Abstract：
BACKGROUND: Glucocorticoids (GCs) plus rituximab (RTX) represent the first-line treatment of nonviral mixed cryoglobulinemia vasculitis (CryoVas). However, data on therapeutic management and outcome of patients refractory to RTX are lacking.
METHODS: We conducted a European collaborative retrospective multicenter study of patients with nonviral mixed CryoVas refractory to RTX and performed a literature review.
RESULTS: Twenty-six original cases and 7 additional patients from the literature were included. All patients but one had type 2 cryoglobulinemia, and causes were autoimmune disease (51%), malignant hemopathy (12%) or essential CryoVas (42%). CryoVas was primary refractory to RTX in 42%, while 58% had an initial response to RTX before immune escape. After RTX failure, patients received a median of 1 (IQR, 1-3) line of treatment, representing 65 treatment periods during follow-up. Main treatments used were GCs in 92%, alkylating agents in 43%, RTX in combination with other treatments in 46%, and belimumab in 17%. Combination of anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents provided the highest rates of clinical response in 100% 82% and 73%, respectively, but showed poor immunological response, in 50%, 30% and 38%, respectively. Rates of severe infection were 57%, 9% and 0% in patients receiving anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents, respectively.
CONCLUSIONS: In patients with nonviral mixed CryoVas refractory to RTX, anti-CD20 plus belimumab, and alkylating agents associated or not with anti-CD20, provide the highest rates of clinical response. However, anti-CD20 plus belimumab was frequently associated with severe infections.
METHODS: We conducted a European collaborative retrospective multicenter study of patients with nonviral mixed CryoVas refractory to RTX and performed a literature review.
RESULTS: Twenty-six original cases and 7 additional patients from the literature were included. All patients but one had type 2 cryoglobulinemia, and causes were autoimmune disease (51%), malignant hemopathy (12%) or essential CryoVas (42%). CryoVas was primary refractory to RTX in 42%, while 58% had an initial response to RTX before immune escape. After RTX failure, patients received a median of 1 (IQR, 1-3) line of treatment, representing 65 treatment periods during follow-up. Main treatments used were GCs in 92%, alkylating agents in 43%, RTX in combination with other treatments in 46%, and belimumab in 17%. Combination of anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents provided the highest rates of clinical response in 100% 82% and 73%, respectively, but showed poor immunological response, in 50%, 30% and 38%, respectively. Rates of severe infection were 57%, 9% and 0% in patients receiving anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents, respectively.
CONCLUSIONS: In patients with nonviral mixed CryoVas refractory to RTX, anti-CD20 plus belimumab, and alkylating agents associated or not with anti-CD20, provide the highest rates of clinical response. However, anti-CD20 plus belimumab was frequently associated with severe infections.
摘要：
背景：糖皮质激素（GC）加利妥昔单抗（RTX）代表非病毒性混合型冷球蛋白血症血管炎（CryoVas）的一线治疗。然而,缺乏RTX难治性患者的治疗管理和结局数据.
方法：我们进行了一项欧洲合作的多中心回顾性研究，研究了RTX难治的非病毒混合CryoVas患者，并进行了文献综述。
结果：纳入了文献中的26例原始病例和7例其他患者。除1例患者外，所有患者均患有2型冷球蛋白血症，原因是自身免疫性疾病（51%），恶性血液病（12％）或原发性CryoVas（42％）。CryoVas对RTX的主要难治性为42％，而58%的人在免疫逃逸之前对RTX有初始反应。RTX失败后，患者接受的中位数为1(IQR，1-3）处理线，代表随访期间的65个治疗期。使用的主要治疗方法是92%的GC，烷基化剂占43%，RTX与其他治疗的组合占46%，和贝利木单抗占17%。抗CD20联合贝利木单抗，单用烷化剂和抗CD20加烷化剂提供了最高的临床反应率，分别为100%82%和73%，分别,但表现出不良的免疫反应，在50%，30%和38%,分别。严重感染率为57%,在接受抗CD20加贝利木单抗的患者中，分别为9%和0%，单独的烷化剂和抗CD20加烷化剂，分别。
结论：在RTX难治的非病毒混合CryoVas患者中，抗CD20加贝利木单抗，和与抗CD20相关或不相关的烷化剂提供最高的临床反应率。然而,抗CD20+贝利木单抗常与严重感染相关.
方法：我们进行了一项欧洲合作的多中心回顾性研究，研究了RTX难治的非病毒混合CryoVas患者，并进行了文献综述。
结果：纳入了文献中的26例原始病例和7例其他患者。除1例患者外，所有患者均患有2型冷球蛋白血症，原因是自身免疫性疾病（51%），恶性血液病（12％）或原发性CryoVas（42％）。CryoVas对RTX的主要难治性为42％，而58%的人在免疫逃逸之前对RTX有初始反应。RTX失败后，患者接受的中位数为1(IQR，1-3）处理线，代表随访期间的65个治疗期。使用的主要治疗方法是92%的GC，烷基化剂占43%，RTX与其他治疗的组合占46%，和贝利木单抗占17%。抗CD20联合贝利木单抗，单用烷化剂和抗CD20加烷化剂提供了最高的临床反应率，分别为100%82%和73%，分别,但表现出不良的免疫反应，在50%，30%和38%,分别。严重感染率为57%,在接受抗CD20加贝利木单抗的患者中，分别为9%和0%，单独的烷化剂和抗CD20加烷化剂，分别。
结论：在RTX难治的非病毒混合CryoVas患者中，抗CD20加贝利木单抗，和与抗CD20相关或不相关的烷化剂提供最高的临床反应率。然而,抗CD20+贝利木单抗常与严重感染相关.
