RESUMO
This study aimed to detect signals of adverse drug reactions (ADRs) associated with biological disease-modifying antirheumatic drugs (DMARDs) and targeted therapies in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients. Utilizing the KOrean College of Rheumatology BIOlogics & Targeted Therapy Registry (KOBIO) data, we calculated relative risks, excluded previously reported drug-ADR pairs, and externally validated remaining pairs using US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and single centre's electronic health records (EHR) data. Analyzing data from 2279 RA and 1940 AS patients, we identified 35 significant drug-ADR pairs in RA and 26 in AS, previously unreported in drug labels. Among the novel drug-ADR pairs from KOBIO, 15 were also significant in the FAERS data. Additionally, 2 significant drug-laboratory abnormality pairs were found in RA using CDM MetaLAB analysis. Our findings contribute to the identification of 14 novel drug-ADR signals, expanding our understanding of potential adverse effects related to biological DMARDs and targeted therapies in RA and AS. These results emphasize the importance of ongoing pharmacovigilance for patient safety and optimal therapeutic interventions.
Assuntos
Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Espondilite Anquilosante , Humanos , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/induzido quimicamente , Preparações Farmacêuticas , Dados de Saúde Coletados Rotineiramente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Antirreumáticos/efeitos adversos , Sistema de Registros , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Produtos Biológicos/efeitos adversos , República da Coreia/epidemiologiaRESUMO
OBJECTIVE: The primary objective of this review is to examine which disease-modifying antirheumatic drugs (DMARDs) and biologics used to treat pregnant individuals with rheumatic conditions have been reported in observational studies using population-based health administrative data. The secondary objective is to describe which adverse pregnancy outcomes (both maternal and neonatal) have been reported, their definitions, and corresponding diagnostic and/or procedural codes. INTRODUCTION: Pregnant individuals are typically excluded from drug trials due to unknown potential risks to both the pregnant person and fetus, leaving most antirheumatic drugs understudied for use in pregnancy. Despite these substantial knowledge gaps, most pregnant individuals continue to be maintained on antirheumatic medications due to the benefits generally outweighing the risks. In contrast to previous systematic reviews of findings from randomized trials, our scoping review aims to leverage this real-world data to generate real-world evidence of antirheumatic drug safety during pregnancy. INCLUSION CRITERIA: Articles must report on observational studies using population-based health administrative data from pregnant individuals with rheumatic conditions (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and psoriatic arthritis) receiving antirheumatic drug therapy (DMARDs and biologics). Randomized trials, reviews, case studies, opinion pieces, and abstracts will be excluded. METHODS: Electronic databases (MEDLINE [Ovid], Embase [Ovid], CINAHL [EBSCOhost]) and gray literature (OpenGrey, Health Services Research Projects in Progress, World Health Organization Library, and Google Scholar) will be searched for relevant evidence. Search terms will combine 4 concepts: rheumatic diseases, drug therapy, pregnancy, and health care administrative data. Identified articles will be independently screened, selected, and extracted by 2 researchers. Data will be analyzed descriptively and presented in tables. REVIEW REGISTRATION: Open Science Framework https://osf.io/5e6tp.
Assuntos
Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Espondilite Anquilosante , Gravidez , Recém-Nascido , Feminino , Humanos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/tratamento farmacológico , Produtos Biológicos/efeitos adversos , Literatura de Revisão como AssuntoRESUMO
BACKGROUND: Janus kinase (JAK) inhibitors and secukinumab have been demonstrated to be effective treatments for ankylosing spondylitis (AS). However, there have been no head-to-head trials comparing the effectiveness and safety characteristics of JAK inhibitors with secukinumab. This study aimed to evaluate the relative effectiveness and safety of JAK inhibitors and secukinumab in patients with active AS. SUMMARY: A Bayesian network meta-analysis was conducted using direct and indirect data from randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib 5 mg, upadacitinib 15 mg, filgotinib 200 mg, and secukinumab 150 mg in patients with active AS who had a poor response or intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs) and were tumor necrosis factor (TNF) inhibitor-naïve. Data from six RCTs comprising 937 patients were analyzed. The Assessment of SpondyloArthritis International Society 20 (ASAS20) response rates were significantly higher in the JAK inhibitors and secukinumab groups than in the placebo group. The surface under the cumulative ranking curve (SUCRA)-based ranking probability based on the ASAS20 response rate suggested that tofacitinib 5 mg had the highest likelihood of being the best treatment for achieving the ASAS20 response rate, followed by filgotinib 200 mg, upadacitinib 15 mg, secukinumab 150 mg, and placebo. The SUCRA-based ranking probability based on the ASAS20 response rate suggested that tofacitinib 5 mg had the highest likelihood of being the best treatment for achieving the ASAS40 response rate, followed by upadacitinib 15 mg, secukinumab 150 mg, filgotinib 200 mg, and placebo. KEY MESSAGES: Tofacitinib 5 mg was the most effective treatment for AS, whereas JAK inhibitors and secukinumab 150 mg were effective treatments in patients with active AS who had a poor response or intolerance to NSAIDs and were TNF inhibitor-naïve.
Assuntos
Antirreumáticos , Inibidores de Janus Quinases , Espondilite Anquilosante , Humanos , Inibidores de Janus Quinases/efeitos adversos , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/induzido quimicamente , Antirreumáticos/efeitos adversos , Resultado do Tratamento , Anti-Inflamatórios não Esteroides/uso terapêuticoRESUMO
OBJECTIVE: To assess the long-term safety, tolerability, and efficacy of bimekizumab in patients with active ankylosing spondylitis (AS). METHODS: Patients with active AS who completed the dose-ranging, 48-week BE AGILE randomized controlled trial were eligible to participate in an open-label extension (OLE) study, in which patients received 160 mg of bimekizumab every 4 weeks. We present the safety and efficacy results through 156 weeks. Missing efficacy data were imputed using nonresponder imputation analysis for binary outcomes and multiple imputation for continuous outcomes. RESULTS: From weeks 0-156, 280 of 303 patients (exposure-adjusted incidence rate 141.0 per 100 patient-years) experienced ≥1 treatment-emergent adverse event; the most frequent adverse events were nasopharyngitis (8.1 per 100 patient-years) and upper respiratory tract infection (5.0 per 100 patient-years). Additionally, 67 of 303 patients (9.8 per 100 patient-years) had mild to moderate localized fungal infections (28 of 303 patients had Candida infections [3.7 per 100 patient-years] and 23 of 303 patients had oral candidiasis [3.0 per 100 patient-years]), 10 patients had serious infections (1.3 per 100 patient-years), and no cases of active tuberculosis were reported. Active inflammatory bowel disease (1.1 per 100 patient-years), anterior uveitis (0.7 per 100 patient-years), and adjudicated major adverse cardiovascular events (0.3 per 100 patient-years) were infrequent. The efficacy of bimekizumab treatment demonstrated at week 48 was sustained in the OLE study. At week 156, nonresponder imputation analysis showed that 53.7% of patients (72.6% of observed cases) met the Assessment of SpondyloArthritis international Society criteria for 40% improvement and 28.0% of patients (37.9% of observed cases) achieved partial remission; Ankylosing Spondylitis Disease Activity Scores were reduced from baseline (mean ± SEM 3.9 ± 0.1) to week 48 (2.1 ± 0.1) and week 156 (1.9 ± 0.1) (multiple imputation). Patients showed sustained improvements in pain, fatigue, physical function, and health-related quality of life. CONCLUSION: The safety profile of bimekizumab was found to be consistent with previously demonstrated findings, and no new safety signals were identified. The efficacy of bimekizumab in patients with AS was sustained through 3 years of treatment.
Assuntos
Espondilite Anquilosante , Humanos , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/induzido quimicamente , Qualidade de Vida , Método Duplo-Cego , Anticorpos Monoclonais Humanizados/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the efficacy and safety of upadacitinib, a Janus kinase inhibitor, in patients with active ankylosing spondylitis (AS) with an inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: Adults with active AS who met modified New York criteria and had an IR to one or two bDMARDs (tumour necrosis factor or interleukin-17 inhibitors) were randomised 1:1 to oral upadacitinib 15 mg once daily or placebo. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Sequentially tested secondary endpoints included Ankylosing Spondylitis Disease Activity score, Spondyloarthritis Research Consortium of Canada MRI spine inflammation score, total back pain, nocturnal back pain, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and Maastricht Ankylosing Spondylitis Enthesitis Score. Results are reported from the 14-week double-blind treatment period. RESULTS: A total of 420 patients with active AS were randomised (upadacitinib 15 mg, n=211; placebo, n=209). Significantly more patients achieved the primary endpoint of ASAS40 at week 14 with upadacitinib vs placebo (45% vs 18%; p<0.0001). Statistically significant improvements were observed with upadacitinib vs placebo for all multiplicity-controlled secondary endpoints (p<0.0001). Adverse events were reported for 41% of upadacitinib-treated and 37% of placebo-treated patients through week 14. No events of malignancy, major adverse cardiovascular events, venous thromboembolism or deaths were reported with upadacitinib. CONCLUSION: Upadacitinib 15 mg was significantly more effective than placebo over 14 weeks of treatment in bDMARD-IR patients with active AS. No new safety risks were identified with upadacitinib. TRIAL REGISTRATION NUMBER: NCT04169373.
Assuntos
Antirreumáticos , Inibidores de Janus Quinases , Espondilartrite , Espondilite Anquilosante , Adulto , Antirreumáticos/efeitos adversos , Terapia Biológica , Método Duplo-Cego , Compostos Heterocíclicos com 3 Anéis , Humanos , Interleucina-17 , Inibidores de Janus Quinases/efeitos adversos , Espondilartrite/tratamento farmacológico , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/tratamento farmacológico , Resultado do Tratamento , Fatores de Necrose TumoralRESUMO
Ankylosing spondylitis (AS) is a systemic, chronic, and inflammatory autoimmune disease associated with the disorder of intestinal microbiota. Unfortunately, effective therapies for AS are lacking. Recent evidence has indicated that indole-3-acetic acid (IAA), an important microbial tryptophan metabolite, can modulate intestinal homeostasis and suppress inflammatory responses. However, reports have not examined the in vivo protective effects of IAA against AS. In this study, we investigated the protective effects and underlying mechanisms through which IAA acts against AS. We constructed a proteoglycan (PG)-induced AS mouse model and administered IAA (50 mg/kg body weight) by intraperitoneal injection daily for 4 weeks. The effects of IAA on AS mice were evaluated by examining disease severity, intestinal barrier function, aryl hydrocarbon receptor (AhR) pathway, T-helper 17 (Th17)/T regulatory (Treg) balance, and inflammatory cytokine levels. The intestinal microbiota compositions were profiled through whole-genome sequencing. We observed that IAA decreased the incidence and severity of AS in mice, inhibited the production of pro-inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin [IL]-6, IL-17A, and IL-23), promoted the production of the anti-inflammatory cytokine IL-10, and reduced the ratios of pro-/anti- inflammatory cytokines. IAA ameliorated pathological changes in the ileum and improved intestinal mucosal barrier function. IAA also activated the AhR pathway, upregulated the transcription factor forehead box protein P3 (FoxP3) and increased Treg cells, and downregulated the transcription factors retinoic acid receptor-related orphan receptor gamma t (RORγt) and signal transducer and activator of transcription 3 (STAT3) and decreased Th17 cells. Furthermore, IAA altered the composition of the intestinal microbiota composition by increasing Bacteroides and decreasing Proteobacteria and Firmicutes, in addition to increasing the abundances of Bifidobacterium pseudolongum and Mucispirillum schaedleri. In conclusion, IAA exerted several protective effects against PG-induced AS in mice, which was mediated by the restoration of balance among the intestinal microbial community, activating the AhR pathway, and inhibiting inflammation. IAA might represent a novel therapeutic approach for AS.
Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Ácidos Indolacéticos/farmacologia , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/patologia , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteoglicanas/toxicidade , Espondilite Anquilosante/induzido quimicamente , Linfócitos T Reguladores/imunologia , Células Th17/imunologiaRESUMO
BACKGROUND: Ankylosing spondylitis (AS) is an immune-mediated, chronic inflammatory rheumatic disorder. The etiology of Parkinson's disease (PD) is multifactorial; however, inflammation is receiving an increasing amount of attention as an underlying cause of the neurodegenerative process of PD. OBJECTIVE: We performed a nationwide longitudinal, population-based matched cohort study to assess the association with the later development of parkinsonism in Korea. METHODS: This study was conducted using records from the Health Insurance Review and Assessment Service database. The cumulative incidence rate of PD was estimated. Fine-Gray subdistribution hazard models were used to identify hazards associated with PD development based on the presence of AS. Exposure to anti-inflammatory drugs was measured and analyzed to determine the protective effect of these medications. Additionally, the hazard ratio (HR) for atypical parkinsonism was estimated. RESULTS: The results of the Fine-Gray subdistribution hazard model revealed that the HR for PD development in the AS group was 1.82 (95%confidence interval [CI], 1.38-2.39, pâ<â0.001). A significant decrease in PD development was observed in patients with AS taking non-steroidal anti-inflammatory drugs (NSAIDs). The HR for atypical parkinsonism in the AS group was 3.86 (95%CI, 1.08-13.78, pâ<â0.05). CONCLUSION: We found that AS was associated with an increased risk of PD and atypical parkinsonism. NSAIDs used for AS control have some protective effects against PD. Further studies assessing whether biological treatment mitigates PD risk in patients with high activity are warranted.
Assuntos
Doença de Parkinson , Transtornos Parkinsonianos , Espondilite Anquilosante , Anti-Inflamatórios não Esteroides/uso terapêutico , Estudos de Coortes , Humanos , Incidência , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Doença de Parkinson/etiologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/etiologia , Estudos Retrospectivos , Fatores de Risco , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/epidemiologiaRESUMO
OBJECTIVES: Recently, there is an increased number of reports being published on Methotrexate (MTX) related cutaneous manifestations. We aimed to identify and critically appraise descriptive studies describing the MTX related skin manifestations, treatment approach, and their outcomes. METHODOLOGY: An extensive literature search was performed in the PubMed, Embase, and Scopus databases from inception to April 2021 without any restrictions along with the bibliographic search of included studies, grey literature search, and a snowball search was performed in Google and Google Scholar to identify the relevant literature. Descriptive studies reporting MTX related cutaneous manifestations were considered for the review. The study selection, data extraction, and quality assessment were conducted by two independent reviewers and any disagreements were settled by consensus with the third reviewer. RESULTS: 31 out of 8,365 descriptive studies including 38 patients (22 females and 16 males) aged between 12 and 78 years prescribed for the management of rheumatoid arthritis, ankylosing spondylitis, and psoriasis were included in this review. Toxic epidermal necrolysis (TEN), papular eruption, vasculitis, erosions of psoriasis, ulcerated psoriatic plaques, local reactions, keratinocyte dystrophy, erythema multiforme, drug rash with eosinophilia and systemic symptoms, Steven Johnson syndrome and photosensitive dermatitis were the majority of MTX induced cutaneous reactions. Immediate withdrawal of MTX, providing appropriate care with anti-inflammatory, topical steroids, and supplementation with folic acid were reported to be effective for the management of the MTX related cutaneous manifestations. CONCLUSIONS: Clinicians and healthcare professionals should be aware of possible acute cutaneous drug reactions induced by MTX to avoid further consequences and fatal conditions. Immediate withdrawal of MTX and supportive care were reported as an efficacious therapeutic management of acute cutaneous drug reactions. PROSPERO REGISTRATION NUMBER: CRD42020220038.
Assuntos
Artrite Reumatoide , Psoríase , Espondilite Anquilosante , Adolescente , Adulto , Idoso , Criança , Feminino , Ácido Fólico/uso terapêutico , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/tratamento farmacológico , Adulto JovemRESUMO
Ankylosing spondylitis (AS) is a type of rheumatic disease characterized by chronic inflammation and pathological osteogenesis in the entheses. Previously, we demonstrated that enhanced osteogenic differentiation of MSC from AS patients (AS-MSC) resulted in pathological osteogenesis, and that during the enhanced osteogenic differentiation course, AS-MSC induced TNF-α-mediated local inflammation. However, whether TNF-α in turn affects AS-MSC remains unknown. Herein, we further demonstrate that a high-concentration TNF-α treatment triggers enhanced directional migration of AS-MSC in vitro and in vivo, which enforces AS pathogenesis. Mechanistically, TNF-α leads to increased expression of ELMO1 in AS-MSC, which is mediated by a METTL14 dependent m6A modification in ELMO1 3'UTR. Higher ELMO1 expression of AS-MSC is found in vivo in AS patients, and inhibiting ELMO1 in SKG mice produces therapeutic effects in this spondyloarthritis model. This study may provide insight into not only the pathogenesis but also clinical therapy for AS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Células-Tronco Mesenquimais/patologia , Osteogênese/genética , Espondilite Anquilosante/patologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Biópsia , Medula Óssea/patologia , Estudos de Casos e Controles , Diferenciação Celular/genética , Movimento Celular/genética , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Feminino , Células HEK293 , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Cultura Primária de Células , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/genética , Microtomografia por Raio-X , beta-Glucanas/administração & dosagem , beta-Glucanas/efeitos adversosRESUMO
OBJECTIVES: The objective of COAST-Y was to evaluate the effect of continuing versus withdrawing ixekizumab (IXE) in patients with axial spondyloarthritis (axSpA) who had achieved remission. METHODS: COAST-Y is an ongoing, phase III, long-term extension study that included a double-blind, placebo (PBO)-controlled, randomised withdrawal-retreatment period (RWRP). Patients who completed the originating 52-week COAST-V, COAST-W or COAST-X studies entered a 24-week lead-in period and continued either 80 mg IXE every 2 (Q2W) or 4 weeks (Q4W). Patients who achieved remission (an Ankylosing Spondylitis Disease Activity Score (ASDAS)<1.3 at least once at week 16 or week 20, and <2.1 at both visits) were randomly assigned equally at week 24 to continue IXE Q4W, IXE Q2W or withdraw to PBO in a blinded fashion. The primary endpoint was the proportion of flare-free patients (flare: ASDAS≥2.1 at two consecutive visits or ASDAS>3.5 at any visit) after the 40-week RWRP, with time-to-flare as a major secondary endpoint. RESULTS: Of 773 enrolled patients, 741 completed the 24-week lead-in period and 155 entered the RWRP. Forty weeks after randomised withdrawal, 83.3% of patients in the combined IXE (85/102, p<0.001), IXE Q4W (40/48, p=0.003) and IXE Q2W (45/54, p=0.001) groups remained flare-free versus 54.7% in the PBO group (29/53). Continuing IXE significantly delayed time-to-flare versus PBO, with most patients remaining flare-free for up to 20 weeks after IXE withdrawal. CONCLUSIONS: Patients with axSpA who continued treatment with IXE were significantly less likely to flare and had significantly delayed time-to-flare compared with patients who withdrew to PBO.
Assuntos
Espondiloartrite Axial , Espondilite Anquilosante , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Humanos , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/tratamento farmacológico , Resultado do TratamentoRESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. The journal was initially contacted by the corresponding author to request the retraction of the article as the data were not reliable. Given the comments of Dr Elisabeth Bik regarding this article " the Western blot bands in all 400+ papers are all very regularly spaced and have a smooth appearance in the shape of a dumbbell or tadpole, without any of the usual smudges or stains. All bands are placed on similar looking backgrounds, suggesting they were copy/pasted from other sources, or computer generated", the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.
Assuntos
Ginsenosídeos/farmacologia , Inflamação/tratamento farmacológico , MicroRNAs/genética , Espondilite Anquilosante/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/genética , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/patologia , Transdução de Sinais/efeitos dos fármacos , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/genética , Espondilite Anquilosante/patologiaRESUMO
Recently, accumulating evidence has suggested that gut microbiota may be involved in the occurrence and development of ankylosing spondylitis (AS). It has been suggested that rifaximin have the ability to modulate the gut bacterial communities, prevent inflammatory response, and modulate gut barrier function. The goal of this work is to evaluate the protective effects of rifaximin in fighting AS and to elucidate the potential underlying mechanism. Rifaximin were administered to the proteoglycan (PG)-induced AS mice for 4 consecutive weeks. The disease severity was measured with the clinical and histological of arthritis and spondylitis. Intestinal histopathological, pro-inflammatory cytokine levels and the intestinal mucosal barrier were evaluated. Then, western blot was performed to explore the toll-like receptor 4 (TLR-4) signal transducer and NF-κB expression. Stool samples were collected to analyze the differences in the gut microbiota via next-generation sequencing of 16S rDNA. We found that rifaximin significantly reduced the severity of AS and resulted in down-regulation of inflammatory factors, such as TNF-α, IL-6, IL-17A, and IL-23. Meanwhile, rifaximin prevented ileum histological alterations, restored intestinal barrier function and inhibited TLR-4/NF-κB signaling pathway activation. Rifaximin also changed the gut microbiota composition with increased Bacteroidetes/Firmicutes phylum ratio, as well as selectively promoting some probiotic populations, including Lactobacillales. Our results suggest that rifaximin suppressed progression of AS and regulated gut microbiota in AS mice. Rifaximin might be useful as a novel treatment for AS.
Assuntos
Antibacterianos/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Microbiota/efeitos dos fármacos , Rifaximina/administração & dosagem , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/patologia , Animais , Análise por Conglomerados , Citocinas/análise , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fatores Imunológicos/análise , Camundongos Endogâmicos BALB C , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Índice de Gravidade de Doença , Espondilite Anquilosante/induzido quimicamente , Resultado do TratamentoRESUMO
Objective: Despite extensive studies, the precise mechanism underlying spondyloarthritis, especially ankylosing spondylitis, remains elusive. This study aimed to develop an ideal animal model for an insight into mechanism of spondyloarthritis and functional relevance of SOCS3 in spondyloarthritis. Methods: Since SOCS3 is a major regulator of IL23-STAT3 signaling, we generated SOCS3 knockdown transgenic (TG) mice for development of an animal model of spondyloarthritis. A hydrodynamic delivery method was employed to deliver minicircle DNA expressing IL23 (mc-IL23) into wild-type (WT) and the TG mice. Knockdown/overexpression systems mediated by lentivirus and retrovirus were used to determine whether SOCS3 regulated osteoblast differentiation. Results: Forced expression of IL23 induced severe joint destruction and extensive bone loss in SOCS3 knockdown TG mice, while this treatment only caused moderate symptoms in WT mice. Furthermore, severe spondyloarthritis was found in IL23-injected TG mice as compared to mild disease observed in WT controls under same condition. Moreover, our studies showed that IL23 promoted osteoblast differentiation via activation of STAT3 pathway and disruption of SOCS3 expression greatly increased phosphorylation of STAT3. In addition, silencing SOCS3 resulted in enhanced osteoblast differentiation through activation of Smad1/5/9 signaling, as evidenced by elevated phosphorylation level of Smad1/5/9. Experiments further demonstrated that SOCS3 interacted with Smad1 and thus suppressed the BMP2-Smad signaling. Conclusions: The results reveal that SOCS3 is involved in IL23-induced spondyloarthritis and acts as a key regulator of osteoblast differentiation, and suggest that SOCS3 knockdown TG mice may be an ideal animal model for further studies of spondyloarthritis.
Assuntos
Diferenciação Celular , Interleucina-23 , Osteoblastos , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular , DNA Circular/efeitos adversos , DNA Circular/genética , DNA Circular/imunologia , DNA Circular/farmacologia , Modelos Animais de Doenças , Inativação Gênica , Interleucina-23/efeitos adversos , Interleucina-23/genética , Interleucina-23/imunologia , Camundongos , Camundongos Knockout , Osteoblastos/imunologia , Osteoblastos/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/imunologiaRESUMO
OBJECTIVE: To investigate the molecular mechanism underlying inflammation-related ectopic new bone formation in ankylosing spondylitis (AS). METHODS: Spinal tissues and sera were collected from patients with AS and healthy volunteers and examined for the expression of Wnt proteins. An in vitro cell culture system mimicking the local inflammatory microenvironment of bone-forming sites was established to study the relationship between inflammation and Wnt expression, the regulatory mechanism of inflammation-induced Wnt expression, and the role of Wnt signaling in new bone formation. Modified collagen-induced arthritis (CIA) and proteoglycan-induced spondylitis (PGIS) animal models were used to confirm the key findings in vivo. RESULTS: The levels of osteoinductive Wnt proteins were increased in sera and spinal ligament tissues from patients with AS. Constitutive low-intensity tumor necrosis factor (TNF) stimulation, but not short-term or high-intensity TNF stimulation, induced persistent expression of osteoinductive Wnt proteins and subsequent bone formation through NF-κB (p65) and JNK/activator protein 1 (c-Jun) signaling pathways. Furthermore, inhibition of either the Wnt/ß-catenin or Wnt/protein kinase Cδ (PKCδ) pathway significantly suppressed new bone formation. The increased expression of Wnt proteins was confirmed in both the modified CIA and PGIS models. A kyphotic and ankylosing phenotype of the spine was seen during long-term observation in the modified CIA model. Inhibition of either the Wnt/ß-catenin or Wnt/PKCδ signaling pathway significantly reduced the incidence and severity of this phenotype. CONCLUSION: Inflammation intensity-dependent expression of osteoinductive Wnt proteins is a key link between inflammation and ectopic new bone formation in AS. Activation of both the canonical Wnt/ß-catenin and noncanonical Wnt/PKCδ pathways is required for inflammation-induced new bone formation.
Assuntos
Inflamação/metabolismo , Osteogênese/fisiologia , Espondilite Anquilosante/metabolismo , Proteínas Wnt/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Humanos , Proteoglicanas/metabolismo , Coluna Vertebral/metabolismo , Espondilite Anquilosante/induzido quimicamente , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , beta Catenina/metabolismoRESUMO
BACKGROUND: Ankylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression. METHODS: PGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation. RESULTS: ETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation. CONCLUSIONS: Early intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients.
Assuntos
Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Proteoglicanas/toxicidade , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/tratamento farmacológico , Animais , Esquema de Medicação , Quimioterapia Combinada , Etanercepte/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Prednisolona/administração & dosagem , Espondilite Anquilosante/patologiaRESUMO
BACKGROUND: In inflammatory bowel disease (IBD), a new biological therapy has recently been approved. Vedolizumab is a humanised IgG1 monoclonal antibody to α4ß7 integrin that modulates gut lymphocyte trafficking. Although an exclusively local effect of vedolizumab could be expected based on the restricted presence of the α4ß7-mucosal vascular addressin cell adhesion molecule 1 complex in the gut, past combined success with anti-tumour necrosis factor, and previous demonstration of α4ß7 integrin in the joint, led to the expectation of a therapeutic efficacy in spondyloarthritis. Nonetheless, the effect of vedolizumab on extraintestinal manifestations-and especially the joint-has not been reported so far. CASE REPORT: A series of five patients with IBD who were treated with vedolizumab and promptly developed new onset or exacerbation of sacroiliitis or arthritis are reported. CONCLUSIONS: Vedolizumab therapy does not seem to show any efficacy in and might even induce arthritis and/or sacroiliitis. However, larger cohort studies are needed to provide information on the prevalence, the evolution and underlying mechanism.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Fármacos Gastrointestinais/efeitos adversos , Sacroileíte/induzido quimicamente , Espondilite Anquilosante/induzido quimicamente , Exacerbação dos Sintomas , Adulto , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-ß1 in serum. The combined treatment with a bacteria-derived complement inhibitor Efb-C (C-terminal of extracellular fibrinogen-binding protein of Staphylococcus aureus) remarkably retarded the progression of mouse AS by reducing osteoblast differentiation. Furthermore, we demonstrated that two important modulators involved in AS disease, TGF-ß1 and RANKL, were elevated upon in vitro complement attack in osteoblast and/or osteoclast cells. These findings further unravel that complement activation is closely related with the pathogenesis of AS, and suggest that complement inhibition may hold great potential for AS therapy.
Assuntos
Anti-Inflamatórios/farmacologia , Dor nas Costas/tratamento farmacológico , Proteínas de Bactérias/farmacologia , Proteínas do Sistema Complemento/genética , Espondilite Anquilosante/tratamento farmacológico , Animais , Dor nas Costas/induzido quimicamente , Dor nas Costas/imunologia , Dor nas Costas/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Proteínas do Sistema Complemento/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/imunologia , Osteoblastos/patologia , Cultura Primária de Células , Proteoglicanas/administração & dosagem , Ligante RANK/genética , Ligante RANK/imunologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologiaRESUMO
Ankylosing spondylitis is a common rheumatic disease involving both inflammatory erosive osteopenia and bony overgrowth. Main disease features are recapitulated in small rodents challenged with complete Freund's adjuvant. MRI was used to follow longitudinally in vivo changes induced in the rat spine and micro-CT as terminal assessment of bone damage. Histochemistry methods were used to validate these imaging modalities in view of preclinical drug testing and translational applications of spine imaging. Animals were examined using a 3D fat-suppressed gradient-echo sequence, following the injection of gadolinium. At the end of the study, spines were excised for micro-CT and histological examination. Signals reflecting inflammation were detected at levels L5-L6 of the lumbar spine throughout the experimental period, peaking at day 27 after adjuvant. At day 14 the inflammatory response occurred along ligaments but it expanded to nearby soft tissues at later time points. From day 27 onwards inflammation was also detected within the bone, in areas where erosion occurred, and bone-like structures were formed. Micro-CT showed bone remodeling. Histology of isolated spines confirmed the inflammation and bone remodeling observed in vivo. The present study including three complementary approaches clearly demonstrates the potential of imaging for longitudinal assessments of changes in the spine in this animal model in view of preclinical pharmacological studies. The excellent correlation seen between the in vivo images and the histology underlines its fundamental role in the validation of non-invasive imaging readouts.
Assuntos
Adjuvante de Freund/efeitos adversos , Imageamento por Ressonância Magnética/métodos , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/patologia , Microtomografia por Raio-X/métodos , Animais , Modelos Animais de Doenças , Adjuvante de Freund/farmacologia , Ratos , Ratos WistarRESUMO
INTRODUCTION: Ankylosing spondylitis (AS) is unique in its pathology where inflammation commences at the entheses before progressing to an osteoproliferative phenotype generating excessive bone formation that can result in joint fusion. The underlying mechanisms of this progression are poorly understood. Recent work has suggested that changes in Wnt signalling, a key bone regulatory pathway, may contribute to joint ankylosis in AS. Using the proteoglycan-induced spondylitis (PGISp) mouse model which displays spondylitis and eventual joint fusion following an initial inflammatory stimulus, we have characterised the structural and molecular changes that underlie disease progression. METHODS: PGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling. RESULTS: Inflammation initiated at the periphery of the intervertebral discs progressing to disc destruction followed by massively excessive cartilage and bone matrix formation, as demonstrated by toluidine blue staining and IHC for collagen type I and osteocalcin, leading to syndesmophyte formation. Expression levels of DKK1 and SOST, Wnt signalling inhibitors highly expressed in joints, were reduced by 49% and 63% respectively in the spine PGISp compared with control mice (P < 0.05) with SOST inhibition confirmed by IHC. Microarray profiling showed genes involved in inflammation and immune-regulation were altered. Further, a number of genes specifically involved in bone regulation including other members of the Wnt pathway were also dysregulated. CONCLUSIONS: This study implicates the Wnt pathway as a likely mediator of the mechanism by which inflammation induces bony ankylosis in spondyloarthritis, raising the potential that therapies targeting this pathway may be effective in preventing this process.
Assuntos
Glicoproteínas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Osteogênese/genética , Espondilite Anquilosante/genética , Via de Sinalização Wnt/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Glicoproteínas/metabolismo , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Articulações/metabolismo , Articulações/patologia , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Osteocalcina/genética , Osteocalcina/metabolismo , Proteoglicanas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Coluna Vertebral/metabolismo , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/metabolismoRESUMO
A 21-year-old patient with ankylosing spondylitis under treatment with the TNF-alpha inhibitor infliximab developed a multifocal, demyelinating axonal neuropathy affecting several peripheral nerves simultaneously (mononeuritis multiplex). This represents an additional rare peripheral nervous system side effect of infliximab therapy. The underlying cause is unknown. Intravenous immunoglobulin therapy (0.4 g/kg per day for five days) led to a complete regression of muscle paresis and sensory defects in this case.