Methylprednisolone

点击“蓝字”关注我们编者按B型胰岛素抵抗是一种罕见的自身免疫性疾病，是人体存在针对胰岛素受体的自身抗体，导致严重难治性高血糖或顽固性低血糖。本文中，广东医科大学附属医院骆梓恒医生分享1例B型胰岛素抵抗患者，总结并分析其临床特征及诊治方法，为临床治疗提供依据。患者基本信息患者：女，52岁。因“口干、多饮、多尿、体重下降5个月”入院。现病史患者5个月前无诱因出现口干、多饮、多尿，日饮水量约6L，尿量与之相当，夜尿3~4次，体重近5个月减轻约20 kg，无发热、关节痛，无尿急、尿痛，无视物模糊、手足麻木，有眼干、龋齿未诊治。3个月前至当地诊所测空腹血糖12 mmol/L，诊为“糖尿病”，给予“二甲双胍片0.5 g tid”治疗1周后，上述症状无缓解，复测空腹血糖波动在14~16 mmol/L。半个月前至当地医院诊断为“糖尿病酮症”，应用胰岛素泵（52~100U/d）联合“二甲双胍片0.5 g tid、格列齐特片60 mg qd”治疗，上述症状不缓解，尿酮体（+~+++），尿糖（++~+++），空腹血糖波动在12~15 mmol/L，餐后2小时血糖波动在15~25 mmol/L。我院门诊以“糖尿病合并酮症”收入院。发病以来，神志清，精神可，饮食、睡眠正常，大便正常，小便及体重如上述。既往史30年前患“糜烂性胃炎”，已治愈。既往无甲亢病史，无含巯基药物服用史，50岁绝经，否认家族类似疾病史。体格检查体温36.5 C，脉搏78次/分，呼吸19次/分，血压109/80 mmHg，身高157cm，体重52.7 kg，BMI 21.3 kg/m2。神志清，精神可，发育正常，营养中等。轻度脱水貌，无深大呼吸，全身浅表淋巴结未触及，双下肢无水肿。检查结果血常规：WBC 2.9x109/L，N 1.44x109/L。血气全项：pH 7.38，PCO2 37.40 mmHg，SBE -2.80 mmol/L，ABE -2.60 mmol/L，AG 20.8 mmol/L。尿常规：酮体（+++），葡萄糖（+++），蛋白（-），尿比重1.015。肿瘤标志物：NSE 20.94 ng/ml，余阴性。粪常规、电解质、肝肾功能、血脂、凝血功能、传染病筛查均正常。13C呼气试验：0.2DOB（‰）（0~4‰）。ECG：正常。HbA1c：12.2%。空腹及餐后2小时血糖、胰岛素及C肽测定：结果见表1。空腹胰高血糖素：70.31 pg/ml。胰岛素相关抗体：GAD-Ab、IA-2A、IAA、ICA、ZnT-8抗体均阴性。甲状腺功能及抗体：FT3 3.17 pmol/L，FT4 11.57 pmol/L，TSH 0.65 μIU/ml，TPOAb 114.2 IU/ml，TGAb 99.92  IU/ml。性激素：血清总睾酮0.84ng/ml，余正常。ACTH-Cor节律、IGF-1、24小时尿UFC均正常。炎症七项：补体C3 0.68 g/L，IgA 4.7 g/L，免疫球蛋白G4 0.32 g/L，余正常。结缔组织病全套：抗核抗体均质型1：640（++）；抗SSA抗体（+++），抗Ro52（+++），抗SSB（+）。类风湿全套、ANCA四项均阴性。血清蛋白电泳：γ球蛋白14.94 g/L，γ球蛋白23.3%。泪膜破裂时间：右眼2秒，左眼3秒。双眼角膜荧光染色：着色。Schirmer I试验：右眼5 mm/5min，左眼5 mm/5min。唾液流率测定结果：（+）。表1. 空腹及餐后2小时血糖、胰岛素及C肽结果胸部CT示肺间质未见纤维化，胰腺CT未见占位。甲状腺、心脏、肝、胆、胰、脾、泌尿系彩超未见异常。垂体MRI平扫及增强未见异常。诊治经过入院后立即给予静脉滴注胰岛素及大量补液，次日复查尿常规示尿酮体（++），遂联合胰岛素泵应用，胰岛素量持续增加，最大达100 U/d，超过2U/kg，并先后加用多种降糖药物，测血糖无明显下降（12~25 mmol/L），尿酮体持续阳性（+~++）、且该患者血胰岛素水平（稀释后）可高达1072 μU/mL，提示存在严重胰岛素抵抗。患者中年女性，体形匀称，无糖尿病家族史，胰岛素相关抗体阴性；存在难治性高血糖、严重胰岛素抵抗；血清雄激素水平升高；合并自身免疫性疾病。因此诊断为：1、特殊类型糖尿病：B型胰岛素抵抗综合征；2、干燥综合征；3、桥本甲状腺炎。治疗方面停用所有口服降糖药，胰岛素逐步减量。给予甲泼尼龙0.25g静脉滴注，1次1日，3天后改为口服醋酸泼尼松片15 mg、3 次/日[约1 mg/(kg·d)]；环磷酰胺（CTX）0.4 g静脉滴注，1 次/周，持续3周。应用该方案2周后，血糖开始逐步下降，尿酮体转阴，3周后血糖恢复正常并停用胰岛素，复查血清胰岛素及C肽水平明显下降。后醋酸泼尼松片逐渐减量（每周减少2.5 mg）至停药，出院后规律至我院门诊复查，血糖控制平稳，尿酮体阴性。于1年后复查OGTT及胰岛功能测定示胰岛素及C肽水平较前降低（表2），患者血糖波动在正常范围，口干、眼干症状明显减轻，体重增加，胰岛素抵抗明显缓解。表2. 出院1年后OGTT及胰岛素、C肽释放试验结果病例诊疗思考与总结胰岛素抵抗，广义的定义是指机体对正常胰岛素浓度的生物学反应低于正常水平。非肥胖者如果空腹胰岛素高于30~50 mU/L（μU/mL）和（或）餐后或葡萄糖负荷后胰岛素水平超过200mU/L，则应进一步评估；如果胰岛素需要量超过1.5~2.0 U/kg，则提示严重胰岛素抵抗。本例患者空腹胰岛素水平570 mU/L，餐后达1072mU/L，且胰岛素用量达到100 U/d时血糖仍难以控制，支持严重胰岛素抵抗诊断[1]。遗传性靶细胞抵抗包括Donohue综合征、Rabson-Mendenhall综合征以及A型胰岛素抵抗。此类疾病往往起病年龄小，病程长，有严重胰岛素抵抗，有时伴随其他先天畸形、本例患者与之不符。其次，某些先天性代谢性疾病可同时合并胰岛素抵抗，如先天性全身性脂肪萎缩、Alstrom综合征、Bloom综合征等。再次，继发性胰岛素抵抗主要见于以下两方面：①存在肥胖、应激、感染、皮质醇增多症等疾病，以及应用药物（如糖皮质激素、口服避孕药等）、制动、妊娠等。本例患者与之不符。免疫介导的胰岛素抵抗性疾病中，胰岛素自身免疫综合征与B 型胰岛素抵抗均与免疫状态异常相关，二者临床特点既有共性也存在差异，共性为均可有严重胰岛素抵抗，均可表现为高血糖与低血糖交替，差异之处见表3。表3. B型胰岛素抵抗与胰岛素自身免疫综合征的临床不同点B型胰岛素抵抗是一种循环中存在针对胰岛素受体抗体的自身免疫综合征，可引起靶细胞胰岛素抵抗和内源性高胰岛素血症。其主要临床特点包括：①糖脂代谢紊乱：多数患者有典型“三多一少”症状，其中体重骤降为高血糖起病患者的显著特征，部分患者合并酮症或酮症酸中毒（DKA），这是由于体内虽胰岛素水平极高，但由于无法结合受体发挥作用，导致机体出现胰岛素缺乏所致的高血糖甚至DKA。由于胰岛素受体抗体的生物学功能具有多样性，与胰岛素受体结合后可表现为激动作用或拮抗作用，因此，不同患者、甚至同一患者在不同时间也可有高血糖或低血糖等不同的临床表现。②皮肤改变：最常见的特征为黑棘皮样改变。本例患者无明显黑棘皮样改变，可能与病程相对较短有关。③高雄激素血症：部分患者因合并高雄激素血症可表现为痤疮、多囊卵巢综合征等，本例患者雄激素水平轻度升高。④合并自身免疫性疾病：多数患者合并自身免疫性疾病，其中系统性红斑狼疮与干燥综合征最常见。⑤胰岛素受体抗体阳性。由于胰岛素受体抗体的测定目前还没有可用的商品化试剂盒，因此，目前并未将该抗体阳性作为诊断B型胰岛素抵抗的必需条件。该患者为中年非肥胖女性，“三多一少”症状明显，有难以控制的高血糖、严重胰岛素抵抗，胰岛素自身抗体阴性，在出现高血糖之前无巯基类药物应用史，合并干燥综合征及桥本甲状腺炎等自身免疫性疾病，符合B型胰岛素抵抗诊断[2,3]。关于B型胰岛素抵抗的治疗，尚缺乏统一规范的治疗原则和方法。目前研究报道的总体原则是在治疗原发病的基础上行免疫抑制治疗，如应用糖皮质激素、环磷酰胺、硫嘌吟、环孢素A、羟氣喹、利妥昔单抗等。血浆置换虽有效，但效果短暂。免疫球蛋白静脉输注也是可选治疗，但其疗效尚不明确，一般不作为首选。既往多数文献报道，在难治性高血糖面前，往往首先考虑增加胰岛素用量，国外报道的治疗B型胰岛素抵抗的最大外源性胰岛素用量为177~500U/d，但仍达不到降低血糖的目的，且长期大量应用外源性胰岛素可引起很多严重副作用。因此，在考虑到可能为该疾病时，应停止持续增加外源性胰岛素用量，尽早采用免疫调节治疗。糖皮质激素联合环磷酰胺方案的疗效在既往多个报道及本例中得到证实。由于糖皮质激素的升糖作用及抗体真正失活需要一段时间，因此，血糖下降一般在免疫抑制治疗2~3周后才会出现。在免疫抑制治疗开始后，应考虑到潜在低血糖风险，建议逐渐减少甚至停用胰岛素，进行密切随访与监测，早期发现和纠正顽固性低血糖，及时调整糖皮质激素用量[4-6]。综上，B型胰岛素抵抗虽然罕见，但有典型的临床表现和合并疾病。当患者有糖代谢异常、严重胰岛素抵抗且合并其他自身免疫性疾病时，应考虑该病可能。胰岛素受体抗体阳性可确诊该病，但不作为诊断的必要条件。糖皮质激素及免疫抑制剂联合治疗可取得良好效果，治疗及随访期间需警惕顽固低血糖的发生。参考文献（上下滑动可查看）[1] Ogawa W, Araki E, Ishigaki Y, Hirota Y, Maegawa H, Yamauchi T, Yorifuji T, Katagiri H. New classification and diagnostic criteria for insulin resistance syndrome. Endocr J. 2022 Feb 28;69(2):107-113. [2] Martins LM, Fernandes VO, Carvalho MMD, Gadelha DD, Queiroz PC, Montenegro Junior RM. Type B insulin resistance syndrome: a systematic review. Arch Endocrinol Metab. 2020 Aug;64(4):337-348. [3] Willard DL, Stevenson M, Steenkamp D. Type B insulin resistance syndrome. Curr Opin Endocrinol Diabetes Obes. 2016 Aug;23(4):318-23. doi: 10.1097/MED.0000000000000263. PMID: 27254267.[4] Sjöholm Å, João Pereira M, Nilsson T, Linde T, Katsogiannos P, Saaf J, W Eriksson J. Typ B-insulinresistenssyndrom – sällsynt tillstånd med hög mortalitet [Type B insulin resistance syndrome]. Lakartidningen. 2020 Aug 6;117:FYLZ. Swedish. [5] Yang G, Dou J, Lyu Z, Wang B, Gu W, Ba J, Du J, Jin N, Zang L, Chen K, Guo Q, Mu Y, Lu J. [Type B insulin resistance syndrome: 3 cases report and literature review]. Zhonghua Nei Ke Za Zhi. 2016 Jan;55(1):11-5. Chinese. [6] Arioglu E, Andewelt A, Diabo C, Bell M, Taylor SI, Gorden P. Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective. Medicine (Baltimore). 2002 Mar;81(2):87-100. 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：《国际糖尿病》编辑部）版权声明版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。

-- Early clinical data indicates that Pre-existing and treatment-induced anti-Ad5 neutralizing antibodies do not impact the safety and effectiveness of PCRX-201 – -- An oral presentation of the data to be featured at the ASGCT Annual Meeting -- BRISBANE, Calif., May 15, 2025 (GLOBE NEWSWIRE) -- Pacira BioSciences, Inc. (NASDAQ: PCRX), the industry leader in the delivery of innovative, non-opioid pain therapies to transform the lives of patients, today announced new preliminary data which suggests that clinical immunogenicity does not reduce sustained improvements in knee pain, stiffness and function provided by its gene therapy candidate, PCRX-201 (enekinragene inzadenovec), following local administration in patients with mild, moderate, as well as severe osteoarthritis of the knee. The research findings are being presented during a podium session at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting in New Orleans on May 15, 2025, at 2:15 CT. “These are encouraging results supporting the potential of PCRX-201 as an effective and durable treatment option for patients with osteoarthritis of the knee, many of whom currently rely on therapies that deliver only short-term, limited relief,” said Mijeong Kim, immunology and pharmacology leader at Pacira BioSciences and lead investigator of the research. “Natural immune responses are a major obstacle for gene therapies, since they can hinder the effectiveness of the treatment and increase adverse reactions. This preliminary data indicates that neither pre-existing nor treatment-induced immunogenicity compromise the safety or long-lasting efficacy of PCRX-201.” PCRX-201 features an innovative design based on the company’s proprietary high-capacity adenovirus, or HCAd, gene therapy vector platform. The HCAd vector is based on adenovirus serotype 5 (Ad5), a well understood serotype that is very common in community circulation. PCRX-201 is injected locally into the knee joint to boost cellular production of interleukin-1 receptor antagonist (IL-1Ra) and block interleukin-1 pathway activation to improve chronic inflammation, pain, and function. PCRX-201’s unique design also features an inducible promoter to mimic the body’s natural response to inflammation by “turning on” the expression of IL-1Ra when inflammation is present in the joint and turning off expression once inflammation is quelled. Study DetailsThe open-label, phase 1 trial evaluated the effect that pre-existing or treatment-induced anti-Ad5 neutralizing antibodies (NAbs) have on PCRX-201 and its impact on dosing and redosing strategy. The study enrolled 72 participants aged 30 to 80 who received a single low, middle or high dose of PCRX-201. One of the two study cohorts (N=36) was pretreated with an intraarticular corticosteroid (methylprednisolone 40 mg) prior to the PCRX-201 injection. The presence of NAb titers in patients’ blood and synovial fluid (SF), as well as the levels of IL-1Ra in SF, were measured over 52 weeks. The data indicates that pre-existing NAbs did not affect the efficacy or safety of PCRX-201 at any of the three doses studied. All doses achieved improved pain, stiffness and function as measured by WOMAC-A and WOMAC-B (The Western Ontario and McMaster Universities Osteoarthritis Index). The findings also demonstrated that using a corticosteroid treatment before PCRX-201 administration appears to help reduce treatment-induced NAb titers and dose-related swelling of the knee joint. Additionally, most serum NAb titers fell below the highest observed baseline levels within 38 to 52 weeks. No serious treatment-emergent AEs related to the treatment or procedure were reported regardless of steroid pretreatment or dose level administered. Treatment-related joint effusions (swelling) were the most common AE, occurring in 36% of patients who received steroid pretreatment vs 61% of patients who were not pretreated. The majority of effusions were mild to moderate in severity and resolved in a median of 33 days among patients in the pretreated group. “Advancing gene therapy as an approach to treating pain is a natural progression of Pacira’s deep commitment to innovation in non-opioid therapies and delivers on our 5x30 strategy for growth and value creation,” said Frank D. Lee, chief executive officer of Pacira Biosciences. “With our Phase 2 study of PCRX-201 currently underway, we see great potential for offering a long-lasting pain relief option to the 14 million patients living with osteoarthritis of the knee, an often debilitating condition that can severely impact mobility and quality of life.” In March 2024, PCRX-201 became the first-ever gene therapy product candidate in osteoarthritis to receive Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA). RMAT designation provides the benefits of intensive FDA guidance on efficient drug development, including the ability for early interactions with the FDA to discuss surrogate or intermediate endpoints, potential ways to support accelerated approval and satisfy post-approval requirements, potential priority review of the Biologics License Application (BLA), and other opportunities to expedite development and review. PCRX-201 was also granted Advanced Therapy Medicinal Products (ATMP) designation by the European Medicines Agency in May 2023. Given the promising Phase 1 results, dosing is underway in a Phase 2 study of PCRX-201 (the ASCEND study) for the treatment of osteoarthritis of the knee. About PCRX-201 (enekinragene inzadenovec)PCRX-201 (enekinragene inzadenovec) features an innovative design based on the company’s proprietary high-capacity adenovirus vector platform. It is currently being studied in the fundamental, underlying chronic inflammatory processes that contribute to “wear and tear” over time in osteoarthritis of the knee, a condition that affects more than 14 million individuals in the U.S. today. In November 2024, Pacira reported promising data from a large Phase 1 study in which PCRX-201 provided sustained improvements in knee pain, stiffness, and function through two years following local administration, with a well-tolerated safety profile. PCRX-201 has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration and Advanced Therapy Medicinal Products (ATMP) designation from the European Medicines Agency. PCRX-201 is the first gene therapy to achieve these clinical results and earn these regulatory designations in osteoarthritis of the knee – a testament to its promise and potential. About PaciraPacira delivers innovative, non-opioid pain therapies to transform the lives of patients. Pacira has three commercial-stage non-opioid treatments: EXPAREL® (bupivacaine liposome injectable suspension), a long-acting local analgesic currently approved for infiltration, fascial plane block, and as an interscalene brachial plexus nerve block, an adductor canal nerve block, and a sciatic nerve block in the popliteal fossa for postsurgical pain management; ZILRETTA® (triamcinolone acetonide extended-release injectable suspension), an extended-release, intra-articular injection indicated for the management of osteoarthritis knee pain; and iovera®º, a novel, handheld device for delivering immediate, long-acting, drug-free pain control using precise, controlled doses of cold temperature to a targeted nerve. The Company is also advancing the development of PCRX-201 (enekinragene inzadenovec), a novel, locally administered gene therapy with the potential to treat large prevalent diseases like osteoarthritis. To learn more about Pacira, visit www.pacira.com. Forward-Looking StatementsAny statements in this press release about Pacira’s future expectations, plans, trends, outlook, projections and prospects, and other statements containing the words “believes,” “anticipates,” “plans,” “estimates,” “expects,” “intends,” “may,” “will,” “would,” “could,” “can” and similar expressions, constitute forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), and the Private Securities Litigation Reform Act of 1995, including, without limitation, statements related to: the settlement described herein, ‘5x30’, our growth and business strategy; our future outlook, our intellectual property and patent terms, our growth and future operating results and trends, our strategy, plans, objectives, expectations (financial or otherwise) and intentions, future financial results and growth potential, including our plans with respect to the repayment of our indebtedness, anticipated product portfolio, development programs, development of products, strategic alliances and other statements that are not historical facts. For this purpose, any statement that is not a statement of historical fact should be considered a forward-looking statement. We cannot assure you that our estimates, assumptions and expectations will prove to have been correct. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including risks relating to, among others: the failure to realize the anticipated benefits and synergies from the acquisition of GQ Bio Therapeutics GmbH; risks associated with acquisitions, such as the risk that the acquired businesses will not be integrated successfully, that such integration may be more difficult, time-consuming or costly than expected or that the expected benefits of the transaction will not occur; our manufacturing and supply chain, global and U.S. economic conditions (including inflation and rising interest rates), and our business, including our revenues, financial condition, cash flow and results of operations; the success of our sales and manufacturing efforts in support of the commercialization of EXPAREL, ZILRETTA and iovera°; the rate and degree of market acceptance of EXPAREL, ZILRETTA and iovera°; the size and growth of the potential markets for EXPAREL, ZILRETTA and iovera° and our ability to serve those markets; our plans to expand the use of EXPAREL, ZILRETTA and iovera° to additional indications and opportunities, and the timing and success of any related clinical trials for EXPAREL, ZILRETTA and iovera°; the commercial success of EXPAREL, ZILRETTA and iovera°; the related timing and success of U.S. Food and Drug Administration supplemental New Drug Applications and premarket notification 510(k)s; the related timing and success of European Medicines Agency Marketing Authorization Applications; our plans to evaluate, develop and pursue additional product candidates utilizing our proprietary multivesicular liposome (“pMVL”) drug delivery technology; the approval of the commercialization of our products in other jurisdictions; clinical trials in support of an existing or potential pMVL-based product; our commercialization and marketing capabilities; our ability to successfully complete capital projects; the outcome of any litigation; the recoverability of our deferred tax assets; assumptions associated with contingent consideration payments; assumptions used for estimated future cash flows associated with determining the fair value of the Company; the anticipated funding or benefits of our share repurchase program; and factors discussed in the “Risk Factors” of our most recent Annual Report on Form 10-K and in other filings that we periodically make with the Securities and Exchange Commission (the “SEC”). In addition, the forward-looking statements included in this press release represent our views as of the date of this press release. Important factors could cause actual results to differ materially from those indicated or implied by forward-looking statements, and as such we anticipate that subsequent events and developments will cause our views to change. Except as required by applicable law, we undertake no intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, and readers should not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this press release. These forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from those expressed or implied by these statements. These factors include the matters discussed and referenced in the “Risk Factors” of our most recent Annual Report on Form 10-K and in other filings that we periodically make with the SEC. Investor Contact: Susan Mesco, (973) 451-4030 susan.mesco@pacira.com Media Contact: Sara Marino, (973) 370-5430 sara.marino@pacira.com