Human papilloma virus-16-specific CD8+ T-cell expansions characterize different clinical forms of lichen planus and not lichen sclerosus et atrophicus.

Lichen planus (LP) is a cutaneomucosal chronic inflammatory disease characterized by a CD8+ cytotoxic T-lymphocytes (CTL) infiltrate. In erosive oral LP, we found HPV16-specific activated CTL in lesions, supporting a pathogenic contribution of HPV16. Here, we investigated whether a similar scenario occurs in other clinical forms of LP and in lichen sclerosus et atrophicus (LSA), another chronic disease also affecting the mucosa and/or the skin. Blood CTL from LP and LSA patients expressed significant higher levels of granzyme B, perforin and CD107a proteins than healthy donors. Expansions of TCRVß3+ CTL, with presence of TCR clonotypes identical to those previously detected in erosive oral LP, were found both in blood and mucosal/skin lesions of LP, and not of LSA patients. These expansions were enriched with HPV16-specific CD8+ T-cells as shown by their recognition of the E711-20 immunodominant epitope. In LSA patients, the peripheral repertoire of CTL was oligoclonal for TCRVß6+ CTL. Finally, although patients with LP and LSA have developed antibodies against HPV16 capsid L1, antibodies against HPV16 E6 were only observed in patients with LP. Overall, our data collectively suggest an involvement of HPV16-specific CTL in different clinical forms of LP, not only in erosive oral LP, while a different scenario operates in LSA.

Treatment of dissecting cellulitis of the scalp with tumour necrosis factor inhibitors: a retrospective multicentre study.

Although retinoids are considered as the most effective treatment, management of dissecting cellulitis of the scalp (DCS) is often challenging. A multicentre retrospective study was conducted to evaluate the efficacy of anti-tumour necrosis factor (TNF) agents in treating DCS after failure of other conventional treatments. Twenty-six patients were included. After a mean treatment duration of 19 months (SD 21), the median Physician's Global Assessment score decreased from 3 to 1. The median number of inflammatory nodules and abscesses decreased from 7 to 0.5 and from 1 to 0, respectively. The median Dermatology Life Quality Index and numerical rating scale score for pain severity decreased from 10 to 8 and 6 to 1, respectively. The median treatment satisfaction was 7 out of 10 on the Patient Satisfaction Index. This study confirms the efficacy of anti-TNF agents in treating patients with DCS that is resistant to conventional therapies.

Efficacy and safety of combination targeted therapies in immune-mediated inflammatory disease: the COMBIO study.

BACKGROUND: Use of a combination of targeted therapies (COMBIO) in patients with refractory/overlapping immune-mediated inflammatory diseases (IMIDs) has increased, but reported data remain scarce. We aimed to assess effectiveness and safety of COMBIO in patients with IMIDs. METHODS: We conducted a French ambispective multicenter cohort study from September 2020 to May 2021, including adults' patients with 1 or 2 IMIDs and treated at least 3-month with COMBIO. RESULTS: Overall, 143 patients were included. The most common IMIDs were Crohn's disease (63.6%), axial spondyloarthritis (37.7%), and ulcerative colitis (14%). Half of patients had only one IMID, of which 60% were Crohn's disease. Mean duration of COMBIO was 274.5±59.3 weeks, and COMBIO persistence at 104 weeks was estimated at 64.1%. The most frequent COMBIOs combined anti-TNF agents with vedolizumab (30%) or ustekinumab (28.7%). Overall, 50% of patients achieved significant and 27% mild-to-moderate improvement in patient-reported outcomes. Extended duration of COMBIO (aOR=1.09; 95% CI: 1.03-1.14; p=0.002) and diagnoses of two IMIDs (aOR=3.46; 95%CI: 1.29-9.26; p=0.013) were associated with significant improvement in patient-reported outcomes. Incidence of serious infection during COMBIO was 4.51 per 100 person-years (95% CI 2.20-8.27) and 5 COMBIOs were discontinued due to adverse events. CONCLUSIONS: COMBIO can be effective and safe in patients with refractory/overlapping IMIDs.

A new de novo heterozygous missense mutation in the desmoplakin gene, causing Naxos and Carvajal disease, associating oligodontia and nail fragility.

A new de novo heterozygous mutation in the desmoplakin gene, causing Naxos and Carvajal disease, has been reported in a 13-year-old Caucasian girl, with expanded clinical phenotype. In addition to woolly hair, palmoplantar keratoderma and cardiomyopathy, she had oligodontia and nail fragility. These additional clinical features may help in the diagnosis of Naxos and Carvajal disease, known to be severe on the cardiac level.

Impact of Childhood Onset Psoriasis on Addictive Behaviours, Socioeconomic and Educational Data in Adulthood.

Paediatric psoriasis has been associated with school absenteeism, limitation of physical activities, psychiatric disorders and, in the longer term, with sexual dysfunction and addictions. This raises the hypothesis that childhood onset psoriasis may affect patients' educational development, and further social and professional outcomes. This study evaluated the relationship between childhood onset psoriasis and patients' educational and socioeconomic characteristics, and the development of addictions in adulthood. This cross-sectional ancillary study captured patients' characteristics at baseline in the French PSOBIOTEQ registry. Data in adulthood included: educational (baccalaureate) and socioeconomic (working activity) groups, smoking status (self-reporting of being a current smoker vs past smoker or non-smoker), alcohol consumption (defined as at least 1 glass of alcoholic beverage per day), and living conditions (alone/family/social institutions; child at home). A total of 1,960 patients were included, of whom 26.2% had childhood onset psoriasis. In multivariate analyses, childhood onset psoriasis was associated with smoker status (p = 0.02). No association was observed with educational level, working activity, living conditions, or alcohol consumption. This study provides reassuring data overall with regard to the impact of childhood onset psoriasis on major social outcomes. Evidence for some association with addictive behaviours paves the way for larger prospective studies assessing in depth the social and educational impact of this disease.

Rituximab and Corticosteroid Effect on Desmoglein-Specific B Cells and Desmoglein-Specific T Follicular Helper Cells in Pemphigus.

Pemphigus is an autoimmune blistering disease mediated by autoantibodies directed against desmogleins (DSGs). We recently showed that first-line treatment with rituximab (RTX) enables more patients to achieve long-lasting remission off therapy than corticosteroids alone. To understand the immunological mechanisms that mediate long-lasting clinical remission after RTX treatment, we analyzed the phenotype of DSG-specific memory B cells and DSG-specific T follicular helper cells by flow cytometry and measured antibody-secreting cells by enzyme-linked immune absorbent spot in patients treated with corticosteroids alone or RTX. This post hoc analysis of the RITUX3 trial showed that RTX induced a significant decrease of IgG-switched DSG-specific memory B cells. Accordingly, anti-DSG antibody-secreting cells were no longer detected in patients in complete remission after RTX. In contrast, corticosteroids did not modify the frequency or the phenotype of DSG-specific memory B cells, and anti-DSG antibody-secreting cells were still detected after treatment, even in patients in remission. Using peptide-HLADRB1∗0402 tetramer staining, we identified DSG-3-specific T follicular helper cells, which dramatically decreased after RTX, while remaining stable after corticosteroid treatment. Our findings suggest that long-lasting response to RTX in pemphigus relies on the decrease of DSG-specific circulating T follicular helper cells, which correlates with a sustained depletion of IgG-switched memory autoreactive B cells, leading to the disappearance of anti-DSG antibody-secreting cells.

New insights into hidradenitis suppurativa diagnosis via salivary infrared biosignatures: A pilot study.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease which can lead to a prolonged physical disability. HS diagnosis is exclusively clinical with the absence of biomarkers. Our study aims at assessing the HS-diagnostic potential of infrared spectroscopy from saliva, as a biofluid reflecting the body's pathophysiological state. Infrared spectra from 127 patients (57 HS and 70 non-HS) were processed by multivariate methods: principal component analysis coupled with Kruskal-Wallis or Mann-Whitney tests to identify discriminant spectral wavenumbers and linear discriminant analysis to evaluate the performances of HS-diagnostic approach. Infrared features, mainly in the 1300 cm-1 -1600 cm-1 region, were identified as discriminant for HS and prediction models revealed diagnostic performances of about 80%. Tobacco and obesity, two main HS risk factors, do not seem to alter the infrared diagnosis. This pilot study shows the potential of salivary "liquid biopsy" associated to vibrational spectroscopy to develop a personalized medical approach for HS patients' management.

Severe Attack of Henoch-Schönlein Purpura With Neurological Involvement During Adalimumab Treatment for Crohn's Disease.

Tumour necrosis factor-α [TNF-α] inhibitors have revolutionised the management of chronic inflammatory conditions. A number of cutaneous adverse events have been reported with TNF inhibition, including vasculitis. Most reactions are mild and rarely warrant treatment withdrawal. Here we describe a patient with Crohn's disease treated with adalimumab in whom severe multivisceral Henoch-Schönlein purpura developed, including neurological involvement, requiring definitive TNF blocker withdrawal.

Characteristic Pattern of IL-17RA, IL-17RB, and IL-17RC in Monocytes/Macrophages and Mast Cells From Patients With Bullous Pemphigoid.

Inflammation is largely implicated in bullous pemphigoid (BP), the most frequent skin auto-immune blistering disease. IL-17, essentially IL-17A/F, has been involved in blister formation through regulation of protease production, and its specific serum profile within BP was related to disease outcome. However, relationships between IL-17 family ligands and receptors are quite complex with six different IL-17 isoforms, and five different receptors. We here aimed at clarifying the contribution of the IL-17 axis in BP by characterizing not only the expression of IL-17 receptor (IL-17R) members within immune cells isolated from BP patients (PMNs, n = 9; T-lymphocytes, n = 10; and monocytes, n = 10) but also the expression of IL-17 isoforms in sera (n = 83), and blister fluid (n = 31) of BP patients. We showed that at diagnosis, IL-17RA and IL-17RC expression were significantly increased in monocytes isolated from BP patients as compared to those from control subjects (p = 0.006 and p = 0.016, respectively). Notably, both IL-17RA and IL-17RC mRNA expression remained elevated in BP monocytes at time of relapse. We further demonstrated a significant increase of all IL-17 isoforms tested in BP blister fluid compared with BP serum (IL-17A, p < 0.0001; IL-17A/F, p < 0.0001; IL-17B, p = 0.0023; IL-17C, p = 0.0022; IL-17E, p < 0.0001). Among all, IL-17B was the only cytokine for which a significant decreased concentration within blister fluid was observed in BP patients with severe disease compared to patients with moderate disease (p = 0.012). We further evidenced a significant negative correlation between IL-17B levels and blister/erosion BPDAI subscore (r = -0.52, p = 0.003). We finally identified mast cells as a potential target of IL-17B in lesional skin of BP patients. In conclusion, we showed here that IL-17RA and IL-17RC expression in monocyte was associated with disease activity and evidenced in situ a negative correlation between BP disease activity and IL-17B, whose effects could be mediated by IL-17RB expressed by mast cell in BP lesional skin.

Association of Transient Palmoplantar Keratoderma With Clinical and Immunologic Characteristics of Bullous Pemphigoid.

Importance: Development of transient palmoplantar keratoderma (PPK) with bullous pemphigoid (BP) has only been described in 2 isolated case reports. The clinical significance and the pathophysiologic mechanisms of this association are unknown. Objective: To examine the clinical characteristics and immunological profile of patients with BP who develop transient PPK and analyze therapeutic options and outcomes. Design, Setting, and Participants: In this case series, patients with BP who developed acquired, transient PPK, and were treated at a single institution from January 1, 2015, through December 31, 2017, were studied. Main Outcomes and Measures: Clinical and immunological activity of BP, treatment administrated before and after PPK appearance, and patient outcomes. Results: Six patients with BP and transient PPK were identified and included in the study. There were 5 women and 1 man with a mean age of 72 years. At baseline, all patients had a generalized, multibullous BP and high serum anti-BP180 antibodies (mean, 130 U/mL; range, 73-150), whereas anti-BP230 antibodies were elevated in only 1 case. The PPK appeared a mean 6.2 (range, 2-12) months after BP diagnosis, following a prolonged period of disease activity with recurrent flares. When the PPK occurred, BP was uncontrolled on therapy (mean Bullous Pemphigoid Disease Activity Index [BPDAI] score, 57; range, 34-105; mean anti-BP180 antibodies titer, 122 U/mL; range, 81-150). On administration of additional systemic immunosuppressive therapies, the PPK healed progressively in a mean 4.3 months (range, 2-9), along with BP clinical remission in 4 of 6 patients. No relationship was found between PPK occurrence and anti-BP180/230 antibodies profiles. In contrast, blister fluids collected at the time of PPK displayed a much higher level of interleukin 1ß (IL-1ß) compared with those collected in the absence of PKK. Expression of IL-17A, IL-17F, and IL-22 was also enhanced in the blister fluid of patients with BP who had PPK. Conclusions and Relevance: To our knowledge, this is the first report of 6 cases of BP with transient PPK with extensive immunological investigation. The PPK appeared after a prolonged period of clinical BP activity punctuated with recurrent relapses, was transient, and healed after BP control with additional immunosuppressive therapy. Enhanced expression of a particular cytokine panel in the blister fluid at time of PPK could support keratinocyte proliferation as described in patients with psoriasis. Transient PPK could represent a clinical marker of severe, treatment-resistant BP.

Elaboration and validation of Crohn's disease anoperineal lesions consensual definitions.

AIM: To establish consensual definitions of anoperineal lesions of Crohn's (APLOC) disease and assess interobserver agreement on their diagnosis between experts. METHODS: A database of digitally recorded pictures of APLOC was examined by a coordinating group who selected two series of 20 pictures illustrating the various aspects of APLOC. A reading group comprised: eight experts from the Société Nationale Française de Colo Proctologie group of study and research in proctology and one academic dermatologist. All members of the coordinating and reading groups participated in dedicated meetings. The coordinating group initially conducted a literature review to analyse verbatim descriptions used to evaluate APLOC. The study included two phases: establishment of consensual definitions using a formal consensus method and later assessment of interobserver agreement on the diagnosis of APLOC using photos of APLOC, a standardised questionnaire and Fleiss's kappa test or descriptive statistics. RESULTS: Terms used in literature to evaluate visible APLOC did not include precise definitions or reference to definitions. Most of the expert reports on the first set of photos agreed with the main diagnosis but their verbatim reporting contained substantial variation. The definitions of ulceration (entity, depth, extension), anal skin tags (entity, inflammatory activity, ulcerated aspect), fistula (complexity, quality of drainage, inflammatory activity of external openings), perianal skin lesions (abscess, papules, edema, erythema) and anoperineal scars were validated. For fistulae, they decided to follow the American Gastroenterology Association's guidelines definitions. The diagnosis of ulceration (κ = 0.70), fistulae (κ = 0.75), inflammatory activity of external fistula openings (86.6% agreement), abscesses (84.6% agreement) and erythema (100% agreement) achieved a substantial degree of interobserver reproducibility. CONCLUSION: This study constructed consensual definitions of APLOC and their characteristics and showed that experts have a fair level of interobserver agreement when using most of the definitions.

Anti-programmed cell death protein 1 tolerance and efficacy after ipilimumab immunotherapy: observational study of 39 patients.

In patients with ipilimumab (IPI)-refractory melanoma, the anti-programmed cell death proteins 1 (PD1s) nivolumab (NIV) and pembrolizumab (PEM) are considered to be a new standard of treatment. Few data are available on anti-PD1 safety in patients who develop IPI-related severe adverse events (AEs) (grade≥3). The aim of this study was to compare the anti-PD1 safety and efficacy in patients with previous severe toxicity to IPI versus in those showing moderate and no previous IPI-related AEs. This single institution-based observational study included all patients treated with anti-PD1 (PEM or NIV) and previously treated with IPI for unresectable stage III or IV melanoma. The patients enrolled were classified according to the occurrence of IPI-related AEs: group A: no previous IPI-related AEs; group B: mild to moderate IPI-related AEs; and group C: severe to life-threatening IPI-related AEs. The main outcome measure was safety of the anti-PD1 among the three groups. The secondary endpoints included response parameters. Groups A, B, and C included, respectively, 16, 13, and 10 patients. The incidence of severe anti-PD1-related AEs (grades 3-4) was 12, 23, and 10% in groups A, B, and C, respectively. One-year estimates of survival were 52.2, 73.4, and 66.7% among the patients in groups A, B, and C, respectively. The number of patients was too small to enable a meaningful statistical comparison. We did not observe any difference in anti-PD1 toxicity onset incidence according to the occurrence of previous IPI AEs. These reassuring real-life data should be confirmed in a wider analysis.

Certolizumab pegol - A new therapeutic option for refractory disseminated pyoderma gangrenosum associated with Crohn's disease.

Systemic steroids, in association or not with cyclosporin, are indicated for the treatment of large or widespread Pyoderma gangrenosum (PG). We report the case of a 27-year-old woman with a 15-year history of severe Crohn's disease, who developed a severe and disseminated PG, refractory to multiple lines of treatment. Infliximab and adalimumab were contraindicated, either because of allergy or of ineffectiveness on Crohn's disease. The addition of certolizumab pegol to the baseline treatment, associating systemic steroids and tacrolimus, finally allowed the complete healing of PG. Oral prednisone was stopped and tacrolimus was decreased, without any cutaneous or digestive relapse. Certolizumab pegol could be an alternative therapy in the treatment of PG in case of intolerance or ineffectiveness of the other anti-tumor necrosis factor (anti-TNF) therapies.