Reduced prescription of TNF-inhibitors in chronic arthritis based on therapeutic drug monitoring: A randomized controlled trial.

OBJECTIVE: Dosing of tumour necrosis factor-α inhibitors (TNFis) is not personalized causing interindividual variation in serum drug levels; however, dose optimization is not widely implemented. We hypothesized that some patients are overdosed; thus, drug prescription could be reduced by therapeutic drug monitoring (TDM). METHOD: Independent of disease activity, 239 adults treated for rheumatoid arthritis (n = 99), psoriatic arthritis 15 (n = 48), or spondyloarthritis (n = 92) were recruited for a 48-week prospective, randomized open-label trial. Standard care alone or plus TDM was applied in chronic arthritis patients treated with infliximab (IFX), (n = 81), etanercept (ETN) (n = 79), or adalimumab (ADA) (n = 79). Serum TNFi trough levels assessed at inclusion and every 4 months determined patients within/outside predefined therapeutic intervals, supporting change in prescription or drug switch. The primary endpoint was reduced drug prescription. RESULTS: Compared to standard care, TDM reduced prescribed IFX [-12% (95% confidence interval -20, -3); p = 0.001] and ETN (-15% (-29, 1); p = 0.01], and prolonged the interdosing intervals of ETN [+235% (38, 432); p = 0.02] and ADA [+28% (6, 51); p = 0.04]. Time to drug switch was accelerated (χ2 = 6.03, p = 0.01). No group differences in adverse events, disease activity, or self-reported outcomes were shown, indicating equally sustained remission. CONCLUSIONS: TDM reduced prescription of IFX, ETN, and ADA and identified patients benefiting from accelerated drug switch, thereby minimizing treatment failure, risk of toxicity, and unnecessary adverse events.

Vagal Nerve Stimulation-Modulation of the Anti-Inflammatory Response and Clinical Outcome in Psoriatic Arthritis or Ankylosing Spondylitis.

OBJECTIVES: The vagal nerve exerts an essential pathway in controlling the cholinergic anti-inflammatory reflex. Thus, the study is aimed at investigating the acute effect of a noninvasive transcutaneous vagus nerve stimulation on clinical disease activity and systemic levels of inflammation in patients with psoriatic arthritis or ankylosing spondylitis. METHODS: Twenty patients with psoriatic arthritis (PsA) and 20 patients with ankylosing spondylitis (AS) were included and stimulated bilaterally with a handheld vagal nerve stimulator for 120 seconds 3 times a day for 5 consecutive days. All patients were in remission. Cardiac vagal tone, clinical scores, CRP, and cytokine levels were assessed. RESULTS: In PsA and AS, decreased heart rate was observed, confirming compliance. Furthermore, in PsA, a clear reduction of clinical disease activity associated with a 20% reduction in CRP was shown. In AS, a reduction in interferon-γ, interleukin- (IL-) 8, and 10 was shown. No side effects were described. CONCLUSION: This open-label study provides support for an anti-inflammatory effect of transcutaneous vagus nerve stimulation in patients with psoriatic arthritis and ankylosing spondylitis. The modulated immune response and reduced disease activity and CRP-levels raise the fascinating possibility of using neuromodulation as an add-on to existing pharmacological treatments.

Feasibility and estimated efficacy of blood flow restricted training in female patients with rheumatoid arthritis: a randomized controlled pilot study.

Objectives: The study aimed to evaluate the feasibility of a blood flow restriction (BFR) training regimen in patients with rheumatoid arthritis (RA); and to compare the effects of 4 weeks of BFR training with low-intensity strength training on muscle strength, muscle endurance, and joint pain in patients with RA.Method: In this non-blinded pilot randomized controlled trial, 18 women with RA aged 18-65 years performed low-intensity strength training for the lower limbs three times a week for 4 weeks, and were randomized to train with or without occlusion bands. The primary outcomes were registration of the recruitment process, compliance with training sessions, side effects, perceived pain, and a satisfaction survey. The secondary outcomes were changes in muscle strength, muscle endurance, and joint pain.Results: The findings of this pilot study included a challenging recruitment process, well tolerated training and test protocols, overall good patient satisfaction, no serious side effects, and high compliance. Both groups achieved significant improvements in knee extensor strength from baseline to follow-up, with a change of 11.5 kg [interquartile range (IQR) 9.8;13.0] in the intervention group and 8.4 kg (IQR 5.5;12.4) in the control group, and a significant between-group difference in favour of the intervention group (p = 0.0342).Conclusions: The feasibility results of this study indicated a challenging recruitment process, general satisfaction with the BFR and exercises, good compliance, and only expected non-serious side effects. BFR training may improve knee extensor strength in women with RA, compared low-intensity strength training without BFR.

Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study.

Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = -0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials.

Vagal influences in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease with a prevalence of 0.5-1% in Western populations. Conventionally, it is treated with therapeutic interventions that include corticosteroids, disease-modifying anti-rheumatic drugs, and biological agents. RA exerts a significant socio-economic burden and despite the use of existing treatments some patients end up with disabling symptoms. The autonomic nervous system (ANS) is a brain-body interface that serves to regulate homeostasis by integrating the external environment with the internal milieu. The main neural substrate of the parasympathetic branch of the ANS is the vagus nerve (VN). The discovery of the role of the ANS and the VN in mediating and dampening the inflammatory response has led to the proposal that modulation of neural circuits may serve as a valuable therapeutic tool. Recent studies have explored the role of the VN in this inflammatory reflex and have provided evidence that stimulation may represent a novel new therapeutic intervention. Accumulating evidence suggests that modulation of the parasympathetic tone results in a broad physiological multi-level response, including decreased pro-inflammatory cytokine response in terms of tumour necrosis factor-α, interleukin-1 (IL-1), and IL-6, and may result in an enhanced macrophage switch from M1 to M2 cells and potentially an increased level of the anti-inflammatory cytokine IL-10. Therefore, therapeutic electrical modulation of the VN may serve as an alternative, non-pharmacological, neuroimmunomodulatory intervention in RA in the future. This review gives a focused introduction to the mechanistic link between the ANS and the immune system.

Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha.

The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which warrants further evaluation in larger controlled studies.

Acute tendon changes in intense CrossFit workout: an observational cohort study.

CrossFit is a fitness program that has become increasingly popular in the Western world, but as in other sports, the risk of injury is present. Only a few studies have addressed health benefits and injuries in CrossFit. It is known that chronically overloaded tendons will thicken and increase the risk of tendinopathy. However, it remains unknown whether acute overload caused by strenuous, high-intensity exercise will exert changes in tendons and if these changes can be detected and described by ultrasonography. The aim of this study is to evaluate the effects of acute overload on tendon thickness using ultrasonography. Standardized ultrasound measurements of the patella, Achilles, and plantaris tendons were performed before and after a specific workout in 34 healthy subjects. Significant increases were observed in patella tendon thickness before (M = 4.5, SD = 0.6) and after (M = 5.0, SD = 0.7) highly intense strenuous exercise, with an estimated mean differences of 0.47 mm (95% CI: 0.35-0.59 mm; P < 0.0001) and in Achilles tendon thickness before (M = 4.4, SD = 0.4) and after (M = 4.5, SD = 0.5) workout, with an estimated difference of 0.17 mm (95% CI: 0.04-0.29 mm; P < 0.01). However, there was no significant difference in fascia plantaris thickness before (M = 3.4, SD = 0.5) and after (M = 3.4, SD = 0.5) workout (P = 0.97). A significant increase in the thickness of the patellar and Achilles tendons was found in response to strenuous, highly intense CrossFit exercises. In order to understand the underlying mechanisms of the findings and possibly utilize this to gain a better understanding, further studies must be conducted.

Ultrasound and MRI measurements of joint cartilage in healthy children: a validation study.

PURPOSE: In juvenile idiopathic arthritis (JIA), proliferative changes in the synovium and synovial fluid accumulation are pathological findings responsible for damage to the cartilaginous tissue and periarticular bone, which are late radiographic findings in conventional radiography. Early detection of these joint changes would allow the clinicians to initiate relevant therapies as is essential for the long-term outcome of JIA. Ultrasonography (US) has shown great potential for this purpose but validation in a pediatric setting is needed. The objective of this study was to validate US measurements of cartilage thickness in target joints in healthy children by comparing them with MRI. MATERIALS AND METHODS: Twenty-five healthy Caucasian children (17 boys/ 8 girls), mean age 11.33 years, were examined with MRI (1.5 T, fat-suppressed T 1-weighted 3D sequences) and US (real-time Hitachi EUB 6500 CFM, B-mode 6 - 14 MHz linear transducer) in the right knee, ankle, wrist, metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. US was obtained according to the EULAR standard scans. RESULTS: All differences in cartilage thickness measurements between MRI and US were less than 0.5 millimeters. The coefficient of variation (CV) was found to be good (16 %) except for in the case of the wrist joint (20 %). CONCLUSION: We found a good level of agreement and no significant systematic joint size-related differences in cartilage thickness measurements between MRI and US. US appears to be a feasible method for evaluating cartilage thickness in JIA target joints, especially when age and sex-related references are defined.

Urinary excretion of alpha-GST and albumin in rheumatoid arthritis patients treated with methotrexate or other DMARDs alone or in combination with NSAIDs.

OBJECTIVE: To evaluate the effect of methotrexate (MTX) and other disease-modifying anti-rheumatic drugs (DMARDs) alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs) on the urinary excretion of alpha-glutathione S-transferase (alpha-GST) and albumin in rheumatoid arthritis (RA) patients. METHODS: Nineteen RA patients starting treatment with MTX were followed for 1 year with measurements of urinary alpha-GST, urinary albumin, and urinary and plasma creatinine at the start of treatment, and after 16, 28, and 52 weeks. A larger group of RA patients (n = 72) undergoing long-term treatment with different DMARDs was compared with 79 healthy controls regarding urinary alpha-GST and albumin. alpha-GST was quantified by an enzyme immunoassay. Urine albumin was measured turbidimetrically. RESULTS: The urine-alpha-GST/urine-creatinine ratio and the urine-albumin/urine-creatinine ratio did not change during 52 weeks of treatment with MTX. The long-term DMARD-treated RA patients and the healthy controls were comparable with regard to the urine-alpha-GST/urine-creatinine ratio and the urine-albumin/urine-creatinine ratio. All patients had preserved renal function as assessed by plasma creatinine, and none had proteinuria using urine dipstick methods. CONCLUSION: DMARD-treated RA patients with normal serum creatinine had no detectable renal injuries assessed by the urinary excretions of alpha-GST and albumin.

Ultrasonography as a tool for diagnosis, guidance of local steroid injection and, together with pressure algometry, monitoring of the treatment of athletes with chronic jumper's knee and Achilles tendinitis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: The diagnosis of Achilles and patella tendinitis has until recently been based on clinical examination, and treatment with local steroid injection has been given blindly. This is the first randomized, double blind, placebo-controlled study of local steroid injection in athletes with chronic tendinitis, which used ultrasonography to increase diagnostic accuracy, to guide the correct placement of local steroid and, conjunctively with pressure algometry, to objectify and monitor the results of treatment. METHOD: Forty-eight athletes each with severe symptomatic tendinitis of a patellar (24) or Achilles tendon (24) for more than 6 months, whose conditions were confirmed ultrasonographically, and who all failed conservative treatment (rehabilitation) were included in this double-blind, placebo-controlled study and treated with three ultrasonographically guided peritendinous injections of steroid or placebo. RESULTS: The conditions of only one-third of the referred athletes with clinically suspected tendinitis were confirmed by ultrasonographic examination. The ultrasonographically guided peritendinous injection of steroid had a significant effect in reducing pain and thickening of tendons. CONCLUSION: Ultrasonography should be used in the future to assure precise diagnosis and to guide the peritendinous injection of steroid in chronic Achilles and patella tendinitis. Ultrasonography and pressure algometry are recommended as objective methods for monitoring the effect of treatment. Ultrasonographically guided injection of long-acting steroid can normalize the ultrasonographic pathological lesions in the Achilles and patellar tendons, and has a dramatic clinical effect but when combined with aggressive rehabilitation with running after a few days, many will have relapse of symptoms within 6 months.

Treatment of rheumatoid arthritis with a peptide diet: a randomized, controlled trial.

Elemental diets provide food in its simplest formulation and have been used in the treatment of rheumatoid arthritis (RA) and other chronic inflammatory diseases. Such a diet is supposed to be less antigenic to the human immune system than normal food. The aim of this study was to evaluate the clinical effect of an artificial peptide diet as a temporary supplement to conventional treatment. Patients with active RA were single-blindly randomized either to a liquid elemental peptide-diet for four weeks or to continuation of the usual food (control group). In the diet group all normal foods were renounced. Thirty patients were included and followed for six months. The outcome measurements were pain intensity, morning stiffness, HAQ-score, number of swollen joints, joint tenderness, erythrocyte sedimentation rate, and patient's global assessment of health. Two of the fifteen patients assigned to the diet dropped out. The diet resulted in a transient but statistically significant improvement in the average level of pain (P = 0.02), in HAQ-score (P=0.03), and a significant reduction in Body Mass Index (P=0.001). Only one patient in the diet group had a clear remission. Side-effects were frequent but compliance good. The study showed that the peptide diet can improve some subjective and objective disease parameters. Due to the low remission ratio the peptide diet is not a treatment of choice in unselected RA-patients. but the peptide diet might be beneficial to a subset of RA-patients, e.g. patients where foods aggravate disease activity.