Chapter 36 Rheumatoid arthritis
With contribution from Greg de Jong
Introduction
Affecting between 0.5–1.% of the population, rheumatoid arthritis is an autoimmune disorder that progressively destroys articular joint function through excessive inflammation of synovial tissue and other local structures.1 This process can be rapid enough that when left untreated 20–30% of people can be seriously afflicted such that they become permanently work disabled as a result of the disease process within 2 years.2 However widespread systemic influences are also prevalent, so much so that mortality amongst rheumatoid arthritis sufferers is 1.5–1.6 times greater than the general population.3
Early identification of rheumatoid arthritis is considered critical as prompt intervention provides a window of opportunity to limit progressive damage from the disease process.5 Significantly one-third of patients with rheumatoid arthritis already have bone and joint damage prior to diagnosis and it has been identified that a delay in initiating treatment, (with Disease Modifying Anti-Rheumatic Drugs DMAR), of as little as 3 months can have significant impact on the amount of observable X-ray damage identified 5 years later.6 (Examples of DMAR: Methotrexate, leflunomide, sulfasalazin, gold, hydroxychloroquinine, etanercept, inflixima, adalimumab.) This has led to growing interest in the use of anti-cyclic citrullinated protein antibody markers as an indication of the early presence and, potentially, a prediction of the development of rheumatoid arthritis amongst both healthy people and those with undifferentiated arthritis.7, 8 Disease progression indicators include early low functional scores, low economic status, early multiple joint involvement, high erythrocyte sedimentation rates, high C-reactive protein measures, early X-ray changes and/or a positive rheumatoid factor.2
Individuals with rheumatoid arthritis commonly use complementary and alternative medicines (CAM). Reasons given include: the inadequacy of conventional treatment to meet the needs of the patient (disease remission, decrease pain, return of function and so on); concern regarding side-effects; a desire to reduce the stress of a disease; patients consider CAM as safer and ‘natural’; and/or that they have been influenced by advertising claims.9 Interestingly, a US study identified that the likelihood of using CAM therapies for a number of musculoskeletal conditions including rheumatoid arthritis increased with the degree of scepticism of the user of mainstream medical approaches.10
Lifestyle factors
Genes
Genetic factors are estimated to comprise 50–60% of the incidence of rheumatoid arthritis.1 Growing evidence suggests an interactive link between genetic susceptibility (e.g. HLA-DR genetic profile) and environmental triggers (e.g. smoking) that lead to the eventual immunological assault of the disease.11, 12
Smoking
The immune system is influenced by smoking on many levels — the induction of an inflammatory response, suppression of immune responses, cytokine imbalance, induction of apoptosis and the formation of anti-DNA antibodies as a result of DNA damage.13 Unsurprisingly therefore, a strong association is present between tobacco use and extra-articular manifestations of rheumatoid arthritis, including cardiovascular events, although not to the extent of radiographic changes.14
In a subset of rheumatoid arthritis patients the presence of an HLA-DR shared epitone gene also interacts with smoking leading to immune system dysregulation and the formation of autoantibodies to citrullinated peptides significant to the disease process.11, 12 Significantly this immune system response as a result of gene-smoking interaction may be initiated years before symptomatic presentation of rheumatoid arthritis.11 Smokers who have the HLA-DR gene are also at higher risk (7.5) of rheumatoid factor seropositive rheumatoid arthritis than non–smokers with the gene (2.8), or smokers without the gene (2.4) as compared with non-smokers/no gene (1.0).15
It has therefore been suggested that smoking cessation counselling should be mandatory for all rheumatoid arthritis patients and their relatives.16
Nutritional influences
Diets
A review of dietary factors considered to diminish the risks of rheumatoid arthritis indicate that foods high in olive oil, oil-rich fish, fruit, vegetables and betacryptoxanthins (found in red fruit and vegetables) were protective for rheumatoid arthritis.17, 18 A review of trials on red meat, coffee and alcohol demonstrated mixed results and no firm conclusions could be made as to their influence on rheumatoid arthritis.17 However, these conclusions differ to a further study of diet and risk which indicated that although consumption of high-fat fish (> or = 8g of fat/100g fish) appear to provide a risk reduction, medium-fat fish (3–7g/100g fish) was actually associated with increased risk of rheumatoid arthritis. A prospective study by the Mayo Clinic suggested that cauliflower, broccoli and other cruciferous vegetables and fruit were protective of rheumatoid arthritis.19 However, a further study indicated that fruit, coffee, olive oil and meat intake showed no association with rheumatoid arthritis risk reduction, nor did intake of vitamins A, E, C, D, zinc, selenium or iron.20 A review of studies into the relationship between obesity and rheumatoid arthritis presently suggests obesity may lead to less changes on radiography and better survival rates, although this needs to be confirmed.21 Hence, the implications of diet on the risk of rheumatoid arthritis is, presently, contradictory.
Vegetarian and vegan diets have been advocated for rheumatoid arthritis patients. A 13-month trial in which a period of fasting was followed by a vegetarian diet indicated that pain diminished but physical function and morning stiffness did not change in the active group.22 A vegan diet free of gluten provided benefit for 40.5% of the active group who completed 1 year of the diet plan. Notably, however, only 25 of 38 patients in the active vegan group were able to comply with 9 months or more of the program, suggesting compliance is a problem.23
Studies of Mediterranean (Cretan) diets, suggests they may be of benefit in reducing the pain of rheumatoid arthritis when committed to over a 12-week period.24, 25 A UK pilot study trialled a pragmatic approach to the Mediterranean diet by providing community-based intervention that included hands-on cooking classes. As a result a change in dietary patterns was noticed with an increase in fruit, vegetable and legume consumption and improvements in monounsaturated: polyunsaturated fats ratios. Significant improvements were observed for pain and morning stiffness scores at 6 months.25
Studies of food allergies and/or intolerances suggest the possibility of an involvement in rheumatoid arthritis. Rheumatoid arthritis patients have been found to have increased immunoglobulin M (IgM) activity to cow’s milk (alpha-lactalbumin, casein), cereals, hen’s eggs (ovalbumin), cod fish and pork meat within their intestinal fluid.26 It was postulated that such activity amongst other examples of cross-reactive food antibodies may ultimately lead to autoimmune responses in the joint via hypersensitivity reactions to circulating immune complexes.26 Consistent with this, small trials of an elemental diet indicate the potential for improvement in rheumatoid arthritis patients.27–29. A review of allergens in 1 trial indicated that grains, milk, beef and eggs were common culprits.27
It must be highlighted that a Cochrane review (2009) concluded that the effects of diet remain uncertain due to the nature of the identified trials and the risk of bias. The review raised further concerns that all of the above diets (Mediterranean, fasting, vegan, vegetarian, elemental) risked both non-compliance and weight loss within patient groups and there was the potential for adverse effects as a result.30
Sleep
Sleep disturbances appear to be common amongst patients with rheumatoid arthritis. Amongst arthritis sufferers in general 60% of patients experience problems with sleep,31 including 72% of patients above 55 years of age.32 The problem also exists amongst children with juvenile rheumatoid arthritis.33 Despite this sleep difficulties are seldom addressed with rheumatoid arthritis sufferers.31 Sleep disturbances include longer times to fall asleep, repetitive night waking and early morning waking with subsequent day tiredness and fatigue.34
Mind–body medicine
Adjustment to the pain and disability that result from rheumatoid arthritis require psychological and emotional resilience. Capacity to initiate active coping strategies has been identified as critical in maintaining psychological wellbeing.35, 36 As a result various mind–body medicine approaches have been advocated to aid coping with rheumatoid arthritis.
Cognitive behavioural therapies (CBTs) and education
CBT approaches may provide additional benefit to depressive symptoms in rheumatoid arthritis receiving routine medical management up to 18 months after an 8-week program.37 However, a study of CBT comparing CBT to a standard education program for newly diagnosed arthritis patients found there was no difference on health status between the 2 approaches over 6 months.38
A Cochrane review (2003) indicated that patient education was of small benefit to rheumatoid arthritis in the short term, improving disability, joint count, depression and psychological status, yet there was little evidence that gains were maintained over the long term.39 However studies continue to mount suggestive of benefits from arthritis education programmes subsequent to this review. Disease specific programs appear to be more valuable than generalised chronic self help programs.40 Internet41 and modular delivered behavioural arthritis programs42 may be viable means of delivering information compared to standardised approaches.
Small studies indicate several mind-body medicines have the potential of influencing aspects of rheumatoid arthritis. Stress management programs decrease pain and psychological functioning by improving self-efficacy, coping strategies and overcoming feelings of helplessness.43 Brief motivational training by telephone has also been demonstrated to assist in cognitive and emotional coping.44 Tentative evidence suggests that private verbal or written emotional disclosure may be effective in the intermediate term to maintain psychological functioning, noting in the short term they may cause an increase in emotionality.45–47. However, results are mixed, and a further study of private emotional disclosure and, in particular, emotional disclosure in the presence of a clinician, was of no significant benefit.48
Meditation and/or relaxation
A study comparing cognitive behavioural therapies, emotional regulation and mindfulness meditation delivered in small group environments identified that rheumatoid arthritis patients who suffered with recurrent depression had greater benefit from meditation in terms of positive and negative effect and physician ratings of joint pain, whereas CBTs provided greater gains in pain control.49 Positive effects of mindfulness-based stress reduction may be beneficial in aiding psychological distress and wellbeing as compared to controls, however, gains may take up to 6 months to be achieved.50 The use of Benson’s Relaxation Technique has shown benefit in a small study of 8 weeks as compared to controls in reducing anxiety, depression and feelings of wellbeing.51 These early studies suggest that meditation and/or relaxation may have potential in improving the wellbeing of rheumatoid arthritis patients.
Physical activity/exercise
Comprehensive multidisciplinary approaches to rehabilitation often involve a combination of therapeutic and general exercise, occupational therapy and the use of orthotic splints. Such programs should be introduced as early as possible and concurrent with pharmacological intervention.52 However, due to a paucity of trials in this area little is known as to the extent of effectiveness other than by inference from evidence for the individual therapies themselves within a program.53
Aerobic exercise
A review of reconditioning programs has established that dynamic and aerobic activity individualised to the patient’s level of disability is more beneficial than rest in patients with rheumatoid arthritis, and the activities do not aggravate inflammation nor cause joint damage. The goal of such programs should be to avoid functional decline.54 There is strong evidence from a systematic review suggesting that exercise, whether of low or high intensity, is effective in improving disease and functional Balneotherapy (hydrotherapy and spatherapy) measures in patients with rheumatoid arthritis.55
Balneotherapy (hydrotherapy and spatherapy)
Noting that methodological flaws and poor study structure in trials of balneotherapy are prevalent (spa therapy, hydrotherapy), present evidence is suggestive that it is of benefit for the patient with rheumatoid arthritis.56
Tai chi
A Cochrane review (2004) of tai chi for rheumatoid arthritis indicated statistically significant benefits were obtained with measures of lower extremity range of motion improving. This form of exercise does not appear to exacerbate symptoms of rheumatoid arthritis, however the review did not identify improvements in most other outcomes of disease activity.57 While subsequent small trials continue to be suggestive of benefits to pain, fatigue and function scores as compared to no intervention,58, 59 tai chi does not appear to provide additional benefit when compared to physically active controls or stretching and an exercise program.60
Nutritional supplements
A New Zealand review of micronutrient adequacy of the diets of patients with rheumatoid arthritis demonstrated that only 23% achieved adequate calcium intake (as compared to recommended dietary intake [RDI]), 29% adequate vitamin E, 10% adequate zinc and only 6% adequate selenium.63 Only 46% reached adequate RDI for folic acid, with a significant reduction noted in the subgroup of patients taking methotrexate. Protein intake and iron were adequate, and unrelated to the presence or absence of anemia.63 A US dietary review suggested that rheumatoid arthritis patients consumed excess total fat but insufficient polyunsaturated fat and fibre, with inadequacies in pyridoxine, zinc and magnesium compared to the RDI, and copper and folate when compared to the typical American diet.64
Omega-3 (fish oils)
High-level evidence now exists for the symptomatic benefit achieved from fish oils and, given the increased risk of cardiovascular events in rheumatoid arthritis patients, they should be recommended to all patients.65 The anti-inflammatory effects of fish oils result from their influence on eicosanoid pathways leading to less pro-inflammatory cytokines, as well as an inhibition of T-lymphocytes and catabolic enzymes.66 A meta-analysis of 3–4 months use of fish oils amongst rheumatoid arthritis patients demonstrated reductions in joint pain intensity, morning stiffness, number of painful/tender joints and a reduction in the consumption of non-steroidal anti-inflammatory drugs (NSAIDs).67 Animal models are also suggestive of the potential for omega-3 oils to slow the disease process and reduce disease severity.68
Gamma linoleic acid (omega-6, evening primrose oil, borage)
A Cochrane review (2000) indicated that evidence existed for the potential benefit of gamma linoleic acid (GLA) in the treatment of rheumatoid arthritis with improvements in pain, morning stiffness and joint tenderness noted.69 Like fish oils, GLA down regulates the pro-inflammatory pathways active in rheumatoid arthritis,70 however, it is not thought to alter the disease process.71 Indeed, although patients are often able to reduce or even stop their NSAID with GLA usage,70 symptoms often return within 3 months once supplementation is ceased.71 Dosages of up to 2.8g/day have been trialled with success.71
Antioxidants
A cohort study of older women examining the relationship between antioxidant and micronutrient intake and the risk of rheumatoid arthritis noted an inverse relationship between intake of vitamin C, vitamin E and betacryptoxanthin (found in red fruit and vegetables) and the presence of rheumatoid arthritis.72 However, a systematic review of randomised clinical trials (RCTs) relating to the use of antioxidant vitamins (2007) indicated that evidence was lacking as to the benefits of supplementation.73
In the abovementioned review, 4 trials of vitamin E suggested that vitamin E was superior to placebo but equivalent to diclofenac in treating rheumatoid arthritis, however, methodology of the trials was weak.73 However, a large trial of near to 40 000 healthy female patients concluded that there was no evidence that the use of 600IU vitamin E supplementation prevented the development of rheumatoid arthritis during a 10-year follow up as compared to a no supplement control group.74
A subsequent trial in 2008 in which a pilot group of rheumatoid patients consumed 20g of an antioxidant rich spread per day (10 weeks) suggested improvements in the number of swollen joints and general health, although no change in laboratory markers was noted.75
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