Omalizumab in the treatment of bullous pemphigoid resistant to first-line therapy: a French national multicentre retrospective study of 100 patients.

BACKGROUND: 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. OBJECTIVES: To assess the effectiveness and safety of omalizumab in BP and to identify predictive factors in response to treatment. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Efficacy of imiquimod in the management of lentigo maligna.

BACKGROUND: Lentigo maligna (LM) is a melanocytic proliferation occurring on photo-exposed skin that may progress to LM melanoma. Surgery is recommended as first-line treatment. Excision margins of 5-10 mm remain, without international consensus. Several studies have shown that imiquimod, an immunomodulator, induces LM regression. This study investigated the effect of imiquimod versus placebo in neoadjuvant settings. PATIENTS AND METHODS: We performed a prospective, randomized, multicentre, phase III clinical study. Patients were randomly assigned in 1:1 ratio to receive imiquimod or placebo for 4 weeks, followed by LM excision 4 weeks after the last application of imiquimod or placebo. The primary endpoint was extra-lesional excision, with a 5 mm margin from the residual pigmentation after imiquimod or vehicle. Secondary endpoints included the gain on the surface removed between the two groups; number of revision surgeries to obtain extra-lesional excisions; relapse-free time; and number of complete remissions after treatment. RESULTS: A total of 283 patients participated in this study; 247 patients, 121 patients in the placebo group and 126 in the imiquimod group, accounted for the modified ITT population. The first extralesional extirpation was performed in 116 (92%) imiquimod patients and in 102 (84%) placebo patients; the difference was not significant (p = 0.0743). Regarding the surface of LM, imiquimod reduced the LM surface (4.6-3.1 cm2 ) significantly (p < 0.001) more compared to the placebo (3.9-4.1 cm2 ). CONCLUSION: Imiquimod reduces the lentigo maligna surface after 1 month of treatment, without a higher risk of intralesional excision and with a positive aesthetic outcome.

Anti-BP180 IgG antibody ELISA values correlate with adverse pregnancy outcomes in pemphigoid gestationis.

BACKGROUND: Adverse pregnancy outcomes (APO) occur in 35% of patients with pemphigoid gestationis (PG). No biological predictor of APO has been established yet. OBJECTIVES: To assess a potential relationship between the occurrence of APO and the serum value of anti-BP180 antibodies at the time of PG diagnosis. METHODS: Multicentre retrospective study conducted from January 2009 to December 2019 in 35 secondary and tertiary care centres. INCLUSION CRITERIA: (i) diagnosis of PG according to clinical, histological and immunological criteria, (ii) ELISA measurement of anti-BP180 IgG antibodies determined at the time of PG diagnosis with the same commercial kit and (iii) obstetrical data available. RESULTS: Of the 95 patients with PG included, 42 had one or more APO, which mainly corresponded to preterm birth (n = 26), intrauterine growth restriction (IUGR) (n = 18) and small weight for gestational age at birth (n = 16). From a ROC curve, we identified a threshold of 150 IU ELISA value as the most discriminating to differentiate between patients with or without IUGR, with 78% sensitivity, 55% specificity, 30% positive and 91% negative predictive value. The threshold >150 IU was confirmed using a cross-validation based on bootstrap resampling, which showed that the median threshold was 159 IU. Upon adjusting for oral corticosteroid intake and main clinical predictors of APO, an ELISA value of >150 IU was associated with the occurrence of IUGR (OR = 5.11; 95% CI: 1.48-22.30; p = 0.016) but not with any other APO. The combination of blisters and ELISA values higher than 150 IU led to a 2.4-fold higher risk of all-cause APO (OR: 10.90; 95% CI: 2.33-82.3) relative to patients with blisters but lower values of anti-BP180 antibodies (OR of 4.54; 95% CI 0.92-34.2). CONCLUSION: These findings suggest that anti-BP180 antibody ELISA value in combination with clinical markers is helpful in managing the risk of APO, in particular IUGR, in patients with PG.

Predictive Factors of Non-Response to Vismodegib in Locally Advanced Basal-Cell Carcinoma.

BACKGROUND: Vismodegib has shown clinical efficacy in the management of locally advanced basal cell carcinomas (laBCC). However, non-response to vismodegib is observed in 2-13.5% of patients in clinical studies. The purpose of this study was to identify factors associated with non-response to vismodegib in patients with laBCC. METHODS: We carried out a retrospective multicenter study, including patients with laBCC treated with vismodegib, from July 2011 to May 2019. Response to treatment was assessed according to the RECIST 1.1 criteria. Patients were categorized as responders with a complete response or a partial response or non-responders with a stable disease or a progressive disease according to what has been observed during follow-up. Patient demographics, tumor profile, and treatment modalities were compared in responders and non-responders. RESULTS: Eighty-three patients with laBCC were included in the study. Twenty-five (30.1%) were non-responders to vismodegib. History of treatment with radiotherapy, presence of muscle involvement and intermittent treatment with vismodegib were significantly associated with a non-response (p < 0.001, p = 0.025, p < 0.001). Bone involvement (p = 0.2) and morpheaform IaBCC subtype (p = 0.056) were more frequent in non-responders without reaching statistical significance. CONCLUSION: In this study, non-response of laBCC to vismodegib therapy was associated with muscle involvement. Previous radiotherapy and intermittent use of vismodegib have been identified as causes favoring non-response to vismodegib. Due to the low numbers of patients included in the study, it is difficult to draw firm conclusions. Further studies are needed to confirm these data.

Annular lipoatrophy of the ankle: Four new pediatric cases and a review of the literature.

Annular lipoatrophy of the ankle is a rare and unique acquired lipoatrophic panniculitis that mainly affects children. There is no consensus on treatment, and the long-term course is not well known. We present four new pediatric cases that contribute to the understanding of this rare disease.

Impregnated acetate gauze compared with lipido-colloid contact layer at dressing removal pain: a single-blind cross-over randomised control trial.

OBJECTIVE: To evaluate the performance of Jelonet Plus (JP) and UrgoTul (UT), assessing pain at dressing removal when managing acute or chronic wounds at granulation and epithelialisation stages. METHODS: This was a randomised, multicentre, controlled single-blinded study using a cross-over design. Hospitalised and ambulatory patients presenting with non-infected acute or chronic wounds (at least 40% of wound area of ≤100cm2 covered with granulation tissue) were randomly allocated to be treated with either JP or UT dressings applied according to a standardised local care procedure for two days. At the following visit, patients received the other dressing for a second 2-day period. Pain was evaluated after two days of dressing application and immediately after its removal using a 100mm Visual Analog Scale (VAS). A pain level >30mm was considered as clinically relevant. A lower limit of -12% was determined as the threshold necessary to demonstrate the non-inferiority of JP compared to UT. RESULTS: For the 99 patients completing the study, a difference of 7.9% was observed in favour of JP (83.8% JP versus 75.9% UT) for pain immediately after dressing removal (VAS score < 30mm) with a confidence interval (CI) lower limit of -2.6%, demonstrating non-inferiority (pre-defined limit of -12%). Concerning pain at dressing removal, a difference of 19.6% was observed in favour of JP (81.6% versus 62.0%; p=0.029 for superiority analysis), with a CI lower limit ranging from 2.4% to 38.9%. Therefore, superiority could be concluded. A statistically significant period effect was detected (p=0.003) with fewer patients experiencing pain after the second period day 2 (D2) to day 4 (D4) than the first day 0 (D0) to D2. A statistically significant cross-over effect was also detected (p=0.047), with fewer patients experiencing pain when JP was applied first followed by UT. This suggests a carry-over effect thus preventing a full cross-over design analysis. Adherence of the dressing was less frequent with the JP than the UT dressing (2.0% JP versus 6.9% with UT). CONCLUSION: Non-inferiority of pain at dressing removal was demonstrated with JP. Superiority on this criteria was non-significant but we found adherence of the dressing to the wound bed to be more rare.

First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.

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.

Sentinel node status and immunosuppression: recurrence factors in localized Merkel cell carcinoma.

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

Severe and refractory solar urticaria treated with intravenous immunoglobulins: a phase II multicenter study.

BACKGROUND: Retrospective data have suggested the effectiveness of intravenous immunoglobulins (IVIG) for solar urticaria (SU). OBJECTIVE: We sought to prospectively assess the efficacy of IVIG for SU. METHODS: We conducted a multicentric phase II study to test the efficacy of a single course of IVIG (2 g/kg) in patients with severe and refractory SU. The primary outcome was remission of SU on phototesting at 12 weeks after IVIG treatment. Secondary objectives included clinical remission, improved quality of life, and 50% improvement in disease intensity as measured on a visual analog scale. RESULTS: Of the 9 patients who received IVIG injection, 2 showed remission of SU on phototesting, corresponding to a response rate of 22.2% (95% confidence interval 2.8%-60.0%). In all, 6 patients (67%) showed at least 1 response criterion after 4 weeks and 5 (56%) after 12 weeks. Response was maintained after 24 weeks for 2 patients and after 48 weeks for 1 patient. About half of the patients (56%) had moderate to severe headache. LIMITATIONS: Lack of control arm and small number of patients are limitations. CONCLUSION: A single course of IVIG appears insufficient to obtain prolonged significant control of SU; future evaluation of different schedules of IVIG administration is warranted.

Ipilimumab in melanoma patients with brain metastasis: a retro-spective multicentre evaluation of thirty-eight patients.

Treatment with ipilimumab, a monoclonal antibody that antagonizes cytotoxic T-lymphocyte antigen-4 (CTLA-4), results in improved survival of patients with stage IIIc-IV melanoma. However, there is a lack of data on the efficacy of ipilimumab in patients with brain metastases. To evaluate the efficacy of ipilimumab for the treatment of brain metastasis in melanoma, a multicentre, retrospective analysis of 38 patients with brain metastases in melanoma, treated with ipilimumab in the context of the French Expanded Access Program, was performed. Three patients had a 3 partial response, 5 stable disease, 15 disease progression and 15 patients died during the induction phase due to disease progression. Median overall survival was 101 days (range 54-154). The brain metastases control rate was 16% (6/38). Ipilimumab may be effective in a few patients with central nervous system metastasis. However, patients with brain metastases and a low life expectancy may not benefit sufficiently from treatment with ipilimumab.

Sustained Remission Without Corticosteroids Among Patients With Pemphigus Who Had Rituximab as First-Line Therapy: Follow-Up of the Ritux 3 Trial.

Importance: The Ritux 3 trial demonstrated the short-term efficacy and safety of first-line treatment with rituximab compared with a standard corticosteroid regimen in pemphigus. No data on the long-term follow-up of patients who received rituximab as first line are available. Objective: To assess the long-term efficacy and safety of the Ritux 3 treatment regimen. Design, Setting, and Participants: This 7-year follow-up study of the Ritux 3 trial included patients with pemphigus from 25 dermatology departments in France from January 1, 2010, to December 31, 2015. Exposure: Patients were initially randomized in the rituximab plus prednisone group or prednisone-alone group. Main outcomes and measures: The primary outcome was the 5- and 7-year disease-free survival (DFS) without corticosteroids, assessed by Kaplan-Meier curves. Secondary outcomes were occurrence of relapse, occurrence of severe adverse events (SAEs), and evolution of antidesmoglein (Dsg) antibody enzyme-linked immunosorbent assay values to predict long-term relapse. Results: Of the 90 patients in the Ritux 3 trial, 83 were evaluated at the end of follow-up study visit (44 in the rituximab plus prednisone group; 39 in the prednisone-alone group) with a median (IQR) follow-up of 87.3 (79.1-97.5) months. Forty-three patients (93%) from the rituximab plus prednisone and 17 patients (39%) from the prednisone-alone group had achieved complete remission without corticosteroids at any time during the follow-up. Patients from the rituximab group had much longer 5- and 7-year DFS without corticosteroids than patients from the prednisone-alone group (76.7% and 72.1% vs 35.3% and 35.3%, respectively; P < .001), and had about half the relapses (42.2% vs 83.7%; P < .001). Patients who received rituximab as second-line treatment had shorter DFS than patients treated as first line (P = .007). Fewer SAEs were reported in the rituximab plus prednisone group compared with the prednisone-alone group, 31 vs 58 respectively, corresponding to 0.67 and 1.32 SAEs per patient, respectively (P = .003). The combination of anti-Dsg1 values of 20 or more IU/mL and/or anti-Dsg3 values of 48 or more IU/mL yielded 0.83 positive predictive value and 0.94 negative predictive value to predict long-term relapse. Conclusions and Relevance: In this secondary analysis of the Ritux 3 trail, first-line treatment of patients with pemphigus with the Ritux 3 regimen was associated with long-term sustained complete remission without corticosteroid therapy without any additional maintenance infusion of rituximab.

Assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including medium- and high-dose corticosteroids.

BACKGROUND: Few studies have evaluated pemphigus treatments according to the definitions of the consensus statement. Prognostic factors for complete remission off therapy (CRoffT) remain unknown. OBJECTIVE: We sought to assess the rate of CRoffT in patients with pemphigus treated with different regimens. METHODS: In all, 134 patients with pemphigus were included in a retrospective, multicenter study. Primary end point was the rate of CRoffT. Prognostic factors for CRoffT were determined using univariate and multivariate analyses. RESULTS: Eighty patients with pemphigus vulgaris, 47 with pemphigus foliaceus, and 7 with paraneoplastic pemphigus were included. Mean age was 60 ± 18 years. Patients were treated either with medium (≤0.5 mg/kg/d) (n = 32) or high (≥1 mg/kg/d) (n = 59) doses of prednisone, or without systemic corticosteroids (n = 43). Mean follow-up was 77 ± 64 months. In all, 68 patients (50.7%) achieved CRoffT (95% confidence interval 42.3%-59.2%) after a mean treatment duration of 36 ± 39 months, including 47 of 80 patients with pemphigus vulgaris (58.7%) and 21 of 47 with pemphigus foliaceus (44.7%). Main prognostic factors for CRoffT were initial mucosal involvement (hazard ratio 2.2; 95% confidence interval 1.05-4.58; P = .036) and younger age (<61 years) (hazard ratio 2.5; 95% confidence interval 1.18-5.12; P = .0167). The rate of long-lasting CRoffT was 44%, with a mean follow-up after treatment withdrawal of 59 ± 50 months. LIMITATIONS: This was a retrospective study. CONCLUSION: The rate of CRoffT was 51%. Patients with pemphigus vulgaris were more likely to achieve CRoffT than those with pemphigus foliaceus.

Gliptin-induced bullous pemphigoid: withdrawal of gliptin allows for faster control of the disease

Background: Gliptins, also called dipeptidyl peptidase-4 inhibitors, have been incriminated in the development of bullous pemphigoid (BP). To date, there are no recommendations regarding the therapeutic approach for BP during gliptin intake. Objectives: The aim of this retrospective study was to evaluate the evolution of BP after three months relative to continuation or discontinuation of gliptin. Materials & Methods: From a series of 372 patients with BP, 40 taking gliptin were included (January 2009 to December 2019). The primary endpoint was complete response, three months after BP diagnosis based on gliptin continuation or discontinuation. The secondary endpoints were complete response after one month and six months. Results: Of BP patients, 67.5% were taking vildagliptin. BP was diagnosed at a mean period of 28.8 months after gliptin initiation. Gliptin was continued and discontinued each in 20 patients. Three months after diagnosis, patients who stopped gliptin had a significatively better clinical status (p = 0.0006). Thirteen patients had complete response when gliptin was stopped, compared to one patient when gliptin was continued. This difference was maintained after six months (p = 0.0031). There was no difference between the treatments received by patients who stopped gliptin and those who continued treatment (p = 0.7515). Conclusion: In this retrospective study, two groups were compared; one that continued gliptin and the other that stopped the drug. The results obtained suggest that stopping gliptin allows for a complete response rate at three months and six months, whereas gliptin maintenance did not allow for complete response.

An open label, non-randomised, phase IIIb study of trametinib in combination with dabrafenib in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: A subgroup analysis of patients with brain metastases.

BACKGROUND: Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T). PATIENTS AND METHODS: This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05. RESULTS: Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors. CONCLUSION: This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.

Solar urticaria treated with intravenous immunoglobulins.

BACKGROUND: Solar urticaria (SU) is a rare idiopathic photodermatosis induced immediately after sun exposure. This disorder may considerably restrict normal daily life and management is extremely difficult when treatment with oral H1 antihistamines and sun avoidance are ineffective. OBJECTIVE: We sought to report the effectiveness of intravenous immunoglobulins (IVIG) in severe SU. METHODS: We performed a retrospective multicentric study via the mailing of a questionnaire to the French photodermatology units to analyze all cases of patients with SU who were treated with IVIG. RESULTS: Seven patients (5 women) with a mean age of 40 years (range 32-55 years) and a mean disease duration of 5 years (range 2-10 years) received IVIG. The administration schedule differed from one patient to another: 1.4 to 2.5 g/kg were infused over 2 to 5 days. Five of 7 patients obtained a complete remission. The number of courses necessary to obtain clinical remission varied from 1 to 3 courses. Complete remission was maintained during 4 to more than 12 months but antihistamines were still required. In one case, psoralen plus ultraviolet A photochemotherapy was administered. LIMITATIONS: Retrospective study design, limited number of patients, and variations in the IVIG administration schedule could limit the interpretation of the results. CONCLUSION: Our case series suggests a beneficial effect of IVIG in severe SU but additional prospective trials including a larger number of patients are needed to demonstrate the effectiveness of IVIG and to specify the optimal modalities of their administration in this disease.