Maintenance treatment of pemphigus with rituximab in real life: A single-center study of 50 patients.

BACKGROUND: Following the RITUX 3 therapeutic trial, the French national diagnosis and care protocol (NDCP) for the treatment of pemphigus was updated in 2018. The updated protocol recommends initial treatment with rituximab (RTX) followed by maintenance therapy at 12 and 18 months, and potentially at 6 months where there are risk factors for early relapse. We evaluated these recommendations regarding the management of our own patients. PATIENTS AND METHODS: Our single-center retrospective study included all patients with pemphigus diagnosed between 01/2015 and 10/2020 and receiving at least one initial infusion of RTX. We collected the following data: type of pemphigus, severity, levels of anti-desmoglein 1 and 3 antibodies at diagnosis and between 2 and 6 months after initial RTX, presence or absence of maintenance therapy and modalities, time to first relapse and duration of associated systemic corticosteroid therapy ≥5 mg/day. Maintenance treatment modalities were as follows: no maintenance treatment, maintenance "on demand" (MT1) i.e. not performed at the rate imposed by the NDCP, and maintenance "according to NDCP" (MT2). RESULTS: Fifty patients were included (women 54%, median age 58 years, pemphigus vulgaris 68%, moderate to severe 68%). Initial RTX was combined with systemic corticosteroid therapy at 0.5 to 1 mg/kg in 74% of cases. Twenty-seven patients (54%) received no maintenance therapy, 13 were on an MT1 regimen (26%), and 10 were on an MT2 regimen (20%). Median follow-up was 42 months. At the last follow-up, 39 patients (78%) were in complete remission. A total of 25 patients (50%) relapsed: 18/27 (67%) patients without maintenance, 5/13 (38%) with MT1, and 2/10 (20%) with MT2 (p = 0.026). The probability of relapse over time was significantly lower in patients receiving maintenance therapy compared to those who receiving none (p = 0.022). The median time to relapse was 15 months in patients without maintenance, and 30 and 28 in those with maintenance (p = 0.27). The median duration of systemic corticosteroid therapy ≥ 5 mg/day in the no-maintenance group was 10 months, compared to 7 and 9 months respectively in MT1 and MT2 (p = 0.91). CONCLUSION: Our study confirms the value of RTX maintenance therapy in pemphigus in real life.

Post-acute phase and sequelae management of epidermal necrolysis: an international, multidisciplinary DELPHI-based consensus.

BACKGROUND: Long-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking. OBJECTIVES: We conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae. METHODS: Participants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method. RESULTS: Fifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index < 1). Among them, 50 statements were agreed upon as 'appropriate'; four statements were considered 'uncertain', and ultimately finally discarded. CONCLUSIONS: Our DELPHI-based expert consensus should help guide physicians in conducting a prolonged multidisciplinary follow-up of sequelae in SJS-TEN.

Erythema multiforme associated with anti-plakin antibodies: a multicentric retrospective case series.

BACKGROUND: Erythema multiforme (EM) is a muco-cutaneous inflammatory disease mainly triggered by herpes simplex virus (HSV) recurrences. Association of EM and circulating auto-antibodies against plakins (anti-PLK-Abs [EM-PLK+]) has been reported. However, little is known about this subset of EM. OBJECTIVES: We aimed to describe the clinical and immunological features and response to treatment of EM-PLK+. METHODS: We conducted a retrospective multicentric study of EM-PLK+ selected from the database of the immunological laboratory of Bichat hospital, Paris, France, from January 2009 to December 2020. Anti-PLK-Abs were detected in ≥1 immunological tests: immunofluorescence assay, immunoblotting and/or ELISA. Patients with alternative diagnoses were excluded. RESULTS: We included 29 patients (16 women, median age 25 [range 2-58] years). EM-PLK+ were mostly major (EM with ≥2 mucosal involvements; n = 24, 83%) and relapsing (≥2 flares; n = 23, 79%). Cutaneous lesions were target (n = 13, 54%) and target-like lesions (n = 9, 38%) with usual topography (acral, n = 19, 79%; limbs, n = 21, 88%). Mucosal lesions affected the mouth (n = 27, 96%) and genitalia (n = 19, 68%), with a median of 2 [range 0-5] mucous membranes. EM-PLK+ were suspected as certain or possible postherpetic (EM-HSV) in 19 cases (65.5%); no triggering factors were detected in 9 (31%) patients. Desmoplakin-I/II Abs were the most frequent anti-PLK-Abs (n = 20, 69%); envoplakin and periplakin Abs were detected in 11 and 9 cases. Relapsing EM-PLK+ (n = 23) were still active (≥1 flare within 6 months) in 13 (57%) patients despite immunosuppressive therapy (n = 8, 62%). Antiviral drugs were ineffective in preventing relapse in 15/16 (94%) EM-HSV. CONCLUSION: The rationale for anti-PLK-Ab detection in EM is not elucidated. More systematic research of anti-PLK-Abs is warranted to better understand whether this association reflects humoral immune activity in a subset of EM or is fortuitous, related to an epitope spreading process. However, EM-PLK+ seems to be associated with major and relapsing subtypes, and difficult-to-treat cases.

Quality of life in neurofibromatosis 1: development and validation of a tool dedicated to cutaneous neurofibromas in adults.

BACKGROUND: Cutaneous neurofibromas (cNF), present in 95% of individuals with neurofibromatosis 1 (NF1), are considered as one of the greatest medical burden because of physical disfigurement. No specific score evaluates their impact on quality of life (QoL). OBJECTIVE: To develop a specific score assessing cNF-related QoL. METHODS: Through a multidisciplinary workshop including 10 patients, 3 expert-in-NF1 physicians, 3 health care workers (nurses and psychologist) and 1 methodologist, the French version of the Skindex-16 was modified by adding 3 items. The new cNF-Skindex was validated among patients with NF1 recruited in the ComPaRe online cohort, in France (N = 284). Construct validity was assessed by comparing it with the EQ-5D-5L, its visual analogue scale and the MYMOP2 and by assessing its association with patients' characteristics. Reliability was assessed by a test-retest. An English version of the tool was developed using a back-forward translation. RESULTS: A total of 228 individuals with NF1, with cNF answered the 19-item questionnaire. These items fitted into 3 domains: emotions, symptoms, functioning. One was dropped during analysis because >90% responders were not concerned. The cNF-Skindex significantly correlated with the EQ-5D-5L (N = 193) and MYMOP2 (N = 210) indicating good external validity: rs 0.38 (P < 0.001), and 0.58 (P < 0.001), respectively. Having >50 cNF was the only independent variable associated with the total score cNF-Skindex (ß = 15.88, 95%CI 6.96-24.81, P = 0.001), and with the 3 sub-scores: 'functioning' (ß = 2.65, 95%CI 0.71-4.59, P = 0.008), 'emotions' (ß = 17.03, 95%CI 4.11-29.96, P = 0.010) and 'symptoms' (ß = 3.90, 95%CI 1.95-5.85, P < 0.001). Test-retest reliability (N = 133) found an ICC at 0.96 demonstrating good reproducibility. CONCLUSION: The cNF-Skindex demonstrated excellent psychometric properties. The global and sub-scores were increased with higher number of cNF arguing for its use in further trials aiming to reduce their number or prevent their development. Cross-cultural validation and evaluation of its responsiveness are the next steps.

Identification of three clinical neurofibromatosis 1 subtypes: Latent class analysis of a series of 1351 patients.

BACKGROUND: Neurofibromatosis 1 (NF1) is one of the most common inherited disorders characterized by mutations in the tumour suppressor gene NF1. Its clinical manifestations are highly variable and unpredictable. A specific NF1 mutation does not predict the severity or complications of the disease. OBJECTIVE: The objective of this study was to build an empirical classification scheme without any a priori hypotheses to identify the underlying NF1 subtypes that best explain the observed heterogeneity. METHODS: We performed latent class analysis (LCA) of 1351 consecutive NF1 patients aged >17 years seen between 2002 and 2014. Data and phenotypic features were collected prospectively on a standardized form. RESULTS: The median age was 36.8 (17-81) years. A three-class model showed the best fit: 706 (52%) belonged to the LC1 'Cutaneous neurofibromas' class having preferentially cutaneous neurofibromas (99%), plexiform neurofibromas (63%) and blue-red macules (29%); 593 (44%) belonged to the LC2 'Subcutaneous neurofibromas' class characterized by the presence of at least 10 subcutaneous neurofibromas (21%) and a familial form (77%) and 52 (4%) belonged to the LC3 'Dysmorphic phenotype' class characterized by dysmorphic features (78%) and learning difficulties (87%). Patients in LC1 had a higher likelihood of developing scoliosis (RR = 1.7, 95% confidence interval (CI) [1.2-2.4]). Patients in LC2 were more likely to be men (RR = 1.4, 95% CI [1.1-1.7]). Patients in LC3 were at higher risk of having an optic pathway glioma (RR = 4.8, 95% CI [1.9-11.8]) and epilepsy (RR = 4.5, 95% CI [1.8-11.6]). CONCLUSION: Our findings invite the performance of a larger cohort study to test whether the various latent classes reflect different underlying genetic modifiers of these phenotypic traits.

Pityriasis lichenoides: a clinical and pathological case series of 49 patients with an emphasis on follow-up.

The classification of pityriasis lichenoides (PL) into pityriasis lichenoides et varioliformis acuta (PLEVA), PL chronica (PLC) and febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is based on both clinical and chronological features. In this retrospective monocentric study, we aimed to investigate the relevance of the classification in routine practice. We enrolled 49 patients (25 female, 24 male; median age 41 years). The lesions were papular in 76% of patients, necrotic in 12% and mixed in 12%. We found three histological patterns: 'classic' (65%), 'lymphomatoid' (13%) and 'mild' (22%). The 'lymphomatoid' pattern was associated with necrotic presentation and the 'mild' pattern with papular lesions (P = 0.01). Among the 27 patients with follow-up, 18% had relapses and 44% had chronic disease. One patient had mycosis fungoides. Neither clinical nor histological findings were correlated with disease progression, and are a reflection of the intensity of epidermal injury rather than of the disease course. The term 'pityriasis lichenoides' should be preferred to the classic PLEVA/PLC/FUMHD classification.

Impact of systemic to topical steroids switch on the outcome of drug reaction with eosinophilia and systemic symptoms (DRESS): A monocenter retrospective study of 20 cases.

BACKGROUND: There is no consensus on the treatment of drug reaction with eosinophilia and systemic symptoms (DRESS). At our center, systemic steroids (SS) are used for severe cases while topical steroids (TS) are used for mild and moderate forms. OBJECTIVES: To investigate the short-term outcome for patients with DRESS receiving SS as first-line therapy before being transferred to our department and then switched to TS after admission. METHODS: A retrospective monocenter study in DRESS patients (RegiSCAR score≥4) transferred to our dermatology department from a different setting between 07/2012 and 06/2018 and who had received SS before being transferred. Epidemiological, clinical and laboratory data were collected, as well as details of treatment modalities and outcome. RESULTS: Twenty patients were included. On admission to our department, 4 were assessed as having severe DRESS and continued on SS, while 16 were assessed as mild/moderate DRESS and were switched to TS. Among these 16 patients, the outcome on TS was favorable for 12 and quickly unfavorable for 4, who had to be switched back to SS. Retrospective analysis of the initial data (before transfer) showed that these 4 patients had previously had a greater number of severity criteria than the other 12. CONCLUSION: Caution is needed not only when deciding to initiate SS in DRESS but also on withdrawal of these drugs. Our series suggests that when SS are used as first-line therapy in DRESS patients with initial severity criteria, they should not be withdrawn quickly for a switch to TS, even where progression appears favorable, due to the risk of relapse.

Towards a better understanding of adult idiopathic epidermal necrolysis: a retrospective study of 19 cases.

BACKGROUND: Most cases of Stevens-Johnson syndrome and toxic epidermal necrolysis are drug-induced. A small subset of cases remain with unknown aetiology (idiopathic epidermal necrolysis [IEN]). OBJECTIVE: We sought to better describe adult IEN and understand the aetiology. METHODS: This retrospective study was conducted in 4 centres of the French national reference centre for epidermal necrolysis. Clinical data were collected for the 19 adults hospitalized for IEN between January 2015 and December 2019. Wide toxicology analysis of blood samples was performed. Histology of IEN cases was compared with blinding to skin biopsies of drug-induced EN (DIEN, 'controls'). Available baseline skin biopsies were analysed by shotgun metagenomics and transcriptomics and compared to controls. RESULTS: IEN cases represented 15.6% of all EN cases in these centres. The median age of patients was 38 (range 16-51) years; 68.4% were women. Overall, 63.2% (n = 12) of cases required intensive care unit admission and 15.8% (n = 3) died at the acute phase. Histology showed the same patterns of early- to late-stage EN with no difference between DIEN and IEN cases. One toxicology analysis showed unexpected traces of carbamazepine; results for other cases were negative. Metagenomics analysis revealed no unexpected pathological microorganism. Transcriptomic analysis highlighted a different pro-apoptotic pathway in IEN compared to DIEN, with an overexpression of apoptosis effectors TWEAK/TRAIL. CONCLUSIONS: IEN affects young people and is a severe form of EN. A large toxicologic investigation is warranted. Different pathways seem involved in IEN and DIEN, leading to the same apoptotic effect, but the primary trigger remains unknown.

Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

[18F]FDG Positron emission tomography with whole body magnetic resonance imaging ([18F]FDG-PET/MRI) as a diagnosis tool in Schwannomatosis.

Schwannomatosis is a rare autosomal dominant genetic syndrome characterized by the presence of multiple schwannomas. The main symptom is neurogenic pain. The diagnosis requires the presence of several schwannomas and whole-body [18F]FDG-PET/MRI might help detect extra schwannomas in patients when the diagnosis is uncertain. Among the 25 patients treated for Schwannomatosis in our tertiary center, three men and two women had had a [18F]FDG-PET/MRI performed, and the number of schwannomas detected by [18F]FDG-PET/MRI outnumbered the number of schwannomas suspected during the clinical examination. The majority of schwannomas exhibited a radiolabeling (median of 66.7%, range 28-93%). Our findings show that [18F]FDG-PET/MRI could prove useful when suspecting schwannomatosis to accelerate diagnosis and offer optimal care to patients.

Chronic pain: a long-term sequela of epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) - prevalence, clinical characteristics and risk factors.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with various sequelae. Chronic pain, one of these sequelae, has never been systematically evaluated. OBJECTIVES AND METHODS: To assess the persistence of pain in a single-centre cohort of 113 consecutive patients with SJS/TEN. From this cohort, 81 patients were interviewed more than 1 year after the initial episode and included in the study. Data were collected according to standardized questionnaires. RESULTS: From the 81 interviewed patients, 52 patients (64%) were painless and 29 patients (36%) were painful. Chronic pain syndrome was associated with a more severe initial acute phase of the disease (larger extent of detachment, higher SCORTEN, increased rate of admission in ICU and complications, and longer hospital stay). Pain was mainly located at the level of eyes (55%), mouth and lower limbs (38-41%), with a moderate daily intensity on average (4.7/10). The 'affective' descriptors prevailed over the 'sensory' descriptors, with the exception of burning and itching sensations. Finally, regarding provoked pain, mechanical allodynia (to brushing and pressure) was more marked than thermal allodynia. DISCUSSION: The persistence of chronic pain after SJS/TEN is a common phenomenon. Sensory descriptors are consistent with sensitization of both small-diameter nerve fibres (burning and itching sensations) and large-diameter nerve fibres (mechanical allodynia), but the affective-emotional components of pain largely predominate. CONCLUSIONS: Complex mechanisms lead to persistent pain as long-term sequela of SJS/TEN, among which mechanisms, psychological factors related to post-traumatic stress disorder probably play a key role.