RESUMO
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.
Assuntos
Pênfigo , Humanos , Rituximab/efeitos adversos , Pênfigo/tratamento farmacológico , Prednisona/efeitos adversos , Seguimentos , Recidiva Local de Neoplasia , Corticosteroides , Recidiva , Resultado do TratamentoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by aberrant immune hyperactivation of T CD8 lymphocytes and macrophages driven by cytokine dysfunction. We report a 64-year-old man, with advanced BRAF-mutant melanoma treated by combined targeted therapies who had a recalcitrant and cortico-dependent Epstein-Barr virus (EBV)-induced HLH. One rituximab cycle led to a rapid and prolonged HLH remission which allowed to switch the targeted therapy for immunotherapy rituximab thus makes it possible to limit the use of corticosteroids, which limits the effectiveness of immunotherapy. The patient finally died of a cerebral tumoral progression 2 years later. Despite secondary hypogammaglobulinemia, we did not observe any severe infections during this period. This case suggests that rituximab can be a valuable option for EBV-induced HLH to avoid the T-suppressive effects of high-dose of corticosteroids in immunotherapy-treated patients.
Assuntos
Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Melanoma , Neoplasias Cutâneas , Masculino , Humanos , Pessoa de Meia-Idade , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Rituximab/farmacologia , Rituximab/uso terapêutico , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Herpesvirus Humano 4 , Melanoma/complicações , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
Many treatments are currently proposed for treating patients with bullous pemphigoid (BP). We assessed treatment modalities of BP depending on the different countries, BP extent, and patients' comorbidities. We surveyed worldwide experts about how they treat patients with BP. A total of 61 experts from 27 countries completed the survey. Severe and moderate BP were treated with oral prednisone (61.4 and 53.7%, respectively) or superpotent topical corticosteroids (CSs) (38.6 and 46.3%, respectively). Conventional immunosuppressants were more frequently combined with oral prednisone (74.5%) than with superpotent topical CS (37.5%) in severe BP. Topical CSs were mainly used in Europe in mild (81.1%), moderate (55.3%), and severe (54.3%) BP. In the United States of America and Asia, systemic CSs were mainly proposed for treating severe (77.8 and 100%, respectively), moderate (70 and 77.8%, respectively), and also mild (47.1 and 33.3%, respectively) BP. Most experts reduced the initial dose of oral CS in patients with diabetes mellitus (48.1%) or cardiac insufficiency (40.2%) but rarely changed BP treatment in patients with neurological disorders or neoplasia. This survey showed major differences in the way patients with BP are treated between AmeriPac countries (United State of America, Latin America, and Australia) and Asia on the one hand and Europe and the Middle East on the other hand.
RESUMO
The efficacy of the B-cell-depleting agent rituximab has been reported in immune diseases but relapses are frequent, suggesting the need for repeated infusions. The B-cell activating factor (BAFF) is an important factor for B cell survival, class switch recombination and selection of autoreactive B cells, as well as maintaining long-lived plasma cells. It has been hypothesized that relapses after rituximab might be due to the increase of serum BAFF levels. From the Ritux3 trial, we showed that baseline serum BAFF levels were higher in pemphigus patients than in healthy donors (308 ± 13 pg/mL versus 252 ± 28 pg/mL, p=0.037) and in patients with early relapse compared who didn't (368 ± 92 vs 297 ± 118 pg/mL, p=0.036). Rituximab and high doses of CS alone have different effects on the BAFF/BAFF-R axis. Rituximab led to an increase of BAFF levels associated to a decreased mRNA (Day 0: 12.3 ± 7.6 AU vs Month 36: 3.3 ± 4.3 AU, p=0.01) and mean fluorescence intensity of BAFF-R in non-autoreactive (Day 0: 3232 vs Month 36: 1527, mean difference: 1705, 95%CI: 624 to 2786; p=0.002) as well as on reappearing autoreactive DSG-specific B cells (Day 0: 3873 vs Month 36: 2688, mean difference: 1185, 95%CI: -380 to 2750; p=0.20). Starting high doses of corticosteroids allowed a transitory decrease of serum BAFF levels that re-increased after doses tapering whereas it did not modify BAFF-R expression in autoreactive and non-autoreactive B cells. Our results suggest that the activation of autoreactive B cells at the onset of pemphigus is likely to be related to the presence of high BAFF serum levels and that the decreased BAFF-R expression after rituximab might be responsible for the delayed generation of memory B cells, resulting in a rather long period of mild pemphigus activity after rituximab therapy. Conversely, the incomplete B cell depletion and persistent BAFF-R expression associated with high BAFF serum levels might explain the high number of relapses in patients treated with CS alone.
Assuntos
Corticosteroides/uso terapêutico , Fator Ativador de Células B/sangue , Receptor do Fator Ativador de Células B/metabolismo , Pênfigo/tratamento farmacológico , Rituximab/uso terapêutico , Receptor do Fator Ativador de Células B/genética , Linfócitos B/citologia , Linfócitos B/metabolismo , Humanos , Fatores Imunológicos/uso terapêutico , Pênfigo/sangue , Pênfigo/imunologia , RNA Mensageiro/metabolismoRESUMO
Pemphigus is an autoimmune blistering disease mediated by autoantibodies directed against desmogleins (DSGs). We recently showed that first-line treatment with rituximab (RTX) enables more patients to achieve long-lasting remission off therapy than corticosteroids alone. To understand the immunological mechanisms that mediate long-lasting clinical remission after RTX treatment, we analyzed the phenotype of DSG-specific memory B cells and DSG-specific T follicular helper cells by flow cytometry and measured antibody-secreting cells by enzyme-linked immune absorbent spot in patients treated with corticosteroids alone or RTX. This post hoc analysis of the RITUX3 trial showed that RTX induced a significant decrease of IgG-switched DSG-specific memory B cells. Accordingly, anti-DSG antibody-secreting cells were no longer detected in patients in complete remission after RTX. In contrast, corticosteroids did not modify the frequency or the phenotype of DSG-specific memory B cells, and anti-DSG antibody-secreting cells were still detected after treatment, even in patients in remission. Using peptide-HLADRB1∗0402 tetramer staining, we identified DSG-3-specific T follicular helper cells, which dramatically decreased after RTX, while remaining stable after corticosteroid treatment. Our findings suggest that long-lasting response to RTX in pemphigus relies on the decrease of DSG-specific circulating T follicular helper cells, which correlates with a sustained depletion of IgG-switched memory autoreactive B cells, leading to the disappearance of anti-DSG antibody-secreting cells.
Assuntos
Corticosteroides/uso terapêutico , Subpopulações de Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunossupressores/uso terapêutico , Pênfigo/imunologia , Rituximab/uso terapêutico , Linfócitos T Auxiliares-Indutores/imunologia , Autoimunidade , Células Cultivadas , Desmogleínas/imunologia , Cadeias HLA-DRB1/metabolismo , Humanos , Memória Imunológica , Imunofenotipagem , Interleucinas/sangue , Pênfigo/tratamento farmacológicoRESUMO
HHV-6B is the subtype most often involved in the systemic manifestations of the DRESS, but also in myelosuppression in bone marrow transplant. We report a new observation of its myelosuppressive effect: a case of DRESS complicated by agranulocytosis with detectable HHV-6 RNA in bone marrow.
RESUMO
BACKGROUND: Immune Checkpoint Inhibitors (ICPIs) are promising new drugs in treatment of advanced tumours targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD1) or its ligand (PDL-1). Ipilimumab is a monoclonal antibody targeting the CTLA-4 receptor used in treatment of metastatic melanoma. By increasing activity of the immune system, ICPIs lead to immune-related adverse events, such as dermatitis, colitis or hepatitis. ICPIs-related kidney adverse events are rare and acute tubulointerstitial nephritis with or without granuloma have mainly been reported. CASE PRESENTATION: We report a case of acute kidney injury in a patient with melanoma treated by ipilimumab. Kidney biopsy revealed acute interlobular and juxtaglomerular granulomatous arteritis, which has not yet been reported in patients treated by ICPIs. Kidney function partially recovered after ipilimumab discontinuation and oral prednisone. Unfortunately, the patient died a few months later from progression of his melanoma. CONCLUSION: This case highlights a new mechanism of acute kidney injury related to ICPIs and supports the interest of kidney biopsy in case of ICPIs related acute renal failure.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Antineoplásicos Imunológicos/efeitos adversos , Ipilimumab/efeitos adversos , Vasculite do Sistema Nervoso Central/induzido quimicamente , Vasculite do Sistema Nervoso Central/diagnóstico , Idoso , Evolução Fatal , Humanos , MasculinoRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Pênfigo/tratamento farmacológico , Prednisolona/administração & dosagem , Rituximab/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/efeitos adversos , Estudos Prospectivos , Rituximab/efeitos adversos , Resultado do TratamentoRESUMO
Bullous pemphigoid, a dermatosis of the elderly. Bullous pemphigoid is the most common autoimmune bullous disease and affects almost exclusively the elderly. Its occurrence is related to the presence of pathogenic autoantibodies directed against structural proteins (BP180 and BP230) of the protein adhesion complex of the dermo-epidermal junction: the hemi-desmosome. Bullous pemphigoid is classically characterized by pruritus and the appearance of blisters on an inflammatory background with a symmetrical topography: thighs, arms and trunk. Blisters eventually break, leading to erosions. Mucosal involvement is rare. Histology of a cutaneous biopsy finds a subepidermal blister containing eosinophils. Direct immunofluorescence confirms the diagnosis by the presence of linear deposits of IgG and C3 along the epidermal basement membrane. The reference treatment is the superpotent topical corticosteroid therapy (clobetasol propionate).
La pemphigoïde bulleuse, une dermatose du sujet âgé. La pemphigoïde bulleuse est la dermatose bulleuse auto-immune la plus fréquente et elle touche quasi exclusivement la personne âgée. Sa survenue est liée à la présence d'autoanticorps pathogènes dirigés contre des protéines de structure (BP180 et BP230) du complexe protéique d'adhésion de la jonction dermo-épidermique : l'hémidesmosome. La pemphigoïde bulleuse se manifeste classiquement par un prurit et l'apparition de bulles sur fond inflammatoire avec une topographie symétrique : cuisses, bras, tronc. Les bulles finissent par se rompre, laissant la place à des érosions. L'atteinte muqueuse est rare. L'histologie d'une biopsie cutanée montre une bulle sous-épidermique contenant des polynucléaires éosinophiles. L'immuno- fluorescence directe affirme le diagnostic par la présence de dépôts linéaires d'immunoglobuline de type G et de C3 le long de la membrane basale épidermique. Le traitement de référence est la corticothérapie locale très forte (propionate de clobétasol).