Objective To evaluate flare risk when tapering or withdrawing biological or targeted synthetic disease-modifying antirheumatic drugs (b-/tsDMARDs) compared to continuation in patients with inflammatory arthritis (IA) in sustained remission or low disease activity. Methods Articles were identified in Cochrane Library, PubMed, EMBASE and Web of Science. Eligible trials were randomised, controlled trials comparing tapering and/or withdrawal of b- and/or tsDMARDs with standard dose in IA. Random-effects meta-analysis was performed with risk ratio (RR), or Peto’s Odds Ratio (POR) for sparse events, and 95% confidence intervals (95%CI). Results The meta-analysis comprised 22 trials: 11 assessed tapering and 7 addressed withdrawal (4 assessed both). Only trials with a rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) population were identified. An increased flare risk was demonstrated when b-/tsDMARD tapering was compared to continuation, RR = 1.45 (95%CI: 1.19 to 1.77, I2 = 42.5%), and potentially increased for persistent flare, POR = 1.56 (95%CI: 0.97 to 2.52, I2 = 0%). Comparing tumour necrosis factor inhibitor (TNFi) withdrawal to continuation, a highly increased flare risk (RR = 2.28, 95%CI: 1.78 to 2.93, I2 = 78%) and increased odds of persistent flare (POR = 3.41, 95%CI: 1.91 to 6.09, I2 = 49%) was observed. No clear difference in flare risk between RA or axSpA was observed. Conclusion A high risk for flare and persistent flare was demonstrated for TNFi withdrawal whereas an increased risk for flare but not for persistent flare was observed for b-/tsDMARD tapering. Thus, tapering seems to be the more favourable approach. Registration PROSPERO (CRD42019136905).

Background/ObjectiveAutoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have been associated with an impaired function of the autonomic nervous system and reduced vagus nerve (VN) tone measured through lower heart rate variability (HRV). Targeting the VN through electrical stimulation has been proposed as a treatment strategy with promising results in patients with RA. Moreover, it has been suggested that the VN can be stimulated physiologically through deep breathing. In this study, the aim was to investigate if the VN can be stimulated through deep breathing in patients with RA and SLE, as measured by HRV.MethodsFifty-seven patients with RA and SLE performed deep breathing exercises for 30 minutes in this explorative study. Before the breathing exercise, 2 electrocardiogram recordings were obtained to determine the patient's baseline HRV during rest. After the 30-minute breathing exercise, 5 minutes of electrocardiogram recordings were obtained to determine postintervention HRV and used as a measure of vagal activity.ResultsNo change was observed in the HRV between the 2 recordings prior the exercise, but the heart rate and HRV significantly decreased and increased, respectively, after the deep breathing exercise.ConclusionsHRV can be modulated in patients with RA and SLE; this may have implications for future treatment with medications in conjunction with deep breathing. However, the biological and clinical effect of deep breathing must be investigated in future studies.

Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are associated with autonomic dysfunction, potentially through reduced vagus nerve tone. Vagus nerve stimulation has been proposed as an anti-inflammatory treatment, and it can be performed through deep breathing (DB) exercises. In this study, the dose-response relationship between DB exercises and heart rate variability (HRV) was investigated in healthy participants and reliability across days in patients with RA and SLE. On three separate days, 41 healthy participants performed DB for: 5, 15, or 30 min. On two separate days, 52 RA or SLE patients performed DB with the dose associated with the highest HRV increase in healthy participants. The HRV was estimated from ECG-recordings recorded prior and post the DB exercises. Increases in dose led to larger HRV-responses. Thirty minutes led to the largest HRV-response. In the RA and SLE patients, this dose increased the HRV-parameters consistently across the two days, indicating reliability. DB increases HRV in healthy participants and RA or SLE patients, which indicates stimulation of the vagus nerve. Of the tested durations, 30 min of DB was the optimal period of stimulation. A potential anti-inflammatory effect of DB exercises should be investigated in future studies.

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are associated with an impaired autonomic nervous system and vagus nerve function. Electrical or physiological (deep breathing—DB) vagus nerve stimulation (VNS) could be a potential treatment approach, but no direct comparison has been made. In this study, the effect of transcutaneous auricular VNS (taVNS) and DB on vagal tone was compared in healthy participants and RA or SLE patients. The vagal tone was estimated using time-domain heart-rate variability (HRV) parameters. Forty-two healthy participants and 52 patients performed 30 min of DB and 30 min of taVNS on separate days. HRV was recorded before and immediately after each intervention. For the healthy participants, all HRV parameters increased after DB (SDNN + RMSSD: 21–46%), while one HRV parameter increased after taVNS (SDNN: 16%). For the patients, all HRV parameters increased after both DB (17–31%) and taVNS (18–25%), with no differences between the two types of VNS. DB was associated with the largest elevation of the HRV parameters in healthy participants, while both types of VNS led to elevated HRV parameters in the patients. The findings support a potential use of VNS as a new treatment approach, but the clinical effects need to be investigated in future studies.

BackgroundPatients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are known to have an autonomic dysfunction, especially reduced parasympathetic activity. The dysfunction can be measured through heart rate variability (HRV), an indicator of vagus nerve tone. Studies have found a potential anti-inflammatory effect of the vagus nerve and proposed vagus nerve stimulation (VNS) as an anti-inflammatory treatment. A way of stimulating the vagus nerve non-invasively could be through deep breathing (DB).ObjectivesThe aims of this study were to examine the dose-response of DB on HRV in healthy participants and to examine the reliability of the effect of DB on HRV in patients with RA and SLE across two days.MethodsThe study was designed as an interventional study, more specifically the healthy subjects participated in a dose-response study and the patients with RA and SLE participated in a study of reliability. Forty-one healthy participants performed DB for 5, 15, and 30 minutes (4 seconds of inspiration and 6 seconds of expiration) in a randomized order on three different days. Fifty-two patients with RA and SLE performed the optimal dose of DB found in healthy participants, and the intervention was repeated on two different days to examine the reliability of the effect. The outcome measure was HRV, which was derived from a 5-minute electrocardiogram recording measured twice before and three times after DB. The extracted HRV measures included in the further analysis were the time domain parameters: a) The standard deviation of the R-R intervals (SDNN), b) the root mean square of successive R-R intervals (RMSSD), and c) the proportion of NN50 (pairs of successive R-R intervals that differ more than 50 milliseconds) divided by the total number of R-R intervals (PNN50).ResultsThirty minutes of DB increased HRV and was the optimal dose of DB in healthy participants. In patients with RA and SLE 30 minutes of DB increased all HRV-parameters similarly across two days indicating reliability, see Figure 1. The effect of DB remained for at least 30 minutes after the intervention.Figure 1.Bar chart showing the heart rate variability-parameters plotted as mean ± standard error in patients with RA and SLE. RA: Rheumatoid Arthritis. SLE: Systemic Lupus Erythematosus. SDNN: The standard deviation of the R-R intervals. RMSSD: The root mean square of successive R-R intervals. PNN50: The proportion of NN50 (pairs of successive R-R intervals that differ more than 50 milliseconds) divided by the total number of R-R intervals.ConclusionDB increases HRV in healthy participants and in patients with RA and SLE, indicating a stimulation of the vagus nerve. Future studies are needed to investigate the potential anti-inflammatory effect as well.AcknowledgementsThe authors thank patients and research personnel at Aalborg University Hospital, Denmark.Disclosure of InterestsNone declared