IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment.

IL-36 cytokines, a subgroup of IL-1 family, comprise IL-36α, IL-36ß, and IL-36γ agonists, abundantly expressed in psoriatic skin, and IL-36RA and IL-38 antagonists. In psoriatic skin, IL-36 cytokines interfere with keratinocyte cornification programs and induce the release of antimicrobial peptides and chemokines active on neutrophils and Th17 lymphocytes. To date, the role of IL-38 antagonist in psoriasis remains to be defined. Here, we demonstrate that skin and circulating IL-38 levels are reduced in psoriatic patients and in other skin diseases characterized by neutrophilic infiltrate. In psoriasis, the balance of IL-36γ agonist/IL-38 antagonist serum levels is in favor of agonists and is closely associated with disease severity. Interestingly, IL-38 is upregulated by anti-IL-17A biological treatment and positively correlates with the therapeutic efficacy of secukinumab in psoriatic patients. The downregulation of IL-38 expression is strictly related to keratinocyte de-differentiation triggered by the inflammatory cytokines IL-36γ, IL-17, and IL-22. Finally, we demonstrate that administration of recombinant full-length IL-38 counteracts in vitro the biological processes induced by IL-36γ in human keratinocytes and endothelial cells and attenuates in vivo the severity of the psoriasiform phenotype induced by IMQ in mice. Such effects are achieved by restoring the physiological programs of keratinocyte proliferation and differentiation, and reducing the immune cell infiltrates.

Factors associated with the prescription of "traditional" or "biological" systemic treatment in psoriasis.

Abstract The choice of an adequate psoriasis treatment is critical to good disease management and to overall patient health. It is estimated that about 20-30% of patients requires systemic treatment: "traditional" (methotrexate, acitretina and cyclosporin) or "biological" (etanercept, adalimumab and infliximab). Clinical records of 784 outpatients with psoriasis were analyzed. 51.5% received traditional treatments and 48.5% a biological treatment. Males were 67.8% of patients. Psoriatic arthritis was observed in 37.3%. Females and younger patients were more likely to receive biological treatments. No differences were observed for Body Mass Index or for presence of comorbidities. Patients with psoriatic arthritis were also more frequently prescribed biological drug treatment. In a multivariate logistic regression model, only the older age-group (≥60 years) had a statistically significant OR (p=0.001) with a reduction of about 80% the likelihood of receiving biological treatment compared to the younger age-group (<40 years). Patients with a PASI score ≥20 and patients with arthritis have a probability to be prescribed biologics about five times higher than the other patients. In conclusion, younger age, psoriatic arthritis and the previous use of systemic drugs are factors associated with the use of biological treatment rather than the traditional systemic drugs.

Glutathione peroxidase activity in the blood cells of psoriatic patients correlates with their responsiveness to Efalizumab.

Biological treatment of psoriasis, a chronic inflammatory immune-mediated pathology of huge social impact, has become a recent revolutionizing breakthrough in the management of the disease. Apart from anti-TNF-alpha biologics, recombinant proteins-inhibitors of the T lymphocytes-antigen presenting cells interaction, Efalizumab among them, have been successfully used in the therapy of psoriasis. Serious concern regarding safety and efficacy of biologics remains because they induce numerous adverse effects and a significant number of patients are non-responders. Up-to-now, there are no biochemical or/and immunological markers of the clinical efficacy of these drugs. This study searches for immunological and redox markers of the clinical response in the group of psoriatic patients treated with Efalizumab. Clinical response to Efalizumab was assessed by Psoriasis Area and Severity Index and correlated with suppression of T-cell functions, plasma cytokines, membrane-associated polyunsaturated fatty acids (PUFAs), antioxidant enzymes and markers of oxidative stress. A 12-week Efalizumab therapy did not affect abnormal plasma levels of pro-inflammatory cytokines and lower-than-normal content of PUFAs esterified in phospholipids of red cell membranes. It did, however, suppress T-cell-mediated functions and decrease nitrites/nitrates and malonyl dialdehyde levels independently on the clinical outcome. On contrast, activities of glutathione peroxidase (GPx) and glutathione S-transferase in granulocytes were remarkably increased and catalase decreased exclusively in non-responders vs complete or partial responders. High baseline GPx in erythrocytes decreased in responders. It is concluded that clinical response to Efalizumab correlates with GPx activity in the blood cells, suggesting that high hydroperoxide levels are involved in psoriasis persistence.

A case of dystrophic epidermolysis bullosa improved with etanercept for concomitant psoriatic arthritis.

Epidermolysis bullosa is a group of inherited, chronic, non-inflammatory skin disorders, and dystrophic epidermolysis bullosa (DEB) is one of the most severe variants. The role of tumour necrosis factor alpha (TNFalpha) has not been reported in the pathogenesis of DEB. A DEB case is reported that appears to have responded well to the TNFalpha inhibitor etanercept given for the treatment of concomitant psoriatic arthritis. A progressive improvement in DEB was apparent over the first 3 months of treatment and persistent good control of DEB was noted over 3 years of therapy. A correlation between DEB improvement and etanercept has not been made, but the case may provide insight into the causal mechanisms of DEB.

Toxic epidermal necrolysis successfully treated with etanercept.

Toxic epidermal necrolysis (TEN) is a rare and acute severe adverse reaction to drugs, characterised by massive apoptosis and widespread epidermal and mucosal detachment. Although no gold standard therapy exists, human i.v. immunoglobulins have recently been described as an effective treatment for this disease. We report a case of phenobarbital-induced TEN in a 59-year-old white woman where the epidermal detachment stopped 48 h after beginning the etanercept treatment with complete healing after 20 days. To the best of our knowledge, this is only the second reported case of TEN successfully treated with etanercept.

Biological drugs targeting the immune response in the therapy of psoriasis.

Chronic plaque psoriasis affects more than 2% of world population, has a chronic recurrent behavior, gives a heavy burden to the patients' quality of life, and hence remains a huge medical and social problem. The clinical results of conventional therapies of psoriasis are not satisfactory. According to the current knowledge of the molecular and cellular basis of psoriasis, it is defined as an immune-mediated chronic inflammatory and hyperproliferative skin disease. A new generation of biological drugs, targeting molecules and cells involved into perturbed pro-inflammatory immune response in the psoriatic skin and joints, has been recently designed and applied clinically. These biological agents are bioengineered proteins such as chimeric and humanized antibodies and fusion proteins. In particular, they comprise the antitumor necrosis factor-alpha agents etanercept, infliximab, and adalimumab, with clinical efficacy in both moderate-severe psoriasis and psoriatic arthritis, and the anti-CD11a efalizumab with selective therapeutic action exclusively in the skin. Here, we overview recent findings on the molecular pathways relevant to the inflammatory response in psoriasis and present our clinical experience with the drugs currently employed in the dermatologic manifestations, namely etanercept, infliximab, and efalizumab. The growing body of clinical data on the efficacy and safety of antipsoriasis biological drugs is reviewed as well. Particular focus is given to long-term safety concerns and feasibility of combined therapeutic protocols to ameliorate clinical results.

Autoimmune progesterone dermatitis.

Autoimmune progesterone dermatitis (APD) is a rare disorder characterized by recurrent polymorphous skin manifestations, which appear or are exacerbated during the luteal phase of the menstrual cycle. The hallmarks for diagnosis include premenstrual flare, its prevention with the inhibition of ovulation, and positive skin reaction to intradermal injection of progesterone. The mainstay of treatment is to inhibit the secretion of endogenous progesterone by suppressing ovulation. Bilateral oophorectomy may be necessary in patients with severe and refractory symptoms. We report herein the case of a 38-year-old woman who developed recurrent and cyclic vesiculobullous eruptions clinically suggestive of erythema multiforme or autoimmune bullous diseases. The skin manifestations turned out to be APD. The patient was treated with tamoxifen 20 mg daily with complete symptom remission after 4 months.

Identification of the keratin K9 R162W mutation in patients of Italian origin with epidermolytic palmoplantar keratoderma.

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant skin disorder characterized by hyperkeratosis of the palms and soles associated with histologic findings of hyperkeratosis and epidermolysis. Ultrastructurally, there is vacuolization of the cytoplasm and abnormal keratin filament network with tonofilament clumping. EPPK is caused by mutations in the keratin 9 gene (KRT9), which is expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis. The mutation R162W is the most frequent keratin 9 alteration reported in patients from different geographical areas. We present three unrelated Italian families affected by EPPK in which we confirmed the presence of the R162W mutation, by RT-PCR analysis followed by sequencing of the KRT9 gene, in all affected members. The finding of the same mutation in all patients, together with the previous reports of the disease, strongly suggest that position 162 of the KRT9 gene represents a mutation "hot-spot", probably due to the peculiarity of the sequence.

Treatment of recalcitrant scleromyxedema with thalidomide in 3 patients.

Scleromyxedema is a generalized, papular, and sclerodermoid form of lichen myxedematosus associated with monoclonal gammopathy and systemic changes. Despite anecdotal reports of success with various agents, no satisfactory treatments are currently available. We report 3 adult patients with recalcitrant scleromyxedema associated with paraproteinemia who were treated with thalidomide. All 3 patients had marked improvement of the skin lesions and joint mobility after the first 2 months of therapy, with further amelioration after 4 months, and reduction in paraprotein levels.

Targeting tumor necrosis factor-alpha in the therapy of psoriasis.

Tumor necrosis factor-alpha (TNF-alpha) plays a fundamental role in the initiation and persistence of skin inflammation in psoriasis. The best evidence of the essential activity of this cytokine in the pathogenesis of psoriasis came from the observation that selective TNF-alpha blockers are dramatically effective in the therapy of this disease. The TNF-alpha inhibitors, infliximab and etanercept, have been employed with success in moderate to severe psoriasis and in psoriatic arthritis in randomized controlled trials. Anti-TNF-alpha biologicals induce rapid disease resolution and long-lasting remission, suggesting that they may alter the natural course of the disease. Further studies are warranted to more precisely establish the biological bases of the action of anti-TNF-alpha agents, better define which subgroup of patients can benefit most from this treatment, and the modalities of combination therapy with other antipsoriatic agents. Many other TNF-alpha inhibitors have been developed but none of them has been yet used in the therapy of psoriasis. Major limitations to the use of selective TNF-alpha blockers include the reactivation of latent tuberculosis, the risk of opportunistic infections, the development of specific antibodies, which is associated with a reduced duration of response to treatment, and the high cost.

Disseminated lupus vulgaris.

Lupus vulgaris is the most common form of cutaneous tuberculosis, and usually presents as a solitary lesion on the face. We report two patients with multiple lesions on different skin areas. The first patient presented a diffuse involvement of the right foot, and reddish-brown plaques on the right leg, the back and the face. Spreading of the lesions followed a prolonged application of topical corticosteroids. The second patient showed a large plaque on the nape and occipital area resulting in scarring alopecia, and plaques on the right inguinal and thigh regions. Ziehl-Neelsen staining was negative in both cases, but diagnosis was supported by histology and polymerase chain reaction analysis. No visceral involvement was present. Antituberculosis polychemotherapy was rapidly effective.

Papular neutrophilic dermatosis and erythema elevatum diutinum following erythropoietin therapy in a patient with myelodysplastic syndrome.

A 65-year-old man with refractory anaemia with an excess of blasts developed an erythematous papular eruption symmetrically distributed on the legs and trunk 3 months after initiation of erythropoietin therapy. The lesions showed a dense neutrophilic infiltrate in the absence of leucocytoclastic vasculitis, and did not fit the criteria of a well-defined neutrophilic dermatosis. Concomitant with the rapid resolution of these skin lesions following erythropoietin discontinuation, typical lesions of erythema elevatum diutinum arose on the extensor surface of the fingers, knees and elbows, which responded to a brief course of dapsone treatment. Although typical and atypical neutrophilic dermatoses have been reported in patients with haematological disorders, they have also been associated with the use of drugs, in particular granulocyte colony-stimulating factor. To our knowledge this is the first report of unclassified neutrophilic dermatosis and erythema elevatum diutinum occurring following the administration of erythropoietin.

Nodular perianal herpes simplex with prominent plasma cell infiltration.

BACKGROUND: Nodules are exceptional manifestations of herpes simplex virus (HSV) infection in immunocompromised patients. Only two cases of nodular HSV-2 infection of the perianal region have been reported previously. GOAL: The case of a 46-year-old homosexual man with AIDS presenting with painful perianal nodules resembling squamous cell carcinoma is described. STUDY DESIGN: This case report presents details of the histologic findings and treatment regimen. RESULTS: Histologic examination showed the presence of rare multinucleated giant epithelial cells and a dense inflammatory infiltrate composed mostly of plasma cells. Polymerase chain reaction analysis was positive for HSV-2 and negative for HSV-1, cytomegalovirus, Epstein-Barr virus, and human herpesvirus types 6 and 7. After being treated ineffectively with oral acyclovir (4 g/d) for 15 days, the patient was treated with oral valacyclovir (6 g/d), resulting in marked improvement in 10 days and complete resolution after 2 months. CONCLUSIONS: In immunocompromised patients, HSV-2 infection may present with atypical clinical and histopathological features.

Localized cutaneous hyalohyphomycosis caused by a Fusarium species infection in a renal transplant patient.

Fusariosis is a hyalohyphomycosis due to Fusarium species that mainly occurs in immunocompromised hosts. The clinical spectrum of Fusarium infection comprises localized and disseminated forms. A case of localized cutaneous fusariosis caused by Fusarium solani in a renal transplant patient is described, and the skin manifestations of the disease are discussed.

Subacute cutaneous lupus erythematosus induced by nifedipine.

BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE) has been reported to be associated with the use of several drugs, including thiazides, terbinafine, and, rarely, calcium channel blockers. OBJECTIVE: A case of SCLE induced by nifedipine is presented. METHODS AND RESULTS: A 48-year-old white woman developed a papulosquamous and annular eruption in sun-exposed areas during the summer. The patient was taking nifedipine for essential hypertension for four years. Serology showed the presence of antinuclear and anti-Ro/SSA as well as antihistone antibodies. Histopathologic and immunopathologic (granular IgM deposits at the dermoepidermal junction) findings confirmed the diagnosis of SCLE. Nifedipine discontinuation led to rapid improvement with almost complete resolution of skin lesions in one month in the absence of active treatment. Reduction of antinuclear, anti-Ro/SSA, and antihistone antibody levels was documented after six months. CONCLUSION: Nifedipine can cause SCLE after a long period of administration. Antihistone antibodies may be associated with drug-induced SCLE.

Idiopathic CD4+ T lymphocytopenia associated with disseminated flat warts and alopecia areata.

Idiopathic CD4+ T lymphocytopenia is a very rare condition characterized by persistent depletion of circulating CD4+ T lymphocytes, without evidence of HIV or HTLV infection, or other identifiable causes of immunodeficiency. The syndrome can present with dermatological diseases, including viral, fungal and bacterial infections, as well as Kaposi's sarcoma, epithelial cell malignancies, lymphoma and inflammatory dermatoses. We report the case of a 47-year-old woman with idiopathic CD4+ T lymphocytopenia who presented with a 10-year history of disseminated and refractory flat warts from which human papillomavirus type 3 DNA was identified. The patient also had alopecia areata.