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Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade ≥3) are described with first-line TTC (17% for vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC.

Background: Methotrexate is currently used to treat atopic dermatitis but has never been assessed versus cyclosporine in adults., Objective: This study evaluated the efficacy and safety of methotrexate versus cyclosporine in patients with moderate-to-severe atopic dermatitis., Methods: Patients were randomized to receive either oral methotrexate (15 mg/wk) or cyclosporine (2.5 mg/kg/d) for 8 weeks. The primary end point was a patient achieving 50% improvement in the SCORing Atopic Dermatitis index (SCORAD 50) at week 8. When the primary end point was not achieved, methotrexate was increased to 25 mg and cyclosporine to 5 mg during the next 16 weeks. The secondary end points were a patient achieving a 50% reduction in the Eczema Area Severity Intensity index (EASI 50) and SCORAD 50 at each visit (ClinicalTrials.gov no. NCT00809172)., Results: A total of 97 patients received methotrexate 15 mg (n = 50) or cyclosporine 2.5 mg (n = 47). Regarding the primary end point at week 8, methotrexate was inferior to cyclosporine because the proportion of patients with SCORAD 50 was 8% (4 of 50) in the methotrexate arm versus 42% (18 of 43) in the cyclosporine arm. The difference in percentages for the 2 treatment groups (2-sided 90% CI) was -34% (-48% to -20%). At week 8, methotrexate and cyclosporine dosages were increased in 56% and 49% of the patients, respectively. Regarding EASI 50, the noninferiority end point was reached at week 20 in 92% (22 of 24) of patients in the methotrexate arm and 87% (26 of 30) of patients in the cyclosporine arm. The treatment-related adverse events were more frequent with cyclosporine (P < .0001)., Conclusions: Methotrexate 15 mg/wk was inferior to cyclosporine 2.5 mg/kg/d at week 8. Increasing the doses of methotrexate to 25 mg/wk induced a significant improvement versus cyclosporine at week 20., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Infliximab (IFX) is effective in inducing and maintaining remission in patients with luminal and anoperineal Crohn's disease (CD). However, treatment failure within 12 months after initiating IFX is observed in a significant proportion of patients. The aim of the present study was to determine whether the body mass index (BMI) affects response to IFX during the first year of treatment in patients with CD., Methods: All patients with luminal CD who began IFX between January 2010 and May 2014 were prospectively included. BMI was calculated before IFX treatment was begun, and patients were divided into 3 groups: normal BMI (BMI < 25 kg/m), overweight patients (BMI of 25.0-30 kg/m), and obese patients (BMI > 30.0 kg/m). The primary outcome was to evaluate the rate and delay of IFX optimization during the first year of treatment among normal weight, overweight, and obese patients., Results: One hundred forty patients were included. Demographic and clinical characteristics at IFX initiation were comparable among the 3 groups. Within 12 months after the initiation of IFX, the rate of IFX optimization was significantly higher in overweight and obese patients than in the normal BMI group: 52%, 56%, and 20%, respectively (P = 0.0002). The median time until optimization of IFX was significantly shorter in overweight and obese patients than in the normal BMI group: 7, 7, and 10 months, respectively (P = 0.03). A BMI >25 kg/m was significantly associated with IFX optimization within 12 months on multivariate analysis., Conclusion: This is the first study to show that optimization of IFX is more frequent and faster in obese and overweight patients with CD and occurs within 12 months after beginning IFX, suggesting that an induction regimen with higher doses of IFX and a tight control of IFX concentrations may be needed in these patients.

The CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3(-)CD4(+) T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome. Atypical CD4(+) T cells lymphoid infiltrates were found in 10 of 12 CD3(-)CD4(+) L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3(-)CD4(+) T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3(-)CD4(+) T cells were CD2(hi) (n=9 of 14), CD5(hi) (n=12 of 14), and CD7(-)(n=4 of 14) or CD7(low) (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3(-)CD4(+) T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative disorder, which should not be confused with angio-immunoblastic T-cell lymphoma., (Copyright© Ferrata Storti Foundation.)

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto-immunity. γδ T cells are recognized as IL-17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3(bright) γδ T-cell subset with an effector memory phenotype to rapidly produce IL-17A, but not interferon-γ. CD3(bright) γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1(+) T-cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor-related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL-23 and NOD-like receptor family, pyrin domain containing 3 (NLRP3)-inflammasome-dependent IL-1β. Finally, we demonstrated that IL-17-producing CD3(bright) γδ T cells responded promptly and strongly to pneumococcal infection and during skin inflammation. Here, we propose a new way to specifically analyze IL-17-producing Vγ6/Vδ1(+) T cells based on the level of CD3 signals. Using this gating strategy, our data reinforce the crucial role of this γδ T-cell subset in respiratory and skin disorders.

The CD3-CD4+ aberrant T-cell phenotype is the most described in the lymphoid variant of hypereosinophilic syndrome (L-HES), a rare form of HES. Only a few cases have been reported, and data for these patients are scarce. To describe characteristics and outcome of CD3-CD4+ L-HES patients, we conducted a national multicentric retrospective study in the French Eosinophil Network. All patients who met the recent criteria of hypereosinophilia (HE) or HES and who had a persistent CD3-CD4+ T-cell subset on blood T-cell phenotyping were included. Clinical and laboratory data were retrospectively collected by chart review. CD3-CD4+ L-HES was diagnosed in 21 patients (13 females, median age 42 years [range, 5-75 yr]). Half (48%) had a history of atopic manifestations. Clinical manifestations were dermatologic (81%), superficial adenopathy (62%), rheumatologic (29%), gastrointestinal (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). The median absolute CD3-CD4+ T-cell count was 0.35 G/L (range, 0.01-28.3), with a clonal TCRγδ rearrangement in 76% of patients. The mean follow-up duration after HES diagnosis was 6.9 ± 5.1 years. All patients treated with oral corticosteroids (CS) (n = 18) obtained remission, but 16 required CS-sparing treatments. One patient had a T-cell lymphoma 8 years after diagnosis, and 3 deaths occurred during follow-up.In conclusion, clinical manifestations related to CD3-CD4+ T cell-associated L-HES are not limited to skin, and can involve all tissue or organs affected in other types of HE. Contrary to FIP1L1-PDGFRA chronic eosinophilic leukemia patients, CS are always effective in these patients, but CS-sparing treatments are frequently needed. The occurrence of T-cell lymphoma, although rare in our cohort, remains a major concern during follow-up.

Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX3CL1 (fractalkine) and its unique receptor, CX3CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX3CR1-deficient mice and upon blocking CX3CL1-CX3CR1 interactions in wild-type mice. CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4(+) T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4(+) T cell retention in inflamed skin, indicating a new function for this chemokine receptor. Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases., (© 2014 Staumont-Sallé et al.)

In 2013, news from research has clearly shown that dermatology is bound to occupy a more important place in fundamental research. Among these evidences are an increasing number of papers devoted to "Skin" in journals with the highest impact factors and the excellence of the scientific program of the International Investigative Dermatology Meeting held in May in Edinburgh. This paper outlines a selection of scientific works published between September 2012 and August 2013 or presented as communications at the IID Meeting. This selection was made based on the quality of methods used by the authors to obtain results, and on the impact of these scientific results in terms of pathophysiological and therapeutical advances., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Eosinophils are key players in T(H)2-driven pathologies, such as allergic lung inflammation. After IL-5- and eotaxin-mediated tissue recruitment, they release several cytotoxic and inflammatory mediators. However, their exact contribution to asthma remains controversial. Indeed, in human subjects anti-IL-5 treatment inhibits eosinophilia but not antigen-induced airway hyperresponsiveness (AHR). Likewise, lung fibrosis is abrogated in 2 strains of eosinophil-deficient mice, whereas AHR is inhibited in only one of them. Finally, eosinophils have been shown to attract T(H)2 lymphocytes at the inflammatory site., Objective: The ability of eosinophils to promote AHR and lung inflammation independently of lymphocytes was investigated., Methods: Adoptive transfers of resting or activated eosinophils from IL-5 transgenic mice were performed into naive BALB/c mice, mice with severe combined immunodeficiency, and IFN-gamma-deficient BALB/c recipients., Results: Adoptively transferred eosinophils induced lung inflammation, fibrosis, collagen deposition, and AHR not only in BALB/c mice but also in recipient mice with severe combined immunodeficiency. Surprisingly, IFN-gamma expression was increased in lungs from eosinophil-transferred animals. Furthermore, IFN-gamma neutralization in recipients partially inhibited eosinophil-induced AHR. Moreover, IFN-gamma-deficient eosinophils or eosinophils treated with a blocking anti-IFN-gamma receptor antibody failed to induce AHR in IFN-gamma-deficient recipients. Finally, in vitro and at low concentrations, IFN-gamma increased eosinophil peroxidase release, potentiated chemotaxis, and prolonged survival, suggesting the existence of an autocrine mechanism., Conclusions: These results support the important and previously unsuspected contribution of eosinophils to lung inflammation independently of lymphocytes through production of IFN-gamma, the prototypical T(H)1 cytokine.

The high-affinity IgE receptor Fc(epsilon)RI and, in some models, the low-affinity IgG receptor Fc(epsilon)RIIII/CD16 play an essential role in allergic diseases. In human skin, they are present on APCs and effector cells recruited into the inflamed dermis. FcRgamma is a subunit shared, among other FcRs, by Fc(epsilon)RI and CD16 and is essential to their assembly and signal transduction. Using an experimental model reproducing some features of human atopic dermatitis and specific FcR-deficient mice, we have herein delineated the respective contribution of Fc(epsilon)RIand Fc(epsilon)RIII/CD16 to the pathology. We demonstrate that symptoms of atopic dermatitis are completely absent in FcRgamma-deficient animals but only partially inhibited in either Fc(epsilon)RI- or FcgammaRIII/CD16-deficient animals. Absence or attenuation of the pathology is correlated to increased skin expression of regulatory IL-10 and Foxp3. While Fc(epsilon)RI controls both Th1 and Th2 skin response, mast cell recruitment into draining lymph nodes and IgE production, CD16 regulates only Th2 skin response, as well as T cell proliferation and IgG1 production. This isotype-specific regulation by the cognate FcR is associated to a differential regulation of IL-4 and IL-21 expression in the draining lymph nodes. Fc(epsilon)RIand CD16 thus contribute to atopic dermatitis but differentially regulate immune responses associated with the disease. Targeting both IgE/Fc(epsilon)RI and IgG/CD16 interactions might represent an efficient therapeutic strategy for allergic diseases.

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.

Background: TNFalpha blockers have recently extended the therapeutic arsenal available in dermatology. However, dermatologists must be informed of their potential adverse dermatological effects. While the chief adverse effect of TNFalpha blockers is risk of infection, cutaneous adverse effects have not yet been clearly elucidated and publications on this topic are few and far between. The aim of our study is to report various dermatological problems noted during treatment with TNFalpha blockers., Patients and Methods: This was a retrospective study of patient files. The study population comprised patients receiving TNFalpha blockers and presenting cutaneous reaction, and seen in the dermatology department between August 2001 and December 2004., Results: Eleven patients were included. The following cutaneous reactions were seen: delayed skin rash (1 case), lupus syndrome (1 case), cutaneous vasculitis (2 cases), palmoplantar pustulosis (2 cases), psoriasis vulgaris (1 case), atopic dermatitis (1 case), lichenoid rash (1 case), purpuric capillaritis (1 case) and melanoma (1 case)., Discussion: The cutaneous manifestations seen represented a wide range of different clinical pictures. Dermatologists must be aware of these potential adverse effects. Future improvement of knowledge of the physiopathological mechanisms as well as the institution of prospective cohort studies should provide clearer guidance on the management of such symptoms.

Objective: To evaluate the efficacy and the tolerance of sulfasalazine in the treatment of chronic lupus erythematosus (CLE)., Patients and Methods: We prescribed sulfasalazine (2 g/d) for 18 patients with severe CLE, all of whom had contraindications for or treatment failure with antimalarial drugs and thalidomide. This study analyses their response to treatment, duration of therapy, reasons for stopping, adverse effects, and the influence of the N-acetyltransferase 2 (NAT2) phenotype., Results: We observed 10 complete and 3 partial responses, and 4 patients maintained complete response for at least 7 years. Eight patients experienced adverse effects, and 2 needed to stop treatment (because of photosensitization and development of antinuclear antibodies). All side effects occurred in the first 3 months of treatment. None of the 18 patients developed systemic lupus erythematosus. Of the 10 complete responders, 9 were rapid acetylators (RA), while 4 of the 5 who failed to respond were slow acetylators (SA). Leukopenia and photosensitization were observed in SA patients, while different side effects occurred in RA patients (headaches, diarrhea, moderate increase in liver enzymes and antinuclear antibodies)., Conclusion: These findings confirm our earlier reports and demonstrate that sulfasalazine can be used successfully to treat severe CLE. NAT2 genotyping before initiating treatment helps to identify potential responders and avoid side effects. In RA patients, sulfasalazine can be an alternative to thalidomide after antimalarial drugs, whereas in SA patients, it should remain a third-line treatment, to be used only after antimalarials and thalidomide.

Previously believed to have an exclusive role in the release of cytotoxic mediators in the defense against helminthic infections, eosinophils are now considered key players in inflammatory reaction and regulation of immune response. Through activation of a large variety of membrane receptors and production of various pharmacologically active mediators, eosinophils may exert a detrimental role in tissues in which they have been recruited and may contribute to the perennization of inflammatory processes. The crucial role of eosinophils has been documented in several eosinophilic skin diseases, such as hypereosinophilic syndrome and bullous pemphigoid, and the literature provides strong evidence for their role in urticaria. The aim of this article is to discuss the mechanisms of specific tissue recruitment of eosinophils, the factors of eosinophil activation, and the contribution of these cells to inflammation and immunoregulation in urticaria. Recent advances in the knowledge of eosinophils will certainly help toward developing new strategies for the management of antihistamines resistant to urticaria.

Purpose: Urticaria is a muco-cutaneous illness which is characterized by a dermal or hypodermal oedema due to a vasodilatation attributed to the release of histamine by mast cells and basophils. Urticaria is a very common complaint, since among 20% of the population will experience at least one episode of urticaria during their life. Chronic urticaria by definition is daily and has persisted for at least six weeks. By contrast with acute urticaria, its etiological and therapeutic approaches can present a significant challenge, leadind to repeated examinations., Current Knowledge and Key Points: Questioning and clinical examination are essential for the etiological diagnosis of chronic urticaria, because they are able to lead rapidly to the suspicion of several causes which can be eradicated to treat the symptoms. If no cause is found, further investigations may be required. Recent studies have shown the lack of profitability of exhaustive laboratory investigations. Thus, many authors at present time advise minimal and non expensive investigations which are determinated by anamnestic data. But most often, the etiology of urticaria remains unknown and this situation leads to the diagnosis of chronic idiopathic urticaria. The treatment of chronic urticaria is above all based on the elimination of the symptoms, either on a specific fashion if the etiological diagnosis is already known, or in a non specific way. The anti-H1 agents are the medications of choice for first line treatment., Future Prospects and Projects: Pathophysiology of chronic urticaria is to date well established. As the mechanisms responsible for chronic urticaria are better defined, more therapeutic agents, which are effective on other targets than histamine, should become available. Moreover, recent advances have supported the notion that an underlying autoimmune process could account for many cases of chronic "idiopathic" urticaria. In such severe and refractory urticaria, immunomodulation therapy may bring about clinical improvement.