Rituximab Therapy Leads to Rapid Decline of Serum IgG4 Levels and Prompt Clinical Improvement in IgG4-Related Systemic Disease
Rituximab Therapy Leads to Rapid Decline of Serum IgG4 Levels and Prompt Clinical Improvement in IgG4-Related Systemic Disease
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DOI：
10.1002/art.27435
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发表时间：
2010-06-01
影响因子：
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通讯作者：
Stone, John H.
中科院分区：
文献类型：
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作者：
Khosroshahi, Arezou;Bloch, Donald B.;Stone, John H.
Objective. IgG 4相关系统性疾病（IgG 4-RSD）患者经常对糖皮质激素和传统疾病缓解抗风湿药物（DMARD）治疗表现出不完全反应。B淋巴细胞耗竭是已知对寻常天疱疮有效的治疗策略，寻常天疱疮是由IgG 4自身抗体介导的自身免疫性疾病。本研究旨在评估利妥昔单抗对IgG 4-RSD患者B淋巴细胞清除治疗的临床和血清学应答。4例IgG 4-RSD患者接受2次静脉给药（每次1 g）利妥昔单抗治疗。通过监测泼尼松和DMARDs的减量/停药，以及通过测量治疗前后B淋巴细胞、免疫球蛋白和IgG亚类的血清浓度来评估临床改善。4例IgG 4-RSD患者的临床特征包括自身免疫性胰腺炎、硬化性胆管炎、淋巴浆细胞性胰腺炎、涎腺受累、眼眶假瘤和泪腺肿大。基线血清IgG和IgG 4水平升高的3例患者的平均IgG浓度为2，003 mg/dl（正常范围600- 1，500 mg/dl），平均IgG 4浓度为2，160 mg/dl（正常范围8-140 mg/dl）。在这些患者中，血清IgG 4浓度在利妥昔单抗给药后2个月内平均下降65%。所有4例患者在开始利妥昔单抗治疗后1个月内均表现出显著的临床改善，所有4例患者均实现了泼尼松和DMARD治疗的逐渐减少或停止。仅观察到IgG 4亚类的IgG浓度降低。利妥昔单抗治疗导致这些难治性IgG 4-RSD患者的临床和血清学迅速改善，是这种疾病的可行治疗选择。血清IgG 4浓度的下降明显比利妥昔单抗有效的免疫介导的疾病（如类风湿性关节炎）中自身抗体浓度的下降更陡。此外，IgG亚类水平的降低似乎对IgG 4具有特异性。IgG 4-RSD的迅速改善表明利妥昔单抗通过耗尽补充短寿命的分泌IgG 4的浆细胞的B淋巴细胞库来实现其在IgG 4-RSD中的作用。
Objective. Patients with IgG4-related systemic disease (IgG4-RSD) frequently show an incomplete response to treatment with glucocorticoids and traditional disease-modifying antirheumatic drugs (DMARDs). B lymphocyte depletion is a therapeutic strategy known to be effective for pemphigus vulgaris, an autoimmune condition mediated by IgG4 autoantibodies. This study was performed to assess the clinical and serologic responses to B lymphocyte depletion therapy with rituximab in patients with IgG4-RSD.Methods. Four patients with IgG4-RSD were treated with 2 intravenous doses (1 gram each) of rituximab. Clinical improvement was assessed by monitoring the tapering/discontinuation of prednisone and DMARDs, and by measuring the serum concentrations of B lymphocytes, immunoglobulins, and IgG subclasses before and after therapy.Results. Clinical features of IgG4-RSD in these 4 patients included autoimmune pancreatitis, sclerosing cholangitis, lymphoplasmacytic aortitis, salivary gland involvement, orbital pseudotumor, and lacrimal gland enlargement. The 3 patients with elevated serum IgG and IgG4 levels at baseline had a mean IgG concentration of 2,003 mg/dl (normal range 600-1,500 mg/dl) and a mean IgG4 concentration of 2,160 mg/dl (normal range 8-140 mg/dl). Among these patients, the serum IgG4 concentrations declined by a mean of 65% within 2 months of rituximab administration. All 4 patients demonstrated striking clinical improvement within 1 month of the initiation of rituximab therapy, and tapering or discontinuation of their treatment with prednisone and DMARDs was achieved in all 4 patients. A decrease in IgG concentration was observed for the IgG4 subclass only.Conclusion. Treatment with rituximab led to prompt clinical and serologic improvement in these patients with refractory IgG4-RSD, and is a viable treatment option for this condition. The decline in serum IgG4 concentrations was substantially steeper than that of the autoantibody concentrations in immune-mediated conditions in which rituximab is effective, such as in rheumatoid arthritis. In addition, the reduction in IgG-subclass levels appeared to be specific for IgG4. The swift improvement of IgG4-RSD suggests that rituximab achieves its effects in IgG4-RSD by depleting the pool of B lymphocytes that replenish short-lived IgG4-secreting plasma cells.