Cytokines are key drivers of inflammation in RA, and anti-cytokine therapy has improved the outcome of RA. Janus Kinases (JAK) are intracellular tyrosine kinases linked to intracellular domains of ...many cytokine receptors. There are four JAK isoforms: JAK1, JAK2, JAK3 and TYK2. Different cytokine receptor families utilize specific JAK isoforms for signal transduction. Phosphorylation of JAK when cytokine binds to its cognate receptor leads to phosphorylation of other intracellular molecules that eventually leads to gene transcription. Oral JAK inhibitors (JAKi) have been developed as anti-cytokine therapy in RA. Two JAKi, tofacitinib and baricitinib, have been approved recently for the treatment of RA, and many JAKi are currently in development. JAKi inhibit JAK isoforms with different selectivity. This review discusses the efficacy and safety of JAKi in RA, in particular the potential clinical significance of JAKi selectivity.
Fibromyalgia is a common cause of chronic widespread pain, characterized by reduced pressure pain thresholds with hyperalgesia and allodynia. In addition to pain, common symptoms include ...nonrestorative sleep, fatigue, cognitive dysfunction, stiffness and mood disturbances. The latest research indicates that the dominant pathophysiology in fibromyalgia is abnormal pain processing and central sensitization. Neuroimaging studies have shown that patients with fibromyalgia have similar neural activation to healthy age-matched and gender-matched individuals; however, they have a lower pressure-pain threshold. Polysomnography data has demonstrated that these patients have reduced short-wave sleep and abnormal α-rhythms, suggestive of wakefulness during non-REM (rapid eye movement) sleep. Sleep deprivation in healthy individuals can cause symptoms of fibromyalgia, including myalgia, tenderness and fatigue, suggesting that sleep dysfunction might be not only a consequence of pain, but also pathogenic. Epidemiological studies indicate that poor sleep quality is a risk factor for the development of chronic widespread pain among an otherwise healthy population. Mechanistically, sleep deprivation impairs descending pain-inhibition pathways that are important in controlling and coping with pain. Clinical trials of pharmacological and nonpharmacological therapies have shown that improving sleep quality can reduce pain and fatigue, further supporting the hypothesis that sleep dysfunction is a pathogenic stimulus of fibromyalgia.
Despite the success of targeted therapies in the treatment of inflammatory arthritides, the lack of predictive biomarkers drives a 'trial and error' approach to treatment allocation, leading to ...variable and/or unsatisfactory responses. In-depth characterization of the synovial tissue in rheumatoid arthritis, as well as psoriatic arthritis and spondyloarthritis, is bringing new insights into the diverse cellular and molecular features of these diseases and their potential links with different clinical and treatment-response phenotypes. Such progress raises the tantalizing prospect of improving response rates by matching the use of specific agents to the cognate target pathways that might drive particular disease subtypes in specific patient groups. Innovative patient-centric, molecular pathology-driven clinical trial approaches are needed to achieve this goal. Whilst progress is clearly being made, it is important to emphasize that this field is still in its infancy and there are a number of potential barriers to realizing the premise of patient-centric clinical trials.
Background
Fibromyalgia (FM) is a clinically well‐defined chronic condition of unknown aetiology characterized by chronic widespread pain that often co‐exists with sleep disturbances, cognitive ...dysfunction and fatigue. Patients often report high disability levels and negative mood. Psychotherapies focus on reducing key symptoms, improving daily functioning, mood and sense of personal control over pain.
Objectives
To assess the benefits and harms of cognitive behavioural therapies (CBTs) for treating FM at end of treatment and at long‐term (at least six months) follow‐up.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8), MEDLINE (1966 to 28 August 2013), PsycINFO (1966 to 28 August 2013) and SCOPUS (1980 to 28 August 2013). We searched http://www.clinicaltrials.gov (web site of the US National Institutes of Health) and the World Health Organization Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/) for ongoing trials (last search 28 August,2013), and the reference lists of reviewed articles.
Selection criteria
We selected randomised controlled trials of CBTs with children, adolescents and adults diagnosed with FM.
Data collection and analysis
The data of all included studies were extracted and the risks of bias of the studies were assessed independently by two review authors. Discrepancies were resolved by discussion.
Main results
Twenty‐three studies with 24 study arms with CBTs were included. A total of 2031 patients were included; 1073 patients in CBT groups and 958 patients in control groups. Only two studies were without any risk of bias. The GRADE quality of evidence of the studies was low. CBTs were superior to controls in reducing pain at end of treatment by 0.5 points on a scale of 0 to 10 (standardised mean difference (SMD) ‐ 0.29; 95% confidence interval (CI) ‐0.49 to ‐0.17) and by 0.6 points at long‐term follow‐up (median 6 months) (SMD ‐0.40; 95% CI ‐0.62 to ‐0.17); in reducing negative mood at end of treatment by 0.7 points on a scale of 0 to 10 (SMD ‐ 0.33; 95% CI ‐0.49 to ‐0.17) and by 1.3 points at long‐term follow‐up (median 6 months) (SMD ‐0.43; 95% CI ‐0.75 to ‐0.11); and in reducing disability at end of treatment by 0.7 points on a scale of 0 to 10 (SMD ‐ 0.30; 95% CI ‐0.51 to ‐0.08) and at long‐term follow‐up (median 6 months) by 1.2 points (SMD ‐0.52; 95% CI ‐0.86 to ‐0.18). There was no statistically significant difference in dropout rates for any reasons between CBTs and controls (risk ratio (RR) 0.94; 95% CI 0.65 to 1.35).
Authors' conclusions
CBTs provided a small incremental benefit over control interventions in reducing pain, negative mood and disability at the end of treatment and at long‐term follow‐up. The dropout rates due to any reason did not differ between CBTs and controls.
Background
Fatigue is a common and potentially distressing symptom for people with rheumatoid arthritis with no accepted evidence based management guidelines. Non‐pharmacological interventions, such ...as physical activity and psychosocial interventions, have been shown to help people with a range of other long‐term conditions to manage subjective fatigue.
Objectives
To evaluate the benefit and harm of non‐pharmacological interventions for the management of fatigue in people with rheumatoid arthritis. This included any intervention that was not classified as pharmacological in accordance with European Union (EU) Directive 2001/83/EEC.
Search methods
The following electronic databases were searched up to October 2012, Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; AMED; CINAHL; PsycINFO; Social Science Citation Index; Web of Science; Dissertation s International; Current Controlled Trials Register; The National Research Register Archive; The UKCRN Portfolio Database. In addition, reference lists of articles identified for inclusion were checked for additional studies and key authors were contacted.
Selection criteria
Randomised controlled trials were included if they evaluated a non‐pharmacological intervention in people with rheumatoid arthritis with self‐reported fatigue as an outcome measure.
Data collection and analysis
Two review authors selected relevant trials, assessed risk of bias and extracted data. Where appropriate, data were pooled using meta‐analysis with a random‐effects model.
Main results
Twenty‐four studies met the inclusion criteria, with a total of 2882 participants with rheumatoid arthritis. Included studies investigated physical activity interventions (n = 6 studies; 388 participants), psychosocial interventions (n = 13 studies; 1579 participants), herbal medicine (n = 1 study; 58 participants), omega‐3 fatty acid supplementation (n = 1 study; 81 participants), Mediterranean diet (n = 1 study; 51 participants), reflexology (n = 1 study; 11 participants) and the provision of Health Tracker information (n = 1 study; 714 participants). Physical activity was statistically significantly more effective than the control at the end of the intervention period (standardized mean difference (SMD) ‐0.36, 95% confidence interval (CI) ‐0.62 to ‐0.10; back translated to mean difference of 14.4 points lower, 95% CI ‐4.0 to ‐24.8 on a 100 point scale where a lower score means less fatigue; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 26) demonstrating a small beneficial effect upon fatigue. Psychosocial intervention was statistically significantly more effective than the control at the end of the intervention period (SMD ‐0.24, 95% CI ‐0.40 to ‐0.07; back translated to mean difference of 9.6 points lower, 95% CI ‐2.8 to ‐16.0 on a 100 point scale, lower score means less fatigue; NNTB 10, 95% CI 6 to 33) demonstrating a small beneficial effect upon fatigue. For the remaining interventions meta‐analysis was not possible and there was either no statistically significant difference between trial arms or findings were not reported. Only three studies reported any adverse events and none of these were serious, however, it is possible that the low incidence was in part due to poor reporting. The quality of the evidence ranged from moderate quality for physical activity interventions and Mediterranean diet to low quality for psychosocial interventions and all other interventions.
Authors' conclusions
This review provides some evidence that physical activity and psychosocial interventions provide benefit in relation to self‐reported fatigue in adults with rheumatoid arthritis. There is currently insufficient evidence of the effectiveness of other non‐pharmacological interventions.
Abstract
RA is a chronic, systemic, autoimmune disease characterized by inflammation and degradation of the joints, causing significant negative impact on quality of life. In addition to joint ...disease, symptoms and co-morbidities associated with RA-namely pain, fatigue and mood disorders-are often as debilitating as the disease itself. The pro-inflammatory cytokine IL-6 plays a critical role in RA-associated pathology. However, a greater understanding of the translational effects of IL-6 outside of the immune system is needed. This review discusses our current understanding of emerging aspects of IL-6 in RA-associated pain, fatigue and mood disorders such as depression and anxiety. This review also describes the clinical effects of IL-6 inhibition on these symptoms and co-morbidities in patients with RA.
•CRP is a valuable marker and regulator of systemic inflammation in RA.•CRP levels appear to be associated with common comorbidities of RA.•CRP appears to play a direct role in bone destruction and ...disease progression in RA.•Pentameric and monomeric isoforms of CRP have different effects.•Stratification by CRP level in clinical trials may provide valuable information.
C-reactive protein (CRP) is routinely assessed as a marker of systemic inflammation in rheumatoid arthritis (RA). However, it is also an immune regulator that plays an important role in inflammatory pathways associated with RA and promotes atherogenic effects. Comorbidities linked to systemic inflammation are common in RA, and CRP has been associated with the risk for cardiovascular disease, diabetes, metabolic syndrome, pulmonary diseases, and depression. The relationship between systemic inflammation, CRP, and comorbidities in RA is complex, and it is challenging to determine how changing CRP levels may affect the risk or progression of these comorbidities. We review the biological role of CRP in RA and its implications for disease activity and treatment response. We also discuss the impact of treatment on CRP levels and whether reducing systemic inflammation and inhibiting CRP-mediated inflammatory pathways may have an impact on conditions commonly comorbid with RA.
Background
Fatigue is a common and potentially distressing symptom for patients with rheumatoid arthritis (RA), with no accepted evidence‐based management guidelines. Evidence suggests that biologic ...interventions improve symptoms and signs in RA as well as reducing joint damage.
Objectives
To evaluate the effect of biologic interventions on fatigue in rheumatoid arthritis.
Search methods
We searched the following electronic databases up to 1 April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Controlled Trials Register, the National Research Register Archive, The UKCRN Portfolio Database, AMED, CINAHL, PsycINFO, Social Science Citation Index, Web of Science, and Dissertation s International. In addition, we checked the reference lists of articles identified for inclusion for additional studies and contacted key authors.
Selection criteria
We included randomised controlled trials if they evaluated a biologic intervention in people with rheumatoid arthritis and had self reported fatigue as an outcome measure.
Data collection and analysis
Two reviewers selected relevant trials, assessed methodological quality and extracted data. Where appropriate, we pooled data in meta‐analyses using a random‐effects model.
Main results
We identified 32 studies for inclusion in this current review. Twenty studies evaluated five anti‐tumour necrosis factor (anti‐TNF) biologic agents (adalimumab, certolizumab, etanercept, golimumab and infliximab), and 12 studies focused on five non‐anti‐TNF biologic agents (abatacept, canakinumab, rituximab, tocilizumab and an anti‐interferon gamma monoclonal antibody). All but two of the studies were double‐blind randomised placebo‐controlled trials. In some trials, patients could receive concomitant disease‐modifying anti‐rheumatic drugs (DMARDs). These studies added either biologics or placebo to DMARDs. Investigators did not change the dose of the latter from baseline. In total, these studies included 9946 participants in the intervention groups and 4682 participants in the control groups. Overall, quality of randomised controlled trials was moderate with a low to unclear risk of bias in the reporting of the outcome of fatigue. We downgraded the quality of the studies from high to moderate because of potential reporting bias (studies included post hoc analyses favouring reporting of positive result and did not always include all randomised individuals). Some studies recruited only participants with early disease. The studies used five different instruments to assess fatigue in these studies: the Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT‐F), Short Form‐36 Vitality Domain (SF‐36 VT), Visual Analogue Scale (VAS) (0 to 100 or 0 to 10) and the Numerical Rating Scale (NRS). We calculated standard mean differences for pooled data in meta‐analyses. Overall treatment by biologic agents led to statistically significant reduction in fatigue with a standardised mean difference of −0.43 (95% confidence interval (CI) −0.38 to −0.49). This equates to a difference of 6.45 units (95% CI 5.7 to 7.35) of FACIT‐F score (range 0 to 52). Both types of biologic agents achieved a similar level of improvement: for anti‐TNF agents, this stood at −0.42 (95% CI −0.35 to −0.49), equivalent to 6.3 units (95% CI 5.3 to 7.4) on the FACIT‐F score; and for non‐anti‐TNF agents, it was −0.46 (95% CI −0.39 to −0.53), equivalent to 6.9 units (95% CI 5.85 to 7.95) on the FACIT‐F score. In most studies, the double‐blind period was 24 weeks or less. No study assessed long‐term changes in fatigue.
Authors' conclusions
Treatment with biologic interventions in patients with active RA can lead to a small to moderate improvement in fatigue. The magnitude of improvement is similar for anti‐TNF and non‐anti‐TNF biologics. However, it is unclear whether the improvement results from a direct action of the biologics on fatigue or indirectly through reduction in inflammation, disease activity or some other mechanism.
Abstract
Fatigue is a common and debilitating symptom in patients with RA. Since 2007, fatigue has been included as one of the core outcome measures in RA. Clinical trials of biologic DMARDs ...(bDMARDs) and targeted synthetic DMARDs (tsDMARDs) have included fatigue as a secondary endpoint. A Cochrane review in 2016 concluded that the bDMARDs have a moderate effect on improving fatigue in RA. More recent clinical trials of the new biologic agent sarilumab and the Janus kinase inhibitors tofacitinib and baricitinib showed similar benefits. It remains unclear whether the effect of bDMARDs and tsDMARDs on fatigue is mediated by direct effects or through a reduction in inflammation. As fatigue was a secondary endpoint, many analyses did not adjust for potential confounding factors, including pain, mood and anaemia, which is a significant limitation.
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