Treatment sequences of biological and targeted synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis: A nationwide population-based study in France

Article

作者: Fautrel, Bruno ; Lemeille, Pauline ; Molto, Anna ; Panes, Arnaud ; Arnaud, Laurent ; Chartier, Mélanie

OBJECTIVES:

The study aimed to describe nationwide treatment sequences in French patients with rheumatoid arthritis (RA) initiating a first biological or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD).

METHODS:

This analysis is based on the French National Health Claims Database (SNDS), covering over 67 million people. Patients with RA (ICD-10 codes M05, M060, M068 or M069) and ≥2 b/tsDMARD dispensings from January 1, 2014 to December 31, 2019 were included, and followed until December 31, 2020 or death. Differences in patients characteristics at each b/tsDMARD initiation were tested with Mann Whitney U tests and χ² tests.

RESULTS:

Overall, 26 478 patients were identified (mean (SD) age 57.0 years (±14.4)) including 70.9% females. The most frequent first-line of b/tsDMARD were TNF inhibitors (TNFi) (62.6%), followed by abatacept (CTLA4-Ig) (12.0%), rituximab (11.0%), IL-6R inhibitors (IL-6Ri) (10.0%), and JAK inhibitors (JAKi) (3.9%). The mean (SD) follow-up duration was 3.8 years (±1.7 years,), for a total of 100 332 person-years. Throughout the study period, 12,662 patients (47.8%) maintained their first b/tsDMARD, while 7531 (28.4%) switched to a second b/tsDMARD, and 3046 (11.1%) to a third b/tsDMARD, after a mean duration of 54.1 (±34.0), 31.9 (±27.8) and 25.9 (±22.2) months, respectively. In terms of mode of action associated profiles, the main discrepancies were age, higher in CD20i and LT modulator patients, and comorbidities, more prevalent in CD20i treated patients.

CONCLUSION:

In this nation-wide analysis of 26 478 patients, TNFi was the most frequently dispensed first-line b/tsDMARD, with LT modulators and IL-6i preferred in second-line therapy.

2026-04-01·Hematology Transfusion and Cell Therapy

Acute fibrinous and organizing pneumonia after bone marrow transplantation, an underrecognized, severe condition

Review

作者: Testagrossa, Leonardo de Abreu ; Pogorzelski, Gabriella ; Novis, Yana ; Seiwald, Maria Cristina Nunez ; Cortez, Anita Cassoli ; Costa, André Nathan ; Ferreira, Aliana Meneses ; da Fonseca, Ana Rita Brito Medeiros

INTRODUCTION:

Allogeneic bone marrow transplantation can lead to various pulmonary complications, including acute fibrinous organizing pneumonia. This condition is rare and presents with aggressive clinical features, distinct from other forms of organizing pneumonia, such as cryptogenic organizing pneumonia.

METHOD:

A literature review using the PubMed, Embase, Lilacs, and Cochrane databases was conducted to analyze cases of acute fibrinous organizing pneumonia following transplantation focusing on clinical features, therapeutic approaches, and outcomes.

CASE REPORT:

The case of a 62-year-old female who developed acute fibrinous organizing pneumonia after transplantation for acute myeloid leukemia is presented. Despite an initial absence of infectious agents, parainfluenza virus was later identified in a bronchoalveolar lavage. The patient progressed to severe hypoxemic respiratory failure and was unresponsive to corticosteroids and rituximab, ultimately dying seven months post-transplant.

CONCLUSION:

This is a rare and severe complication following allogeneic bone marrow transplantation. Early diagnosis, histopathological confirmation, and prompt initiation of corticosteroid therapy are critical for improving outcomes. Patients diagnosed before Day +100 generally have a better response to treatment and more favorable clinical outcomes. The need for a more effective and targeted treatment strategy remains an unmet challenge in managing this condition.

2026-04-01·RADIOTHERAPY AND ONCOLOGY

Secondary outcomes of the TROG 99.03 randomized trial of systemic therapy after involved-field radiotherapy in early-stage follicular lymphoma, including toxicity, relapse and second malignancy data

Article

作者: Johnstone, Philippa ; MacManus, Michael ; Ahmad, Haris ; Bressel, Mathias ; Seymour, John F ; Juneja, Surender

BACKGROUND AND PURPOSE:

The recently-updated TROG 99.03/ALLGLow5 multicentre randomised controlled trial showed that long-term progression-free survival (PFS) in early-stage (I-II) follicular lymphoma (ESFL) after involved-field radiotherapy (IFRT) was dramatically improved by adjuvant rituximab-cyclophosphamide/vincristine/prednisolone (R-CVP) but not CVP. Secondary analyses are presented here.

MATERIALS AND METHODS:

We analysed toxicity of RT and RT plus systemic therapy, outcomes for discontinuous stage II disease, second malignancy risks, prognostic impact of indeterminate bone marrow (BM) aggregates and the effect of rituximab on histological transformation. BM trephines from 55 patients from the pre-rituximab era were centrally reviewed.

RESULTS:

As previously-reported, 150 patients were randomised to IFRT (n = 75) or IFRT plus systemic therapy (n = 75). After 11.3 years median follow-up, IFRT + R-CVP was associated with improved PFS compared to IFRT or IFRT + CVP (HR 0.36, p = 0.01). Short-term RT-related grade I-II toxicity occurred in >90%, but toxicity after >6 months was rare. Worst acute systemic therapy toxicity was G1 (16 patients, G2 31 and G3 20) with 3 grade 3 neuropathies. R-CVP and CVP were equally toxic. Only 2 of 5 patients with non-contiguous stage II relapsed. Of 64 relapsed patients, 39 commenced salvage therapies and 17 had second progressions. Second malignancies showed no relationship to irradiated-volumes or systemic therapy use. Indeterminate BM aggregates did not worsen PFS.

CONCLUSION:

The improvement in PFS, reduced salvage therapy requirements, and prevention of histological transformation with R-CVP outweigh its significant but transient toxicity, supporting its justifiable use. Patients with indeterminate BM lymphoid aggregates or non-contiguous stage II FL may merit consideration for curative-intent treatment.

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项与利妥昔单抗生物类似药（DNARX）相关的新闻（医药）

2026-01-27

·国际糖尿病idiabetes

肾例明鉴丨八旬老人ANCA又升高、肾功能恶化，一定是血管炎复发吗？重复肾活检揭开罕见新发IgA肾病真相

点击“蓝字”关注我们编者按：抗中性粒细胞胞浆抗体（ANCA）相关血管炎（AAV）是一组以中小血管炎症和坏死及外周血中存在ANCA为特征的自身免疫性疾病，常累及肾脏，临床表现多为快速进展性肾小球肾炎（RPGN）。虽然AAV在维持治疗期间复发较为常见，但其合并或后续发生其他肾小球疾病，如IgA肾病的情况极为罕见。本文报道一例长期接受维持治疗的显微镜下多血管炎（MPA）患者，在出现临床指标恶化时，初诊考虑为AAV复发，但经重复肾活检最终诊断为新发IgA肾病[1]。本案例强调了在AAV患者出现病情变化时，应警惕合并其他肾小球疾病的可能，并及时进行肾活检以明确病理类型、指导个体化治疗。一、病历摘要 1. 患者基本信息患者81岁，女性。既往史：50岁时曾因直肠癌接受手术及化疗，无糖尿病、高血压等慢性病史。 2. 初次发病与诊断过程患者于9年前因“全身乏力”就诊，实验室检查提示蛋白尿、镜下血尿，血清肌酐在3个月内从0.56 mg/dl上升至2.01 mg/dl，符合快速进展性肾小球肾炎（RPGN）表现。图1展示了患者自首次发生急进性肾小球肾炎后的临床病程。进一步检查发现髓过氧化物酶-抗中性粒细胞胞浆抗体（MPO-ANCA）显著升高（110 U/ml），高度怀疑ANCA相关血管炎（AAV）。图1. 患者临床病程首次肾活检病理结果：光镜检查：共获取34个肾小球，其中1个呈全球性硬化。其余33个肾小球中，10个出现新月体形成（1个为细胞性新月体，9个为纤维细胞性新月体），3个见节段性坏死但无新月体形成（图2a, b）。肾小管萎缩与间质纤维化呈片状分布，伴单核细胞浸润。小动脉内膜增厚。免疫荧光检查：未见免疫复合物沉积（图2c）。电镜检查：未见电子致密物沉积（图2d）。病理诊断：符合寡免疫复合物新月体性肾炎，临床诊断为肾脏局限性AAV（显微镜下多血管炎，MPA）。图2. 首次肾活检病理表现 3. 初始治疗与维持期管理诱导缓解治疗：口服泼尼松龙30 mg/d（0.6 mg/kg/d）。治疗过程中，患者MPO-ANCA水平峰值达148.2 U/ml，血肌酐峰值达 2.97 mg/dl；经治疗后，MPO-ANCA水平逐渐下降至正常范围（<3.5 U/ml），血清肌酐稳定在约0.9 mg/dl，未需透析，后续尿常规检查显示恢复正常。维持治疗：泼尼松龙逐步减量，至治疗第3年时减至2 mg/d，并以此剂量长期维持。维持期波动：在维持治疗期间，患者曾两次出现MPO-ANCA升高伴镜下血尿，均通过暂时增加泼尼松龙剂量后缓解，临床考虑为AAV轻度复发。 4. 本次就诊与病情变化入院前1年，患者MPO-ANCA水平再次开始上升，最高达36.9 U/ml，但当时肌酐稳定，无血尿或蛋白尿。入院前3周，出现显著蛋白尿（尿蛋白/肌酐比值UPCR 3.22 g/gCr）、镜下血尿（20-29 RBC/HPF），血清肌酐升至1.01 mg/dl。临床考虑MPA复发，将泼尼松龙加量至15 mg/d。两周后，蛋白尿进一步加重（UPCR 3.44 g/gCr），血尿持续，肌酐升至1.28 mg/dl。遂将泼尼松龙增至30 mg/d，并收治入院进一步评估。入院时的关键实验室检查结果如下：MPO-ANCA 19 U/ml，血清肌酐 1.28 mg/dl，eGFR 31.3 mL/min/1.73 m²，UPCR 3.44 g/gCr，尿红细胞，50-99/HPF；补体C3、C4水平正常。表1. 第二次肾活检时的实验室检查结果 5. 重复肾活检与诊断转折因临床高度怀疑AAV复发，入院后予阿伐可泮（avacopan，60 mg/d）并输注利妥昔单抗（RTX），并于入院一周后行重复肾活检。重复肾活检病理结果：光镜检查：39个肾小球中10个球性硬化。其余肾小球主要表现为系膜增生，无毛细血管内增生（图3a, b）。1个肾小球见节段性粘连，另1个见节段性纤维素样坏死伴小细胞新月体（图3c）。肾皮质25%区域可见间质纤维化与肾小管萎缩，10%区域伴炎性细胞浸润。小动脉可见玻璃样变，细小动脉内膜纤维性增厚显著。免疫荧光检查：系膜区见IgA（3+）、C3（2+）、纤维蛋白原（+）、κ及λ轻链（2+）沉积（图3d）。电镜检查：系膜区可见少量电子致密物沉积（图3e）。病理诊断：新发IgA肾病。根据牛津分型，诊断为M0 SI E0 T0 C1型。图3. 第二次肾活检病理表现 6. 治疗调整与随访结果基于重复肾活检结果，治疗方案立即调整：停用阿伐可泮，逐步减量泼尼松龙，并启动血管紧张素Ⅱ受体阻滞剂（ARB）治疗。暂缓后续利妥昔单抗治疗。转归：调整治疗后，患者MPO-ANCA水平下降，血清肌酐趋于稳定。3个月后复查，蛋白尿显著减少至0.46 g/gCr，镜下血尿消失，肾功能保持稳定。二、讨论及启示本病例为一罕见病例：显微镜下多血管炎患者接受低剂量泼尼松龙维持治疗期间，曾多次出现MPO-ANCA水平升高，临床高度怀疑抗AAV相关急进性肾小球肾炎复发，且每次增加泼尼松龙剂量后好转。本次就诊再次出现该抗体水平升高，重复肾活检却提示新发IgA肾病。 1. AAV合并其他肾小球疾病的罕见性 AAV的典型肾脏病理表现为寡免疫性新月体肾炎。尽管罕见，但文献中确有AAV合并其他肾小球疾病的个案报道。目前国内外报道的系统性红斑狼疮与AAV重叠病例约40例[2]。一项研究显示约12%的AAV患者并发膜性肾病[3]。AAV合并抗肾小球基底膜病的发病率较低，每年每百万人群中发病不足2例[4]，但在Goodpasture综合征患者中，约8.7%同时存在AAV[5] 。 IgA肾病与AAV共存则更为罕见。文献报道，在IgA肾病患者中，ANCA阳性率仅为0.2%~2%[6-10]。ANCA阳性的IgA肾病患者若伴有新月体形成，其临床与病理表现相较ANCA抗体阴性者更为严重，采用与肾受累型AAV相似的免疫抑制治疗方案可取得一定疗效[6,7,9]。 2. 本病例的诊断启示与临床挑战本例患者在长期MPA维持治疗中出现ANCA升高、蛋白尿、血尿及肾功能恶化，临床表现极似AAV复发。然而，重复肾活检揭示了截然不同的病理真相——新发IgA肾病。这突显了几个重要临床问题： ANCA滴度并非血管炎活动的绝对指标：ANCA水平升高可提示复发风险，但也可能与其他免疫活动或合并症相关。重复肾活检的关键作用：在临床与血清学表现不一致或预期治疗反应不佳时，重复肾活检是明确诊断、避免误治的“金标准”。高龄发病的思考：本例患者81岁时确诊为新发IgA肾病，该年龄段发病的IgA肾病本身即较为罕见，需考虑是否为继发性改变或与长期免疫抑制状态相关。 3. 治疗策略的差异与调整 AAV与IgA肾病的标准治疗方案存在显著不同。AAV（如MPA）常用糖皮质激素、利妥昔单抗、阿伐可泮、环磷酰胺诱导并维持缓解，控制血管炎活动；IgA肾病常用RAS阻滞剂（ACEI/ARB）、SGLT2i、靶向药物，旨在控制蛋白尿，延缓肾功能进展。利妥昔单抗和阿伐可泮并非IgA肾病的标准治疗药物。尽管有部分研究提示利妥昔单抗可有效减少IgA肾病患者的蛋白尿[11]，但一项开放标签随机对照试验显示，该药物对患者的肾功能及蛋白尿均无明显改善作用[12]。补体系统在包括 IgA 肾病在内的多种病因所致肾小球疾病的发病机制中均发挥关键作用，近年来多款靶向补体通路的新型治疗药物已研发上市[13]。一项开放标签探索性研究提示，阿伐可泮或可帮助减少IgA肾病患者的蛋白尿，但其研究样本量小、治疗周期短，研究结论存在一定局限性[14] 。本例患者因初诊怀疑显微镜下多血管炎复发，故使用了阿伐可泮和利妥昔单抗，此类药物是否对后续临床病程产生了一定影响，目前尚无法完全排除。但在确诊IgA肾病后，及时停用阿伐可泮、减量激素、加用ARB，患者病情迅速好转。这印证了病理指导治疗的重要性。 4. 发病机制的探讨：偶发还是关联？关于AAV与IgA肾病并存，学界存在不同观点：重叠综合征假说：Haas等人提出可能存在“ANCA相关性新月体肾炎与IgA肾病重叠综合征”[6]。ANCA相关性新月体肾炎虽通常被定义为“寡免疫复合物型”，但有研究对126例ANCA阳性和/或伴坏死性动脉炎的新月体肾小球肾炎患者进行检测，发现54%的病例存在电子致密免疫复合物沉积，提示该疾病可能与IgA肾病等免疫复合物介导的肾小球肾炎存在一定关联[15] 。偶然共存：两者均为免疫介导的肾病，在同一个体先后发生可能纯属偶然。Chebotareva等指出，IgA肾病合并抗中性粒细胞胞浆抗体阳性是偶然现象，还是一种独立的疾病亚型，目前仍存争议[16]。共同通路激活：ANCA介导的中性粒细胞活化与补体系统激活，可能加剧IgA免疫复合物在肾脏的沉积与炎症反应，形成恶性循环。该患者长期接受免疫抑制治疗，其免疫环境改变是否促发了IgA肾病的发生，值得进一步探究。 5. 临床实践建议与未来方向基于本案例，我们提出以下建议：提高临床警惕：对于AAV患者，尤其是长期维持治疗者，若出现ANCA升高伴蛋白尿/血尿，除考虑复发外，应纳入合并其他肾小球疾病的鉴别诊断。积极实施重复肾活检：当临床怀疑与初始诊断不符或治疗反应不佳时，应积极考虑重复肾活检以明确病理。个体化治疗决策：治疗方案应严格基于当前病理诊断，动态评估，避免盲目强化免疫抑制。加强病例积累与研究：此类罕见共存病例的详细记录与长期随访，有助于厘清两者关联，优化治疗策略。总结本案例揭示，在ANCA相关血管炎的长期管理过程中，临床医生需保持开阔的鉴别诊断思维。即使面对典型的复发征象，也存在合并其他肾小球疾病（如IgA肾病）的可能性。重复肾活检在此类复杂情境中具有不可替代的诊断价值，是实现精准医疗、改善患者预后的关键步骤。未来亟待更多病例的积累与跨学科研究，以深入理解AAV与IgA肾病之间的潜在联系与机制。参考文献上下滑动可查看 1.Seina Iwami, et al. Repeat kidney biopsy reveals new-onset IgA nephropathy in a patient with ANCA-associated vasculitis. CEN Case Rep. 2026 Jan 20;15(1):23. doi: 10.1007/s13730-025-01056-4. 2.Hounoki H, Shinoda K, Matsui A, et al. A case of systemic lupus erythematosus and antineutrophil cytoplasmic antibodies-associated vasculitis overlap syndrome. Case Rep Rheumatol. 2021;2021:6690658. 3.Zou R, Liu G, Cui Z, Chen M, Zhao MH. Clinical and immunologic characteristics of patients with ANCA-associated glomerulonephritis combined with membranous nephropathy: a retrospective cohort study in a single Chinese center. Med (Baltimore). 2015;94:e1472. 4.Canney M, O’Hara PV, McEvoy CM, et al. Spatial and temporal clustering of anti-glomerular basement membrane disease. Clin J Am Soc Nephrol. 2016;11:1392–9. 5.Thongprayoon C, Kaewput W, Boonpheng B, et al. Impact of ANCA-associated vasculitis on outcomes of hospitalizations for goodpasture’s syndrome in the United States: nationwide inpatient sample 2003-2014. Med (Kaunas). 2020;56:103. 6.Haas M, Jafri J, Bartosh SM, Karp SL, Adler SG, Meehan SM. ANCA-associated crescentic glomerulonephritis with mesangial IgA deposits. Am J Kidney Dis. 2000;36:709–18. 7.Bantis C, Stangou M, Schlaugat C, et al. Is presence of ANCA in crescentic IgA nephropathy a coincidence or novel clinical entity? A case series. Am J Kidney Dis. 2010;55:259–68. 8.Huang X, Wang Y, Xie L, et al. IgA nephropathy with anti-neutrophil cytoplasmic antibody seropositivity. Clin Nephrol. 2015;84:156–64. 9.Yang YZ, Shi SF, Chen YQ, et al. Clinical features of IgA nephropathy with serum ANCA positivity: a retrospective case-control study. Clin Kidney J. 2015;8:482–8. 10.Xie L, He J, Liu X, et al. Clinical value of systemic symptoms in IgA nephropathy with ANCA positivity. Clin Rheumatol. 2018;37:1953–61. 11.Li J, Nie Z, Li G, Bao B. Efficacy and safety of rituximab in primary IgA nephropathy: a retrospective study. Clin Exp Nephrol. 2025;29:616–23. 12.Lafayette RA, Canetta PA, Rovin BH, et al. A randomized, controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction. J Am Soc Nephrol. 2017;28:1306–13. 13.Cheung CK, Dormer JP, Barratt J. The role of complement in glomerulonephritis-are novel therapies ready for prime time? Nephrol Dial Transpl. 2023;38:1789–97.24. 14.Bruchfeld A, Magin H, Nachman P, et al. C5a receptor inhibitor avacopan in immunoglobulin A nephropathy-an open-label pilot study. Clin Kidney J. 2022;15:922–8. 15.Haas M, Eustace JA. Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int. 2004;65:2145–52. 16.Chebotareva N, Kamyshova E, Bulanov N, Lysenko L, Moiseev S. Antineutrophil cytoplasmic autoantibody (ANCA) positive immunoglobulin A (IgA) nephropathy: case reports and review of literature. Egypt Rheumatol. 2020;42:251–4. 声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！（来源：《肾医线》编辑部）

2026-01-19

·免疫新视野

突破性研究！利妥昔单抗治疗原发性干燥综合征，疗效与安全性再添新证

干燥综合征（Sjögrensyndrome，SS）是一种系统性自身免疫性疾病，以淋巴细胞增殖、外分泌腺进行性破坏和自身抗体的存在为特征。SS常见的临床表现为干燥、疲劳及肌肉骨骼疼痛等，亦可出现全身症状。SS可分为原发性和继发性，不合并其他结缔组织病的SS称为原发性干燥综合征（primarySjögrensyndrome，pSS）。流行病学调查显示SS为全球性疾病，我国患病率为0.33%～0.77%，好发于中老年人，且以女性多见[1]。该病治疗现状不佳，生物制剂、免疫抑制剂在临床随机对照试验（RCT）或系统评价与Meta分析中并未提示显著的临床疗效。利妥昔单抗，作为一种靶向清除B细胞的明星药物，在治疗红斑狼疮、类风湿关节炎等领域已显身手。那么，它能否成为攻克干燥综合征的一把“密钥”？近期，一项发表在《FrontiersinImmunology》（免疫学前沿）的高质量荟萃分析，对现有临床试验数据进行了全面梳理，为我们揭示了利妥昔单抗在pSS治疗中的“真实力”。研究背景原发性干燥综合征的发病机制复杂，目前认为与遗传、环境因素引发的异常免疫反应密切相关，其中 B 细胞的过度活化和自身抗体产生是关键病理环节。然而，当前临床缺乏基于循证医学的有效治疗药物，多数治疗依赖经验用药或借鉴同类疾病方案，效果有限。利妥昔单抗（RTX）是一种靶向 B 细胞表面 CD20 抗原的嵌合单克隆抗体，通过触发免疫反应破坏 B 细胞，已在类风湿关节炎、系统性红斑狼疮等自身免疫病中广泛应用。早在 2003 年，就有研究证实其对合并淋巴瘤的干燥综合征患者有效，但关于其治疗 pSS 的临床证据一直存在争议：部分研究显示可改善疲劳、社会功能等指标，另一部分则认为其临床效果和成本效益均不理想。因此，亟需通过荟萃分析整合现有研究，明确其在 pSS 治疗中的真实价值。研究目的本研究旨在系统评估利妥昔单抗治疗原发性干燥综合征的有效性和安全性。研究方法文献检索策略系统检索了PubMed、Embase、Cochrane Library及Web of Science数据库，检索时间自各库建库起，2023年12月，并辅以手工检索相关综述及参考文献。检索词围绕“干燥综合征”及其同义词与“利妥昔单抗”及其相关名称进行组合。纳入与排除标准 ◉ 纳入标准： ①研究类型为国内外发表的中、英文随机对照试验； ②旨在评估利妥昔单抗治疗pSS的疗效，观察期为24周； ③试验组符合2010年ACR/EULAR分类标准； ④干预措施为利妥昔单抗单药或联合糖皮质激素/改善病情抗风湿药；对照组为安慰剂、糖皮质激素或改善病情抗风湿药； ⑤报告了指定的疗效或安全性结局指标。 ◉ 排除标准： ①无对照组或对照组仅为单药改善病情抗风湿药研究； ②利妥昔单抗给药剂量与频率非“1000mg、每两周一次”方案； ③随访期未涵盖24周； ④无法获取全文或精确数据。数据提取与质量评价由两名研究者独立提取资料，包括研究基本信息（如样本量、年龄、干预措施）和结局指标数据。使用QUADAS-2工具对纳入研究的偏倚风险进行独立评价，分歧通过协商或咨询专家解决。统计分析使用Stata 14.0软件进行分析。根据异质性检验结果（采用I²统计量进行评估），选择随机效应模型或固定效应模型合并数据。对连续变量，根据度量单位一致性采用加权MD或标准化MD作为效应量。采用漏斗图与Egger检验评估发表偏倚，若存在偏倚则使用“剪补法”评估结果的稳健性。研究结果本项荟萃分析共纳入5篇文献（图1），涉及338名患者（表1），其中实验组183人，对照组155人。所有参与者均接受标准药物治疗。图 1 研究筛选表 1 纳入研究的基本特征 ESSDAI研究纳入三项RCTs，共277人。采用固定效应模型的荟萃分析显示，利妥昔单抗组与对照组在治疗前后的ESSDAI评分均无统计学显著差异[MD=0.28, 95%CI (-0.59, 1.14)]。此外，利妥昔单抗组未显著降低患者的ESSDAI评分（图2）。图 2 第24周ESSDAI评分的荟萃分析结果 ESSPRI评分纳入两项RCTs，共157名参与者。采用固定效应模型的荟萃分析显示，与对照组相比，利妥昔单抗组的ESSPRI评分显著降低[MD=0.78，95% CI（0.24, 1.33）]。这表明利妥昔单抗治疗能有效降低患者的ESSPRI评分（图3）。图 3 第24周ESSPRI评分的荟萃分析结果两项RCTs共144例患者，使用视觉模拟量表（VAS）评估疼痛。采用固定效应模型的荟萃分析显示，利妥昔单抗组治疗前后疼痛VAS评分的差异更大。这表明利妥昔单抗显著降低了患者的疼痛VAS评分，具有统计学显著差异[MD=0.39，95% CI（0.06, 0.72）]（图4）。 VAS疲劳评分纳入四项RCTs，共294例患者。采用随机效应模型的荟萃分析显示，利妥昔单抗组与对照组在疲劳VAS评分治疗前后的变化无显著差异[MD = -0.28，95% CI（-0.93, 0.37）]。利妥昔单抗组未显著降低VAS疲劳评分（图4）。三项RCTs（15, 19, 21）共174例患者评估了口腔干燥VAS评分。根据固定效应模型荟萃分析，利妥昔单抗组与对照组在治疗前后的口干VAS评分均无显著差异[MD = -0.51，95% CI（-0.87, -0.15）]。利妥昔单抗组未显著降低口干VAS评分（图4）。图 4 第24周视觉模拟量表（VAS）评分的荟萃分析结果四项RCTs涉及300例患者，使用了SF-36评分。采用随机效应模型的荟萃分析表明，利妥昔单抗组与对照组在SF-36评分方面，无论治疗前后均无显著差异[MD=5.83，95%CI（-1.02, 12.69）]。利妥昔单抗治疗组未显示SF-36评分显著降低（图5）。图 5 第24周SF-36生活质量的荟萃分析结果两项RCTs共54名参与者评估了刺激性唾液流率。固定效应模型荟萃分析显示，利妥昔单抗组与对照组之间无统计学显著差异[MD=0.10，95%CI（-0.20, 0.40）]。表明利妥昔单抗未增加患者的刺激性唾液流率（图6）。四项RCTs共307例患者测量了非刺激性唾液流率。采用固定效应模型的荟萃分析显示，两组之间未观察到统计学显著差异[MD = 0.05，95% CI（-0.01, 0.11）]。显然，利妥昔单抗对唾液流率没有积极影响（图7）。图 6 第24周刺激性唾液流率的荟萃分析结果图 7 第24周非刺激性唾液流率的荟萃分析结果 Schirmer试验包含四项RCTs，共312例患者。采用随机效应模型的荟萃分析显示，两组之间无统计学显著差异[MD=0.35，95% CI（-0.22, 0.91）]。已发现利妥昔单抗对患者的泪腺功能没有积极影响（图8）。图 8 第24周Schirmer试验结果的荟萃分析两项RCTs，共144例患者，对IgG指标进行评估，采用固定效应模型的荟萃分析显示，与对照组相比，利妥昔单抗组的IgG水平显著降低[MD=-1.19，95%CI(-1.61，-0.77)]。但两组间IgG水平无明显统计学差异（图9）。图 9 第24周免疫球蛋白G（IgG）水平的荟萃分析结果两项RCTs共54名参与者使用了RF评分。固定效应模型荟萃分析显示，两组之间无统计学显著差异[MD = -56.52，95% CI（-141.27, 28.22）]。利妥昔单抗组未降低RF水平（图10）。图 10 第24周类风湿因子（RF）水平的荟萃分析结果 C4评分包含两项RCTs，共144例患者。根据随机效应模型荟萃分析，两组无统计学显著差异[MD=0.05，95%CI（-0.04, 0.15）]。结果表明利妥昔单抗组未能升高C4水平（图11）。图 11 第24周补体C4水平的荟萃分析结果 B细胞分别纳入两项RCTs，共54例患者。采用随机效应模型的荟萃分析显示，两组之间无统计学显著差异[MD]= -1.29，95%CI（-1.91, -0.67）]。结果表明，利妥昔单抗治疗组的B细胞浓度显著降低（图12）。图 12 第24周B细胞水平的荟萃分析结果为评估感染可能性，分析了三项RCTs，共402例患者。采用固定效应模型的荟萃分析表明，两组之间无统计学显著差异[MD = 1.00，95% CI（0.61, 1.63）]。两组间的感染风险无显著差异。研究结论研究表明，利妥昔单抗可以降低干燥综合征患者的血清IgG和血清B细胞水平，并能显著改善患者的ESSPRI评分和疼痛VAS评分。然而，它对腺体功能没有显著影响。不良事件的发生率与对照组相似。参考文献 [1]姜泉 ,周新尧 ,唐晓颇 ,等.干燥综合征病证结合诊疗指南[J].中医杂志,2024,65(04):434-444.DOI:10.13288/j.11-2166/r.2024.04.017. [2] Zheng X, Di J, Chen X, Li F, Liu Y, Cao J, et al. Meta-analysis of the efficacy and safety of rituximab in the treatment of primary Sjögren's syndrome[J]. Front Immunol. 2025 Jun 24;16:1561214. DOI: 10.3389/fimmu.2025.1561214.

2026-01-16

·FiercePharma

After AbbVie and Genmab's ph. 3 survival miss for Epkinly in DLBCL, what's next?

In the wake of the mixed results, the partners "will engage global regulatory authorities to discuss next steps," according to the release. Just days after AbbVie unveiled a major new oncology play in the form of its high-dollar RemeGen collab, the Illinois drugmaker closed out the week with some mixed news for its marketed cancer offering Epkinly.Friday afternoon, the company and its partner Genmab shared word that the phase 3 Epcore DLBCL-1 trial missed on its primary endpoint of overall survival. Specifically, the partners' Epkinly failed to mount a statistically significant OS benefit among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The trial enrolled 483 adult patients with relapsed/refractory DLBCL, 73% of whom had previously tried at least two prior lines of therapy. Investigators tested AbbVie and Genmab's CD3xCD20 bispecific antibody, Epkinly, as a monotherapy compared with investigator's choice of chemoimmunotherapy.OS is the trial's primary outcome measure, according to the study plan shown on ClinicalTrials.gov.Despite the primary endpoint miss, AbbVie and Genmab were quick to point out that the trial showed a 26% improvement in the risk of disease progression or death, a secondary measure.Besides demonstrating an improvement in progression-free survival, Epkinly also showed improvements in complete response rates, duration of response and time to next treatment, the partners said. Those are secondary outcome measures, as well, according to the ClinicalTrials.gov listing.The partners didn't share the full phase 3 data but said they would be presented at an upcoming medical meeting. In the Friday release, the companies said they "will engage global regulatory authorities to discuss next steps." In addition, the companies plan to look at how "various factors," including the pandemic and the availability of novel anti-lymphoma agents, may have played into the results. The trial started in early 2021 and is ongoing. Epkinly already carries an accelerated approval as a third-line treatment for relapsed/refractory DLBCL, based on overall response rate (ORR) and duration of response (DOR) results from a prior trial, its FDA label shows. Specifically, in the open-label phase 1/2 Epcore NHL-1 trial, the overall response rate was 61%. Of those responders, the median duration of response was 15.6 months.While the Epcore DLBCL-1 result may raise more questions than answers, the companies have another major shot on goal for Epkinly underway with the Epcore DLBCL-2 trial. The phase 3 study in first-line DLBCL is expected to read out this year after starting in 2023, which should make its results free from pandemic-era variability. The study includes the R-CHOP treatment regimen in both the Epkinly and control arms. While Epkinly isn't AbbVie's largest sales driver, the drug has continued its commercial upswing since its initial nod back in 2023. Worldwide sales reported by AbbVie through the first nine months of 2025 were $190 million compared with $146 million during all of 2024.The drug in November scored an approval in second-line follicular lymphoma (FL) when combined with rituximab and lenalidomide, further expanding its reach in the lymphoma space. Before that, it was cleared as a third-line FL therapy.