The role of proteasome in muscle wasting of experimental arthritis

Abstract Background Rheumatoid arthritis is an autoimmune inflammatory disease that often leads patients to muscle impairment and physical disability. This study aimed to evaluate changes in the activity of proteasome system in skeletal muscles of mice with collagen-induced arthritis (CIA) and treated with etanercept or methotrexate. Methods Male DBA1/J mice were divided into four groups (n = 8 each): CIA-Vehicle (treated with saline), CIA-ETN (treated with etanercept, 5.5 mg/kg), CIA-MTX (treated with methotrexate, 35 mg/kg) and CO (healthy control group). Mice were treated two times a week for 6 weeks. Clinical score and hind paw edema were measured. Muscles were weighted after euthanasia and used to quantify proteasome activity, gene (MuRF-1, PMSα4, PSMβ5, PMSβ6, PSMβ7, PSMβ8, PSMβ9, and PSMβ10), and protein (PSMβ1, PSMβ5, PSMβ1i, PSMβ5i) expression of proteasome subunits. Results Both treatments slowed disease development, but only CIA-ETN maintained muscle weight compared to CIA-MTX and CIA-Vehicle groups. Etanercept treatment showed caspase-like activity of 26S proteasome similar to CO group, while CIA-Vehicle and CIA-MTX had higher activity compared to CO group (p: 0.0057). MuRF-1 mRNA expression was decreased after etanercept administration compared to CIA-Vehicle and CO groups (p: 0.002, p: 0.007, respectively). PSMβ8 and PSMβ9 mRNA levels were increased in CIA-Vehicle and CIA-MTX compared to CO group, while CIA-ETN presented no difference from CO. PMSβ6 mRNA expression was higher in CIA-Vehicle and CIA-MTX groups than in CO group. Protein levels of the PSMβ5 subunit were increased in CO group compared to CIA-Vehicle; after both etanercept and methotrexate treatments, PSMβ5 expression was higher than in CIA-Vehicle group and did not differ from CO group expression (p: 0.0025, p: 0.001, respectively). The inflammation-induced subunit β1 (LMP2) was enhanced after methotrexate treatment compared to CO group (p: 0.043). Conclusions The results of CIA-Vehicle show that arthritis increases muscle proteasome activation by enhanced caspase-like activity of 26S proteasome and increased PSMβ8 and PSMβ9 mRNA levels. Etanercept treatment was able to maintain the muscle weight and to modulate proteasome so that its activity and gene expression were compared to CO after TNF inhibition. The protein expression of inflammation-induced proteasome subunit was increased in muscle of CIA-MTX group but not following etanercept treatment. Thus, anti-TNF treatment may be an interesting approach to attenuate the arthritis-related muscle wasting.

Incidence of Active Tuberculosis within One Year after Tumor Necrosis Factor Inhibitor Treatment according to Latent Tuberculosis Infection Status in Patients with Inflammatory Bowel Disease

BACKGROUND: We investigated the incidence of active tuberculosis among patients with inflammatory bowel disease (IBD) treated with tumor necrosis factor (TNF) inhibitors, with or without latent tuberculosis infection (LTBI). METHODS: The study was performed at a Korean tertiary referral center between January 2011 and June 2017. In total, 740 patients with IBD who underwent LTBI screening tests and were followed-up for ≥ 1 year after TNF inhibitor treatment initiation were enrolled. LTBI was detected on the basis of tuberculin skin test results, interferon-gamma release assay results, chest X-ray findings, and previous tuberculosis treatment history. The patients were classified into LTBI (n = 84) or non-LTBI (n = 656) group. The risk of developing tuberculosis in each group was assessed on the basis of standardized incidence ratio (SIR) and 95% confidence interval (CI) for active tuberculosis. RESULTS: Mean patient age was 33.1 years, and patients with Crohn's disease were predominant (80.7%). Within 1 year after the initiation of TNF inhibitor treatment, 1 patient in the LTBI group (1/84; 1.2%) and 7 patients in the non-LTBI group (7/656; 1.1%) developed active tuberculosis. The overall 1-year incidence of tuberculosis among the patients was significantly higher than that among the general population (SIR, 14.0; 95% CI, 7.0–28.0), and SIR was not affected by LTBI status (LTBI group: 14.5, 95% CI, 2.0–102.6; non-LTBI group: 14.0, 95% CI, 6.7–29.4). CONCLUSION: Patients with IBD undergoing TNF inhibitor treatment showed a higher 1-year incidence of tuberculosis than the general population irrespective of LTBI status.

Drug Survival Rates of Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis

We investigated the compliance of Korean patients using tumor necrosis factor (TNF) inhibitors to treat rheumatoid arthritis (RA) and ankylosing spondylitis (AS), and identified potential predictors associated with treatment discontinuation. The study population comprised 114 RA and 310 AS patients treated with TNF inhibitors at a single tertiary center for at least 1 yr from December 2002 to November 2011. Of the 114 RA patients, 64 (56.1%) discontinued their first TNF inhibitors with a mean duration of 18.1 months. By contrast, 65 of 310 patients (21.0%) with AS discontinued their first TNF inhibitors, with a mean duration of 84 months. Although the survival rate did not differ among the three TNF inhibitors in the AS patients, the etanercept group had a lower discontinuation rate than the infliximab group in the RA patients. In addition, RA patients who received corticosteroids in combination with TNF inhibitors were more likely to discontinue their TNF inhibitors. The independent predictors of drug discontinuation in AS patients were male gender and complete ankylosis on radiographs of the sacroiliac joint. Our results provide further evidence that real-life treatment outcomes of RA and AS patients may be different from those observed in randomized clinical trials.

Drug Survival Rates of Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis

We investigated the compliance of Korean patients using tumor necrosis factor (TNF) inhibitors to treat rheumatoid arthritis (RA) and ankylosing spondylitis (AS), and identified potential predictors associated with treatment discontinuation. The study population comprised 114 RA and 310 AS patients treated with TNF inhibitors at a single tertiary center for at least 1 yr from December 2002 to November 2011. Of the 114 RA patients, 64 (56.1%) discontinued their first TNF inhibitors with a mean duration of 18.1 months. By contrast, 65 of 310 patients (21.0%) with AS discontinued their first TNF inhibitors, with a mean duration of 84 months. Although the survival rate did not differ among the three TNF inhibitors in the AS patients, the etanercept group had a lower discontinuation rate than the infliximab group in the RA patients. In addition, RA patients who received corticosteroids in combination with TNF inhibitors were more likely to discontinue their TNF inhibitors. The independent predictors of drug discontinuation in AS patients were male gender and complete ankylosis on radiographs of the sacroiliac joint. Our results provide further evidence that real-life treatment outcomes of RA and AS patients may be different from those observed in randomized clinical trials.

Prediction for TNF Inhibitor Users in RA Patients According to Reimbursement Criteria Based on DAS28

OBJECTIVE: The purpose of this study is to examine the difference between the numbers of patients in rheumatoid arthritis (RA) who are eligible to TNF inhibitors by the past Korean National Health Insurance reimbursement guideline and by the disease activity score with 28-joint assessment (DAS28) based criteria. METHODS: Data were obtained from a multi-center registry for biologics users in Korean RA patients, BIOlogics Pharmacoepidemiologic StudY (BIOPSY). DAS28 was calculated based on either ESR or CRP, and DAS28 of more than 5.1 or between 3.2 and 5.1 with radiographic changes was defined as a cut-off point for the initiation of TNF inhibitors. For the maintenance criteria, we used both of improving in DAS28 score (>1.2) and low disease activity (DAS 28<3.2). Differences between the numbers in each step by two criteria were described with Chi-square test and Kappa agreement. RESULTS: Of the 489 patients in BIOPSY, 299 were included in this study. Among them, 278 patients (93.0%) were eligible of TNF inhibitors when we applied the new initiation criteria with DAS28-ESR, and 244 patients (81.6%) were indicated for TNF inhibitors with DAS28-CRP. For the maintenance criteria, a low disease activity (DAS28<3.2) in 3 months after starting TNF inhibitors is too strict for achieving (33.6% with DAS28-ESR and 50.0% with DAS28-CRP). Instead, decreasing DAS28 by more than 1.2 is more reasonable as a tool for deciding early responsiveness of TNF inhibitors in RA patients (81.2% both with DAS28-ESR and DAS28-CRP). CONCLUSION: Our results show that the candidates for TNF inhibitors will be enormously changed according to a change in the reimbursement criteria. To define appropriate patients to receive TNF inhibitors, a further study with regard to the impact of changes in the reimbursement criteria on the outcomes of RA patients will be required.

A Case of Rituximab Use in Rheumatoid Arthritis Following Anti-TNF-Associated Tuberculosis

Rituximab has been shown to be effective in rheumatoid arthritis (RA) and is recommended for patients exhibiting an inadequate response to tumor necrosis factor (TNF) inhibitors. To date, there have been no reports of tuberculosis in RA patients treated with rituximab. We report the use of rituximab in a TNF inhibitor-refractory RA patient who had developed tuberculosis. A 52-year-old man with RA had been treated with adalimumab for 3 months, but failed to respond well to the treatment. He reported fever, coughing, sputum, and weight loss. He was diagnosed with pulmonary tuberculosis and started anti-tuberculosis medication. His arthritis was not controlled for despite increasing the dose of prednisolone. He was treated with rituximab without serious adverse effects. Sixteen weeks later, he demonstrated improvement with both arthritis and tuberculosis.

A Case of Rituximab Use in Rheumatoid Arthritis Following Anti-TNF-Associated Tuberculosis

Rituximab has been shown to be effective in rheumatoid arthritis (RA) and is recommended for patients exhibiting an inadequate response to tumor necrosis factor (TNF) inhibitors. To date, there have been no reports of tuberculosis in RA patients treated with rituximab. We report the use of rituximab in a TNF inhibitor-refractory RA patient who had developed tuberculosis. A 52-year-old man with RA had been treated with adalimumab for 3 months, but failed to respond well to the treatment. He reported fever, coughing, sputum, and weight loss. He was diagnosed with pulmonary tuberculosis and started anti-tuberculosis medication. His arthritis was not controlled for despite increasing the dose of prednisolone. He was treated with rituximab without serious adverse effects. Sixteen weeks later, he demonstrated improvement with both arthritis and tuberculosis.

TNF Inhibitor Use during the Perioperative Period / 대한류마티스학회지

Tumor necrosis factor (TNF) inhibitors are now established as therapeutic agents for treating active rheumatoid arthritis (RA) that is resistant to conventional drug treatment. However, TNF Inhibitors decrease resistance to infection, including unusual infections such as tuberculosis, and they have been shown to impair wound healing in an experimental setting. To date, there is limited data on patients with RA regarding their infections or the complications of surgery performed while taking TNF inhibitors and there is no professional consensus about this. This problem emphasizes a need for awareness and communication between patients, the rheumatologist and the surgeon when treating patients with RA. We reviewed the effects of TNF inhibitors on the incidence of surgical site infection (SSI) and the risk factors for SSIs after performing elective surgery in patients with RA. TNF inhibitors should not be used during the perioperative period until conclusive evidence to the contrary is available.

TNF Inhibitors and Uveitis in Ankylosing Spondylitis / 대한류마티스학회지

Uveitis is the most common extra-articular manifestation of ankylosing spondylitis, and this occurs in 30~50% of the patients with ankylosing spondylitis. The main symptoms of ankylosing spondylitis are usually highly responsive to TNF inhibitors, but the effects of TNF inhibitors on uveitis are inconsistent. We report here on sixteen cases of new onset uveitis during etanercept therapy in patients with ankylosing spondylitis and they had no histories of uveitis. The symptoms of ankylosing spondyltiis, other than the uveitis, were well controlled during etanercept therapy. Six patients had histories of infliximab therapy before undergoing etanercept therapy, and uveitis did not develop during this infliximab therapy. Uveitis can develop during the course of ankylosing spondylitis, yet there is a possibility of a temporal relationship between etanercept therapy and uveitis.

Guidelines for Prevention of Tuberculosis in Patients with Rheumatoid Arthritis Treated with TNF-alpha Blockers / 대한류마티스학회지

Introduction of tumor necrosis factor (TNF) inhibitor for the treatment of rheumatoid arthritis (RA) induces not only significant improvement of symptoms and signs of RA but also substantial inhibition of progressive joint damage. Such therapeutic efficacies of TNF inhibitor have led to a paradigm shift in the treatment of RA. In spite of its dramatic effect against RA, it is now well established that the use of TNF inhibitor significantly increases the risk of tuberculosis in patients with RA. Therefore some countries have presented guidelines in the use of TNF inhibitors for rheumatoid arthritis to reduce the risk of tuberculosis. Korea Food and Drug Association (KFDA) have also provided guidelines for treating latent tuberculosis when using TNF inhibitors. In this article, we reviewed the general epidemiology of tuberculosis and incidence rates of tuberculosis in RA patients and those of RA patients treated with TNF inhibitors. We also introduced methods for the diagnosis of latent tuberculosis, and various guidelines published in different countries in managing tuberculosis in RA patients who were to be treated with TNF inhibitors. Finally, we suggest requirement of more appropriate guidelines for Korean RA patients who are candidates for treatment with TNF-inhibitors.