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OBJECTIVE: To investigate the nature of polyarthritis in patients with moderate to severe psoriasis undergoing treatment with efalizumab, a humanized anti-CD11a monoclonal antibody. METHODS: In a multicenter study, we retrospectively analyzed patients who developed arthritis during treatment with efalizumab. The relationship between joint manifestations and psoriatic disease was addressed by using different classification criteria for psoriatic arthritis (PsA). The course of arthritis and its response to treatment were also investigated. RESULTS: Sixteen patients developed de novo inflammatory rheumatic disease, with a mean delay of 15 weeks following the start of treatment, and with exclusive asymmetric peripheral monarthritis or oligoarthritis (8 patients), inflammatory spinal disease (1 patient), or both (7 patients), associated in some cases with enthesitis and dactylitis. All patients fulfilled at least 2 different sets of classification criteria for PsA. In most of them, an improvement in skin lesions was observed at the onset of PsA, as measured using the Psoriasis Area and Severity Index (mean score 24.88 before efalizumab versus 18.78 at the time of arthritis). Efalizumab treatment was stopped in 11 patients and was followed by the elimination of rheumatologic symptoms in 1 patient, while 8 patients required treatment with nonsteroidal antiinflammatory drugs with or without methotrexate, with 2 later being switched to tumor necrosis factor alpha inhibitors. Reintroduction of efalizumab (2 patients) was followed by a relapse of PsA. CONCLUSION: This study questions the role of efalizumab in the induction of PsA. It also emphasizes the discrepancy between the courses of psoriatic skin and joint manifestations under treatment. Prospective case-control studies are needed to accurately investigate the impact of efalizumab on PsA. [ABSTRACT FROM AUTHOR]

During the last few years, considerable progress has been made in the understanding of the structure and function of various components of the dermo-epidermal junction. Bullous pemphigoid is a disease of the elderly characterized by the production of autoantibodies mainly directed against a 220–240 kDa polypeptide, the major BP antigen located in the hemidesmosome. Labib et al demonstrated that a 180 kDa protein was also recognized by a number of pemphigoid sera. The 180 kD BPA is a transmembrane molecule with a predicted type II orientation. The C-terminal domain is extracellular and consists of a series of collagen triple helical domains. Recent studies have located one of the major epitopes in a non collagenous stretch of the extracellular domain of the 180 kD BPA very close to the keratinocyte membrane. Recent evidence largely from DNA sequency suggest that multiple epitopes are present on the 180 kD BPA. Using rabbit antisera raised against different domains, we have demonstrated that the C-terminal domain was localized in the lower part of the lamina lucida. Double labelling performed with C-terminal antibodies and anti-kalinin antibodies have shown a common localization in the interface of the lamina lucida and lamina densa where it is believed to be associated with anchoring filaments. Our ultrastructural mapping confirm that the 180 kD BPA has a very long extracellular domain extending on the entire lamina lucida from the hemisdesmosome to the lamina densa. Recent report of non-lethal junctional epidermolysis bullosa have demonstrated that absence of expression of the 180 kD BPA may have a critical pathogenetic significance in adhesion between epidermis and the dermis. The 180 kD BPA which is mainly in its extracellular portion a collagenous molecule is probably a major component of the anchoring filaments network and certainly plays an important role in the adhesion process between basal keratinocytes and the dermis. The 97 and 120 kDa antigens recognized by IgA autoantibodies in linear IgA disease correspond to the soluble extracellular domain of BP 180. The development of Elisa systems using recombinant or synthetic proteins will be a very sensitive tool for the detection of antibodies and new antigenic sites allowing a better classification and understanding of the pathogenesis of subepidermal bullous disorders in the future. [ABSTRACT FROM AUTHOR]

Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%; partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS < 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.

Bullous Pemphigoid is the most common auto-immune bullous skin disease. It is characterized by the production of auto-antibodies directed against 2 proteins of the hemi-desmosome (BP180 and BP230). We assessed the efficacy and mechanisms of action of rituximab, an anti-CD20 monoclonal antibody, in 17 patients with severe and relapsing type of bullous pemphigoid. The phenotype, cytokine gene expression, and rearrangement of BP180-specific B-cell receptor genes were performed over 2 years following treatment. At the end of the study, 5 patients had died, 3 had withdrawn from the study, and 9 patients were in complete remission. The one- and two-year relapse rates were 44.1% (95% Confidence Interval (CI): 21.0-76.0%) and 66.5%, (95% CI: 38.4-91.4%), respectively. Phenotypic analyses confirmed dramatic B-cell depletion, which lasted for 9 to 12 months. The ELISA values of serum anti-BP180 antibodies and the frequency of BP180-specific circulating B cells decreased dramatically following treatment, which paralleled the improvement of skin lesions. During B-cell reconstitution, a polyclonal IgM repertoire appeared and a shift in the rearrangement of the B-cell receptor genes of BP180-specific circulating B cells was observed. Concurrently, we observed a decrease of IL-15, IL-6 and TNFα expressing BP180-specific B cells, and the emergence of IL-10 and IL-1RA-expressing BP180-specific IgM+ B cells in patients in complete remission off therapy, suggesting the functional plasticity of BP180-specific auto-immune B cells after rituximab treatment.

The Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity-Score (ABSIS) scores have been proposed to provide an objective measure of pemphigus activity. These scores have been evaluated only on already treated patients mainly with mild to moderate activity. The objective was to assess the interrater reliability of ABSIS and PDAI scores and their correlation with other severity markers in a large international study. Consecutive patients with newly diagnosed pemphigus were enrolled in 31 centers. Severity scores were recorded during a 24-month period by the same two blinded investigators. Serum was collected at each visit for ELISA measurement of anti-desmoglein antibodies. The intraclass correlation coefficient (ICC) and Spearman rank correlation coefficient were calculated. A total of 116 patients with pemphigus vulgaris (n = 84) or pemphigus foliaceus (n = 32) were included. At baseline, the ABSIS and PDAI ICCs were 0.90 (95% confidence interval [CI] = 0.85-0.93), and 0.91(95% CI = 0.87-0.94), respectively. The ICCs for PDAI were higher in moderate and extensive pemphigus (ICC = 0.82, 95% CI = 0.63-0.92 and ICC = 0.80, 95% CI = 0.62-0.90, respectively) than in patients with intermediate (significant) extent (ICC = 0.50, 95% CI = 0.27-0.68). Conversely, the ICCs for ABSIS were lower in patients with moderate extent (ICC = 0.44, 95% CI = 0.004-0.74) than in those with intermediate or extensive forms, (ICC = 0.69, 95% CI = 0.51-0.81 and ICC = 0.75, 95% CI = 0.51-0.88, respectively). During patients' follow-up, the ICCs of both ABSIS and PDAI scores remained higher than 0.70. ABSIS and PDAI skin (r = 0.71 and r = 0.75) but not mucosal (r = 0.32 and r = 0.37) subscores were correlated with the evolution of anti-DSG1 and anti-DSG3 ELISA values, respectively. ABSIS and PDAI scores are robust tools to accurately assess pemphigus activity., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC ( n = 4) or IV ( n = 6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 10 9 to 22.9 × 10 9 . Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation.

Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Bullous pemphigoid (BP) is an inflammatory autoimmune bullous disease involving cytokines and proteases in the process of blister formation. Recently, IL-17 and IL-23 were evidenced in lesional skin and serum of BP patients at time of diagnosis, but their involvement in disease outcome has still not been investigated yet. We then analysed IL-17 and IL-23 serum levels during the first months of follow-up upon treatment. Compared with age- and sex- matched controls, high levels of IL-23 were observed at baseline in BP patients serum (P < 0.01), while IL-17 levels was not. However, some BP patients expressed high IL-17 serum level, independently of disease severity. In these patients, those with ongoing remission reduced IL-17 concentration upon treatment (P < 0.001), whereas IL-17 level remained elevated in patients who relapsed. Meanwhile, IL-23 serum levels increased during the first month of treatment in BP patients who later relapsed (P < 0.01) and MMP-9 serum level was not controlled. Accordingly, we found that both IL-17 and IL-23 increased MMP-9 secretion from leukocytes in-vitro. Then, we showed that elevated IL-17/IL-23 serum concentrations helped to discriminate BP patients who later relapsed. Such uncontrolled inflammatory response raises the question whether these molecules could become biological target for BP patients resistant to steroid treatment.

Objective: To determine the type and frequency of musculoskeletal symptoms at onset and during followup of cryopyrin-associated periodic syndromes (CAPS)., Methods: We retrospectively recorded the articular and muscular symptoms of patients with CAPS followed up in French hospitals. Data were presented as frequencies or the median (range), and patient groups were compared using chi-square test, Fisher's exact test, and Mann-Whitney test., Results: The study included 133 patients (33 children), 20 with familial cold autoinflammatory syndrome, 88 with Muckle-Wells syndrome, 22 with chronic infantile neurologic, cutaneous, articular syndrome, and 3 with unclassified CAPS. The median age was 35 years (range 0-78 years) at the time of the study, 1 year (range 0-41 years) at symptom onset, and 23 years (range 0-58 years) at diagnosis. The disease was sporadic in 17% of the patients. Cutaneous symptoms predominated at onset (77%), followed by articular symptoms (30%). The p.Thr348Met and p.Arg260Trp NLRP3 mutations were significantly associated with the presence and absence of articular symptoms at onset, respectively. During followup, 86% of the patients had musculoskeletal symptoms, 88% had arthralgia, and 58% had arthritis, but only 9% had joint destruction. Tendinopathies occurred in 21.5% of the patients, tender points in 16.5%, and myalgia in 33%. Only 3 patients had typical knee deformities. Radiographs were rarely obtained. Except for bone deformities, osteoarticular symptoms occurred at similar frequencies in the different CAPS phenotypes., Conclusion: Joint manifestations were frequent in all CAPS phenotypes. Bone deformities were rare. Musculoskeletal manifestations varied within given families but tended to worsen over time., (© 2015, American College of Rheumatology.)

The prognostic value of the sentinel lymph node in Merkel cell carcinoma (MCC) has been examined previously in heterogeneous retrospective studies. The current retrospective study included a homogeneous population of patients with a localized MCC, all staged with sentinel lymph node biopsy. Factors associated with 3-year progression-free survival were analysed using logistic regression. The sentinel lymph node was positive in 32% of patients. The recurrence rate was 26.9%. In first analyses (n = 108), gender (p = 0.0115) and the presence of immunosuppression (p = 0.0494) were the only significant independent factors. In further analyses (n = 80), excluding patients treated with regional radiotherapy, sentinel lymph node status was the only significant prognostic factor (p = 0.0281). Immunosuppression and positive sentinel lymph node are associated with a worse prognosis in patients with MCC. Nodal irradiation impacts on the prognostic value of the sentinel lymph node status.

A rise in the incidence of bullous pemphigoid (BP) was documented recently in Europe, and the main risk factors for BP remain unknown. We conducted a multicenter case-control study to evaluate risk factors for BP. We identified 201 incident BP cases and 345 controls individually matched for age, gender, center, and place of residence (home, nursing home, or extended-care facility). We used univariate and multivariate logistic regression analyses to compare drugs used for over 3 months, comorbidities, and physical and cognitive impairments between cases and controls. Mean age of BP patients was 84.2 (±8.7) years. Factors independently associated with BP by multivariate analysis were major cognitive impairment (odds ratio (OR), 2.19; 95% confidence interval (95% CI), 1.24-3.87), bedridden condition (OR, 2.19; 95% CI, 1.23-3.89), Parkinson's disease (OR, 2.16; 95% CI, 1.09-4.27), unipolar or bipolar disorder (OR, 5.25; 95% CI, 1.21-22.86), and chronic use of spironolactone (OR, 2.30; 95% CI, 1.20-4.46) or phenothiazines with aliphatic side chains (OR, 3.70; 95% CI, 1.21-11.34). Chronic analgesic use was associated with a lower risk of BP (OR, 0.49; 95% CI, 0.30-0.81). Thus, risk factors for BP include neurological disorders, particularly dementia and Parkinson's disease, psychiatric disorders (unipolar and bipolar disorders), bedridden condition, and chronic use of several drugs.

Unlabelled: The large number of studies devoted to the effect of ultraviolet light on biological systems, contrasts with the lack of experimental data concerning the direct effects of visible light. It has been shown that blue light inhibited the growth of B16F10 melanoma cell lines and reduced the percentage of S phase cells. Yet these effects are poorly understood., Materials and Methods: Two cell lines and irradiation with blue light were used. Cell mortality and a possible mechanism of action were investigated., Results: Exposure of B16F10 melanoma and bovine endothelial cells to blue light (wavelength 450 nm, 10 J/cm(2) from a Waldman lamp) induced a rapid and large reduction in viability followed by the death of virtually all the irradiated cells within 24 h. These results led us to expose a patient with haemorrhagic cutaneous melanoma metastasis to blue light. Irradiation led to an immediate arrest of haemorrhage, an inhibition of tumour growth and extensive tumour necrosis 24h after irradiation., Conclusion: Exposure to blue light may offer new approaches to the treatment of superficial skin carcinomas in humans.

Superpotent topical corticosteroids (CS) have been demonstrated to improve bullous pemphigoid (BP) patients' survival. We assessed whether a mild regimen using lower doses of topical CS and a shorter duration could improve the outcome of BP patients even more. Three-hundred and twelve BP patients were included in a multicenter randomized controlled trial and stratified depending on the extent of BP as moderate (n=134) or extensive (n=178). Patients were randomly assigned to the standard regimen (clobetasol propionate cream, 40 g per day initially, with CS tapering over 12 months) or the mild regimen (10-30 g per day), with CS tapering over 4 months. A noninferior rate of BP control was obtained with the mild regimen 156/159 (98%) as compared with the standard regimen 150/150 (100%; P=0.005). Event-free survival, that is, the combined outcome of deaths and life-threatening adverse events did not differ between the two treatment groups (P=0.77). However, upon adjusting through the Cox model for age and Karnofsky score, a strong beneficial effect of the mild regimen was observed in patients with moderate BP, with an almost twofold decrease in the risk of death or life-threatening adverse events relative to the standard regimen (hazard ratio=0.54; 95% confidence interval, 0.30-0.97; P=0.039). This mild regimen allows a 70% reduction of the cumulative doses of CS and improves BP patients' outcome.

Pemphigus are B-cell-mediated autoimmune diseases affecting skin and mucous membranes. They are characterized by the production of pathogenic autoantibodies directed against desmogleins (Dsg). In this prospective study, we treated 21 pemphigus patients with rituximab and analyzed immunological modifications induced by anti-CD20 immunotherapy. The total depletion of peripheral B cells led to a significant decrease of total serum IgM but not IgG levels. The B-cell depletion was followed by a progressive re-emergence of naive blood B lymphocytes, with one-third of them expressing a transitional CD19+CD38(high)CD24(high) phenotype. In most patients, clinical response to rituximab was closely related to the evolution of anti-Dsg autoantibodies that decreased in patients who achieved complete remission, whereas they remained unchanged or reincreased in relapsing patients. In contrast, serum antimicrobial IgG remained stable after rituximab treatment. B-cell repertoire analysis of three patients using immunoscope showed distortions of VH-IgM and VH-IgG immunoscope profiles before treatment, particularly clonal and oligoclonal expansions in some VH families, which were not found after B-cell reconstitution, following anti-CD20 immunotherapy. The depletion of autoreactive B cells leading to the elimination of anti-Dsg autoantibodies in most remitted patients and the restoration of a diverse B-cell repertoire by naive B lymphocytes may provide an explanation for the long-lasting efficacy of rituximab in pemphigus patients.

Eczema craquele, or asteatotic eczema, has been associated with malignant lymphoma although this is rare. Since 1986, we have observed seven patients, six men and one woman, mean age 71.5 years (range 43-86 years), with systemic lymphoma and concurrent eczema craquele. Five patients had T-cell lymphoma, one had a B-cell lymphoma and one had Hodgkin's disease. All patients shared several characteristics: (1) a synchronous onset of eczema craquele and lymphoma, (2) generalized eczema, (3) absence of alternative disease or conditions that could favour the onset of eczema craquele, and (4) eczema refractory to topical corticosteroids and emollients, but which resolved upon lymphoma remission and invariably recurred with the lymphoma relapse. All the patients except one died within 1 year, most with active lymphoma. The finding of recalcitrant generalized eczema craquele should prompt a search for lymphoma, particularly in older men. Lymphoma-associated eczema craquele has most characteristics of paraneoplastic syndromes and may be a hallmark of aggressive lymphoma.

Cicatricial pemphigoid (CP) is an autoimmune blistering disease that primarily affects mucosal tissues. Autoantibodies to laminin-5 have previously been detected in certain patients with a CP-like disease; however, individuals that exhibit this reactivity profile apparently represent a small subset of CP patients. In the present investigation, 0 of 18 CP sera showed reactivity with laminin-5 by immunoblotting. In contrast, 18 of 23 CP sera (78%) recognized a 180-kDa epidermal antigen that, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, co-migrated with BP180, a hemidesmosomal glycoprotein associated with two other autoimmune blistering diseases, bullous pemphigoid and herpes gestationis. To investigate further the CP autoimmune response, various segments of human BP180 were expressed as bacterial fusion proteins and assayed by immunoblotting for reactivity with CP patients' sera. The results of this investigation demonstrated that the BP180 autoantigen is indeed a major target of CP autoantibodies. Further, two distinct CP-reactive sites were identified on the extracellular domain of the BP180 protein, one located in the non-collagenous (NC) 16A domain (at or near the previously defined autoantibody-reactive site recognized by bullous pemphigoid and herpes gestationis sera) and the other in the carboxy-terminal region of this protein. Sixteen of 23 CP sera (70%) reacted with one or both of these antigenic sites of BP180. Other immunologic data suggested that BP180 may harbor additional CP-reactive sites. In conclusion, there are now three bullous diseases, bullous pemphigoid, herpes gestationis, and cicatricial pemphigoid, that are known to be associated with an autoimmune response against the extracellular domain of the BP180 antigen.

We studied 11 consecutive patients with classical cicatricial pemphigoid (CP) using direct immunoelectron microscopy (IEM) and Western immunoblotting analysis. Direct IEM performed in the skin or gingival mucosa revealed in all 11 CP patients that immunoglobulins and complement deposits were usually thick and discontinuous along the dermoepidermal junction, mostly localized on the lamina densa and occasionally in the lamina lucida. By direct IEM, the ultrastructural aspect in CP differs from the pattern observed in bullous pemphigoid (BP) and from that of chronic epidermolysis bullosa acquisita (EBA). Nine CP patients were studied by Western immunoblotting and, of these nine, only two had detectable anti-basement membrane zone (BMZ) antibodies by indirect immunofluorescence on salt-split skin. By immunoblotting performed on protein extracts of heat-separated epidermis, eight out of the nine CP sera specifically reacted with two protein bands of approximately 230-240 kD and 180 kD, similar to those recognized by BP sera in co-migration experiments. By immunoblotting on skin BMZ extracts, none of these nine CP sera recognized the 290-kD major polypeptide of EBA antigen. Taken together, these results suggest that, in CP, the target-antigen, as identified on immunoblots, is similar to BP antigen, but with an abnormal expression within the dermoepidermal junction of patients, which may in part explain the scarring course of the disease.