Comparison of incidence, causes and prognosis of adult and pediatric epidermal necrolysis: a population-based study in France.

BACKGROUND: Epidermal necrolysis (EN), comprising Stevens Johnson syndrome and toxic epidermal necrolysis is a rare and severe blistering reaction, mainly induced by drugs. Differences have been discussed between pediatric and adult patients regarding incidence, causes, and outcomes, but only based on a limited number of patients, in small case-series. OBJECTIVES: To directly compare incidence, causes and prognosis between adult and pediatric EN patients. METHODS: We used the French Health System Database from January 1st 2013 to December 31st 2022. We included adult and pediatric patients hospitalized for EN using the international classification of diseases, 10th revision codes combined with validated algorithms. The outcomes were incidence of EN; presence of a suspected drug before EN onset, defined by a new drug dispensation from 5 to 56 days before hospitalization; and in-hospital mortality. To estimate the association between pediatric EN and the presence of a suspected drug, we computed a multivariable logistic regression with odd ratios (OR). To estimate the association with mortality, we computed a multivariable Cox proportional hazard ratio (HR) model. RESULTS: A total of 1440 EN patients were included, with 799 (55.5%) females, comprising 219 children and 1221 adults. Among children, EN incidence was 1.5 cases (95%CI: 1.3-1.7) per million people year compared with 2.6 cases (95%CI: 2.5-2.7) in adults. Moreover, children had less chances to have a culprit drug before EN onset (93/219 (42.5%) versus 829/1221 (67.9%)), with an adjusted OR of 0.43 (95%CI: 0.32-0.59), p < 0.0001, together with a better prognosis, with death rates of 1.4% (95%CI: 0.4%-3.7%) in pediatric patients compared with 19.4% (95%CI: 17.3%-21.7%) in adult patients, and an adjusted HR of 0.12 (95%CI: 0.04-0.38), p = 0.0003 for in-hospital mortality. CONCLUSION: Pediatric EN seems to be rarer, with less chances to be caused by drugs, together with a better prognosis than adult EN. These results suggest the existence of different underlying pathophysiological mechanisms and clinical particularities between adult and pediatric patients.

Risk of major adverse cardiovascular and venous thromboembolism events in patients with rheumatoid arthritis exposed to JAK inhibitors versus adalimumab: a nationwide cohort study.

OBJECTIVES: To assess the risk of major adverse cardiovascular events (MACEs) and venous thromboembolism events (VTEs) among patients initiating a Janus kinase inhibitor (JAKi) (tofacitinib and baricitinib) versus adalimumab in a large real-world population of patients with rheumatoid arthritis. METHODS: We conducted a nationwide population-based cohort study of the French national health data system, the exposed group initiating a JAKi and non-exposed group initiating adalimumab. We included all individuals who had their first dispensation of a JAKi or adalimumab between 1 July 2017 and 31 May 2021 and had rheumatoid arthritis. The primary endpoints were the occurrence of a MACE or VTE. Weighted hazard ratio (HRw) values were estimated with the inverse probability of treatment weighting method to account for confounding factors with concomitant administration of methotrexate as a time-varying variable. RESULTS: The cohort included 15 835 patients: 8481 and 7354 in the exposed and non-exposed groups (mean age 59.3 and 55.3 years, female 78.3% and 71.2%, respectively). During follow-up, 54 and 35 MACEs and 75 and 32 VTEs occurred in the exposed and non-exposed groups, respectively. Risk of MACEs for the exposed versus non-exposed group was not significant: HRw 1.0 (95% CI 0.7 to 1.5) (p=0.99), nor was risk of VTEs significant: HRw 1.1 (0.7 to 1.6) (p=0.63). Despite a lack of power, results were consistent among patients aged 65 years or older with at least one cardiovascular risk factor. CONCLUSIONS: This study provides reassuring data regarding the risks of MACEs and VTEs in patients initiating a JAKi versus adalimumab, including patients at high risk of cardiovascular diseases.

Persistence of second-line biologics in psoriasis after first-line biologic failure: a nationwide cohort study from the French health insurance database (SNDS).

BACKGROUND: Many biologics are available for psoriasis and have been compared in real-life studies based on their persistence (i.e. time between initiation and discontinuation). However, after first-line biologic failure, data are lacking on the choice of second-line biologic among the four available classes [tumour necrosis factor inhibitors (TNFi); interleukin (IL)-12/IL-23 inhibitor (IL-12/IL-23i); IL-17 inhibitors (IL-17i); and IL-23 inhibitors (IL-23i)]. OBJECTIVES: To compare the long-term persistence of available second-line biologics in psoriasis according to prior exposure. METHODS: This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to a hospital discharge database. Participants were adults with psoriasis, defined as having at least two prescriptions of a topical vitamin D derivative within a 2-year period, with initiation of a second-line biologic between 1 January 2015 and 31 December 2021. We included patients who initiated a second-line biologic directly after first-line discontinuation (i.e. without a 'washout' period). The end of follow-up was 30 June 2022. Discontinuation was defined as > 90 days without filling a prescription for the same treatment after the period covered by the previous prescription. Comparison of persistence by biologic class involved using propensity score-weighted Cox models (inverse probability treatment weighting) and adjustment of specific systemic nonbiologics (time-dependent variables). RESULTS: We included 8693 patients [mean (SD) age 50 (14) years; 50.5% male]; 2824 (32.5%) started TNFi, 1561 (18.0%) IL-12/IL-23i, 2707 (31.1%) IL-17i and 1601 (18.4%) IL-23i. Overall, 1- and 3-year persistence rates were 60% and 30%, respectively. After weighting and adjustment, persistence was longer with IL-12/IL-23i [weighted hazard ratio (HRw) 0.68, 95% confidence interval (CI) 0.62-0.76)], IL-17i (HRw 0.70, 95% CI 0.64-0.78) and IL-23i (HRw 0.36, 95% CI 0.31-0.42) than TNFi, except after first-line IL-17i treatment, with no difference between IL-12/IL-23i, IL-17i and TNFi second-line persistence. Persistence was longer with IL-23i as a second-line treatment than IL-12/IL-23i (HRw 0.53, 95% CI 0.44-0.63) and IL-17i (HRw 0.51, 95% CI 0.44-0.60), regardless of first-line treatment, with no difference seen between IL-12/IL-23i and IL-17i (HRw 0.97, 95% CI 0.87-1.09). CONCLUSIONS: This real-life study suggests the longer persistence of IL-23i than TNFi, IL-17i and IL-12/IL-23i as second-line treatment for psoriasis. Persistence rates for all biologics remained low at 3 years.

A prospective study of the association between living in a rural environment during childhood and risk of psoriasis.

Psoriasis is one of the most common immune-mediated inflammatory diseases (IMIDs). Living in a rural environment during childhood is associated with a decreased risk of certain IMIDs, like asthma, in adulthood. However, its role in other IMIDs, such as psoriasis is still unclear. To evaluate the relationships between different factors related to the environment during childhood and the risk of psoriasis in adulthood we conducted a study in E3N, a French prospective cohort composed of 98 995 women. During the 1990-2018 follow-up of 72 154 study participants, we identified 1 967 incident cases of psoriasis from self-reports in self-administered structured questionnaires. During the 2004-2018 follow-up of 67 917 study participants, 188 moderate-to-severe cases of psoriasis were identified through self-reports and from data from a drug reimbursement database. We fitted Cox proportional hazards regression models with age as the time scale from which we estimated hazard ratios adjusted for putative confounders (aHRs). We found inverse associations with risk of psoriasis for rural birthplace [aHR: 0.89 (95%CI: 0.79-0.96)] and for having farming parents [aHR: 0.84 (95%CI: 0.72-0.97)]. For moderate-to-severe psoriasis we found a nominally similar inverse association with rural birthplace but not with having farming parents. Our results suggest that an exposure to a rural environment during childhood may be associated with a reduced risk of psoriasis. These findings may help to improve our understanding of the pathogenesis of psoriasis.

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

BACKGROUND: Psoriasis is an immune-mediated disease with either skin or joints manifestations, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. The relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. OBJECTIVES: To compare the benefits and harms of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their benefits and harms. SEARCH METHODS: For this update of the living systematic review, we updated our searches of the following databases monthly to October 2022: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic treatments in adults over 18 years with moderate-to-severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent. The primary outcomes were: proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90; proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation). DATA COLLECTION AND ANALYSIS: We conducted duplicate study selection, data extraction, risk of bias assessment, and analyses. We synthesised data using pairwise and network meta-analysis (NMA) to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs). We assessed the certainty of NMA evidence for the two primary outcomes and all comparisons using CINeMA, as very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer treatment hierarchy, from 0% (worst for effectiveness or safety) to 100% (best for effectiveness or safety). MAIN RESULTS: This update includes an additional 12 studies, taking the total number of included studies to 179, and randomised participants to 62,339, 67.1% men, mainly recruited from hospitals. Average age was 44.6 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo-controlled (56%). We assessed a total of 20 treatments. Most (152) trials were multicentric (two to 231 centres). One-third of the studies (65/179) had high risk of bias, 24 unclear risk, and most (90) low risk. Most studies (138/179) declared funding by a pharmaceutical company, and 24 studies did not report a funding source. Network meta-analysis at class level showed that all interventions (non-biological systemic agents, small molecules, and biological treatments) showed a higher proportion of patients reaching PASI 90 than placebo. Anti-IL17 treatment showed a higher proportion of patients reaching PASI 90 compared to all the interventions. Biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha showed a higher proportion of patients reaching PASI 90 than the non-biological systemic agents. For reaching PASI 90, the most effective drugs when compared to placebo were (SUCRA rank order, all high-certainty evidence): infliximab (risk ratio (RR) 49.16, 95% CI 20.49 to 117.95), bimekizumab (RR 27.86, 95% CI 23.56 to 32.94), ixekizumab (RR 27.35, 95% CI 23.15 to 32.29), risankizumab (RR 26.16, 95% CI 22.03 to 31.07). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab and ixekizumab were significantly more likely to reach PASI 90 than secukinumab. Bimekizumab, ixekizumab, and risankizumab were significantly more likely to reach PASI 90 than brodalumab and guselkumab. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab, and brodalumab), and anti-IL23 drugs except tildrakizumab were significantly more likely to reach PASI 90 than ustekinumab, three anti-TNF alpha agents, and deucravacitinib. Ustekinumab was superior to certolizumab. Adalimumab, tildrakizumab, and ustekinumab were superior to etanercept. No significant difference was shown between apremilast and two non-biological drugs: ciclosporin and methotrexate. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. The risk of SAEs was significantly lower for participants on methotrexate compared with most of the interventions. Nevertheless, the SAE analyses were based on a very low number of events with very low- to moderate-certainty evidence for all the comparisons. The findings therefore have to be viewed with caution. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1), the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. AUTHORS' CONCLUSIONS: Our review shows that, compared to placebo, the biologics infliximab, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes measured from 8 to 24 weeks after randomisation), and is not sufficient for evaluating longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean 44.6 years) and high level of disease severity (PASI 20.4 at baseline) may not be typical of patients seen in daily clinical practice. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the safety evidence for most interventions was very low to moderate quality. More randomised trials directly comparing active agents are needed, and these should include systematic subgroup analyses (sex, age, ethnicity, comorbidities, psoriatic arthritis). To provide long-term information on the safety of treatments included in this review, an evaluation of non-randomised studies is needed. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Clinical features, therapeutic choice and response by phototype in psoriasis: analysis of the French PsoBioTeq cohort.

BACKGROUND: Little is known about phototype and the response to systemic treatment in psoriasis. OBJECTIVES: To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype. METHODS: We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index (DLQI) 0/1. RESULTS: Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I-II, III-IV and V-VI groups, respectively. The V-VI group had a higher initial DLQI, and more frequently initiated ustekinumab. Patients in the V-VI group maintained the initial biologic prescribed as did the other phototype groups, even though the proportion of patients reaching PASI 90 and DLQI 0/1 at 12 months was lower in this group than the other groups. CONCLUSIONS: Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. The phototype V-VI group less frequently switched treatments than did the other groups when the response was not efficient.

Risk of major adverse cardiovascular events in patients initiating biologics/apremilast for psoriatic arthritis: a nationwide cohort study.

OBJECTIVE: Several biological DMARDs (bDMARDs) have demonstrated anti-inflammatory effects in PsA. However, their comparative cardiovascular safety profiles remain unknown. We evaluated the risk of major adverse cardiovascular events (MACEs) in PsA patients on therapy with different classes of bDMARDs and apremilast. METHODS: This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database. All adults with PsA who were new users of bDMARDs/apremilast (neither in the year before the index date) during 2015-19 were included. Patients with previous cardiovascular diseases were excluded. End of follow-up was 31 December 2019. The primary endpoint was an occurrence of MACEs in a time-to-event analysis with propensity score-weighted Cox and Fine-Gray models. RESULTS: Between 2015 and 2019, we included 9510 bDMARD new users [mean age 48.5 (s.d. 12.7) years; 42% men], including 7289 starting a TNF inhibitor, 1058 an IL-12/23 inhibitor and 1163 an IL-17 inhibitor, with 1885 apremilast new users [mean age 54.0 (s.d. 12.5) years; 44% men]. MACEs occurred in 51 (0.4%) patients. After propensity score weighting, the risk of MACEs was significantly greater with IL-12/23 (weighted hazard ratio 2.0, 95% CI 1.3, 3.0) and IL-17 (weighted hazard ratio 1.9, 95% CI 1.2, 3.0) inhibitors than TNF inhibitors, with no significant increased risk with apremilast (weighted hazard ratio 1.3, 95% CI 0.8, 2.2). Similar results were observed with the Fine-Gray competing risks survival model. CONCLUSION: Analysis of a large database revealed a small overall number of MACEs, and the risk of MACEs was greater for PsA new users of IL-12/23 and IL-17 vs TNF inhibitors.

Factors associated with remission at 5-year follow-up in recent-onset axial spondyloarthritis: results from the DESIR cohort.

OBJECTIVE: The factors contributing to long-term remission in axial SpA (axSpA) are unclear. We aimed to characterize individuals with axSpA at the 5-year follow-up to identify baseline factors associated with remission. METHODS: We included all patients from the DESIR cohort (with recent-onset axSpA) with an available Ankylosing Spondylitis Disease Activity Score-CRP (ASDAS-CRP) at 5-year follow-up. Patients in remission (ASDAS-CRP < 1.3) were compared with those with active disease by demographic, clinical, biological and imaging characteristics. A logistic model stratified on TNF inhibitor (TNFi) exposure was used. RESULTS: Overall, 111/449 patients (25%) were in remission after 5 years. Among those never exposed to TNFi, 31% (77/247) were in remission compared with 17% (34/202) of those exposed to TNFi. Patients in remission after 5 years were more likely to be male, HLA-B27+, have a lower BMI, and a higher education level. Baseline factors associated with 5-year remission in patients never exposed to TNFi included lower BASDAI [adjusted odds ratio (ORa) 0.9, 95% CI: 0.8, 0.9) and history of peripheral arthritis (ORa 2.1, 95% CI: 1.2, 5.3). In those exposed to TNFi, remission was associated with higher education level (ORa 2.9, 95% CI: 1.6, 5.1), lower enthesitis index (ORa 0.8, 95% CI: 0.7, 0.9), lower BASDAI (ORa 0.9, 95% CI: 0.9, 0.9) and lower BMI (ORa 0.8, 95% CI: 0.7, 0.9). CONCLUSION: This study highlights the difficulty in achieving 5-year remission in those with recent-onset axSpA, especially for the more active cases, despite the use of TNFi. Socio-economic factors and BMI are implicated in the outcome at 5 years.

Plasma cell-directed therapies in monoclonal gammopathy-associated scleromyxedema.

Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French multicenter retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an immunoglobulin G isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4 of 33 patients (12%) (smoldering myeloma, n = 2; chronic lymphoid leukemia, n = 1; and refractory cytopenia with multilineage dysplasia, n = 1). Carpal tunnel syndrome (33%), arthralgia (25%), and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. High-dose IV immunoglobulin (HDIVig), alone or in combination with steroids, appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4 of 5 patients. Quantitative reverse-transcriptase polymerase chain reaction analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor ß and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management.

Paradoxical reactions and biologic agents: a French cohort study of 9303 patients.

BACKGROUND: Paradoxical reactions (PRs) are defined as the occurrence during biologic therapy of a pathological condition that usually responds to these drugs. OBJECTIVES: To estimate the incidence of PRs and identify risk factors. METHODS: Multicentre study of the database for the Greater Paris University Hospitals, including biologic-naive patients receiving anti-tumour necrosis factor-α, anti-interleukin-12/23, anti-interleukin-17 or anti-α4ß7-integrin agents for psoriasis, inflammatory rheumatism or inflammatory bowel disease (IBD). We used natural language processing algorithms to extract data. A cohort and a case-control study nested in the cohort with controls selected by incidence density sampling was used to identify risk factors. RESULTS: Most of the 9303 included patients (median age 43·0, 53·8% women) presented an IBD (3773, 40·6%) or a chronic inflammatory rheumatic disease (3708, 39·9%), and 8489 (91·3%) received anti-TNF-α agents. A total of 297 (3·2%) had a PR. The global incidence rate was 7·6 per 1000 person-years [95% confidence interval (CI) 6·8-8·5]. The likelihood of PR was associated with IBD [adjusted odds ratio (aOR) 1·9, 95% CI 1·1-3·2, P = 0·021] and a combination of at least two inflammatory diseases (aOR 6·1, 95% CI 3·6-10·6, P < 0·001) and was reduced with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and corticosteroids (aOR 0·6, 95% CI 0·4-0·8, P = 0·002; and OR 0·4, 95% CI 0·2-0·6, P = 0·002, respectively). CONCLUSIONS: The likelihood of PRs was associated with IBD or a combination of a least two inflammatory diseases. More studies are needed to assess the benefit of systematically adding csDMARDs for such high-risk patients. What is already known about this topic? Most published studies about paradoxical reactions concern paradoxical psoriasis in patients receiving anti-tumour necrosis factor-α agents. Few data are available for other paradoxical reactions and the most recent biologics. What does this study add? Risk of paradoxical reactions was increased with inflammatory bowel disease and a combination of at least two inflammatory diseases. Risk of paradoxical reactions was reduced with conventional synthetic disease-modifying antirheumatic drugs or corticosteroid therapy, which could be added for high-risk patients.

Overlapping network meta-analyses on psoriasis systemic treatments, an overview: quantity does not make quality.

BACKGROUND: Network meta-analyses (NMAs) have become successful in addressing gaps in the comparative effectiveness of systemic treatments in moderate-to-severe psoriasis. However, their increasing number carries both a risk of overlap and reproducibility issues that can hamper clinical decision-making. OBJECTIVES: In this overview, we aimed to assess redundancy across these NMAs and to describe their characteristics. MATERIALS AND METHODS: We considered all systematic reviews with NMAs of randomized controlled trials that included adult patients with moderate-to-severe psoriasis and that evaluated the efficacy and/or safety of systemic treatments compared with placebo or with an active comparator. PubMed/MEDLINE, Epistemonikos, PROSPERO and the Evidence update of the Centre of Evidence-Based Dermatology of the University of Nottingham were searched up to 25 February 2021. Our main outcome was the number per year of redundant NMAs and the extent of their overlap. We also described their features, especially, the confidence in the results of the reviews, the funding of the studies and the presence of spin (a description that overstates efficacy and/or understates harm), reporting issues and methodological characteristics. RESULTS: In total, 47 redundant NMAs were included. Only two of 47 (4%) included all available treatments. Both efficacy and safety were evaluated in 14 of 47 (30%) NMAs and both short- and long-term evaluations were assessed in five of 47 (11%). Confidence in the results was critically low for 39 of 47 (83%) NMAs and only 10 of 47 (21·3%) registered a protocol. Twenty-six of 47 NMAs (55%) received pharmaceutical funding. Contract research organizations were involved in 19 of 47 (40%) NMAs. Reporting was poor across most of the NMA abstracts and spin was present in all of the abstracts. Almost half of the NMAs failed to consider important limitations such as heterogeneity (considered in 32%) or consistency (considered in 66%). CONCLUSIONS: In addition to a duplication of efforts, our overview showed heterogeneous methods and poor confidence in the results in a majority of the included NMAs, further distorted by reporting issues and spin. Clinicians need to interpret NMAs with caution when looking for the most reliable and comprehensive evidence.

Three-Year Outcomes in Kidney Transplant Recipients Switched From Calcineurin Inhibitor-Based Regimens to Belatacept as a Rescue Therapy.

Background: The long-term benefits of conversion from calcineurin inhibitors (CNIs) to belatacept in kidney transplant recipients (KTr) are poorly documented.Methods: A single-center retrospective work to study first-time CNI to belatacept conversion as a rescue therapy [eGFR <30 ml/min/1.73 m2, chronic histological lesions, or CNI-induced thrombotic microangiopathy (TMA)]. Patient and kidney allograft survivals, eGFR, severe adverse events, donor-specific antibodies (DSA), and histological data were recorded over 36 months after conversion. Results: We included N = 115 KTr. The leading cause for switching was chronic histological lesions with non-optimal eGFR (56.5%). Three years after conversion, patient, and death-censored kidney allograft survivals were 88% and 92%, respectively, eGFR increased significantly from 31.5 ± 17.5 to 36.7 ± 15.7 ml/min/1.73 m2 (p < 0.01), the rejection rate was 10.4%, OI incidence was 5.2 (2.9-7.6) per 100 person-years. Older age was associated with death, eGFR was not associated with death nor allograft loss. No patient developed dnDSA at M36 after conversion. CNI-induced TMA disappeared in all cases without eculizumab use. Microvascular inflammation and chronic lesions remained stable. Conclusion: Post-KT conversion from CNIs to belatacept, as rescue therapy, is safe and beneficial irrespective of the switch timing and could represent a good compromise facing organ shortage. Age and eGFR at conversion should be considered in the decision whether to switch.

Efficacy and safety of treatments in cutaneous polyarteritis nodosa: A French observational retrospective study.

BACKGROUND: Cutaneous polyarteritis nodosa is a form of medium-sized vessel vasculitis. Despite a disabling and prolonged course, data on treatment efficacy and safety remain scarce. OBJECTIVES: We aimed to describe treatment efficacy and safety in patients with cutaneous polyarteritis nodosa. METHODS: This multicenter retrospective, observational study, recorded clinical and biologic data together with treatments received. The primary outcome was the rate of complete response at month 3. Secondary outcomes assessed drug survival and safety. RESULTS: We included 68 patients who received a median of 2 therapeutic lines (interquartile range, 1-3). Overall, complete response was achieved in 13 of 42 (31%) patients with colchicine, 4 of 17 (23%) with dapsone, 11 of 25 (44%) with glucocorticoids (GCs) alone, 1 of 9 (11%) with nonsteroidal anti-inflammatory drugs, 11 of 13 (84%) with GCs+azathioprine, and 7 of 15 (47%) with GCs+methotrexate. GCs+azathioprine had the best drug survival (median duration, 29.5 months; interquartile range, 19.5-36.0). Response at month 3 was decreased with peripheral neurologic involvement (odds ratio, 0.19; 95% confidence interval, 0.03-0.81; P = .04). Overall, the rate of treatment-related adverse events was 18%, which led to the discontinuation of treatment in 7% of patients. LIMITATION: Retrospective study. CONCLUSION: Colchicine seems to confer good benefit-risk balance in cutaneous polyarteritis nodosa without peripheral sensory neuropathy. GCs+azathioprine seem the best treatment in the event of relapse.

Biases associated with epidermal necrolysis reporting in pharmacovigilance: An exploratory analysis using World Health Organization VigiBase.

BACKGROUND: Possible biases in pharmacovigilance reporting may impact epidermal necrolysis (EN) and drugs associations. OBJECTIVES: To assess biases associated with EN-reporting. METHODS: Using VigiBase, the World Health Organization-pharmacovigilance database, among drugs associated with EN between 2016 and 2020, we used an unsupervised clustering including reports characteristics, that is, reporter quality, time from drug intake to EN onset, and only one suspected drug in the report. RESULTS: Among 152 drugs, three clusters were identified. Cluster 1 (n = 41) exhibited drugs frequently reported within a time from intake to onset longer than 4 days, in 57 ± 13% of reports. It corresponded to well-reported drugs and was composed mainly of antivirals and antiepileptics. Cluster 2 (n = 42) exhibited drugs frequently reported within a time from drug intake to onset shorter than 4 days, in 31 ± 12% of reports. It corresponded to drugs with a high risk of protopathic bias and was composed of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and antibiotics. Cluster 3 (n = 69) exhibited drugs frequently reported with an unavailable time from drug intake to reaction, in 66 ± 11% of reports, and reported by a high frequency of consumers (9 ± 9%). It corresponded to drugs reported with a high risk of classification bias, and was composed of anticancer therapies and cardiovascular drugs. CONCLUSION: Protopathic and classification biases impact EN-reporting and should be considered regarding associations with antibiotics, NSAIDs, analgesics, anticancer therapies, and cardiovascular drugs.

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.

Evolution of Drug Survival with Biological Agents and Apremilast Between 2012 and 2018 in Patients with Psoriasis from the PsoBioTeq Cohort.

Drug survival reflects treatment effectiveness and safety in real life. There is limited data on the variation of drug survival with the availability of systemic treatments with additional biological disease-modifying antirheumatic drugs (bDMARDs) or synthetic disease-modifying antirheumatic drugs (sDMARDs). The aim of this study was to determine whether the increasing number of available systemic treatments for psoriasis affects drug survival over time. Patients were selected from the PsoBioTeq cohort, a French prospective observational cohort enrolling patients with moderate to severe psoriasis. All patients initiating a first bDMARD or sDMARD were included. The primary outcome was comparison of drug survival over time. A multivariate Cox proportional hazard ratio model was computed. A total of 1,866 patients were included; 739 females (39%), median age 47 years. In the multivariate Cox model, no association was found between the calendar year of initiation and drug survival (hazard ratio) overlapping from 0.80 (0.42-1.52) to 1.17 (0.64-2.17), p = 0.633). In conclusion, drug survival in psoriasis is not affected by the year of initiation.

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

BACKGROUND: Psoriasis is an immune-mediated disease with either skin or joints manifestations, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. The relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. OBJECTIVES: To compare the efficacy and safety of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: For this update of the living systematic review, we updated our searches of the following databases monthly to October 2021: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic treatments in adults over 18 years with moderate-to-severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent. The primary outcomes were: proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90; proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation). DATA COLLECTION AND ANALYSIS: We conducted duplicate study selection, data extraction, risk of bias assessment and analyses. We synthesised data using pairwise and network meta-analysis (NMA) to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs). We assessed the certainty of NMA evidence for the two primary outcomes and all comparisons using CINeMA, as very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer treatment hierarchy, from 0% (worst for effectiveness or safety) to 100% (best for effectiveness or safety). MAIN RESULTS: This update includes an additional 19 studies, taking the total number of included studies to 167, and randomised participants to 58,912, 67.2% men, mainly recruited from hospitals. Average age was 44.5 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo-controlled (57%). We assessed a total of 20 treatments. Most (140) trials were multicentric (two to 231 centres). One-third of the studies (57/167) had high risk of bias; 23 unclear risk, and most (87) low risk. Most studies (127/167) declared funding by a pharmaceutical company, and 24 studies did not report a funding source. Network meta-analysis at class level showed that all interventions (non-biological systemic agents, small molecules, and biological treatments) showed a higher proportion of patients reaching PASI 90 than placebo. Anti-IL17 treatment showed a higher proportion of patients reaching PASI 90 compared to all the interventions, except anti-IL23. Biologic treatments anti-IL17, anti-IL12/23, anti-IL23 and anti-TNF alpha showed a higher proportion of patients reaching PASI 90 than the non-biological systemic agents. For reaching PASI 90, the most effective drugs when compared to placebo were (SUCRA rank order, all high-certainty evidence): infliximab (risk ratio (RR) 50.19, 95% CI 20.92 to 120.45), bimekizumab (RR 30.27, 95% CI 25.45 to 36.01), ixekizumab (RR 30.19, 95% CI 25.38 to 35.93), risankizumab (RR 28.75, 95% CI 24.03 to 34.39). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab, ixekizumab and risankizumab showed a higher proportion of patients reaching PASI 90 than other anti-IL17 drugs (secukinumab and brodalumab) and guselkumab. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab and brodalumab) and anti-IL23 drugs (risankizumab and guselkumab) except tildrakizumab showed a higher proportion of patients reaching PASI 90 than ustekinumab and three anti-TNF alpha agents (adalimumab, certolizumab and etanercept). Ustekinumab was superior to certolizumab; adalimumab and ustekinumab were superior to etanercept. No significant difference was shown between apremilast and two non-biological drugs: ciclosporin and methotrexate. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. The risk of SAEs was significantly lower for participants on methotrexate compared with most of the interventions. Nevertheless, the SAE analyses were based on a very low number of events with low- to moderate-certainty for all the comparisons (except methotrexate versus placebo, which was high-certainty). The findings therefore have to be viewed with caution. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1), the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. AUTHORS' CONCLUSIONS: Our review shows that, compared to placebo, the biologics infliximab, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes measured from 8 to 24 weeks after randomisation), and is not sufficient for evaluating longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean 44.5 years) and high level of disease severity (PASI 20.4 at baseline) may not be typical of patients seen in daily clinical practice. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the safety evidence for most interventions was low to moderate quality. More randomised trials directly comparing active agents are needed, and these should include systematic subgroup analyses (sex, age, ethnicity, comorbidities, psoriatic arthritis). To provide long-term information on the safety of treatments included in this review, an evaluation of non-randomised studies and postmarketing reports from regulatory agencies is needed. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Face transplantation: A longitudinal histological study focusing on chronic active and mucosal rejection in a series with long-term follow-up.

The 2007 Banff working classification of skin-containing Tissue Allograft Pathology addressed only acute T cell-mediated rejection in skin. We report the longitudinal long-term histological follow-up of six face transplant recipients, focusing on chronic and mucosal rejection. We identified three patterns suggestive of chronic rejection (lichen planus-like, vitiligo-like and scleroderma-like). Four patients presented lichen planus-like and vitiligo-like chronic rejection at 52 ± 17 months posttransplant with severe concomitant acute T cell-mediated rejection. After lichen planus-like rejection, two patients developed scleroderma-like alterations. Graft vasculopathy with C4d deposits and de novo DSA led to subsequent graft loss in one patient. Chronic active rejection was frequent and similar patterns were noted in mucosae. Concordance between 124 paired skin and mucosal biopsies acute rejection grades was low (κ = 0.2, p = .005) but most grade 0/I mucosal rejections were associated with grade 0/I skin rejections. We defined discordant (grade≥II mucosal rejection and grade 0/I skin rejection) (n = 55 [70%]) and concordant (grade≥II rejection in both biopsies) groups. Mucosal biopsies of the discordant group displayed lower intra-epithelial GranzymeB/FoxP3 ratios suggesting a less aggressive phenotype (p = .08). The grading system for acute rejection in mucosa may require phenotyping. Whether discordant infiltrates reflect a latent allo-immune reaction leading to chronic rejection remains an open question.

Epidemiologic study of patients with psoriatic arthritis in a real-world analysis: a cohort study of the French health insurance database.

OBJECTIVE: PsA is a chronic inflammatory arthritis with heterogeneous disease manifestations. Data on the prevalence of PsA in adults differ widely depending on the study and the country. This study aimed to estimate the prevalence and incidence of PsA in France, characterize comorbidities associated to PsA and identify prescribed treatments. METHODS: This nationwide cohort study involved the administrative healthcare database (Système National des Données de Santé) of the French health insurance scheme linked to the national hospital discharge database. All adults with PsA registered in the database and identified with a specific International Classification of Diseases, 10th revision code (M07) were included between 1 January 2015 and 31 December 2018. RESULTS: A total of 63 598 patients were identified as having PsA [55.9 years (s.d. 14.4), 45.6% males]. The prevalence of PsA was estimated at 0.1% and the incidence at 8.4 per 100 000 person-years in the general population. The most common comorbidities were hypertension, diabetes, chronic obstructive pulmonary disease and dyslipidaemia. The prevalence of treatment with conventional synthetic DMARDs (csDMARDs), biological or biosimilar DMARDs (b/bsDMARDs) and apremilast for PsA was 25.9% (16 453), 30.4% (19 325) and 3.5% (2231), respectively. Overall, 8966 (14.1%) patients were new users of csDMARDs, 8311 (13.1%) were new users of b/bsDMARDs and 1529 (7.4%) were new users of apremilast. The most common first-line csDMARD was methotrexate (70.9%) and the most frequent first-line b/bsDMARD was adalimumab (30.8%). CONCLUSION: Our results lead to a better understanding of PsA. Results were similar to those from other published studies using other data sources, which highlights the reliability of insurance databases for studies.

Bone Status According to Neurofibromatosis Type 1 Phenotype: A Descriptive Study of 60 Women in France.

There is an increased risk of osteoporosis and an abnormal bone turn over in neurofibromatosis 1 (NF1). Our objective is to evaluate bone status in NF1 and to look for associations with cutaneous phenotype. We conducted a descriptive, monocentric study. We included 60 NF1 women, 18-51 years old, non-menopausal, divided in 2 groups: «at risk phenotype¼ (ARP) composed by 30 patients with at least 2 subcutaneous neurofibromas (SC-NF) and «classical phenotype¼ (CP) composed by 30 patients with none or 1 SC-NF. We evaluated low bone mineral density (BMD) risk factors and measured BMD, calcium and phosphorus homeostasis and bone turnover markers. Before 50 years old, Z-score has to be used to assess BMD. Z-score < - 2 is below expected range and represents 2.5% of the population. There was no difference between the two groups. Overall, Z-scores were low and 5 patients had a Z-score < - 2 (8.3%), which is 3 times general population low BMD frequency. 10 fragility fractures occurred in 8 patients, among which 2 were vertebral fractures. 85% had low calcium intake. 12 patients had hypophosphoremia, 25 elevated PTH. Vitamin D levels were low for 86.4%. 41 patients (69.5%) had at least one abnormal bone turnover markers. Low BMD is 3.3 times more frequent in NF1 than in general population, with high fracture risk, regardless of the skin phenotype, classical or at risk, because of high bone turn over and secondary hyperparathyroidism due to vitamin D deficiency and poor calcium intake.