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ID PMID Title PublicationDate abstract
32685641 Knee Rheumatoid Arthritis With Lateral Tibial Plateau and Tibial Stress Fractures Managed 2020 Sep Rheumatoid arthritis (RA) is a chronic systemic disease that causes progressive joint damage, bony defects, and ligament imbalance. These sequelae of RA present major difficulties to surgeons during hip or knee arthroplasty. The presence of coexistent periarticular fractures adds to these difficulties and represents a surgical dilemma. No guidance exists within the literature for the medical and surgical management of complicated cases of RA with coexistent fractures. So far, the evidence has focused on fixation techniques, arthroplasty, and conservative management for periarticular fractures of osteoarthritic joints without significant degeneration of anatomical structures. We report a case of advanced knee RA with associated ipsilateral tibial plateau fracture and a tibial shaft stress fracture that was treated successfully with a single-stage joint replacement procedure. The case study presents a well-planned, single-stage arthroplasty with a lateral parapatellar approach as a management option that allows for early weight-bearing and restoration of function and provides a detailed guide for surgeons when managing similar cases.
33234499 Clinical Management and Discontinuation of Treatment in Patients with Recent Onset Rheumat 2020 Nov 21 INTRODUCTION: The treatment of rheumatoid arthritis has changed dramatically in recent years, especially with the use of disease modifying drugs (DMARDs). Data on the management of this disease in clinical trials are abundant, but not so in real life. The aim of our study is to describe the management of an early rheumatoid arthritis cohort in daily clinical practice, especially DMARD discontinuations and reasons. METHODS: A retrospective observational study of patients with rheumatoid arthritis diagnosed between 01/07 and 12/14 followed up to 01/17, using>1 DMARD≥3 months. VARIABLES: sociodemographic, clinical, treatment, DMARD discontinuation and reason. Descriptive analysis of sociodemographic, clinical and treatment characteristics. Discontinuation incidence rate (DIR) due to survival techniques, expressed in 100 patients/year with 95% confidence interval. RESULTS: 814 patients were included with 2,388 courses of treatment, 77% women, mean age 57.5 years. First course: monotherapy (92.75%), especially methotrexate (56.06%). In later courses there was increased combined therapy and use of biologicals (mainly etanercept). There were 1,094 discontinuations (29.5 [27.8-31.3]). The DIR was higher for adverse events (15.9 [14.7-17.3]), biologicals (49.6 [43.1-57.2]) and combined therapy. The DMAR with the lowest DIR was methotrexate (25.8 [23.8-28.1]). CONCLUSION: Methotrexate was the most used drug, biologicals increased throughout the follow-up, the most frequent being Etanercept. The DMARD DIR was 29/100 patients per year, mainly due to adverse events. It seems to be higher in the therapies that include biologicals and combined therapies. Methotrexate is the drug with the lowest DIR.
32335755 Rheumatology care of migrants from sub-Saharan Africa: a literature review and qualitative 2021 Sep INTRODUCTION: Rheumatologists practising in the UK National Health Service (NHS) are likely to treat migrant patients from sub-Saharan Africa. This study aimed to conduct a literature review about rheumatoid arthritis prevalence in Africa and understand the experiences of patients with rheumatological conditions, about their past healthcare in sub-Saharan Africa and their transition of care to the United Kingdom (UK). METHODS: A systematic search and a pilot study using semi-structured interviews to gain the views of migrants from sub-Saharan Africa with rheumatological conditions was conducted. RESULTS: Thirty-two studies reported on the prevalence of rheumatoid arthritis in Africa. Studies were small and out-of-date, and there was significant heterogeneity in prevalence rates. For the qualitative study, seven participants were recruited. Four themes were highlighted: (i) the physical and emotional impact of rheumatological conditions on participants; (ii) limited rheumatology care in sub-Saharan Africa with high costs, limited access to specialists, lack of investigations and treatments, the use of traditional medicines and poor communication by clinicians; (iii) barriers to rheumatology care in the UK such as migrants' poor understanding of rheumatological conditions and NHS entitlements; (iv) and ways to improve access to care such as patient, public and general practitioner education. CONCLUSION: This study has highlighted the paucity of rheumatoid arthritis prevalence data in Africa and described, for the first time, the migrant's perspective of rheumatology care in sub-Saharan Africa and the transition of care to the UK. This description begins to allow healthcare providers in the UK to tailor management for this migrant population. Key Points • Rheumatological conditions are common in Africa, but there is a paucity of epidemiological data regarding the prevalence of specific conditions such as rheumatoid arthritis. • UK clinicians need to be mindful when treating migrants that access to rheumatologists and specialist investigations and treatment is limited in sub-Saharan Africa and that there is often limited public and patient understanding of rheumatological conditions. • Migrants continue to lack understanding of their NHS entitlements and fear data sharing with immigration services which can be a barrier to seeking care. • This study has exposed the lack of understanding about rheumatological conditions by the public and some general practitioners which needs to be addressed with effective education and awareness campaigns.
32114644 Effect of Golimumab Dose Escalation in Japanese Patients With Rheumatoid Arthritis: Post-H 2020 Jun INTRODUCTION: While dose escalation of golimumab has been used for patients with rheumatoid arthritis who demonstrate an inadequate response to the standard dose, its effectiveness has not been fully evaluated. The aim of this study was to assess the clinical outcome observed by dose escalation of golimumab for patients with rheumatoid arthritis in the daily clinical setting. METHODS: A post hoc analysis was performed of data from the 24-week post-marketing surveillance conducted in Japan (n = 5154). A total of 301 patients with moderate or high disease activity at baseline who underwent dose escalation of golimumab were assessed for effectiveness at 24 weeks based on several variables, such as DAS28-CRP, SDAI, and CDAI, as well as for medication persistence through 24 weeks. In addition, the study population was stratified by the time to dose escalation, and effectiveness was likewise evaluated. Logistic regression analysis was performed to identify factors associated with a moderate/good EULAR response to golimumab at 24 weeks. RESULTS: Patients with golimumab dose escalation showed significant improvement of the clinical signs and symptoms of rheumatoid arthritis at 24 weeks, as indicated by reduction of the DAS28-CRP (∆0.89), SDAI (∆8.64), and CDAI (∆8.28) scores. This result was relatively consistent across the subgroups stratified by the timing of dose escalation. According to Kaplan-Meier analysis, 78.1% of the patients continued to receive golimumab at 24 weeks, and this was also similar among the subgroups stratified by the time to dose escalation. Multivariate analysis identified male sex and previous biologic therapy as factors that were significantly associated with the clinical response at 24 weeks. CONCLUSION: In real-world clinical practice, improvement of disease activity was observed after uptitration of golimumab from 50 to 100 mg regardless of the timing. Male patients and biologic-naive patients were more likely to respond to dose escalation of golimumab. TRIAL REGISTRATION: UMIN-CTR, Identifier: UMIN000015895.
32071617 Baricitinib exposure during pregnancy in rheumatoid arthritis. 2020 We here describe the case of a 43-year-old White woman who was diagnosed with rheumatoid arthritis treated with anti-tumour necrosis factor drugs that caused an adverse drug reaction. The objective of this study was to describe the outcome of a pregnancy under baricitinib, a JAK-inhibitor drug, in a woman affected by rheumatoid arthritis. Scant data are available about the safety of JAK inhibitors during pregnancy. A case report and review of literature about JAK-inhibitor exposure during pregnancy were conducted. After the failure of biologic disease-modifying antirheumatic drugs due to a loss of efficacy and adverse drug reaction, the patient was started on baricitinib when it was marketed. During the fifth month of this treatment, she reported missing her period and a pregnancy was confirmed, despite a previous recommendation of adequate contraception. Thus, she had been exposed to baricitinib for several weeks before conception and during the whole first-trimester until the 17th week of gestation. The treatment with baricitinib was promptly discontinued and she was regularly examined. Foetal growth was normal throughout pregnancy and ultrasound examination did not detect any macroscopic abnormality. This is the first report of exposure to baricitinib during pregnancy outside the drug registration study program. We report the positive pregnancy outcome of a continuous exposure to baricitinib during the first 17 weeks of pregnancy. Small molecules, such as JAK inhibitors, are increasingly being used in clinical practice in rheumatoid arthritis and in other diseases. Hence, more broad and focused studies are required to have an insight of safety for this drug class in the case of accidental exposure before or during pregnancy.
32573694 Neuronal interleukin-1 receptors mediate pain in chronic inflammatory diseases. 2020 Sep 7 Chronic pain is a major comorbidity of chronic inflammatory diseases. Here, we report that the cytokine IL-1β, which is abundantly produced during multiple sclerosis (MS), arthritis (RA), and osteoarthritis (OA) both in humans and in animal models, drives pain associated with these diseases. We found that the type 1 IL-1 receptor (IL-1R1) is highly expressed in the mouse and human by a subpopulation of TRPV1+ dorsal root ganglion neurons specialized in detecting painful stimuli, termed nociceptors. Strikingly, deletion of the Il1r1 gene specifically in TRPV1+ nociceptors prevented the development of mechanical allodynia without affecting clinical signs and disease progression in mice with experimental autoimmune encephalomyelitis and K/BxN serum transfer-induced RA. Conditional restoration of IL-1R1 expression in nociceptors of IL-1R1-knockout mice induced pain behavior but did not affect joint damage in monosodium iodoacetate-induced OA. Collectively, these data reveal that neuronal IL-1R1 signaling mediates pain, uncovering the potential benefit of anti-IL-1 therapies for pain management in patients with chronic inflammatory diseases.
33002783 Polymer colloids as drug delivery systems for the treatment of arthritis. 2020 Nov The most common types of arthritis are osteoarthritis (OA) and rheumatoid arthritis (RA) which are themain causes of disability and pain among older people. Current treatment of arthritis mainly consists of oral and intra-articular medications. Despite the efficacy of the intraarticular injections over the oral treatment, it is still limited by the rapid clearance of the injected drug. Therefore, a rational design of drug delivery systems (DDSs) able to delivery drugs in controlled manner and for required period of time to the arthritis joint is a key in developing safe and effective formulations for OA and RA. In this paper various colloidal systems like nanoparticles, liposomes, cationic carriers, hydrogels, and emulsion-based carriers were presented and discussed in light of their use and efficacy as delivery systems to transport therapeutics for arthritis treatment. Factors influencing the delivery efficacy such as size, charge, structure, drug uptake, retention and its release profile alongside with cytocompatibility and safety were addressed. Moreover, the advantages and disadvantages of the different colloidal systems were emphasised.
32817113 Lung complications of Sjogren syndrome. 2020 Sep 30 Primary Sjogren syndrome (pSS) is a systemic autoimmune disease characterised by lymphocytic infiltration of exocrine glands and by a number of systemic manifestations, including those regarding the lung. Pulmonary involvement in pSS includes interstitial lung disease (ILD) and airway disease, together with lymphoproliferative disorders.Patients with pSS-ILD report impaired health-related quality of life and a higher risk of death, suggesting the importance of early diagnosis and treatment of this type of pulmonary involvement. In contrast, airway disease usually has little effect on respiratory function and is rarely the cause of death in these patients.More rare disorders can be also identified, such as pleural effusion, cysts or bullae.Up to date, available data do not allow us to establish an evidence-based treatment strategy in pSS-ILD. No data are available regarding which patients should be treated, the timing to start therapy and better therapeutic options. The lack of knowledge about the natural history and prognosis of pSS-ILD is the main limitation to the development of clinical trials or shared recommendations on this topic. However, a recent trial showed the efficacy of the antifibrotic drug nintedanib in slowing progression of various ILDs, including those in pSS patients.
33292866 Insights on mental health when living with rheumatoid arthritis: a descriptive qualitative 2020 Nov 26 BACKGROUND: Reddit is a highly visited social news and discussion website where individuals anonymously ask questions, post opinions and share experiences, which provide a valuable pool of publicly available data. Our objective was to systematically search and analyze threads on the social news website, Reddit, to understand experiences of individuals with rheumatoid arthritis (RA) regarding their mental health. METHODS: We conducted a patient-oriented descriptive qualitative study. We identified threads from two subreddits, "r/Thritis" and "r/Rheumatoid", using keywords such as "mood", "mental health", "stressed", "depressed", "anxious" over a 1-year period between June 2018 and June 2019. For included threads, we extracted the title, original post, and corresponding comments and responses. We applied thematic analysis using an inductive approach. RESULTS: Of 81 threads identified, we included 27. We identified four themes: 1) Navigating the management of RA explores how the physical impacts of the disease, lack of health resources/support and the complexity of medications affect mental health; 2) Experiencing impact on relationships and social isolation includes experiencing misconceptions of RA, feeling misunderstood and feeling guilt; 3) Experiencing loss, touches on the helplessness brought by challenges with performing self-defining activities such as self-care, work, and childbearing/parenting; and finally, 4) Experiencing emotional struggles captures how tension between fighting through and despair has led some to suicide ideation and thoughts of death. CONCLUSIONS: Online forums and communities such as Reddit have created opportunities for individuals with RA to share experiences on mental health matters, which they may not necessarily be able to share with others.
32556360 Multiple Annular Eruptions in a Patient with Sjögren's Syndrome: A Quiz. 2020 Aug 17 is missing (Quiz).
32377275 Osteochondrogenesis derived from synovial fibroblasts in inflammatory arthritis model. 2020 Rheumatoid arthritis (RA) is characterized by chronic joint inflammation, which forms pannus with bone destruction. Bony ankylosis is also observed following inflammation; however, the mechanism behind this aberrant bone formation in RA had remained unclear. Based on our recent findings obtained using a novel arthritis model called D1BC mouse, we found that synovial fibroblasts in pannus consist of at least three different populations with the osteochondrogenic lineage being predominant. We also found endochondral ossification like that in embryonic bone development adjacent to invasive synovial fibroblasts. Such ectopic endochondral ossification leads to the failure of bone repair and results in ankylosis. In this review, we describe the character of synovial fibroblasts toward the osteochondrogenic lineage and ectopic endochondral ossification in an inflammatory arthritis mouse model.
32000595 Trends in Proximal Interphalangeal and Metacarpophalangeal Joint Arthroplasty Utilization 2020 Mar Background: Arthritis can have profound debilitating effects on the hand secondary to finger deformities and pain. Arthroplasty of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) can be performed to reduce pain while maintaining joint range of motion. Methods: We used outpatient surgery registries from the states of California and Florida to assess the trends of arthroplasty across several recent years and to determine if the outcomes differ based on disease etiology. Results: We found that there has been a steady decline in number of MCP arthroplasty procedures performed annually between 2005 and 2011 while PIP arthroplasty procedures peaked in 2007 and have since also declined. There was an overall complication rate of 2.4% and no difference in cardiac, respiratory, deep venous thrombosis and infection between patients with osteoarthritis and other arthritic etiologies. However, the risk of device failure in patients with rheumatoid arthritis is found to be significantly higher than for patients with osteoarthritis (p < 0.01). Conclusions: PIP and MCP arthroplasty are safe procedures with an overall low complication rate. The increased risk of device related complications observed in patients with rheumatoid arthritis can be used to appropriately counsel this patient population regarding post-operative expectations and prognosis.
33367218 Abatacept Improves Intractable Protein-Losing Enteropathy Secondary to AA Amyloidosis in a 2020 Dec A 71-year-old Japanese woman with a history of rheumatoid arthritis of 50 years' duration was admitted to our hospital with refractory diarrhea. Endoscopic biopsy revealed AA amyloid deposition in the large intestine. Although the patient had been prescribed 5 tumor necrosis factor inhibitors over the past 10 years, rheumatoid arthritis was poorly controlled, with a Disease Activity Score 28 using C-reactive protein score of 6.52 on admission. Treatment with tocilizumab (8 mg/kg every 2 weeks) was initiated, but this was ineffective. After 3 months, abatacept (cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin) was initiated (750 mg/mo) and the patient's diarrhea began to improve. After 3 months of abatacept treatment, serum albumin, C-reactive protein, and serum amyloid A levels had all decreased to within normal ranges. After 3 years of abatacept treatment, a repeat biopsy of the large intestine revealed a marked improvement in amyloid deposition. Interleukin 6 is a key factor in AA amyloid formation, but this case suggests that T-cell activation increases the production of cytokines (including interleukin 6) via a mechanism involving cytotoxic T-lymphocyte-associated antigen 4, resulting in a second key factor of AA amyloid formation.
32715099 Factors associated with osteoporosis medication use in Japanese patients with rheumatoid a 2020 Jun OBJECTIVES: This study aimed to evaluate factors associated with osteoporosis medication use in Japanese patients with rheumatoid arthritis (RA). METHODS: Patients with RA who enrolled in our cohort completed self-administered questionnaires which included questions regarding their osteoporosis medications. Logistic regression was used to determine the association of variables with the use of these medications. RESULTS: Among 5660 Japanese patients with RA who responded to the questionnaires (mean age, 61.8 years; 86.0% female), 1983 patients (35.0%) and 1211 patients (21.4%) reported taking osteoporosis medications and antiresorptive agents, respectively. In multivariate models, age, female sex, lower body mass index (BMI), self-reported fracture history, Japanese Health Assessment Questionnaire-Disability Index (JHAQ-DI), daily dosage of prednisone (PSL), weekly dosage of methotrexate (MTX), and concomitant use of hypertension and hyperlipidemia medications were significantly associated with the use of osteoporosis medications (P < 0.05). Among women with RA, the use of hypertension medications was significantly correlated with the use of both osteoporosis medications and antiresorptive agents (P < 0.05). CONCLUSIONS: Age, female sex, a lower BMI, duration of RA, self-reported fracture history, JHAQ-DI, daily dosage of PSL, weekly dosage of MTX, and the use of medications for hypertension and hyperlipidemia appear to be associated with the use of osteoporosis medications in Japanese patients with RA.
31988799 Genetic architecture study of rheumatoid arthritis and juvenile idiopathic arthritis. 2020 BACKGROUND: Rheumatoid arthritis and juvenile idiopathic arthritis are two types of autoimmune diseases with inflammation at the joints, occurring to adults and children respectively. There are phenotypic overlaps between these two types of diseases, despite the age difference in patient groups. METHODS: To systematically compare the genetic architecture of them, we conducted analyses at gene and pathway levels and constructed protein-protein-interaction network based on summary statistics of genome-wide association studies of these two diseases. We examined their difference and similarity at each level. RESULTS: We observed extensive overlap in significant SNPs and genes at the human leukocyte antigen region. In addition, several SNPs in other regions of the human genome were also significantly associated with both diseases. We found significantly associated genes enriched in 32 pathways shared by both diseases. Excluding genes in the human leukocyte antigen region, significant enrichment is present for pathways like interleukin-27 pathway and NO2-dependent interleukin-12 pathway in natural killer cells. DISCUSSION: The identification of commonly associated genes and pathways may help in finding population at risk for both diseases, as well as shed light on repositioning and designing drugs for both diseases.
32181104 Rheumatoid Arthritis Related Interstitial Lung Disease: Patterns of High-resolution Comput 2020 Feb 4 Background and aim Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease characterized by bilateral involvement of mostly small joints of hands and feet. There can be various extra-articular manifestations of the disease including lung parenchymal disease. Pulmonary involvement in RA patients leads to increased morbidity and mortality. The overall burden of RA related pulmonary disease is underestimated due to the limitation of resources in underdeveloped countries. High-resolution computed tomography (HRCT) is an important tool used to diagnose different abnormalities in RA related interstitial lung disease (ILD). The objective of the study was to evaluate HRCT findings in patients of RA related ILD and categorize the radiological findings according to clinical findings. Method This descriptive prospective observational study was conducted at Mayo Hospital, Lahore from June 2014 to June 2015. Patients of RA suspected of lung disease after selection underwent HRCT chest on 128-slice Hitachi CT scanner (Hitachi Global, Tokyo, Japan) in the radiology department. Images were reconstructed and evaluated by experienced radiologists. Findings were recorded on a questionnaire. Data was analyzed on SPSS version 21 (IBM Corp, Armonk, US). Results Out of the 54 patients scanned, interlobular septal thickening was the most common finding found in 22 of the patients. Ground-glass opacification was recognized in 21 patients, honeycombing in nine and bronchiectasis in two patients. Regarding zonal predilection of disease pattern, lower zones of lungs were found involved in most of the cases. The disease was found to be bilateral in 15 patients. Based on these findings, usual interstitial pneumonitis (UIP) was diagnosed in six patients and non-specific interstitial pneumonitis (NSIP) in 14 others. Conclusion This study concluded that HRCT images are very useful in diagnosing interstitial lung disease related to rheumatoid arthritis.
33330531 Polypharmacy in Middle-European Rheumatoid Arthritis-Patients: A Retrospective Longitudina 2020 Objective: To assess polypharmacy and related medication aspects in Middle-European rheumatoid arthritis (RA) patients, and to discuss the results in view of a systematic literature review. Methods: In this retrospective cohort study, charts were reviewed from RA-patients consecutively recruited between September 27, 2017 and April 29, 2019. Drugs were assigned to the Anatomical Therapeutic Chemical (ATC) groups as proposed by the World Health Organization (WHO). Results were compared to those of a systematic literature review. Results: One hundred seventy-five consecutive RA-patients were included. The mean number of drugs was 6.6 ± 3.5, with 2.4 ± 1.2 drugs taken specifically for RA-compared to 2.6 in the literature. 33.7% of patients experienced polypharmacy defined by ≥5 drugs, compared to 61.6% in the literature-with women affected more frequently than men. After 7 years of follow-up, the number of drugs increased in all ATC-groups by an average of 12.7 %, correlating with age (Corrcoeff = 0.46) and comorbidities (Corrcoeff = 0.599). In the literature, polypharmacy is not always defined precisely, and has not been considered in management guidelines so far. Conclusion: Polypharmacy is a frequent issue in RA-management. With an increasing number of comorbidities during the course of the disease, polypharmacy becomes even more relevant.
32351819 New Diagnosis of Obstructive Sleep Apnea Following Anterior Cervical Discectomy Complicate 2020 Mar 27 Obstructive sleep apnea (OSA) is the most common variant of sleep-disordered breathing that often goes undiagnosed. OSA is characterized mainly by anatomical obstruction or partial collapse of upper airways during sleep. The obstruction is multifactorial, and a lesser-known fact is that damage to the pharyngeal plexus during head and neck procedures or placement of hardware in the cervical area can lead to narrowing or collapse of the upper airway. We present such a case of a 59-year-old female who developed new-onset OSA after undergoing anterior cervical discectomy and fusion (ACDF). The severity of OSA worsened with the progression of her rheumatoid arthritis (RA) in the cervical region. This case report aims to raise awareness of such an association among clinicians to enable them to screen appropriate patients for sleep-disordered breathing and treat them accordingly.
32904998 Expression of miR-495 and miR-326 in peripheral blood of rheumatoid arthritis patients and 2020 Oct The aim of the present study was to investigate the expression of microRNA (miR)-495 and miR-326 in the peripheral blood of patients with rheumatoid arthritis (RA). A total of 107 RA patients, admitted to the Yidu Central Hospital of Weifang (Weifang, China) from February 2016 to February 2019, and 112 healthy subjects, who underwent physical examination during the same period, were selected as the research subjects for prospective analysis. The RA patients served as the study group and the healthy subjects as the control group. The expression levels of miR-495 and miR-326 in the peripheral blood of the two groups of subjects were compared. The association between miR-495 and miR-326 with RA clinical pathology and the diagnostic value of miR-495 and miR-326 for RA were analyzed. In the study group, miR-495 expression was significantly higher than that in the control group, and miR-326 expression was significantly lower than that in the control group (P<0.001). miR-495 and miR-326 combined diagnosis showed good predictive value for the occurrence of RA (P<0.001) and was closely related to RA clinical pathology (P<0.001). After treatment, miR-495 expression was significantly decreased in the study group, whereas miR-326 expression was significantly increased (P<0.001). Pearson's correlation coefficient analysis showed that rheumatoid factor (RF) was positively correlated with miR-495 expression and negatively correlated with miR-326 expression (P<0.001). In conclusion, miR-495 was highly expressed in patients with RA, whereas miR-326 was poorly expressed in RA patients, and the combined detection of miR-495 and miR-326 has good diagnostic value for RA.
33456528 Association between IL-33 and other inflammatory factors in patients with rheumatoid arthr 2021 Feb IL-33 is a member of the IL-1 family of cytokines whose role remains controversial in rheumatoid arthritis (RA). The present study was performed to evaluate the correlation of IL-33 with other cytokines and chemokines in serum and the synovia, and to explore the nature of the association. The concentration of IL-33 in samples from 96 patients with RA was analyzed. The response of fibroblast-like synoviocytes (FLSs) to treatment with different concentrations of IL-33 was assessed in vitro. IL-33 was indicated to exhibit an association with multiple cytokines and chemokines in synovial fluid with an inverted-U-shaped trend, including IL-6, IL-1β, IL-8, MIG and IP-10, but not in the serum. Furthermore, in vitro experiments confirmed that IL-33 also exerted a U-type dose-dependent regulatory effect on FLS function. In addition, the data-points do not exactly follow the U-shaped curve fit in most cases, therefore, the applicability of this mathematical model in clinical practice is limited.