Pathogenesis and treatment studies in patients with NOMID and related diseases

NOMID及相关疾病患者的发病机制和治疗研究

• 批准号: 7732815
• 负责人: Raphaela Goldbach-Mansky
• 金额: $ 176.84万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732815
• 关键词: Adult; Adult-Onset Still' s Disease; Age; Anemia; Aseptic Meningitis; Autoimmune Diseases; Behcet Syndrome; Binding; Biological Markers; Blindness; Blood; Blood Cells; Bone Density; Bone Diseases; Bone Growth; CCL2 gene; CCL3 gene; Candidate Disease Gene; Cartilage; Child; Chronic; Classification; Clinical; Clinical Research; Collaborations; Complex; Contracture; Daily; Data; Deficiency Diseases; Development; Disease; Disease remission; Disease-Modifying Second-Line Drugs; Dose; Ear; Evaluation; Exanthema; Eye; Fever; Frameshift Mutation; Functional disorder; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Goals; Growth; Height; Hospitals; Hyperostosis; IL8 gene; Immune; Immune response; Impairment; In complete remission; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-6; Intervention; Investigation; Joints; Juvenile-Onset Still' s Disease; Laboratories; Lead; Lesion; Leukocytosis; Life; Light; Lytic Metastatic Lesion; Mediating; Mental Retardation; Metabolic; Missense Mutation; Molecular Profiling; Motor; Multicenter Studies; Mutation; Neonatal; Neurologic; Neutrophil Activation; Numbers; Organ; Osteolytic; Osteomyelitis; Outcome; Pain; Papilledema; Pathogenesis; Pathway interactions; Patients; Periostitis; Pharmaceutical Preparations; Prevention Protocols; Primary Prevention; Process; Production; Progressive Disease; Proteins; Psyche structure; Publishing; Pustular psoriasis; Recruitment Activity; Regulation; Research; Resolution; Role; Safety; Secondary Prevention; Sensorineural Hearing Loss; Sensory; Signal Pathway; Signs and Symptoms; Skin; Skin Manifestations; Small Inducible Cytokine A3; Steroids; Symptoms; Syndrome; TNF gene; Testing; Therapeutic Effect; Thinking; Time; Tissues; United States Food and Drug Administration; Urticaria; Vasculitis; Weight Gain; Whole Blood; anakinra; base; bone; bone loss; chemokine; clinical phenotype; cognitive function; concept; cysteine rich protein; cytokine; day; disability; disorder control; drug distribution; hearing impairment; improved; in vitro Model; inhibitor/antagonist; long bone; loss of function; mutant; novel; prevent; response; secretion process; thrombocytosis; treatment duration; treatment effect

RESEARCH ACCOMPLISHMENTS NOMID STUDIES: Neonatal-onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory/ autoimmune disorder characterized by urticarial rash, fever, aseptic meningitis, papilledema, sensorineural hearing loss, epiphyseal overgrowth of the long bones, growth retardation, and, in some cases, mental impairment. NOMID is at the severe end of a spectrum of disorders caused by mutations in CIAS1, which encodes a protein, cryopyrin, that is a key regulator of interleukin 1 (IL-1) beta activation. Results over the last year: CLINICAL: 1. We analyzed 3 year outcome data in 20 patients with NOMID who have been receiving escalating doses of anakinra in the attempt to achieve clinical complete remission of inflammatory symptoms. The initially observed good clinical response persists and the drug is overall well tolerated. However, in 3 patients with severe hearing loss at the beginning of the study, hearing loss progressed and intermittent low grade leptomeningeal inflammation was seen in up to 50% of patients at 3 years. Although no new bone lesions occurred with anakinra treatment, preexisting bony lesions continued to expand on treatment. 2. We assessed disability on treatment with anakinra and have seen significant improvement in pain and motor disability but not cognitive function. 3. In untreated patients, the chronic inflammation leads to significant metabolic changes that include growth retardation, bone loss and anemia. We showed that bone mineral density increases above the age-expected increase and see a rapid and sustained change in bone markers that indicate an increase in bone production. Anemia rapidly resolves and catch-up height and weight gains are seen when the inflammation is suppressed. LABORATORY: 1. IL-1 secretion in CIAS1 mutation-positive and -negative patients differs when PBMCs are examined and a new mutation was identified in Dr Kastners laboratory in a patient who was thought to be mutation negative. 2. Dr Kastners laboratory identified a specific microarray signature that distinguishes NOMID patients from patients with other autoinflammatory diseases. The disease specific gene expression profile will allow us to define an IL-1 signature that may allow us to identify shared immune pathways in other yet uncharacterized inflammatory diseases. FCAS STUDY: 1. We have published long term outcome data in patients on the mild end of the spectrum of cryopyrin associated periodic syndromes (CAPS). IL-1 Trap, rilonacept (Acrolyst), is a long-acting IL-1 inhibitor and compared to anakinra, which is administered daily, rilonacept needs to be injected weekly. IL-1 Trap is effective in controlling inflammation in FCAS patients and a multicenter study based on our initial PK and PD data has been conducted and led to the FDA approval of rilonacept for the indication of FCAS and MWS. ADULT ONSET STILL'S STUDIES We have currently recruited 5 patients with adult-onset Still's disease (AOSD) who are also treated with rilonacept. Initial data indicates a less uniform response to rilonacept with inflammatory remission observed in 2 out of 5 patients. Biomarker studies that help distinguish patients with and without an immediate response to IL-1 blockade are ongoing. OTHER AUTOINFLAMMATORY DISEASES: Treatment with the IL-1 inhibitor, anakinra, of a patient with neonatal-onset multifocal osteomyelitis, periostitis and pustulosis and severe systemic inflammation who was hospital bound, led to rapid resolution of all inflammatory signs and symptoms and prompted evaluation of new mutations in the IL-1 pathway. In collaboration with Drs. Kastner and Ferguson, sequencing of candidate genes in the IL-1 signaling pathway led to the identification of so far 3 different mutations in the IL1RN gene. In 2 cases a homozygous frameshift mutation (N52KfsX25) and a missense mutation (E77X) lead to premature truncation of the IL-1 receptor antagonist protein. A third patient is homozygous for a 170kb deletion that includes the IL1RN gene. Functional studies confirmed absent or very low expression of the mutant protein and complete loss of function. LPS or IL-1beta stimulation lead to increased expression of the pro-inflammatory cytokines and chemokines, IL-6, IL-8, MIP-1 alpha, TNF, and MCP-1, which are associated with neutrophil activation and recruitment upon stimulation of whole blood cells from the 3 patients. All children have been unresponsive to several DMARDs including high doses of steroids but had a uniformly rapid clinical response with complete resolution of skin and bone lesions and complete normalization of inflammatory markers including ESR and CRP, leukocytosis, anemia and thrombocytosis within 7-14 days of treatment with the IL-1 receptor antagonist anakinra. Deficiency of the Interleukin-1 Receptor Antagonist, DIRA, is a novel autoinflammatory syndrome that exemplifies once more the crucial role of IL-1 and expands the organ- specific disease manifestations to aseptic osteomyelitis, periostitis, pustulosis and vasculitis (in one patient). CONCLUSIONS AND SIGNIFICANCE 1. In now 2 severe autoinflammatory syndromes, cryopyrin associated periodic syndromes, CAPS (which includes FACS, MWS and NOMID), and deficiency in IL-1 receptor syndrome, DIRA, the crucial role for IL-1 in the pathophysiology of these illnesses with multiorgan involvement has been demonstrated. 2. Our studies on the long-term treatment effect of IL-1 blockade in patients with NOMID indicate that treatment is safe and effective in the treatment of this devastating illness for at least up to 3 years and improves disability and retards/stops progression of hearing loss and vision loss. Patients treated with this agent for longer periods of time have continued to show significant improvement in their symptoms, and we will continue to evaluate patients for long term efficacy and safety. 3. A primary prevention protocol targets very young children with NOMID and will allow us to determine how effective early therapy is in the primary prevention of permanent organ damage that would develop if children remained untreated or partially treated with other DMARDs and steroids. 4. The development of long acting IL-1 inhibitors may allow for better disease control in those patients who are not in complete remission and offer more convenient treatment options particularly in children in whom daily injections can be quite traumatic. 5. The heterogeneous response to IL-1 blockade in patients with AOSD suggests a more complex cause for the inflammatory response in patients with AOSD. 6. The role of IL-1 in aseptic multifocal osteomyelitis, pustulosis, hyperostosis and vasculitis suggests the evaluation of the contribution of IL-1 in other diseases with overlapping clinical phenotypes and expands the spectrum of downstream IL-1 mediated organ manifestations to osteolytic bone lesions and skin pustulosis. These findings could also stimulate the evaluation of upstream IL-1 dysregulation in phenotypically related diseases such as pustular psoriasis, diseases with inflammatory skin and bone manifestations (skibo diseases), Behcet's disease and other forms of vasculitis such as panarteritis nodosa. 7. The phenotypic difference between NOMID and DIRA (no CNS, eye and ear inflammation in DIRA, compared to NOMID) and difference in skin manifestations, urticaria-like versus pustulosis, allow us to study the organ- specific immune responses downstream of IL-1 and may shed light on processes that determine specific organ manifestations.

研究成果 诺米德研究： 新生儿发病的多系统炎症性疾病 (NOMID) 是一种罕见的自身炎症/自身免疫性疾病，其特征为荨麻疹、发热、无菌性脑膜炎、视乳头水肿、感音神经性听力损失、长骨骨骺过度生长、生长迟缓，在某些情况下还会出现精神障碍。 NOMID 属于由 CIAS1 突变引起的一系列疾病的严重一端，CIAS1 编码一种蛋白质 Cryopyrin，它是白细胞介素 1 (IL-1) β 激活的关键调节因子。 去年的结果： 临床： 1. 我们分析了 20 名 NOMID 患者的 3 年结果数据，这些患者一直在接受递增剂量的阿那白滞素，试图实现炎症症状的临床完全缓解。最初观察到的良好临床反应持续存在，并且药物总体耐受性良好。然而，在研究开始时有 3 名严重听力损失的患者中，听力损失出现进展，并且在 3 年时，高达 50% 的患者出现间歇性低度软脑膜炎症。尽管阿那白滞素治疗后没有出现新的骨病变，但先前存在的骨病变在治疗后继续扩大。 2. 我们评估了阿那白滞素治疗后的残疾情况，发现疼痛和运动残疾有显着改善，但认知功能没有改善。 3. 在未经治疗的患者中，慢性炎症会导致显着的代谢变化，包括生长迟缓、骨质流失和贫血。 我们发现，骨矿物质密度的增加超过了年龄预期的增加，并且骨标志物发生了快速而持续的变化，表明骨生成有所增加。 当炎症受到抑制时，贫血会迅速消失，身高和体重也会随之增加。 实验室： 1. 当检查 PBMC 时，CIAS1 突变阳性和阴性患者的 IL-1 分泌有所不同，并且 Kastner 博士实验室在一名被认为突变阴性的患者中发现了新的突变。 2. Kastner 博士的实验室发现了一种特定的微阵列特征，可以将 NOMID 患者与其他自身炎症性疾病患者区分开来。疾病特异性基因表达谱将使我们能够定义 IL-1 特征，从而使我们能够识别其他尚未表征的炎症性疾病中的共享免疫途径。 FCAS 研究： 1. 我们已经发表了冷热蛋白相关周期性综合征 (CAPS) 轻症患者的长期结果数据。 IL-1 Trap，利洛那西普 (Acrolyst)，是一种长效 IL-1 抑制剂，与每天给药的阿那白滞素相比，利洛那西普需要每周注射一次。 IL-1 Trap 可有效控制 FCAS 患者的炎症，并且基于我们的初始 PK 和 PD 数据进行了一项多中心研究，并导致 FDA 批准利洛西普用于 FCAS 和 MWS 的适应症。 成人发作静态研究 我们目前招募了 5 名成人斯蒂尔病 (AOSD) 患者，他们也接受利洛西普治疗。 初始数据表明，在 5 名患者中观察到 2 名患者对利洛那西普的反应不太一致，且炎症缓解。 有助于区分对 IL-1 阻断有或没有立即反应的患者的生物标志物研究正在进行中。 其他自身炎症性疾病： 一名患有新生儿多灶性骨髓炎、骨膜炎和脓疱病以及严重全身炎症的住院患者接受 IL-1 抑制剂阿那白滞素治疗后，所有炎症体征和症状迅速消退，并促使对 IL-1 通路中的新突变进行评估。 与博士合作。 Kastner 和 Ferguson 对 IL-1 信号通路中的候选基因进行测序，结果鉴定出 IL1RN 基因中迄今为止 3 种不同的突变。 在 2 例中，纯合移码突变 (N52KfsX25) 和错义突变 (E77X) 导致 IL-1 受体拮抗剂蛋白过早截短。第三名患者是纯合子，存在包含 IL1RN 基因的 170kb 缺失。 功能研究证实突变蛋白不存在或表达非常低，并且功能完全丧失。 LPS 或 IL-1β 刺激导致促炎细胞因子和趋化因子、IL-6、IL-8、MIP-1 α、TNF 和 MCP-1 的表达增加，这与 3 名患者全血细胞刺激后中性粒细胞的激活和募集有关。所有儿童对包括高剂量类固醇在内的多种 DMARD 均无反应，但在使用 IL-1 受体拮抗剂阿那白滞素治疗后 7-14 天内，均出现了一致的快速临床反应，皮肤和骨骼病变完全消退，炎症标志物（包括 ESR 和 CRP、白细胞增多、贫血和血小板增多）完全正常化。白细胞介素 1 受体拮抗剂缺乏症 DIRA 是一种新型自身炎症综合征，它再次体现了 IL-1 的关键作用，并将器官特异性疾病表现扩大到无菌性骨髓炎、骨膜炎、脓疱病和血管炎（一名患者）。 结论及意义 1. 在目前 2 种严重自身炎症综合征、冷热蛋白相关周期性综合征、CAPS（包括 FACS、MWS 和 NOMID）和 IL-1 受体缺陷综合征 DIRA 中，IL-1 在这些多器官受累疾病的病理生理学中的关键作用已得到证实。 2. 我们对 NOMID 患者 IL-1 阻断的长期治疗效果的研究表明，治疗这种毁灭性疾病至少长达 3 年是安全有效的，可以改善残疾并延缓/阻止听力损失和视力损失的进展。 使用该药物进行较长时间治疗的患者的症状持续显示出显着改善，我们将继续评估患者的长期疗效和安全性。 3. 一级预防方案针对患有 NOMID 的幼儿，使我们能够确定早期治疗在一级预防永久性器官损伤方面的效果如何，如果儿童未接受治疗或部分接受其他 DMARD 和类固醇治疗，就会出现永久性器官损伤。 4. 长效IL-1抑制剂的开发可能有助于那些未完全缓解的患者更好地控制疾病，并提供更方便的治疗选择，特别是对于每日注射可能造成相当大创伤的儿童。 5. AOSD 患者对 IL-1 阻断的异质反应表明 AOSD 患者炎症反应的原因更为复杂。 6. IL-1在无菌性多灶性骨髓炎、脓疱病、骨质增生和血管炎中的作用提示评估IL-1在具有重叠临床表型的其他疾病中的贡献，并将下游IL-1介导的器官表现范围扩大到溶骨性骨病变和皮肤脓疱病。这些发现还可以刺激对表型相关疾病（例如脓疱性银屑病、具有炎症性皮肤和骨骼表现的疾病（skibo 病）、白塞氏病和其他形式的血管炎（例如结节性动脉炎））中上游 IL-1 失调的评估。 7. NOMID 和 DIRA 之间的表型差异（与 NOMID 相比，DIRA 没有 CNS、眼睛和耳朵炎症）以及皮肤表现（荨麻疹样与脓疱病）的差异，使我们能够研究 IL-1 下游的器官特异性免疫反应，并可能揭示决定特定器官表现的过程。

项目成果

Blocking interleukin-1 in rheumatic diseases.

• DOI: 10.1111/j.1749-6632.2009.05159.x
• 发表时间: 2009-12
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Goldbach-Mansky R

The T348M mutated form of cryopyrin is associated with defective lipopolysaccharide-induced interleukin 10 production in CINCA syndrome.

T348M 突变型冷热蛋白与 CINCA 综合征中脂多糖诱导的白细胞介素 10 产生缺陷有关。

• DOI: 10.1136/ard.2004.031179
• 发表时间: 2005
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4
• 作者: Bihl,T;Vassina,E;Boettger,MK;Goldbach-Mansky,R;Seitz,M;Villiger,PM;Simon,HU
• 通讯作者: Simon,HU

Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial.

• DOI: 10.7326/0003-4819-151-4-200908180-00005
• 发表时间: 2009-08-18
• 期刊: Annals of internal medicine
• 影响因子: 39.2
• 作者: Goldbach-Mansky R;Wilson M;Fleischmann R;Olsen N;Silverfield J;Kempf P;Kivitz A;Sherrer Y;Pucino F;Csako G;Costello R;Pham TH;Snyder C;van der Heijde D;Tao X;Wesley R;Lipsky PE
• 通讯作者: Lipsky PE

Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*).

• DOI: 10.1146/annurev.immunol.25.022106.141627
• 发表时间: 2009
• 期刊: Annual review of immunology
• 影响因子: 29.7
• 作者: Masters SL;Simon A;Aksentijevich I;Kastner DL
• 通讯作者: Kastner DL

S100A12 is a novel molecular marker differentiating systemic-onset juvenile idiopathic arthritis from other causes of fever of unknown origin.

• DOI: 10.1002/art.24137
• 发表时间: 2008-12
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Wittkowski, Helmut;Frosch, Michael;Wulffraat, Nico;Goldbach-Mansky, Raphaela;Kallinich, Tilmann;Kuemmerle-Deschner, Jasmin;Fruehwald, Michael C.;Dassmann, Sandra;Pham, Tuyet-Hang;Roth, Johannes;Foell, Dirk
• 通讯作者: Foell, Dirk