BACKGROUND Sporadic cases of rheumatoid arthritis(RA)due to unsatisfactory responses to Abatacept(ABT)have been reported;however,the rescue therapy has not been finalized.Here,we present a case with difficult-to-treat...BACKGROUND Sporadic cases of rheumatoid arthritis(RA)due to unsatisfactory responses to Abatacept(ABT)have been reported;however,the rescue therapy has not been finalized.Here,we present a case with difficult-to-treat RA(D2T RA)that was resistant to either a single ABT or a Janus kinase(JAK)inhibitor(Tofacitinib),but improved with a combination of ABT and JAK inhibitor(Baricitinib,BAT).CASE SUMMARY A 46-year-old Chinese woman who had RA for ten years that was resistant to Tocilizumab,Etanercept,Adalimumab,and ABT.According to the European League Against Rheumatism definition,the patient was diagnosed with D2T RA.It was then improved with a combination of ABT and a JAK inhibitor BAT.CONCLUSION ABT combined with BAT may be an acceptable strategy for treating D2T RA.展开更多
BACKGROUND Cytotoxic T Lymphocyte Antigen-4(CTLA4)deficiency is a genetic defect that causes a common variable immunodeficiency(CVID)clinical phenotype.Several studies have reported an association between CTLA mutatio...BACKGROUND Cytotoxic T Lymphocyte Antigen-4(CTLA4)deficiency is a genetic defect that causes a common variable immunodeficiency(CVID)clinical phenotype.Several studies have reported an association between CTLA mutations or variants and various autoimmune diseases.Targeted therapy models,which have become increasingly popular in recent years,have been successful in treating CTLA4 deficiency.In this article,we discuss the clinical outcomes of abatacept treatment in a patient with CTLA4 and lipopolysaccharide-responsive beige-like anchor(LRBA)variants that was previously diagnosed with CVID.CASE SUMMARY A 25-year-old female patient,who was visibly cachectic,visited our clinic over the course of five years,complaining of diarrhea.The patient was diagnosed with ulcerative colitis in the centers she had visited previously,and various treatments were administered;however,clinical improvement could not be achieved.Severe hypokalemia was detected during an examination.Her serum immunoglobulin levels,CD19+B-cell percentage,and CD4/CD8 ratio were low.An endoscopic examination revealed erosive gastritis,nodular duodenitis,and pancolitis.Histopathological findings supported the presence of immune mediated enteropathy.When the patient was examined carefully,she was diagnosed with CVID,and intravenous immunoglobulin treatment was initiated.Peroral and rectal therapeutic drugs including steroid therapy episodes were administered to treat the immune mediated enteropathy.Strict follow-ups and treatment were performed due to the hypokalemia.After conducting genetic analyses,the CTLA4 and LRBA variants were identified and abatacept treatment was initiated.With targeted therapy,the patient’s clinical and laboratory findings rapidly regressed,and there was an increase in weight.CONCLUSION The heterozygous CTLA4 variant identified in the patient has been previously shown to be associated with various autoimmune diseases.The successful clinical outcome of abatacept treatment in this patient supports the idea that this variant plays a role in the immunopathogenesis of the disease.In the presence of severe disease,abatacept therapy should be considered until further testing can be conducted.展开更多
The incidence of anaphylactic reaction after the long-term use of abatacept has not been reported until now. Herein, we present a case of rheumatoid arthritis (RA) in which the patient experienced an anaphylactic reac...The incidence of anaphylactic reaction after the long-term use of abatacept has not been reported until now. Herein, we present a case of rheumatoid arthritis (RA) in which the patient experienced an anaphylactic reaction one year after initiation of treatment with abatacept. A 75-year-old woman visited our hospital with symptoms of bilateral knee pain and swelling. She was initially treated with methotrexate (6 mg/week increased to 8 mg/week). Two months later, because of inadequate response, self-injections of abatacept (subcutaneous;125 mg every two weeks) were prescribed. However, 6 months later, because of frequent stomatitis, the methotrexate dose was decreased to 6 mg/week, which resulted in worsening of RA. We changed the route of abatacept administration from subcutaneous injection to intravenous infusion (500 mg/month as a drip). After 30 min of starting the drip, the patient experienced itchiness and drop in vital signs, which were managed using methylprednisolone (2 doses, 125 mg each), dopamine hydrochloride (8 mg/h), and oxygen therapy (flow decreased from 3 L/min to 1 L/min). Wheals and redness were treated with oral antihistamines. Six hours after the onset of the anaphylactic reaction, the vital signs were stabilized. On the subsequent day, the patient’s general state was confirmed to be normal. One month later, etanercept (25 mg) treatment was initiated. The patient is currently in remission. We recommend caution when changing the route of administration and dosage of abatacept in anti-cyclic citrullinated peptide antibody-positive patients or those with a history of mild infusion-related reaction.展开更多
目的:临床中治疗类风湿性关节炎的生物制剂多种多样,其疗效及安全性差异尚不明确,文章旨在比较不同生物制剂治疗类风湿性关节炎的有效性及安全性的差异。方法:检索中国知网、维普、万方、中国生物医学文献系统数据库、PubMed、Cochrane...目的:临床中治疗类风湿性关节炎的生物制剂多种多样,其疗效及安全性差异尚不明确,文章旨在比较不同生物制剂治疗类风湿性关节炎的有效性及安全性的差异。方法:检索中国知网、维普、万方、中国生物医学文献系统数据库、PubMed、Cochrane图书馆、Web of Science和Embase数据库的文献,收集各数据库建库至2022-10-01符合要求的关于类风湿性关节炎生物制剂治疗的随机对照试验。运用EndNote软件筛选文献,RevMan 5.3软件对纳入的文献进行质量评价;采用Stata 14.2软件对ACR20(美国风湿学会20%缓解率)、ACR50(美国风湿学会50%缓解率)、ACR70(美国风湿学会70%缓解率)、红细胞沉降率及不良反应指标进行直接Meta分析及网状Meta分析。结果:共纳入符合要求的文献39篇,5篇低风险文献,4篇含高风险文献,剩余30篇含有风险未知偏倚,共13种治疗措施。网状Meta分析结果:①在ACR20方面,英夫利昔单抗联合甲氨蝶呤(OR=5.54,95%CI:1.33-23.01,P<0.05)、阿巴西普+甲氨蝶呤片(OR=3.21,95%CI:1.13-9.10,P<0.05)、托珠单抗(OR=2.95,95%CI:1.61-5.44,P<0.05)的治疗效果均优于甲氨蝶呤片,且排名靠前;ACR20概率排序结果为:英夫利昔单抗+甲氨蝶呤片>阿巴西普+甲氨蝶呤片>托珠单抗>培塞利珠单抗>依那西普+甲氨蝶呤片。②在ACR50方面,依那西普联合甲氨蝶呤片(OR=4.04,95%CI:2.13-7.66,P<0.05)、英夫利昔单抗联合甲氨蝶呤片(OR=4.79,95%CI:1.19-19.26,P<0.05)、托珠单抗联合甲氨蝶呤片(OR=3.54,95%CI:1.36-9.22,P<0.05)治疗效果优于甲氨蝶呤片,且排名靠前;ACR50概率排序结果为:依那西普+甲氨蝶呤片>英夫利昔单抗+甲氨蝶呤片>托珠单抗+甲氨蝶呤片>托珠单抗>培塞利珠单抗+甲氨蝶呤片。③在ACR70方面,英夫利昔单抗联合甲氨蝶呤片(OR=8.00,95%CI:2.31-27.69,P<0.05)、依那西普联合甲氨蝶呤片(OR=4.26,95%CI:2.51-7.21,P<0.05)、托珠单抗+甲氨蝶呤片(OR=3.51,95%CI:1.82-6.80,P<0.05)的治疗效果优于甲氨蝶呤片;ACR70概率排序结果为英夫利昔单抗+甲氨蝶呤片>依那西普+甲氨蝶呤片>托珠单抗+甲氨蝶呤片>培塞利珠单抗>阿达木单抗+甲氨蝶呤片。④在红细胞沉降率方面,依那西普联合甲氨蝶呤片(SMD=-9.23,95%CI:-16.55至-1.92,P<0.05)治疗效果优于依那西普及甲氨蝶呤片(SMD=14.59,95%CI:7.28-21.91,P<0.05)。红细胞沉降率概率排序结果为依那西普+甲氨蝶呤片>英夫利昔单抗+甲氨蝶呤片>依那西普>阿达木单抗+甲氨蝶呤片>甲氨蝶呤片。⑤在不良反应方面,安慰剂(OR=0.62,95%CI:0.39-0.99,P<0.05)优于英夫利昔单抗和培塞利珠单抗(OR=0.44,95%CI:0.25-0.78,P<0.05)。不良反应概率排序结果为安慰剂>英夫利昔单抗>依那西普+甲氨蝶呤片>培塞利珠单抗>依那西普。结论:基于39篇随机对照试验的文献证据表明,英夫利昔单抗联合甲氨蝶呤片(高级强推荐)在临床中可作为治疗类风湿性关节炎首选,有效性及安全性相对较好,依那西普联合甲氨蝶呤片(高级强推荐)可作为次选。展开更多
CTLA4 deficiency and LRBA deficiency are a group disorders of immune dysregula-tion that affect CTLA4 pathway.The patients mainly present with autoimmunity,antibody defi-ciency and recurrent infections.Here we reporte...CTLA4 deficiency and LRBA deficiency are a group disorders of immune dysregula-tion that affect CTLA4 pathway.The patients mainly present with autoimmunity,antibody defi-ciency and recurrent infections.Here we reported three Chinese patients with LRBA and CTLA4 mutations.They all presented with chronic diarrhea,hypokalemia,organomegaly,recurrent in-fections,and hypogammaglobulinemia.Reduced Treg cells and increased percentage of circu-lating follicular helper T(cTfh)cells were revealed in these patients.Although steroid and immunoglobulin therapy were given,the enteropathy was persistent.Therefore,abatacept treatment was provided to these patients.They showed a marked improvement of enteropathy and gastrointestinal endoscopy showed alleviated inflammatory lesion and follicular hyperpla-sia.Furthermore,the frequency of cTfh cells was reduced after abatacept therapy.Taken together,targeted therapy with abatacept is a promising treatment modality for patients with LRBA and CTLA4 deficiency.The findings also suggest that the frequency of cTfh cells could serve as a marker for tracking disease activity and the response to abatacept therapy.展开更多
Hepatitis B virus(HBV) reactivation in rheumatoid arthritis(RA) patients undergoing biological therapy is not infrequent. This condition can occur in patients with chronic hepatitis B as well as in patients with resol...Hepatitis B virus(HBV) reactivation in rheumatoid arthritis(RA) patients undergoing biological therapy is not infrequent. This condition can occur in patients with chronic hepatitis B as well as in patients with resolved HBV infection. Current recommendations are mainlyfocused on prevention and management strategies of viral reactivation under tumor necrosis factor-α inhibitors or chimeric monoclonal antibody rituximab. In recent years, growing data concerning HBV reactivation in RA patients treated with newer biological drugs like tocilizumab and abatacept have cumulated. In this review, epidemiology, pathogenesis and natural history of HBV infection have been revised first, mainly focusing on the role that specific therapeutic targets of current biotechnological drugs play in HBV pathobiology; finally we have summarized current evidences from scientific literature, including either observational studies and case reports as well, concerning HBV reactivation under different classes of biological drugs in RA patients. Taking all these evidences into account, some practical guidelines for screening, vaccination, prophylaxis and treatment of HBV reactivation have been proposed.展开更多
Costimulatory pathways(Cluster of differentiation 28,tumor necrosis factor-related,adhesion and T Cell Ig-and mucin-domain molecules) regulating the interactions between receptors on the T cells andtheir ligands expre...Costimulatory pathways(Cluster of differentiation 28,tumor necrosis factor-related,adhesion and T Cell Ig-and mucin-domain molecules) regulating the interactions between receptors on the T cells andtheir ligands expressed on several cell types,have a key role in controlling many immunological and non immunological processes.Indeed,accumulating evidence indicate that these molecules are involved in the pathogenesis of numerous conditions,such as allograft rejection,atherosclerosis,rheumatoid arthritis,psoriasis and renal diseases,including glomerulonephritis.Primary or secondary(i.e.,associated with infections,drugs or systemic diseases,such as systemic lupus erythematosus,diabetes,etc.) glomerulonephritis represent a group of heterogeneous diseases with different pathogenic mechanisms.Since costimulatory molecules,in particular CD80 and CD40,have been found to be expressed on podocytes in the course of different experimental and clinical glomerulonephritis,costimulation has been thought as a new therapeutic target for patients with glomerular diseases.However,although experimental data suggested that the blockade of costimulatory pathways is effective and safe in the prevention and treatment of glomerular diseases,clinical trials reported contrasting results.So,at this moment,there is not a strong evidence for the general use of costimulatory blockade as an alternative treatment strategy in patients with primary or secondary glomerulonephritis.Here,we critically discuss the current data and the main issues regarding the development of this innovative therapeutic approach.展开更多
文摘BACKGROUND Sporadic cases of rheumatoid arthritis(RA)due to unsatisfactory responses to Abatacept(ABT)have been reported;however,the rescue therapy has not been finalized.Here,we present a case with difficult-to-treat RA(D2T RA)that was resistant to either a single ABT or a Janus kinase(JAK)inhibitor(Tofacitinib),but improved with a combination of ABT and JAK inhibitor(Baricitinib,BAT).CASE SUMMARY A 46-year-old Chinese woman who had RA for ten years that was resistant to Tocilizumab,Etanercept,Adalimumab,and ABT.According to the European League Against Rheumatism definition,the patient was diagnosed with D2T RA.It was then improved with a combination of ABT and a JAK inhibitor BAT.CONCLUSION ABT combined with BAT may be an acceptable strategy for treating D2T RA.
文摘BACKGROUND Cytotoxic T Lymphocyte Antigen-4(CTLA4)deficiency is a genetic defect that causes a common variable immunodeficiency(CVID)clinical phenotype.Several studies have reported an association between CTLA mutations or variants and various autoimmune diseases.Targeted therapy models,which have become increasingly popular in recent years,have been successful in treating CTLA4 deficiency.In this article,we discuss the clinical outcomes of abatacept treatment in a patient with CTLA4 and lipopolysaccharide-responsive beige-like anchor(LRBA)variants that was previously diagnosed with CVID.CASE SUMMARY A 25-year-old female patient,who was visibly cachectic,visited our clinic over the course of five years,complaining of diarrhea.The patient was diagnosed with ulcerative colitis in the centers she had visited previously,and various treatments were administered;however,clinical improvement could not be achieved.Severe hypokalemia was detected during an examination.Her serum immunoglobulin levels,CD19+B-cell percentage,and CD4/CD8 ratio were low.An endoscopic examination revealed erosive gastritis,nodular duodenitis,and pancolitis.Histopathological findings supported the presence of immune mediated enteropathy.When the patient was examined carefully,she was diagnosed with CVID,and intravenous immunoglobulin treatment was initiated.Peroral and rectal therapeutic drugs including steroid therapy episodes were administered to treat the immune mediated enteropathy.Strict follow-ups and treatment were performed due to the hypokalemia.After conducting genetic analyses,the CTLA4 and LRBA variants were identified and abatacept treatment was initiated.With targeted therapy,the patient’s clinical and laboratory findings rapidly regressed,and there was an increase in weight.CONCLUSION The heterozygous CTLA4 variant identified in the patient has been previously shown to be associated with various autoimmune diseases.The successful clinical outcome of abatacept treatment in this patient supports the idea that this variant plays a role in the immunopathogenesis of the disease.In the presence of severe disease,abatacept therapy should be considered until further testing can be conducted.
文摘The incidence of anaphylactic reaction after the long-term use of abatacept has not been reported until now. Herein, we present a case of rheumatoid arthritis (RA) in which the patient experienced an anaphylactic reaction one year after initiation of treatment with abatacept. A 75-year-old woman visited our hospital with symptoms of bilateral knee pain and swelling. She was initially treated with methotrexate (6 mg/week increased to 8 mg/week). Two months later, because of inadequate response, self-injections of abatacept (subcutaneous;125 mg every two weeks) were prescribed. However, 6 months later, because of frequent stomatitis, the methotrexate dose was decreased to 6 mg/week, which resulted in worsening of RA. We changed the route of abatacept administration from subcutaneous injection to intravenous infusion (500 mg/month as a drip). After 30 min of starting the drip, the patient experienced itchiness and drop in vital signs, which were managed using methylprednisolone (2 doses, 125 mg each), dopamine hydrochloride (8 mg/h), and oxygen therapy (flow decreased from 3 L/min to 1 L/min). Wheals and redness were treated with oral antihistamines. Six hours after the onset of the anaphylactic reaction, the vital signs were stabilized. On the subsequent day, the patient’s general state was confirmed to be normal. One month later, etanercept (25 mg) treatment was initiated. The patient is currently in remission. We recommend caution when changing the route of administration and dosage of abatacept in anti-cyclic citrullinated peptide antibody-positive patients or those with a history of mild infusion-related reaction.
文摘目的:临床中治疗类风湿性关节炎的生物制剂多种多样,其疗效及安全性差异尚不明确,文章旨在比较不同生物制剂治疗类风湿性关节炎的有效性及安全性的差异。方法:检索中国知网、维普、万方、中国生物医学文献系统数据库、PubMed、Cochrane图书馆、Web of Science和Embase数据库的文献,收集各数据库建库至2022-10-01符合要求的关于类风湿性关节炎生物制剂治疗的随机对照试验。运用EndNote软件筛选文献,RevMan 5.3软件对纳入的文献进行质量评价;采用Stata 14.2软件对ACR20(美国风湿学会20%缓解率)、ACR50(美国风湿学会50%缓解率)、ACR70(美国风湿学会70%缓解率)、红细胞沉降率及不良反应指标进行直接Meta分析及网状Meta分析。结果:共纳入符合要求的文献39篇,5篇低风险文献,4篇含高风险文献,剩余30篇含有风险未知偏倚,共13种治疗措施。网状Meta分析结果:①在ACR20方面,英夫利昔单抗联合甲氨蝶呤(OR=5.54,95%CI:1.33-23.01,P<0.05)、阿巴西普+甲氨蝶呤片(OR=3.21,95%CI:1.13-9.10,P<0.05)、托珠单抗(OR=2.95,95%CI:1.61-5.44,P<0.05)的治疗效果均优于甲氨蝶呤片,且排名靠前;ACR20概率排序结果为:英夫利昔单抗+甲氨蝶呤片>阿巴西普+甲氨蝶呤片>托珠单抗>培塞利珠单抗>依那西普+甲氨蝶呤片。②在ACR50方面,依那西普联合甲氨蝶呤片(OR=4.04,95%CI:2.13-7.66,P<0.05)、英夫利昔单抗联合甲氨蝶呤片(OR=4.79,95%CI:1.19-19.26,P<0.05)、托珠单抗联合甲氨蝶呤片(OR=3.54,95%CI:1.36-9.22,P<0.05)治疗效果优于甲氨蝶呤片,且排名靠前;ACR50概率排序结果为:依那西普+甲氨蝶呤片>英夫利昔单抗+甲氨蝶呤片>托珠单抗+甲氨蝶呤片>托珠单抗>培塞利珠单抗+甲氨蝶呤片。③在ACR70方面,英夫利昔单抗联合甲氨蝶呤片(OR=8.00,95%CI:2.31-27.69,P<0.05)、依那西普联合甲氨蝶呤片(OR=4.26,95%CI:2.51-7.21,P<0.05)、托珠单抗+甲氨蝶呤片(OR=3.51,95%CI:1.82-6.80,P<0.05)的治疗效果优于甲氨蝶呤片;ACR70概率排序结果为英夫利昔单抗+甲氨蝶呤片>依那西普+甲氨蝶呤片>托珠单抗+甲氨蝶呤片>培塞利珠单抗>阿达木单抗+甲氨蝶呤片。④在红细胞沉降率方面,依那西普联合甲氨蝶呤片(SMD=-9.23,95%CI:-16.55至-1.92,P<0.05)治疗效果优于依那西普及甲氨蝶呤片(SMD=14.59,95%CI:7.28-21.91,P<0.05)。红细胞沉降率概率排序结果为依那西普+甲氨蝶呤片>英夫利昔单抗+甲氨蝶呤片>依那西普>阿达木单抗+甲氨蝶呤片>甲氨蝶呤片。⑤在不良反应方面,安慰剂(OR=0.62,95%CI:0.39-0.99,P<0.05)优于英夫利昔单抗和培塞利珠单抗(OR=0.44,95%CI:0.25-0.78,P<0.05)。不良反应概率排序结果为安慰剂>英夫利昔单抗>依那西普+甲氨蝶呤片>培塞利珠单抗>依那西普。结论:基于39篇随机对照试验的文献证据表明,英夫利昔单抗联合甲氨蝶呤片(高级强推荐)在临床中可作为治疗类风湿性关节炎首选,有效性及安全性相对较好,依那西普联合甲氨蝶呤片(高级强推荐)可作为次选。
基金This work was supported by the Research Fund for Outstanding Youth Scholar of Chongqing Talents[grant number CQYC201905003]Science and Technology Research Program of Chongqing Municipal Education Commission[grant number KJZD-M201800401]High-level Medical Reserved Personnel Training Project of Chongqing[grant number 2019181].
文摘CTLA4 deficiency and LRBA deficiency are a group disorders of immune dysregula-tion that affect CTLA4 pathway.The patients mainly present with autoimmunity,antibody defi-ciency and recurrent infections.Here we reported three Chinese patients with LRBA and CTLA4 mutations.They all presented with chronic diarrhea,hypokalemia,organomegaly,recurrent in-fections,and hypogammaglobulinemia.Reduced Treg cells and increased percentage of circu-lating follicular helper T(cTfh)cells were revealed in these patients.Although steroid and immunoglobulin therapy were given,the enteropathy was persistent.Therefore,abatacept treatment was provided to these patients.They showed a marked improvement of enteropathy and gastrointestinal endoscopy showed alleviated inflammatory lesion and follicular hyperpla-sia.Furthermore,the frequency of cTfh cells was reduced after abatacept therapy.Taken together,targeted therapy with abatacept is a promising treatment modality for patients with LRBA and CTLA4 deficiency.The findings also suggest that the frequency of cTfh cells could serve as a marker for tracking disease activity and the response to abatacept therapy.
文摘Hepatitis B virus(HBV) reactivation in rheumatoid arthritis(RA) patients undergoing biological therapy is not infrequent. This condition can occur in patients with chronic hepatitis B as well as in patients with resolved HBV infection. Current recommendations are mainlyfocused on prevention and management strategies of viral reactivation under tumor necrosis factor-α inhibitors or chimeric monoclonal antibody rituximab. In recent years, growing data concerning HBV reactivation in RA patients treated with newer biological drugs like tocilizumab and abatacept have cumulated. In this review, epidemiology, pathogenesis and natural history of HBV infection have been revised first, mainly focusing on the role that specific therapeutic targets of current biotechnological drugs play in HBV pathobiology; finally we have summarized current evidences from scientific literature, including either observational studies and case reports as well, concerning HBV reactivation under different classes of biological drugs in RA patients. Taking all these evidences into account, some practical guidelines for screening, vaccination, prophylaxis and treatment of HBV reactivation have been proposed.
文摘Costimulatory pathways(Cluster of differentiation 28,tumor necrosis factor-related,adhesion and T Cell Ig-and mucin-domain molecules) regulating the interactions between receptors on the T cells andtheir ligands expressed on several cell types,have a key role in controlling many immunological and non immunological processes.Indeed,accumulating evidence indicate that these molecules are involved in the pathogenesis of numerous conditions,such as allograft rejection,atherosclerosis,rheumatoid arthritis,psoriasis and renal diseases,including glomerulonephritis.Primary or secondary(i.e.,associated with infections,drugs or systemic diseases,such as systemic lupus erythematosus,diabetes,etc.) glomerulonephritis represent a group of heterogeneous diseases with different pathogenic mechanisms.Since costimulatory molecules,in particular CD80 and CD40,have been found to be expressed on podocytes in the course of different experimental and clinical glomerulonephritis,costimulation has been thought as a new therapeutic target for patients with glomerular diseases.However,although experimental data suggested that the blockade of costimulatory pathways is effective and safe in the prevention and treatment of glomerular diseases,clinical trials reported contrasting results.So,at this moment,there is not a strong evidence for the general use of costimulatory blockade as an alternative treatment strategy in patients with primary or secondary glomerulonephritis.Here,we critically discuss the current data and the main issues regarding the development of this innovative therapeutic approach.
