Pub Date : 2024-12-23DOI: 10.1186/s13075-024-03429-z
Prachi Agnihotri, Mohd Saquib, Lovely Joshi, Swati Malik, Debolina Chakraborty, Ashish Sarkar, Uma Kumar, Sagarika Biswas
Rheumatoid arthritis (RA) is a chronic inflammatory condition that, despite available approaches to manage the disease, lacks an efficient treatment and timely diagnosis. Using the most advanced omics technique, metabolomics and proteomics approach, we explored varied metabolites and proteins to identify unique metabolite-protein signatures involved in the disease pathogenesis of RA. Untargeted metabolomics (n = 20) and proteomics (n = 60) of RA patients’ plasma were carried out by HPLC/LC-MS/MS and SWATH, respectively and analyzed by Metaboanalyst. The targets of metabolite retrieved by PharmMapper were matched with SWATH data, and joint pathway analysis was carried out. An in-vitro study of metabolites in TNF-α induced SW982 cells was conducted by Western, RT-PCR, scratch, and ROS scavenging assay. The effect of GUDCA was also evaluated in the CIA rat model. A Total of 82 metabolites and 231 differential proteins were revealed. Porphyrin and chlorophyll pathway and its metabolite Glycoursodeoxycholic acid (GUDCA) was found to be significantly altered. In vitro analysis has shown that GUDCA reduces inflammation thus offering protection against ROS production and cell proliferation. PharmMapper analysis revealed that GUDCA was significantly linked with identified SWATH proteins insulin like growth factor-1(IGF1), and Transthyretin (TTR) and it upregulates the expression of IGF1 and downregulates the expression of TTR in both in vitro and in vivo models. GUDCA was found to possess antioxidative, antiproliferative properties and an effective anti-inflammatory property at a low dosage. It may be considered as a potential therapeutic option for reducing the inflammatory parameters associated with RA.
类风湿性关节炎（RA）是一种慢性炎症，尽管有治疗方法，但缺乏有效的治疗和及时的诊断。利用最先进的组学技术，代谢组学和蛋白质组学方法，我们探索了各种代谢物和蛋白质，以确定参与RA疾病发病机制的独特代谢物-蛋白质特征。采用HPLC/LC-MS/MS和SWATH分别对RA患者血浆进行非靶向代谢组学（n = 20）和蛋白质组学（n = 60），并采用Metaboanalyst进行分析。将PharmMapper检索到的代谢物靶点与SWATH数据进行匹配，并进行联合通路分析。采用Western、RT-PCR、scratch和ROS清除实验对TNF-α诱导的SW982细胞代谢产物进行体外研究。在CIA大鼠模型中评价GUDCA的作用。共发现82种代谢物和231种差异蛋白。卟啉和叶绿素途径及其代谢物甘氨酸脱氧胆酸（GUDCA）发生了显著改变。体外分析表明，GUDCA可以减少炎症，从而提供抗ROS产生和细胞增殖的保护。PharmMapper分析显示，GUDCA与SWATH蛋白胰岛素样生长因子-1（insulin like growth factor-1, IGF1）和转甲状腺素（Transthyretin， TTR）显著相关，在体外和体内模型中上调IGF1的表达，下调TTR的表达。发现GUDCA在低剂量下具有抗氧化、抗增殖和有效的抗炎特性。它可能被认为是一种潜在的治疗选择，以减少与RA相关的炎症参数。
{"title":"Integrative metabolomic-proteomic analysis uncovers a new therapeutic approach in targeting rheumatoid arthritis","authors":"Prachi Agnihotri, Mohd Saquib, Lovely Joshi, Swati Malik, Debolina Chakraborty, Ashish Sarkar, Uma Kumar, Sagarika Biswas","doi":"10.1186/s13075-024-03429-z","DOIUrl":"https://doi.org/10.1186/s13075-024-03429-z","url":null,"abstract":"Rheumatoid arthritis (RA) is a chronic inflammatory condition that, despite available approaches to manage the disease, lacks an efficient treatment and timely diagnosis. Using the most advanced omics technique, metabolomics and proteomics approach, we explored varied metabolites and proteins to identify unique metabolite-protein signatures involved in the disease pathogenesis of RA. Untargeted metabolomics (n = 20) and proteomics (n = 60) of RA patients’ plasma were carried out by HPLC/LC-MS/MS and SWATH, respectively and analyzed by Metaboanalyst. The targets of metabolite retrieved by PharmMapper were matched with SWATH data, and joint pathway analysis was carried out. An in-vitro study of metabolites in TNF-α induced SW982 cells was conducted by Western, RT-PCR, scratch, and ROS scavenging assay. The effect of GUDCA was also evaluated in the CIA rat model. A Total of 82 metabolites and 231 differential proteins were revealed. Porphyrin and chlorophyll pathway and its metabolite Glycoursodeoxycholic acid (GUDCA) was found to be significantly altered. In vitro analysis has shown that GUDCA reduces inflammation thus offering protection against ROS production and cell proliferation. PharmMapper analysis revealed that GUDCA was significantly linked with identified SWATH proteins insulin like growth factor-1(IGF1), and Transthyretin (TTR) and it upregulates the expression of IGF1 and downregulates the expression of TTR in both in vitro and in vivo models. GUDCA was found to possess antioxidative, antiproliferative properties and an effective anti-inflammatory property at a low dosage. It may be considered as a potential therapeutic option for reducing the inflammatory parameters associated with RA. ","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"64 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To assess immunogenicity and safety in patients with active rheumatoid arthritis (RA) transitioning from rituximab [US-licensed rituximab: Reference Product (RP); EU-approved rituximab: Reference Medicinal Product (RMP)] to DRL_RI (proposed rituximab biosimilar), in comparison to those continuing on RP/RMP. This double-blind, randomized, Phase 3 study included 140 RA patients having prior exposure to RP/RMP; transitioned to DRL_RI (n = 70) or continued with RP/RMP (n = 70) for two 1000 mg infusions on Days 1 and 15. Assessments included Time-matched Rituximab Concentration (TMRC), anti-drug antibodies (ADAs), neutralizing antibodies (NAbs) and ADA titre over 12 weeks, and safety follow-up till 26 weeks. The mean age of subjects was 59.8 years (range: 24, 86) and the mean BMI was 27.76 kg/m2 (range: 17.5, 52.0). Incidence of ADA after dosing was low in both groups: 1.4% in DRL_RI group on Day 15, Week 8, and Week 12; and 2.9% in RP/RMP group at Week 12. Only 1 patient in DRL_RI group was positive for NAbs at Week 8. ADA titre values did not significantly differ between the two groups. The time-matched rituximab concentration was comparable between groups, indicating no interference for immunogenicity assessment. Treatment-emergent adverse events (TEAEs) were reported by 34.3% and 38.6% patients, respectively, in DRL_RI and RP/RMP groups. Incidences of TEAEs that were drug-related, leading to treatment discontinuation, grade ≥ 3, or serious, were also comparable. Immunogenicity was low and comparable in RA patients transitioning to DRL_RI or continuing on RP/RMP. The overall safety profile in patients transitioning to DRL_RI did not appear to differ in frequency, severity, or quality from patients continuing on RP/RMP and was in line with the known safety profile of rituximab. ClinicalTrials.gov identifier NCT0426877 EudraCT:2019-002810-37 US IND 112766. • Immunogenicity and safety in patients with active RA transitioning from reference rituximab to DRL_RI (biosimilar rituximab) were comparable to those continuing with reference rituximab. • Incidence of ADA after dosing was low and similar between patients transitioning to DRL_RI vs. continuing with reference rituximab. • Adverse events in patients who transitioned to DRL_RI or continuing treatment with the reference rituximab were comparable, and overall, in line with the known safety profile of rituximab.
评估活动性类风湿关节炎（RA）患者从美罗华过渡的免疫原性和安全性[美罗华：参考产品（RP）；欧盟批准的利妥昔单抗：参考药物（RMP）]到DRL_RI（拟议的利妥昔单抗生物仿制药），与继续使用RP/RMP的药物进行比较。这项双盲、随机、3期研究纳入了140名RA患者，他们之前曾暴露于RP/RMP；过渡到DRL_RI （n = 70）或继续RP/RMP (n = 70)，在第1天和第15天两次1000 mg输注。评估包括12周时间匹配利妥昔单抗浓度（TMRC）、抗药物抗体（ADAs）、中和抗体（nab）和ADA滴度，以及安全随访至26周。受试者平均年龄为59.8岁（范围：24、86），平均BMI为27.76 kg/m2（范围：17.5、52.0）。两组给药后ADA的发生率均较低：DRL_RI组在第15天、第8周和第12周的发生率为1.4%；第12周，RP/RMP组为2.9%。DRL_RI组只有1例患者在第8周nab阳性。两组间ADA滴度值无显著差异。时间匹配的利妥昔单抗浓度在两组之间具有可比性，表明对免疫原性评估没有干扰。DRL_RI组和RP/RMP组出现治疗不良事件（teae）的比例分别为34.3%和38.6%。与药物相关、导致停药、≥3级或严重teae的发生率也具有可比性。在过渡到DRL_RI或继续RP/RMP的RA患者中，免疫原性较低且相当。过渡到DRL_RI的患者的总体安全性与继续使用RP/RMP的患者在频率、严重程度或质量上没有差异，并且与利妥昔单抗的已知安全性一致。ClinicalTrials.gov编号NCT0426877稿号：2019-002810-37 US IND 112766。•活动性RA患者从参考利妥昔单抗过渡到DRL_RI（生物仿制药利妥昔单抗）的免疫原性和安全性与继续使用参考利妥昔单抗的患者相当。•在过渡到DRL_RI和继续使用利妥昔单抗的患者中，给药后ADA的发生率较低且相似。•过渡到DRL_RI或继续使用参考利妥昔单抗治疗的患者的不良事件具有可比性，总体而言，符合利妥昔单抗已知的安全性。
{"title":"Comparing immunogenicity and safety following transition from reference rituximab to biosimilar rituximab (DRL_RI) in patients with rheumatoid arthritis: a randomized, double-blind, phase 3 study","authors":"Narendra Maharaj, Dharma Rao Uppada, Naveen Reddy, Pramod Reddy, Anastas Batalov, Delina lvanova, Nedyalka Staykova, Asta Baranauskaite, Laila Amirali Hassan","doi":"10.1186/s13075-024-03456-w","DOIUrl":"https://doi.org/10.1186/s13075-024-03456-w","url":null,"abstract":"To assess immunogenicity and safety in patients with active rheumatoid arthritis (RA) transitioning from rituximab [US-licensed rituximab: Reference Product (RP); EU-approved rituximab: Reference Medicinal Product (RMP)] to DRL_RI (proposed rituximab biosimilar), in comparison to those continuing on RP/RMP. This double-blind, randomized, Phase 3 study included 140 RA patients having prior exposure to RP/RMP; transitioned to DRL_RI (n = 70) or continued with RP/RMP (n = 70) for two 1000 mg infusions on Days 1 and 15. Assessments included Time-matched Rituximab Concentration (TMRC), anti-drug antibodies (ADAs), neutralizing antibodies (NAbs) and ADA titre over 12 weeks, and safety follow-up till 26 weeks. The mean age of subjects was 59.8 years (range: 24, 86) and the mean BMI was 27.76 kg/m2 (range: 17.5, 52.0). Incidence of ADA after dosing was low in both groups: 1.4% in DRL_RI group on Day 15, Week 8, and Week 12; and 2.9% in RP/RMP group at Week 12. Only 1 patient in DRL_RI group was positive for NAbs at Week 8. ADA titre values did not significantly differ between the two groups. The time-matched rituximab concentration was comparable between groups, indicating no interference for immunogenicity assessment. Treatment-emergent adverse events (TEAEs) were reported by 34.3% and 38.6% patients, respectively, in DRL_RI and RP/RMP groups. Incidences of TEAEs that were drug-related, leading to treatment discontinuation, grade ≥ 3, or serious, were also comparable. Immunogenicity was low and comparable in RA patients transitioning to DRL_RI or continuing on RP/RMP. The overall safety profile in patients transitioning to DRL_RI did not appear to differ in frequency, severity, or quality from patients continuing on RP/RMP and was in line with the known safety profile of rituximab. ClinicalTrials.gov identifier NCT0426877 EudraCT:2019-002810-37 US IND 112766. • Immunogenicity and safety in patients with active RA transitioning from reference rituximab to DRL_RI (biosimilar rituximab) were comparable to those continuing with reference rituximab. • Incidence of ADA after dosing was low and similar between patients transitioning to DRL_RI vs. continuing with reference rituximab. • Adverse events in patients who transitioned to DRL_RI or continuing treatment with the reference rituximab were comparable, and overall, in line with the known safety profile of rituximab.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"113 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-20DOI: 10.1186/s13075-024-03457-9
Terese Geraghty, Shingo Ishihara, Alia M. Obeidat, Natalie S. Adamczyk, Rahel S. Hunter, Jun Li, Lai Wang, Hoomin Lee, Frank C. Ko, Anne-Marie Malfait, Rachel E. Miller
Osteoarthritis (OA) is a painful degenerative joint disease and a leading source of years lived with disability globally due to inadequate treatment options. Neuroimmune interactions reportedly contribute to OA pain pathogenesis. Notably, in rodents, macrophages in the DRG are associated with onset of persistent OA pain. Our objective was to determine the effects of acute systemic macrophage depletion on pain-related behaviors and joint damage using surgical mouse models in both sexes. We depleted CSF1R + macrophages by treating male macrophage Fas-induced apoptosis (MaFIA) transgenic mice 8- or 16-weeks post destabilization of the medial meniscus (DMM) with AP20187 or vehicle control (10 mg/kg i.p., 1x/day for 5 days), or treating female MaFIA mice 12 weeks post partial meniscectomy (PMX) with AP20187 or vehicle control. We measured pain-related behaviors 1–3 days before and after depletion, and, 3–4 days after the last injection we examined joint histopathology and performed flow cytometry of the dorsal root ganglia (DRGs). In a separate cohort of male 8-week DMM mice or age-matched naïve vehicle controls, we conducted DRG bulk RNA-sequencing analyses after the 5-day vehicle or AP20187 treatment. Eight- and 16-weeks post DMM in male mice, AP20187-induced macrophage depletion resulted in attenuated mechanical allodynia and knee hyperalgesia. Female mice showed alleviation of mechanical allodynia, knee hyperalgesia, and weight bearing deficits after macrophage depletion at 12 weeks post PMX. Macrophage depletion did not affect the degree of cartilage degeneration, osteophyte width, or synovitis in either sex. Flow cytometry of the DRG revealed that macrophages and neutrophils were reduced after AP20187 treatment. In addition, in the DRG, only MHCII + M1-like macrophages were significantly decreased, while CD163 + MHCII- M2-like macrophages were not affected in both sexes. DRG bulk RNA-seq revealed that Cxcl10 and Il1b were upregulated with DMM surgery compared to naïve mice, and downregulated in DMM after acute macrophage depletion. Acute systemic macrophage depletion reduced the levels of pro-inflammatory macrophages in the DRG and alleviated pain-related behaviors in established surgically induced OA in mice of both sexes, without affecting joint damage. Overall, these studies provide insight into immune cell regulation in the DRG during OA.
{"title":"Acute systemic macrophage depletion in osteoarthritic mice alleviates pain-related behaviors and does not affect joint damage","authors":"Terese Geraghty, Shingo Ishihara, Alia M. Obeidat, Natalie S. Adamczyk, Rahel S. Hunter, Jun Li, Lai Wang, Hoomin Lee, Frank C. Ko, Anne-Marie Malfait, Rachel E. Miller","doi":"10.1186/s13075-024-03457-9","DOIUrl":"https://doi.org/10.1186/s13075-024-03457-9","url":null,"abstract":"Osteoarthritis (OA) is a painful degenerative joint disease and a leading source of years lived with disability globally due to inadequate treatment options. Neuroimmune interactions reportedly contribute to OA pain pathogenesis. Notably, in rodents, macrophages in the DRG are associated with onset of persistent OA pain. Our objective was to determine the effects of acute systemic macrophage depletion on pain-related behaviors and joint damage using surgical mouse models in both sexes. We depleted CSF1R + macrophages by treating male macrophage Fas-induced apoptosis (MaFIA) transgenic mice 8- or 16-weeks post destabilization of the medial meniscus (DMM) with AP20187 or vehicle control (10 mg/kg i.p., 1x/day for 5 days), or treating female MaFIA mice 12 weeks post partial meniscectomy (PMX) with AP20187 or vehicle control. We measured pain-related behaviors 1–3 days before and after depletion, and, 3–4 days after the last injection we examined joint histopathology and performed flow cytometry of the dorsal root ganglia (DRGs). In a separate cohort of male 8-week DMM mice or age-matched naïve vehicle controls, we conducted DRG bulk RNA-sequencing analyses after the 5-day vehicle or AP20187 treatment. Eight- and 16-weeks post DMM in male mice, AP20187-induced macrophage depletion resulted in attenuated mechanical allodynia and knee hyperalgesia. Female mice showed alleviation of mechanical allodynia, knee hyperalgesia, and weight bearing deficits after macrophage depletion at 12 weeks post PMX. Macrophage depletion did not affect the degree of cartilage degeneration, osteophyte width, or synovitis in either sex. Flow cytometry of the DRG revealed that macrophages and neutrophils were reduced after AP20187 treatment. In addition, in the DRG, only MHCII + M1-like macrophages were significantly decreased, while CD163 + MHCII- M2-like macrophages were not affected in both sexes. DRG bulk RNA-seq revealed that Cxcl10 and Il1b were upregulated with DMM surgery compared to naïve mice, and downregulated in DMM after acute macrophage depletion. Acute systemic macrophage depletion reduced the levels of pro-inflammatory macrophages in the DRG and alleviated pain-related behaviors in established surgically induced OA in mice of both sexes, without affecting joint damage. Overall, these studies provide insight into immune cell regulation in the DRG during OA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"31 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1186/s13075-024-03454-y
Lu Liu, Karina de Leeuw, Harry van Goor, Berber Doornbos-van der Meer, Suzanne Arends, Johanna Westra
To investigate the levels of plasma neutrophil extracellular traps (NETs) and free thiols, the latter reflecting systemic oxidative stress (OS), and to explore the relationship between NETs and OS in quiescent systemic lupus erythematosus (SLE) patients with and without renal involvement. Plasma levels of NETs and free thiols were measured cross-sectionally in 100 SLE patients with low disease activity (SLEDAI < 5), of whom 73 patients had no renal involvement (non-LN) and 27 patients had lupus nephritis (LN). Additionally, 22 healthy controls (HCs) were included. NETs were measured using a myeloperoxidase-DNA complex ELISA and free thiols were measured using a thiol assay kit. NETs levels were significantly higher in both non-LN and LN patients compared to HCs (p < 0.001, p = 0.013), with no difference between the two patient groups (p = 0.799). Free thiol levels were not significantly different between groups. Interestingly, NETs were negatively correlated with free thiols in all 100 SLE patients (rho = -0.32) and non-LN patients (rho = -0.38), but not in LN patients. Levels of free thiols were significantly lower in subgroups of patients with estimated glomerular filtration rate (eGFR) < 60, serum creatinine (sCr) ≥ 90, C reactive protein (CRP) levels ≥ 5 and body mass index (BMI) ≥ 30. In multivariable regression, disease duration, NETs levels, and eGFR were independently associated with free thiol levels. Levels of NETs were increased in quiescent SLE patients. Although free thiol levels did not differ among the groups. The levels of NETs and free thiols were independently associated in SLE patients, suggesting a potential role of OS in NETs formation. Therefore, reducing OS might be an additional therapeutic target for SLE treatment.
{"title":"Neutrophil extracellular traps and oxidative stress in systemic lupus erythematosus patients with and without renal involvement","authors":"Lu Liu, Karina de Leeuw, Harry van Goor, Berber Doornbos-van der Meer, Suzanne Arends, Johanna Westra","doi":"10.1186/s13075-024-03454-y","DOIUrl":"https://doi.org/10.1186/s13075-024-03454-y","url":null,"abstract":"To investigate the levels of plasma neutrophil extracellular traps (NETs) and free thiols, the latter reflecting systemic oxidative stress (OS), and to explore the relationship between NETs and OS in quiescent systemic lupus erythematosus (SLE) patients with and without renal involvement. Plasma levels of NETs and free thiols were measured cross-sectionally in 100 SLE patients with low disease activity (SLEDAI < 5), of whom 73 patients had no renal involvement (non-LN) and 27 patients had lupus nephritis (LN). Additionally, 22 healthy controls (HCs) were included. NETs were measured using a myeloperoxidase-DNA complex ELISA and free thiols were measured using a thiol assay kit. NETs levels were significantly higher in both non-LN and LN patients compared to HCs (p < 0.001, p = 0.013), with no difference between the two patient groups (p = 0.799). Free thiol levels were not significantly different between groups. Interestingly, NETs were negatively correlated with free thiols in all 100 SLE patients (rho = -0.32) and non-LN patients (rho = -0.38), but not in LN patients. Levels of free thiols were significantly lower in subgroups of patients with estimated glomerular filtration rate (eGFR) < 60, serum creatinine (sCr) ≥ 90, C reactive protein (CRP) levels ≥ 5 and body mass index (BMI) ≥ 30. In multivariable regression, disease duration, NETs levels, and eGFR were independently associated with free thiol levels. Levels of NETs were increased in quiescent SLE patients. Although free thiol levels did not differ among the groups. The levels of NETs and free thiols were independently associated in SLE patients, suggesting a potential role of OS in NETs formation. Therefore, reducing OS might be an additional therapeutic target for SLE treatment.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"47 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Limb-girdle muscular dystrophy (LGMD) is usually confused with idiopathic inflammatory myopathy (IIM) in clinical practice. Our study aimed to establish convenient and reliable diagnostic models for distinguishing between LGMD and IIM. A total of 71 IIM patients, 24 LGMDR2 patients and 22 LGMDR1 patients diagnosed at our neuromuscular center were enrolled. Differences in clinical, laboratory and histopathological characteristics were comprehensively compared. A nomogram and a decision tree were developed to distinguish between LGMD and IIM patients. Compared to patients with LGMD, IIM patients exhibited a significantly older age of onset, a higher prevalence of cervical flexor weakness and a more commonly diffuse MHC-I expression on muscle pathology. The ratio of synchronous serum myoglobin (Mb, ng/ml) to creatine kinase (CK, U/L) before immunotherapy was significantly higher in IIM patients than in LGMD patients. Receiver operating characteristic analysis indicated a high differential diagnostic efficiency of synchronous Mb/CK with a cutoff value of 0.18. A nomogram prediction model and a decision tree were developed based on four independent indicators (age of onset, cervical flexor weakness, synchronous Mb/CK and diffuse MHC-I expression). Five-fold cross-validation and bootstrapping techniques substantiated the discriminate efficacy of the nomograph and decision tree. We developed two practical differential diagnosis models for LGMD and IIM based on the analysis of four accessible indicators, including the age of onset, cervical flexor weakness, the ratio of synchronous Mb/CK values and diffuse MHC-I expression. Further studies with larger samples are needed to refine the predictive efficiency of the differential diagnostic models.
{"title":"Development of differential diagnostic models for distinguishing between limb-girdle muscular dystrophy and idiopathic inflammatory myopathy","authors":"Guangyu Wang, Lijun Fu, Lining Zhang, Kai Shao, Ying Hou, Tingjun Dai, Pengfei Lin, Chuanzhu Yan, Bing Zhao","doi":"10.1186/s13075-024-03458-8","DOIUrl":"https://doi.org/10.1186/s13075-024-03458-8","url":null,"abstract":"Limb-girdle muscular dystrophy (LGMD) is usually confused with idiopathic inflammatory myopathy (IIM) in clinical practice. Our study aimed to establish convenient and reliable diagnostic models for distinguishing between LGMD and IIM. A total of 71 IIM patients, 24 LGMDR2 patients and 22 LGMDR1 patients diagnosed at our neuromuscular center were enrolled. Differences in clinical, laboratory and histopathological characteristics were comprehensively compared. A nomogram and a decision tree were developed to distinguish between LGMD and IIM patients. Compared to patients with LGMD, IIM patients exhibited a significantly older age of onset, a higher prevalence of cervical flexor weakness and a more commonly diffuse MHC-I expression on muscle pathology. The ratio of synchronous serum myoglobin (Mb, ng/ml) to creatine kinase (CK, U/L) before immunotherapy was significantly higher in IIM patients than in LGMD patients. Receiver operating characteristic analysis indicated a high differential diagnostic efficiency of synchronous Mb/CK with a cutoff value of 0.18. A nomogram prediction model and a decision tree were developed based on four independent indicators (age of onset, cervical flexor weakness, synchronous Mb/CK and diffuse MHC-I expression). Five-fold cross-validation and bootstrapping techniques substantiated the discriminate efficacy of the nomograph and decision tree. We developed two practical differential diagnosis models for LGMD and IIM based on the analysis of four accessible indicators, including the age of onset, cervical flexor weakness, the ratio of synchronous Mb/CK values and diffuse MHC-I expression. Further studies with larger samples are needed to refine the predictive efficiency of the differential diagnostic models.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"24 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1186/s13075-024-03455-x
Khaled A. Elsaid, Ling X. Zhang, Thomas Zhao, Ava Marks, Derek Jenkins, Tannin A. Schmidt, Gregory D. Jay
Synovial macrophages (SMs) are important effectors of joint health and disease. A novel Cx3CR1 + TREM2 + SM population expressing the tight junction protein claudin-5, was recently discovered in synovial lining. Ablation of these SMs was associated with onset of arthritis. Proteoglycan 4 (PRG4) is a mucinous glycoprotein that fulfills lubricating and homeostatic roles in the joint. The aim of this work is to study the role of PRG4 in modulating synovitis in the context of SM homeostasis and assess the contribution of xanthine oxidase (XO)-hypoxia inducible factor alpha (HIF-1a) axis to this regulation. We used Prg4FrtloxP/FrtloxP;R26FlpoER/+, a novel transgenic mouse, where the Prg4Frt allele normally expresses the PRG4 protein and was designed to flank the first two exons of Prg4 with a flippase recognition target and “LOXP” sites. Inducing flippase activity with tamoxifen (TAM) inactivates the Frt allele and thus creates a conditional knockout state. We studied anti-inflammatory SMs and XO by quantitative immunohistochemistry, isolated RNA and studied immune pathway activations by multiplexed assays and isolated SMs and studied PRG4 signaling dysfunction in relation to glycolytic switching due to pro-inflammatory activation. Prg4 inactivated mice were treated with oral febuxostat, a specific XO inhibitor, and quantification of Cx3CR1 + TREM2 + SMs, XO immunostaining and synovitis assessment were conducted. Prg4 inactivation induced Cx3CR1 + TREM2 + SM loss (p < 0.001) and upregulated glycolysis and innate immune pathways in the synovium. In isolated SMs, Xdh (p < 0.01) and Hif1a (p < 0.05) were upregulated. Pro-inflammatory activation of SMs was evident by enhanced glycolytic flux and XO-generated reactive oxygen species (ROS). Febuxostat reduced glycolytic flux (p < 0.001) and HIF-1a levels (p < 0.0001) in SMs. Febuxostat also reduced systemic inflammation (p < 0.001), synovial hyperplasia (p < 0.001) and preserved Cx3CR1 + TREM2 + SMs (p < 0.0001) in synovia of Prg4 inactivated mice. PRG4 is a biologically significant modulator of synovial homeostasis via inhibition of XO expression and downstream HIF-1a activation. PRG4 signaling is anti-inflammatory and promotes synovial homeostasis in chronic synovitis, where direct XO inhibition is potentially therapeutic in chronic synovitis.
{"title":"Proteoglycan 4 (Lubricin) and regulation of xanthine oxidase in synovial macrophage as a mechanism of controlling synovitis","authors":"Khaled A. Elsaid, Ling X. Zhang, Thomas Zhao, Ava Marks, Derek Jenkins, Tannin A. Schmidt, Gregory D. Jay","doi":"10.1186/s13075-024-03455-x","DOIUrl":"https://doi.org/10.1186/s13075-024-03455-x","url":null,"abstract":"Synovial macrophages (SMs) are important effectors of joint health and disease. A novel Cx3CR1 + TREM2 + SM population expressing the tight junction protein claudin-5, was recently discovered in synovial lining. Ablation of these SMs was associated with onset of arthritis. Proteoglycan 4 (PRG4) is a mucinous glycoprotein that fulfills lubricating and homeostatic roles in the joint. The aim of this work is to study the role of PRG4 in modulating synovitis in the context of SM homeostasis and assess the contribution of xanthine oxidase (XO)-hypoxia inducible factor alpha (HIF-1a) axis to this regulation. We used Prg4FrtloxP/FrtloxP;R26FlpoER/+, a novel transgenic mouse, where the Prg4Frt allele normally expresses the PRG4 protein and was designed to flank the first two exons of Prg4 with a flippase recognition target and “LOXP” sites. Inducing flippase activity with tamoxifen (TAM) inactivates the Frt allele and thus creates a conditional knockout state. We studied anti-inflammatory SMs and XO by quantitative immunohistochemistry, isolated RNA and studied immune pathway activations by multiplexed assays and isolated SMs and studied PRG4 signaling dysfunction in relation to glycolytic switching due to pro-inflammatory activation. Prg4 inactivated mice were treated with oral febuxostat, a specific XO inhibitor, and quantification of Cx3CR1 + TREM2 + SMs, XO immunostaining and synovitis assessment were conducted. Prg4 inactivation induced Cx3CR1 + TREM2 + SM loss (p < 0.001) and upregulated glycolysis and innate immune pathways in the synovium. In isolated SMs, Xdh (p < 0.01) and Hif1a (p < 0.05) were upregulated. Pro-inflammatory activation of SMs was evident by enhanced glycolytic flux and XO-generated reactive oxygen species (ROS). Febuxostat reduced glycolytic flux (p < 0.001) and HIF-1a levels (p < 0.0001) in SMs. Febuxostat also reduced systemic inflammation (p < 0.001), synovial hyperplasia (p < 0.001) and preserved Cx3CR1 + TREM2 + SMs (p < 0.0001) in synovia of Prg4 inactivated mice. PRG4 is a biologically significant modulator of synovial homeostasis via inhibition of XO expression and downstream HIF-1a activation. PRG4 signaling is anti-inflammatory and promotes synovial homeostasis in chronic synovitis, where direct XO inhibition is potentially therapeutic in chronic synovitis.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"7 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1186/s13075-024-03452-0
Tanu Dixit, Anuradha Vaidya, Selvan Ravindran
In an age where there is a remarkable upsurge in developing precision medicines, antibody-drug conjugates (ADCs) have emerged as a progressive therapeutic strategy. ADCs typically consist of monoclonal antibodies (mAb) conjugated to the cytotoxic payloads by utilizing a linker, combining the benefits of definitive target specificity of mAbs and potent killing impact of payload to achieve precise and efficient elimination of target cells. In addition to their well-established role in oncology, ADCs are currently demonstrating encouraging potential in addressing the unmet requirements in the treatment of autoimmune conditions such as rheumatoid arthritis (RA). Prevalent long-term autoimmune disease RA costs billions of dollars annually but still, there is a lack of precision-targeted therapeutics with minimal side effects. This review provides an overview of the RA pathogenesis, pre-existing therapies, and their limitations, the introduction of ADCs in RA treatment, the mechanism of ADCs, and a summary of ADCs in preclinical and clinical trials. Based on the literature we also propose a strategy in ADC synthesis, which may increase the efficiency in targeting multifactorial diseases like RA. We propose to utilize DMARDs (Disease-modifying anti-rheumatic drugs), the first-line treatment for RA, as a payload for ADC synthesis. DMARDs are the only class of medication that limits the disease progression, but their efficacy is limited due to off-target toxicities. Hence, utilizing them as payload will help to deliver them directly at the targeted site, reducing their off-target toxicity, which in turn will increase their efficiency in targeting disease. Also, as mAbs are not sufficient to achieve remission, they are given in combinations with DMARDs. Hence, synthesizing ADCs may reduce the multiple and higher dosages given to patients, which in turn may enhance patient compliance.
{"title":"Therapeutic potential of antibody-drug conjugates possessing bifunctional anti-inflammatory action in the pathogenies of rheumatoid arthritis","authors":"Tanu Dixit, Anuradha Vaidya, Selvan Ravindran","doi":"10.1186/s13075-024-03452-0","DOIUrl":"https://doi.org/10.1186/s13075-024-03452-0","url":null,"abstract":"In an age where there is a remarkable upsurge in developing precision medicines, antibody-drug conjugates (ADCs) have emerged as a progressive therapeutic strategy. ADCs typically consist of monoclonal antibodies (mAb) conjugated to the cytotoxic payloads by utilizing a linker, combining the benefits of definitive target specificity of mAbs and potent killing impact of payload to achieve precise and efficient elimination of target cells. In addition to their well-established role in oncology, ADCs are currently demonstrating encouraging potential in addressing the unmet requirements in the treatment of autoimmune conditions such as rheumatoid arthritis (RA). Prevalent long-term autoimmune disease RA costs billions of dollars annually but still, there is a lack of precision-targeted therapeutics with minimal side effects. This review provides an overview of the RA pathogenesis, pre-existing therapies, and their limitations, the introduction of ADCs in RA treatment, the mechanism of ADCs, and a summary of ADCs in preclinical and clinical trials. Based on the literature we also propose a strategy in ADC synthesis, which may increase the efficiency in targeting multifactorial diseases like RA. We propose to utilize DMARDs (Disease-modifying anti-rheumatic drugs), the first-line treatment for RA, as a payload for ADC synthesis. DMARDs are the only class of medication that limits the disease progression, but their efficacy is limited due to off-target toxicities. Hence, utilizing them as payload will help to deliver them directly at the targeted site, reducing their off-target toxicity, which in turn will increase their efficiency in targeting disease. Also, as mAbs are not sufficient to achieve remission, they are given in combinations with DMARDs. Hence, synthesizing ADCs may reduce the multiple and higher dosages given to patients, which in turn may enhance patient compliance.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"4 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1186/s13075-024-03448-w
Xun Hu, Inmaculada Xu Lou, Qilan Chen
Accumulated evidence supports the tendency of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis(AAV) to coexist with atherosclerosis (AS). However, the common etiology of these two diseases remains unclear. This study aims to explore the mechanisms underlying the concurrent occurrence of ANCA and AS. Microarray data of AAV and AS were examined in a comprehensive gene expression database. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis (GEO2R) were performed to identify common genes between AAV and AS. Based on the co-expressed genes, functional enrichment analysis, protein-protein interaction (PPI) network analysis, and identification of hub genes (HGs) were conducted. Subsequently, co-expression analysis of HGs was performed, and their expression and diagnostic value were validated. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells. Finally, the reliability of the selected pathways was verified. The results of the common gene analysis suggest that immune and inflammatory responses may be common features in the pathophysiology of AAV and AS. Through the interaction of different analysis results, we confirmed five HGs (CYBB, FCER1G, TYROBP, IL10RA, CSF1R). The CytoHubba plugin and HG validation demonstrated the reliability of the selected five HGs. Co-expression network analysis revealed that these five HGs could influence monocyte migration. Analysis of immune cell infiltration showed that monocytes in ANCA and M0 macrophages in AS constituted a higher proportion of all infiltrating immune cells, with significant differences in infiltration. We also found significant positive correlations between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and monocytes/M0 macrophages in AAV, as well as between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and M0 macrophages in AS. These five HGs can promote monocyte differentiation into macrophages, leading to the concurrent occurrence of AAV and AS. Our study provides insights into the mechanisms underlying the coexistence of AAV and AS.
{"title":"Integrated bioinformatic analysis of the shared molecular mechanisms between ANCA-associated vasculitis and atherosclerosis","authors":"Xun Hu, Inmaculada Xu Lou, Qilan Chen","doi":"10.1186/s13075-024-03448-w","DOIUrl":"https://doi.org/10.1186/s13075-024-03448-w","url":null,"abstract":"Accumulated evidence supports the tendency of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis(AAV) to coexist with atherosclerosis (AS). However, the common etiology of these two diseases remains unclear. This study aims to explore the mechanisms underlying the concurrent occurrence of ANCA and AS. Microarray data of AAV and AS were examined in a comprehensive gene expression database. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis (GEO2R) were performed to identify common genes between AAV and AS. Based on the co-expressed genes, functional enrichment analysis, protein-protein interaction (PPI) network analysis, and identification of hub genes (HGs) were conducted. Subsequently, co-expression analysis of HGs was performed, and their expression and diagnostic value were validated. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells. Finally, the reliability of the selected pathways was verified. The results of the common gene analysis suggest that immune and inflammatory responses may be common features in the pathophysiology of AAV and AS. Through the interaction of different analysis results, we confirmed five HGs (CYBB, FCER1G, TYROBP, IL10RA, CSF1R). The CytoHubba plugin and HG validation demonstrated the reliability of the selected five HGs. Co-expression network analysis revealed that these five HGs could influence monocyte migration. Analysis of immune cell infiltration showed that monocytes in ANCA and M0 macrophages in AS constituted a higher proportion of all infiltrating immune cells, with significant differences in infiltration. We also found significant positive correlations between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and monocytes/M0 macrophages in AAV, as well as between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and M0 macrophages in AS. These five HGs can promote monocyte differentiation into macrophages, leading to the concurrent occurrence of AAV and AS. Our study provides insights into the mechanisms underlying the coexistence of AAV and AS.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"47 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Minor salivary gland (MSG) biopsy is a critical but invasive method for the classification of primary Sjögren’s disease (pSjD). Here we aimed to identify salivary proteins as potential biomarkers and to establish a non-invasive prediction model for pSjD. Liquid chromatography-tandem mass spectrometry was conducted on whole saliva samples from patients with pSjD and non-Sjögren control subjects (non-pSjD). Proteins involved in immune processes were upregulated in the pSjD group, such as complement C3 (C3), complement factor B (CFB), clusterin (CLU), calreticulin (CALR), and neutrophil elastase (NE), which were further confirmed by ELISA. Multivariate logistic regression analyses were performed to identify markers that differentiated pSjD from non-pSjD; receiver operating characteristic (ROC) curves were constructed. A diagnostic model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA /Ro60 and anti-SSA/Ro52), and Schirmer’s test was evaluated in 186 patients (derivation cohort) with replication in 72 patients (validation cohort). In multivariate analyses, CFB, CLU, and NE were independent predictors of pSS. A model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA and anti-Ro52), and Schirmer’s test achieved significant discrimination of pSS. In the derivation cohort, the area under curve (AUC) of the ROC was 0.930 (95% CI 0.877–0.965, P < 0.001), with a sensitivity and specificity of 84.85% and 92.45%, respectively. Notably, similar results were obtained in a validation cohort. The 6-biomarker panel could provide a novel non-invasive tool for the classification of pSjD.
小唾液腺（MSG）活检是原发性Sjögren病（pSjD）分类的一种关键但有创的方法。本研究旨在鉴定唾液蛋白作为潜在的生物标志物，并建立pSjD的非侵入性预测模型。采用液相色谱-串联质谱法对pSjD患者和non-Sjögren对照组（非pSjD）的全唾液样本进行分析。pSjD组参与免疫过程的蛋白如补体C3 （C3）、补体因子B （CFB）、聚簇蛋白（CLU）、钙网蛋白（CALR）和中性粒细胞弹性酶（NE）上调，ELISA进一步证实了这一点。进行多变量logistic回归分析，以确定区分pSjD与非pSjD的标记；构建受试者工作特征（ROC）曲线。基于唾液生物标志物（CFB、CLU和NE）、血清自身抗体（抗ssa /Ro60和抗ssa /Ro52）和Schirmer试验的诊断模型在186例患者（衍生队列）中进行了评估，并在72例患者（验证队列）中进行了复制。在多变量分析中，CFB、CLU和NE是pSS的独立预测因子。基于唾液生物标志物（CFB、CLU和NE）、血清自身抗体（抗ssa和抗ro52）和Schirmer检验联合建立的模型对pSS有显著的鉴别效果。衍生队列的ROC曲线下面积（AUC）为0.930 (95% CI 0.877 ~ 0.965, P < 0.001)，敏感性为84.85%，特异性为92.45%。值得注意的是，在验证队列中获得了类似的结果。6-生物标志物面板可为pSjD的分类提供一种新的无创工具。
{"title":"A non-invasive model for diagnosis of primary Sjogren’s disease based on salivary biomarkers, serum autoantibodies, and Schirmer’s test","authors":"Xinwei Zhang, Zhangdi Liao, Yangchun Chen, Huiqin Lu, Aodi Wang, Yingying Shi, Qi Zhang, Ying Wang, Yan Li, Jingying Lan, Chubing Chen, Chaoqiong Deng, Wuwei Zhuang, Lingyu Liu, Hongyan Qian, Shiju Chen, Zhibin Li, Guixiu Shi, Yuan Liu","doi":"10.1186/s13075-024-03459-7","DOIUrl":"https://doi.org/10.1186/s13075-024-03459-7","url":null,"abstract":"Minor salivary gland (MSG) biopsy is a critical but invasive method for the classification of primary Sjögren’s disease (pSjD). Here we aimed to identify salivary proteins as potential biomarkers and to establish a non-invasive prediction model for pSjD. Liquid chromatography-tandem mass spectrometry was conducted on whole saliva samples from patients with pSjD and non-Sjögren control subjects (non-pSjD). Proteins involved in immune processes were upregulated in the pSjD group, such as complement C3 (C3), complement factor B (CFB), clusterin (CLU), calreticulin (CALR), and neutrophil elastase (NE), which were further confirmed by ELISA. Multivariate logistic regression analyses were performed to identify markers that differentiated pSjD from non-pSjD; receiver operating characteristic (ROC) curves were constructed. A diagnostic model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA /Ro60 and anti-SSA/Ro52), and Schirmer’s test was evaluated in 186 patients (derivation cohort) with replication in 72 patients (validation cohort). In multivariate analyses, CFB, CLU, and NE were independent predictors of pSS. A model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA and anti-Ro52), and Schirmer’s test achieved significant discrimination of pSS. In the derivation cohort, the area under curve (AUC) of the ROC was 0.930 (95% CI 0.877–0.965, P < 0.001), with a sensitivity and specificity of 84.85% and 92.45%, respectively. Notably, similar results were obtained in a validation cohort. The 6-biomarker panel could provide a novel non-invasive tool for the classification of pSjD.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"4 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1186/s13075-024-03442-2
Dafna D. Gladman, Peter Nash, Philip J. Mease, Oliver FitzGerald, Stephanie Duench, Mary Jane Cadatal, Karim R. Masri
Data on treatment switching directly from tumor necrosis factor inhibitors to tofacitinib in psoriatic arthritis (PsA) are limited. This post hoc analysis assessed efficacy and safety outcomes in patients with PsA who directly switched to tofacitinib in a long-term extension (LTE) study after receiving adalimumab (ADA) in a Phase 3 study, compared with those who continued to receive tofacitinib. Patients with active PsA received tofacitinib 5 mg twice daily (BID) or ADA 40 mg once every 2 weeks in a 12-month, randomized, double-blind study (OPAL Broaden) and then continued or switched to tofacitinib 5 mg BID and maintained this dose in an open-label LTE study (OPAL Balance). Efficacy was assessed 3 months before the last visit and at the last visit in the Phase 3 study, and at month 3 (or month 6 for select outcomes) in the LTE study and included rates of ≥ 20/50/70% improvement in American College of Rheumatology response criteria, Psoriasis Area and Severity Index ≥ 75% improvement, Health Assessment Questionnaire-Disability Index (HAQ-DI) response (decrease from baseline ≥ 0.35 for patients with baseline HAQ-DI ≥ 0.35), Psoriatic Arthritis Disease Activity Score ≤ 3.2, and minimal disease activity; and change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue score. Safety was assessed at months 3 and 12 in both studies via incidence rates (patients with first events/100 patient-years). Overall, 180 patients were included (ADA→tofacitinib 5 mg BID: n = 91; continuing tofacitinib 5 mg BID: n = 89). At Phase 3 baseline, patients in the ADA→tofacitinib 5 mg BID group tended to be younger and have less active disease compared with those continuing tofacitinib. Efficacy was similar between groups in the Phase 3 study, and was maintained to month 3 or 6 in the LTE study. Treatment-emergent adverse events (AEs), serious AEs, and serious infections were generally similar in the Phase 3 and LTE studies, and between groups within each study. Tofacitinib efficacy and safety were similar in patients with PsA who directly switched from ADA to tofacitinib and those who continued tofacitinib, suggesting that patients can be directly switched from ADA to tofacitinib without any washout period. NCT01877668; NCT01976364
银屑病关节炎（PsA）直接从肿瘤坏死因子抑制剂转为托法替尼治疗的数据有限。这项事后分析评估了PsA患者在接受阿达木单抗（ADA）后，与继续接受托法替尼的患者相比，在长期延长（LTE）研究中直接切换到托法替尼的疗效和安全性结果。在一项为期12个月的随机双盲研究（OPAL拓宽）中，活动性PsA患者接受托法替尼5 mg每日2次（BID）或ADA 40 mg每2周1次（每2周1次），然后在一项开放标签LTE研究（OPAL Balance）中继续或切换到托法替尼5 mg BID，并维持该剂量。在3期研究的最后一次访问前3个月和最后一次访问时以及LTE研究的第3个月（或选择结果的第6个月）评估疗效，包括美国风湿病学会反应标准≥20/50/70%的改善率，银屑病面积和严重程度指数≥75%的改善率，健康评估问卷-残疾指数（HAQ-DI）反应（基线HAQ-DI≥0.35的患者从基线≥0.35下降）。银屑病关节炎疾病活动性评分≤3.2，且疾病活动性最小；慢性疾病治疗功能评估-疲劳评分与基线的变化。两项研究在第3个月和第12个月通过发病率（首次事件患者/100患者-年）评估安全性。总共纳入180例患者(ADA→tofacitinib 5 mg BID: n = 91；继续服用法替尼5mg BID: n = 89)。在3期基线时，与继续使用托法替尼的患者相比，ADA→托法替尼5mg BID组患者更年轻，活动性疾病更少。在3期研究中，两组之间的疗效相似，在LTE研究中维持到第3个月或第6个月。在3期和LTE研究中，以及每个研究的组之间，治疗出现的不良事件（ae）、严重ae和严重感染通常相似。在PsA患者中，直接从ADA切换到托法替尼和继续使用托法替尼的患者，托法替尼的疗效和安全性相似，提示患者可以直接从ADA切换到托法替尼，无需任何洗脱期。NCT01877668;NCT01976364
{"title":"Efficacy and safety of tofacitinib in an open-label, long-term extension study in patients with psoriatic arthritis who received adalimumab or tofacitinib in a Phase 3 randomized controlled study: a post hoc analysis","authors":"Dafna D. Gladman, Peter Nash, Philip J. Mease, Oliver FitzGerald, Stephanie Duench, Mary Jane Cadatal, Karim R. Masri","doi":"10.1186/s13075-024-03442-2","DOIUrl":"https://doi.org/10.1186/s13075-024-03442-2","url":null,"abstract":"Data on treatment switching directly from tumor necrosis factor inhibitors to tofacitinib in psoriatic arthritis (PsA) are limited. This post hoc analysis assessed efficacy and safety outcomes in patients with PsA who directly switched to tofacitinib in a long-term extension (LTE) study after receiving adalimumab (ADA) in a Phase 3 study, compared with those who continued to receive tofacitinib. Patients with active PsA received tofacitinib 5 mg twice daily (BID) or ADA 40 mg once every 2 weeks in a 12-month, randomized, double-blind study (OPAL Broaden) and then continued or switched to tofacitinib 5 mg BID and maintained this dose in an open-label LTE study (OPAL Balance). Efficacy was assessed 3 months before the last visit and at the last visit in the Phase 3 study, and at month 3 (or month 6 for select outcomes) in the LTE study and included rates of ≥ 20/50/70% improvement in American College of Rheumatology response criteria, Psoriasis Area and Severity Index ≥ 75% improvement, Health Assessment Questionnaire-Disability Index (HAQ-DI) response (decrease from baseline ≥ 0.35 for patients with baseline HAQ-DI ≥ 0.35), Psoriatic Arthritis Disease Activity Score ≤ 3.2, and minimal disease activity; and change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue score. Safety was assessed at months 3 and 12 in both studies via incidence rates (patients with first events/100 patient-years). Overall, 180 patients were included (ADA→tofacitinib 5 mg BID: n = 91; continuing tofacitinib 5 mg BID: n = 89). At Phase 3 baseline, patients in the ADA→tofacitinib 5 mg BID group tended to be younger and have less active disease compared with those continuing tofacitinib. Efficacy was similar between groups in the Phase 3 study, and was maintained to month 3 or 6 in the LTE study. Treatment-emergent adverse events (AEs), serious AEs, and serious infections were generally similar in the Phase 3 and LTE studies, and between groups within each study. Tofacitinib efficacy and safety were similar in patients with PsA who directly switched from ADA to tofacitinib and those who continued tofacitinib, suggesting that patients can be directly switched from ADA to tofacitinib without any washout period. NCT01877668; NCT01976364","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"115 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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