利妥昔单抗在天疱疮的应用

天疱疮是一种严重的自身免疫性大疱病,部分病例对传统治疗的疗效不佳.近几年临床研究发现,利妥昔单抗可明显提高天疱疮患者的临床治愈率,且可获得长期缓解,复发后再次治疗的安全性与临床缓解率仍较理想.利妥昔单抗不仅适用于重症难治性天疱疮,也有治疗轻至中度甚至儿童天疱疮的相关报道.目前已有较多关于利妥昔单抗不同单次治疗剂量或总剂量使天疱疮病情缓解的报道.利妥昔单抗可联合用药提高临床缓解率,其在安全剂量内仍会出现相关不良反应.     

低剂量利妥昔单抗治疗51例天疱疮患者的护理

<正>近年来,糖皮质激素联合使用利妥昔单抗(Rituximab,RTX)已成为天疱疮患者一线治疗方案,且利妥昔单抗治疗天疱疮的效果得到了充分认可[1]。联合使用利妥昔单抗既可有效缩短糖皮质激素减量时间,减少糖皮质激素或免疫抑制剂的用量,又可有效避免长期大剂量糖皮质激素和免疫抑制带来的严重并发症(如严重感染、股骨头坏死、白内障等)。     

自体外周血造血干细胞移植治疗重症天疱疮三例

目的 探讨自体外周血造血干细胞移植治疗天疱疮的疗效及安全性.方法 选择经糖皮质激素、免疫抑制剂等治疗6个月以上病情仍难以控制或病情进展、且出现治疗相关并发症的3例寻常型天疱疮患者进行自体外周血造血干细胞移植治疗,并随访5年以上.3例中男1例,女2例,平均年龄27.3(21～39)岁.造血干细胞的动员方案为环磷酰胺4g/m2、重组人粒细胞集落刺激因子(G-CSF)、利妥昔单抗375 mg/m2;预处理方案为环磷酰胺50 mg·kg-1·d-1连用4d(移植前第6天到移植前第3天)、抗胸腺细胞球蛋白2.5 mg·kg-1·d-1连用4d(移植前第3天至移植当天)、利妥昔单抗600 mg/d于移植当天和移植后第7天静脉滴注.结果 3例天疱疮患者均获得成功植入,平均植活时间白细胞13.3 d(11 ～ 16d),血小板16.3 d(16～ 17d).监测各项免疫指标及相关抗体未见异常,免疫重建良好.随访期间,所有患者无严重并发症,生活质量较前明显提高.结论 自体外周血造血干细胞移植可能是治疗天疱疮有效且安全的新方法之一.     

抗CD20单克隆抗体治疗寻常型天疱疮研究进展

寻常型天疱疮是一种累及皮肤、黏膜,以泛发性水疱为特征的自身免疫性皮肤病,药物治疗寻常型天疱疮主要是通过抑制免疫系统,减少相关特异性抗体的产生,从而控制疾病的发展.目前糖皮质激素仍作为常规治疗的首选,而利妥昔单抗作为辅助治疗的一种抗CD20单克隆抗体,近年来已在寻常型天疱疮治疗中获得满意疗效.由于利妥昔单抗治疗可出现严重输液相关反应,增加感染风险,且价格昂贵、治疗累积时间长、易复发及耐药等缺点,临床上已减少了利妥昔单抗在寻常型天疱疮中的应用.新一代抗CD20单克隆抗体,克服了利妥昔单抗治疗的不良反应,有改善用药方式、减少治疗时间等优点,逐渐用于寻常型天疱疮治疗,新的研究成果给患者提供更多治疗选择.     

利妥昔单抗联合糖皮质激素治疗难治性大疱性皮肤病临床分析

目的:观察利妥昔单抗(联合糖皮质激素)治疗难治性大疱性皮肤病的临床疗效及不良反应.方法:14例确诊的难治性大疱性皮肤病(8例寻常型天疱疮、3例大疱性类天疱疮、2例获得性大疱性表皮松解症、1例红斑型天疱疮)患者,按体表面积375 mg/m2静脉滴注利妥昔单抗,每周1次,共4次(第1、8、15、22天).治疗前均做血、尿常规,肝、肾功能,血脂,血糖,电解质,免疫球蛋白,血清疱病特异抗体及外周血流式细胞仪CD3、CD19、CD20细胞计数等检查,并在治疗中以及治疗结束后定期复查.结果:14例患者中11例完全缓解,3例部分缓解.完全缓解的11例患者中,2例已完全停药;其余患者糖皮质激素逐渐减量中.3例部分缓解患者,皆已停用所有药物,皮损仅在外力碰撞后出现.出现2例复发病例;还有1例在治疗后3个月因肺部感染死亡.结论:利妥昔单抗(联合糖皮质激素)治疗难治性大疱性皮肤病有明确的疗效,且不良反应较少.     

抗CD20单克隆抗体在天疱疮治疗中的应用进展

天疱疮的传统治疗药物为糖皮质激素和免疫抑制剂,但副作用较大且易复发.利妥昔单抗是第一代人鼠嵌合型抗CD20的单克隆抗体,与B淋巴细胞跨膜抗原CD20结合后可通过多种机制将其清除.目前利妥昔单抗常用于中重度天疱疮患者的治疗,不仅有助于改善病情、减少复发,而且可以减少糖皮质激素用量从而减少激素相关不良反应.新一代人源化的抗...     

小剂量利妥昔单抗联合激素治疗难治性大疱性类天疱疮1例

报告1例大疱性类天疱疮患者。该患者曾接受过大剂量糖皮质激素和多种免疫抑制剂的治疗,但是皮损控制不佳,治疗期间皮疹多次复发,同时伴有多种治疗相关并发症。后停用免疫抑制剂,予利妥昔单抗（每次500 mg,共2次,间隔2周）联合中剂量激素进行治疗,皮疹得到控制。在治疗过程中和治疗后未出现严重不良反应。因此,利妥昔单抗可以作为难治性大疱性类天疱疮的一种有效治疗手段。     

利妥昔单抗治疗自身免疫性大疱病

自身免疫性大疱性皮肤病是一类少见的重症疾病,主要包括天疱疮和类天疱疮.近年来,多种生物制剂和靶向治疗陆续应用于自身免疫性大疱性皮肤病.目前在美国与欧洲,利妥昔单抗已作为中重度寻常型天疱疮的一线治疗方案.本文将对利妥昔单抗治疗自身免疫性大疱病的作用机制、治疗方案以及安全性做一概述.     

利妥昔单抗治疗自身免疫性大疱病的研究进展

自身免疫性大疱病是以患者体内B淋巴细胞产生自身抗体,破坏皮肤黏附结构为特征的一组皮肤病。利妥昔单抗作为一种新型的生物制剂,以B淋巴细胞表面的CD20抗原为靶点,导致B淋巴细胞清除,减少自身抗体的生成,从而达到治疗疾病的目的。在自身免疫性大疱病的治疗中,利妥昔单抗应用越来越多。该文对利妥昔单抗在天疱疮、大疱性类天疱疮、疱疹样皮炎、获得性大疱性表皮松解症等自身免疫性大疱病治疗中的应用进行综述。     

生物制剂和生物技术治疗天疱疮进展

天疱疮是一种慢性、复发性表皮内棘层松解性大疱性皮肤病,生物制剂和生物工程技术在天疱疮治疗中发挥一定作用。利妥昔单抗作为一种生物制剂,被国际专家共识推荐为天疱疮一线治疗方案。造血干细胞移植可重建患者的免疫系统,基于前期临床试验确切的疗效,造血干细胞移植已被应用于难治性天疱疮的治疗。调节性T细胞（regulatory T cells,Tregs）在维持自身免疫耐受和避免免疫反应过度损伤中发挥重要作用,应用Tregs过继回输治疗天疱疮前期试验疗效显著。本文综述了利妥昔单抗、干细胞技术以及Tregs过继治疗天疱疮的进展。     

Childhood pemphigus vulgaris successfully treated with rituximab

Pemphigus is a potentially fatal autoimmune epidermal bullous disorder. Rituximab is a novel therapy for the treatment of refractory pemphigus. However, there is limited clinical data on safety and efficacy of rituximab in pediatric age group. Herein, we report an 11-year-old boy of childhood pemphigus vulgaris who failed to respond to dexamethasone pulse therapy and was subsequently treated with rituximab and achieved complete remission.     

Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective open-label pilot study in five patients

BACKGROUND: Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B lymphocytes. There are reports of its efficacy in the treatment of autoimmune diseases, including pemphigus. OBJECTIVES: Prospectively to evaluate the efficacy of rituximab as adjuvant treatment for pemphigus vulgaris (PV). METHODS: Patients with PV were treated with intravenous rituximab (375 mg m(-2)) weekly for 4 weeks in this prospective open-label pilot study. Other concurrent immunosuppression was continued. RESULTS: Of five patients, one achieved complete remission and was able to cease all medication, while two achieved clearance of clinical lesions but continued on systemic therapy. Two patients had progressive disease. Time to response was 2-8 months, with a 13- to 18-month response duration. Response was associated with reduction in serum antiepithelial antibodies. Two patients had significant infectious complications (one developed community-acquired pneumonia associated with delayed-onset neutropenia and the other developed cytomegalovirus infection). CONCLUSIONS: Rituximab has shown efficacy in the treatment of PV. Patients on multiple immunosuppressives should be closely monitored for infectious complications.     

Treatment of severe pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins

BACKGROUND: Pemphigus is a life-threatening autoimmune blistering disease usually treated with high-dose corticosteroids and other immunosuppressants. However, this regimen may prove inadequate in severe cases and cause dangerous side-effects. While protein A immunoadsorption (PAIA) induces a rapid remission in severe pemphigus, the disease usually recurs once the treatment is stopped. In contrast, anti-CD20 antibody rituximab has a delayed onset of action but may lead to a long-term remission of pemphigus. OBJECTIVE: To develop a treatment protocol combining the rapid remission induced by PAIA with the positive long-term effects of rituximab. PATIENTS AND METHODS: Five patients with pemphigus vulgaris and two patients with pemphigus foliaceus were treated with a combination of PAIA, rituximab and conventional immunosuppressants. Patients who failed to respond to this therapy subsequently received intravenous immunoglobulins (IVIg). RESULTS: All seven patients showed a sharp decline of circulating autoantibody levels and rapid improvement of cutaneous and mucosal lesions within 4 weeks of therapy. Long-term remission was induced in three patients and one further patient showed a partial improvement of his disease. The three remaining patients who could not be weaned off PAIA and remained resistant to rituximab treatment showed a good response to IVIg therapy. CONCLUSION: The combination of PAIA and rituximab induces a rapid and durable remission in a subset of patients with severe pemphigus. IVIg therapy appears to be a good treatment option for rituximab nonresponders.     

Adjuvant rituximab treatment for pemphigus: A retrospective study of 45 patients at a single center with long‐term follow up

To evaluate the long‐term outcomes of rituximab in the treatment of pemphigus and the influence of disease duration and different dose of rituximab on the clinical response, 45 patients with refractory pemphigus treated with at least one cycle of two infusions of rituximab (375 mg/m² per infusion weekly) were retrospectively studied. All patients were followed up for more than 2 years. All patients achieved complete or partial remission within 8 months of the first cycle. Thirty‐four (76%) patients relapsed at a median of 17 months. All patients who received additional cycles after relapse achieved new remissions. Early use of rituximab within 1 year of disease duration and high‐dose therapy induced better outcomes, although the results in early use were not statistically significant. Acute respiratory distress syndrome occurred in one patient. Rituximab is effective in treating pemphigus, but relapses are frequent during long‐term follow up, and additional cycles are beneficial in relapsed cases. Early and high‐dose rituximab therapy may be more effective.     

Efficacy and safety of rituximab treatment in Indian pemphigus patients

Background Pemphigus is a potentially fatal autoimmune epidermal bullous disorder. Various treatment modalities have been described to treat pemphigus. In cases where the disease fails to respond to conventional therapy, rituximab has been shown to be effective. Objective To study the efficacy of rituximab in the treatment of resistant or severe pemphigus in Indian patients. Methods Patients with pemphigus were treated with intravenous rituximab 1000 mg in adults or 375 mg/m² body surface area in children by two doses, 15 days apart in this open labelled pilot study. Anti‐desmoglein1 (anti‐Dsg1) antibodies and anti‐desmoglein3 (anti‐Dsg3) antibodies were measured at the start of therapy and at the end of the follow‐up period. The outcome was studied in terms of control of disease activity (CD), complete remission (CR), partial remission (PR) and time to disease control (TDC) as defined by the consensus statement from the International Pemphigus Committee. Results A total of 9 (90%) of 10 patients responded to the treatment. Three (30%) had CR of disease and were off all treatment. Four (40%) patients had CR and were on low dose oral prednisolone. Two (20%) patients had PR and were on low dose prednisolone. One patient died of sepsis. The mean TDC was 8 weeks. Response to treatment showed good correlation with index values of anti‐Dsg1 antibody. Infusion‐related angioedema and sepsis were seen as complications due to rituximab administration. Conclusion Rituximab is effective in treating resistant and severe pemphigus in Indian patients. Acute complications can occur during rituximab infusion and require close monitoring.     

Low-dose rituximab is effective in pemphigus

Background Rituximab, an anti‐CD20 antibody, was shown in open series studies to be effective in treating pemphigus at a dose of 4 × 375 mg m^?2 as approved for B‐cell malignancies. Objectives We investigated whether a lower dose of rituximab is also effective for pemphigus. Methods Patients with pemphigus were treated with a single course of two infusions of rituximab (500 mg each) at an interval of 2 weeks. Clinical consensus late end points, B‐cell number, desmoglein 1 and desmoglein 3 indices were monitored. Results We enrolled 15 patients in the study: three with pemphigus foliaceus (PF) and 12 with pemphigus vulgaris (PV). The follow‐up was 32–152 weeks (median 94). All 15 patients responded to therapy. Eight patients achieved complete remission in a median period of 51 weeks (four on minimal therapy, four off therapy). Seven patients achieved partial remission in a median period of 34·5 weeks (five on minimal therapy, two off therapy). Relapses (40%) were seen between 53 and 103 weeks (median 97) after start of therapy. B‐cell numbers dropped to < 1% after first infusion, and remained undetectable in patients with sustained remission. The antidesmoglein 1 index correlated well with the clinical severity in PF, but this was less obvious in PV. Conclusions A low dose of rituximab is an effective and safe treatment for pemphigus. Relapses may occur, mostly at the end of the second year. Cost–effectiveness studies with a long follow‐up are required to determine the proper dosage of this expensive drug in pemphigus.     

Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature

BACKGROUND: Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab--to our knowledge the largest series of patients so far--and review the existing literature on the topic. OBSERVATION: The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m(2) once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed. CONCLUSIONS: Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease.     

Nocardiosis in a patient with pemphigus foliaceus treated with rituximab

Rituximab is a chimeric human/murine monoclonal anti‐CD20 antibody. This agent is an effective therapeutic option in severe types of pemphigus. However, rituximab may cause opportunistic infections if used in immunosuppressed patients. We reported a case of diffuse Nocardia infection following rituximab treatment in pemphigus foliaceus. Rheumatoid arthritis protocol applied in our patient. Rituximab was used at a dose of 1000 mg every 2 weeks. Because the disease was not adequately controlled, rituximab treatment was administered six times every 15 days. One week after the sixth dose of the rituximab, she presented lassitude and multiple palpable masses in soft tissue of the upper extremity. Thereafter, the aspirate culture of the abscess on the left shoulder was taken and confirmed to be disseminated nocardiosis. She was treated with linezolid and meropenem for 1 month; however, amikacin was added because the patient did not respond adequately to linezolid and meropenem therapy. The patient died of cardiac arrest because of her comorbidities. In this case, prolonged administration of rituximab therapy may have caused the development of nocardiosis. Therefore, all patients should have a sensible balance of risk and benefit, considering the use of rituximab.     

Rituximab therapy for refractory autoimmune bullous diseases: A multicenter,open‐label,single‐arm,phase 1/2 study on 10 Japanese patients

This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m² of body surface area). The primary end‐points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19‐positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan.