Summary Background High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening ...side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. Methods We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18–80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov , number NCT00784589. Findings Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4–71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71–3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39–2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3–4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 SD 1·25) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 1·15; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 21% with prednisone alone vs six 22% with rituximab plus prednisone), myopathy (ten 19% vs three 11%), and bone disorders (five 9% vs five 19%). Interpretation Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. Funding French Ministry of Health, French Society of Dermatology, Roche.
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.
Bullous pemphigoid (BP) is the most common autoimmune blistering disease in Europe and its treatment can be challenging. Several published cases have reported dupilumab efficiency in ...treatment-refractory patients. We conducted a retrospective multicentric study of 36 patients to evaluate the real-life efficiency of dupilumab in BP. Our results suggest that dupilumab, in association with high-potency topical steroids, could be rapidly effective in various clinical forms of BP and seems to be well tolerated in the elderly.
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.
Rituximab and short-term corticosteroid therapy are the criterion standard treatments for patients with newly diagnosed moderate to severe pemphigus.
To examine factors associated with short-term ...relapse in patients with pemphigus treated with rituximab.
This post hoc analysis of a randomized clinical trial (Comparison Between Rituximab Treatment and Oral Corticosteroid Treatment in Patients With Pemphigus RITUX 3) conducted from January 1, 2010, to December 31, 2015, included patients from 20 dermatology departments of tertiary care centers in France from the RITUX 3 trial and 3 newly diagnosed patients treated according to the trial protocol. Data analysis was performed from February 1 to June 30, 2019.
Patients randomly assigned to the rituximab group in the RITUX 3 trial and the 3 additional patients were treated with 1000 mg of intravenous rituximab on days 0 and 14 and 500 mg at months 12 and 18 combined with a short-term prednisone regimen.
Baseline (pretreatment) clinical and biological characteristics (Pemphigus Disease Area Index PDAI score, ranging from 0-250 points, with higher values indicating more severe disease) and changes in anti-desmoglein (DSG) 1 and anti-DSG3 values as measured by enzyme-linked immunosorbent assay during the 3 months after rituximab treatment were compared between patients with disease relapse and those who maintained clinical remission during the first 12 months after treatment. The positive and negative predictive values of these factors were calculated.
Among 47 patients (mean SD age, 54.3 17.0 years; 17 36% male and 30 64% female) included in the study, the mean (SD) baseline PDAI score for patients with relapsing disease was higher than that of the patients with nonrelapsing disease (54 33 vs 28 24; P = .03). At month 3, 7 of 11 patients with relapsing disease (64%) vs 7 of 36 patients with nonrelapsing disease (19%) had persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher (P = .01). A PDAI score of 45 or higher defining severe pemphigus and/or persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher at month 3 provided a positive predictive value of 50% (95% CI, 27%-73%) and a negative predictive value of 94% (95% CI, 73%-100%) for the occurrence of relapse after rituximab.
The findings suggest that initial PDAI score and changes in anti-DSG antibody values after the initial cycle of rituximab might help differentiate a subgroup of patients with high risk of relapse who might benefit from maintenance rituximab infusion at month 6 from a subgroup of patients with low risk of relapse who do not need early maintenance therapy.
NCT00784589.
Interest in the use of omalizumab to treat bullous pemphigoid (BP) in the event of resistance or contraindication to conventional therapies is currently based on limited evidence.
To assess the ...effectiveness and safety of omalizumab in BP and to identify predictive factors in response to treatment.
We conducted a French national multicentre retrospective study including patients with a confirmed diagnosis of BP treated with omalizumab after failure of one or several treatment lines. We excluded patients with clinically atypical BP, as per Vaillant's criteria. The criteria for clinical response to omalizumab were defined according to the 2012 international consensus conference. Anti-BP180-NC16A IgE enzyme-linked immunosorbent assay was performed on sera collected before initiating omalizumab, when available.
Between 2014 and 2021, 100 patients treated in 18 expert departments were included. Median age at diagnosis was 77 years (range 20-98). Complete remission (CR) was achieved in 77% of patients, and partial remission in an additional 9%. CR was maintained 'off therapy' in 11.7%, 'on minimal therapy' in 57.1%, and 'on non-minimal therapy' in 31.2%. Median time to CR was 3 months (range 2.2-24.5). Relapse rate was 14%, with a median follow-up time of 12 months (range 6-73). Adverse events occurred in four patients. CR was more frequently observed in patients with an increased serum baseline level of anti-BP180-NC16A IgE (75% vs. 41%; P = 0.011). Conversely, urticarial lesions, blood total IgE concentration or eosinophil count were not predictive of CR. Patients with an omalizumab dosage > 300 mg every 4 weeks showed a similar final outcome to those with a dosage ≤ 300 mg every 4 weeks, but control of disease activity median 10 days (range 5-30) vs. 15 days (range 10-60); P < 0.001 and CR median 2.4 months (range 2.2-8.2) vs. 3.9 months (range 2.3-24.5); P < 0.001 were achieved significantly faster.
We report the largest series to date of BP treated by omalizumab and confirm its effectiveness and safety in this indication. Serum baseline level of anti-BP180-NC16A IgE may predict response to treatment.
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