic venous disease.3 Further causes of phlebolymphedema are vein stripping (saphenectomy) for varicosities, vein-harvesting procedures for coronary bypass grafting or other vascular surgery, orthopedic surgery, or penetrating trauma involving the medial aspect of a lower limb (Brodell syndrome).4 In all of these conditions, lymph stasis occurs in the involved district as a consequence of the almost inevitable surgical cutting of the lymph collectors

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.

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.

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 Kobner 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.

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.

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.

Background In earlier papers, we suggested that the aggravation of psoriasis by antimalarial drugs (analogous to hypolipidemic drugs) could be initiated by a break in the epidermal barrier. We suggested that these drugs exerted their effect by inhibiting epidermal transglutaminase activity, and supported this hypothesis by demonstrating the effect of hydroxychloroquine sulfate (HCQS) on the morphology of cultured skin and on liver transglutaminase activity. In the present article, we describe, for the first time, the morphologic changes induced by HCQS on cultured skin of psoriatic patients. Methods Uninvolved (apparently normal) skin explanted from the back of two psoriatic patients was cultured in the presence of 9.2 and 13.8 m m of HCQS for 3 days. The morphologic changes were evaluated in a blind manner. The experiment was repeated twice. Results Significant changes in the epidermal morphology of psoriatic skin cultured in the presence of HCQS, compared with skin cultured without the presence of the drug, were observed. The most striking changes were enhanced and irregular keratinization and dermo–epidermal detachment and cleft formation. No parakeratosis or other characteristics of psoriasis were observed. Conclusions The first changes caused by HCQS on the cultured skin of psoriatic patients are not characteristic of psoriasis, and include hyperproliferation and enhanced and irregular keratinization. The present experimental study gives further support to the hypothesis that HCQS causes an initial break in the barrier function of the epidermis (probably by inhibiting transglutaminase activity), which is followed by a physiologic response of the epidermis aimed at barrier restoration. This rather nonspecific stimulus to epidermal proliferation is probably sufficient to trigger psoriasis, in vivo, among genetically predisposed patients.

d -Penicillamine (DP) is widely used nowadays in the treatment of rheumatoid arthritis, despite its well known side effects of an autoimmune nature, often associated with specific histocompatibility antigens (HLA). We report the case of a woman, suffering from rheumatoid arthritis (RA), treated with DP, who developed myasthenia gravis (MG) and pemphigus foliaceus (PF) and whose phenotype has only antigens usually associated with pemphigus. This may be the second published case of concurrent pemphigus and myasthenia gravis induced by d -penicillamine therapy, in the absence of thymoma.

We read with great interest the report recently published in the European Journal of Dermatology by Thimon et al.[1], which describes an intriguing case of pemphigus vulgaris (PV) induced by radiotherapy for breast cancer [1]. Bullous lesions, strictly localized on the irradiated zone, appeared three weeks after the last cycle of radiotherapy, suggesting induction by ionizing radiation. After two weeks, the bullous eruption spread onto the entire body [1].PV may have a location potentially confined [...]

The onset and course of pemphigus depend on the interaction between predisposing and inducing factors. Genetic predisposition is known to be associated with human leukocyte antigens (HLAs), in particular with DR4, 14 and DQ1. Long-term treatment with systemic IFN-α often induces the appearance of pemphigus antibodies in nonpemphigus patients.4 Repeated administration of imiquimod, whilst altering the local immune response, may cause acantholytic lesions as a result of the production of IFN-α, a cytokine commonly identified as a pemphigus-inducing drug.

1. Some authors consider a separate variant of generalized psoriasis, well described by Lapiere, as recurrent circinate erythematous psoriasis. It presents with erythematous, annular or polycyclic lesions, and an eruption of small sterile pustules and fine desquamation. The patches extend from the center and resolve within some weeks, leaving scales and changes in pigmentation and pigmentary changes. Frequent relapses are described in the bordering areas 2,3 . In this study, we report the case of a woman affected by generalized annular pustular (Lapiere) psoriasis. This patient had previously been treated with conventional therapeutics, and demonstrated a significant improvement after treatment with etanercept. This 70-year-old Caucasian woman, described in our report, has a 35-year history of psoriasis. Physical examination revealed the presence of small erythematous papules, centered by a pustule, a few millimeters in diameter (Fig. 1). Histological examination showed Kogoj-Lapiere spongiform multilocular typical pustules (an epidermal pustule formed by infiltration of neutrophils into necrotic areas of the epidermis, where the cell walls form a swampy network), features compatible with the clinical diagnosis of Lapiere psoriasis. The patient had previously been treated with other topical and systemic drugs (colchicine, acitretin, ciclosporin, methotrexate) and ultraviolet B narrow band phototherapy, with partial and temporary benefits, side effects, and frequent relapses. Differential diagnosis of our case included other generalized pustular psoriasis: acute generalized exanthematous pustolosis (AGEP) was perhaps the most important differential diagnosis. AGEP, which occurs as an acute, spontaneously healling reaction to drugs (usually antibiotics), was excluded on the basis of the absence of vasculitis associated with spongiform pustules and based on the presence of psoriatic anamnesis. Lapiere psoriasis can be differentiated from pustular lesions caused by prolonged application of topical steroids or tar ointments on the periphery of pre-existent psoriatic plaques. Unlike the Von Zumbusch generalized form, the general state of health is not compromised. The patient was treated with 50 mg of etanercept twice weekly subcutaneously for three months. There was an

Alcohol is the most widely self-prescribed drug in the world, and the undesired effects resulting from its abuse represent a major social and medical problem. Although detrimental consequences of acute and chronic excessive alcohol consumption are obvious and readily recognized, less attention is generally devoted to the association between alcohol misuse and skin disease. The cutaneous changes associated with alcoholic cirrhosis are well documented and more widely recognized than those occurring secondary to alcohol misuse or during the early stages of alcohol abuse.1–4 Most of the underlying pathogenic mechanisms by which alcohol misuse affects the skin are still under investigation, even though impaired immune responses and vascular alterations are accounted for. The present review aims to discuss both the classical stigmata of alcoholic cirrhosis and newer dermatological signs associated with alcohol cirrhosis.