Rheumatoid arthritis: clinical review

The epidemiology, aetiology, diagnosis, monitoring and treatment of rheumatoid arthritis, including the latest advice on investigations and the role of early referral and treatment in halting disease progression.

Section 1 Epidemiology and aetiology

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects approximately 1% of the UK population.

It is the most common inflammatory joint disease and about 20,000 people are diagnosed with RA in the UK each year.1

RA affects more women than men (female to male ratio 3:1) and prevalence increases with age, most commonly presenting between 50 and 70 years of age.2

The total cost of RA in the UK, including the indirect costs of absenteeism, early retirement and loss of productivity, as well as the medical costs of care, is in excess of £4bn per year.3


RA is an autoimmune disorder involving the migration of inflammatory cells into the synovium that surrounds the joints, causing cytokines, the chemicals of inflammation, to be secreted and inflammation to occur within joints and soft tissues (swelling, pain and loss of function).

RA: chronic inflammation will cause joint damage

Chronic inflammation (present for more than three months) will cause joint damage and result in permanent loss of function unless it is reversed early with effective treatments. Damaged joints may then need orthopaedic surgery.

It is important to realise that RA is a systemic disease and can affect more than simply the joints, tendons and ligaments.

Systemic release of inflammatory cytokines (TNF-alpha, interleukin (IL)-1 and IL-6 among others) drives the inflammatory process in the joints and can affect other parts of the body, such as the lungs, skin, nerves and arteries. Although genetic factors have been shown to influence both susceptibility to, and severity of, the disease, the relationship is not straightforward and families who experience RA in more than two generations are unusual.

Studies in twins have shown a concordance for RA of only 12-15% in monozygotic twins and 4% in dizygotic twins,4 suggesting the importance of factors other than genes. Environmental factors, such as stress, smoking, excessive coffee drinking and the make-up of the microbial population in the bowel, have all been implicated in higher susceptibility to RA.

Section 2 Making the diagnosis

RA is defined using the American Rheumatism Association (ARA) 1987 criteria.5

Patients with RA develop a symmetrical polyarthritis, which characteristically affects the small joints of the hands and feet (sparing the distal interphalangeal joints), along with involvement of other joints as the disease progresses.

Although useful for classification, the ARA criteria should not be used for initial diagnosis, because some ARA diagnostic features are found more in advanced disease.

Patients may have developed irreversible deformities, such as Boutonniere, swan neck and z-thumb deformities, by the time they meet the ARA criteria.

Early diagnosis

It is important to diagnose RA early, even before the development of its classic features, and to start DMARDs as early as possible and certainly within three months of disease onset (the so-called window of opportunity). This will reduce symptoms, prevent damage and minimise other risks, such as osteoporosis and cardiac disease, which can result from uncontrolled RA.

Many rheumatology departments have early arthritis clinics to facilitate urgent referral from general practice. Although initial RA joint symptoms usually develop slowly and progressively, acute presentation can occur in 20% of cases.

Patients with RA may not meet established criteria for RA, so it is important for the GP to have a high index of suspicion, to identify early symptoms and signs, and to refer to the rheumatology department urgently, even if there is some clinical doubt as to the diagnosis and RA serology tests are negative.

Patients should be referred urgently if they present with any of the following:

  • Persistent (more than six weeks) pain or inflammation in the small joints of the hands and feet
  • Pain or inflammation in more than one joint
  • Early morning stiffness in joints lasting more than 30 minutes

Detecting inflammation

Elevated inflammatory markers, such as CRP and ESR, are usually found in association with RA, but may be normal in some people, especially early in the disease.

Rheumatoid factor (RhF) and anticitrullinated antibodies, such as anticyclic citrullinated peptide (anti-CCP) are found in only 50-60% of confirmed RA cases during the initial presentation, so negative serological tests should not deflect from referral.

Anti-CCP is as sensitive as RhF and even more specific for RA (90-95%) and costs about £8.60, rather than £7.05 for RhF. Anti-CCP and is an indicator of potentially aggressive erosive disease with a worse prognosis.

Early significant inflammation in the small joints may not present with obvious signs (joint swelling, erythema), making the diagnosis even more difficult in some cases.

Rheumatologists may need imaging (Doppler ultrasound or MRI) to detect inflammation in joints, which may not be available to primary care physicians.

X-rays may be normal in early cases, because bony erosions and joint damage appear later and may be irreversible. Negative findings should not deter the primary care physician from referring to secondary care if the history is suggestive of inflammatory joint disease.

Section 3 Managing the condition

The drug management of patients with RA has two objectives: symptom control, and disease modification and complete suppression of progressive inflammation.

Combinations of analgesics and DMARDs are often needed to achieve both of these aims, especially in the early stages of the disease, because most DMARDs are slow to take effect.

Early therapy can help to prevent the damage seen in advanced disease

Pain control

Pain control drugs include analgesics as well as NSAIDs for general pain. Although low-dose oral corticosteroids can be considered as a DMARD, steroids used either IM or orally have a fast onset of action and are effective in many patients for immediate relief of signs and symptoms of inflammation.

Preventing progression

The most important development in the management of RA in the past decade is the use of multiple DMARDs early in the disease, to prevent joint damage and systemic complications of RA.

RA disease activity is routinely measured using a Disease Activity Score (DAS), which is a composite measure of joint tenderness and swelling, ESR and the patient’s visual analogue assessment of disease activity.

DASs are used to measure how effective drugs are and how severe RA is at any point in time.

The rationale behind treatment is to suppress inflammation effectively enough to prevent the development of complications and therefore aim for a very low DAS to achieve ‘remission’.

DMARDs can be subdivided into two subgroups.

Conventional DMARDs

Commonly used conventional DMARDs include methotrexatesulfasalazinehydroxychloroquineleflunomide and corticosteroids.

Combinations of these drugs are often used early in disease, depending on the rheumatologist’s judgment and the patient’s willingness to take several drugs at once for their RA.

The patient’s general health and comorbidities, along with their views on lifestyle and potential side-effects, will influence their choice of drugs and adherence.

It is important to understand that many DMARDs, especially when used in combination, can have adverse effects and will need careful monitoring, including regular blood tests. DMARDs should only be initiated by a rheumatologist and patients need to be given adequate drug information before starting treatment.

The main DMARD side-effects relate to immediate intolerance, such as nausea, together with more serious problems, such as potential bone marrow suppression, deranged LFTs and some risks of infection.


Biologics are a group of drugs developed with the hypothesis that reversal of the effects of the inflammatory cytokines may allow disease control.

Results of clinical trials and anecdotal experience have demonstrated just how effective these drugs can be in controlling RA.

Biologics now include monoclonal antibodies against TNF-alpha (infliximabadalimumab), TNF receptor (etanercept), IL-6 (tocilizumab), beta-cell CD20 receptors (rituximab) and T cells (abatacept). Many are self-administered by subcutaneous injection and new biologics are being developed.

Biologics are expensive and their use is reserved for patients with RA who have failed at least two conventional DMARDs.

Newer biosimilar biologics will become available over the next few years, which will result in cheaper biologics and easier access to treatment with these effective drugs.

NICE recommends levels of DAS above which biologics can be considered and their continued use will depend on how well tolerated they are and how effective they prove, as measured by DASs.

These drugs have made a significant impact on the lives of many patients with severe RA, but they are strong immunosuppressants, leaving patients more open to intercurrent infection. During any infection requiring antibiotics, patients are told to temporarily suspend the biologic until the infection has passed.

Other rarer adverse effects, such as reactivation of latent TB, inflammatory lung disease and exacerbation of congestive heart failure, can occur. The British Society for Rheumatology has compiled a patient database to collect reports of adverse effects with biologics, to ensure they are safe in the long term. Initial worries that they might cause cancer have proved to be unfounded.

A multidisciplinary team approach to the management of RA is usually adopted by rheumatology centres, with teams that include nurse specialists, physiotherapists, occupational therapists, podiatrists and orthopaedic surgeons.

There is no strong evidence that any dietary or complementary treatments can suppress inflammation in RA, although current research is focusing on how the bacterial microbiome (the pattern of personal bowel flora) may affect susceptibility to the development of RA and to its disease course.

Section 4 Prognosis

Factors that indicate a more severe disease state include:6

  • Positive RhF and/or anti-CCP antibody at presentation
  • Elevated CRP/ESR
  • A higher number of swollen/tender joints
  • Early X-ray evidence of joint erosions
  • Rheumatoid nodules or involvement of extra-articular sites, such as eyes or lungs

These and other factors may influence the rheumatologist’s choice on DMARDs, biologics and escalation of treatment. Early aggressive treatment from the start of the disease is now much more common than it was in the past.

It is important for patients to be aware they have a chronic disease and their medication is for long-term control; remission can be achieved, but may not be a cure.

From an occupational perspective, data suggest that approximately one-third of RA patients cease work because of the disease within two years of onset, and this prevalence increases thereafter.3 This figure may change as early aggressive treatment preserves function and controls disease to an optimum level.

Life expectancy is also reduced in RA patients. A woman aged 50 years with RA is expected to die four years earlier than a similarly aged woman without the disease.

This can be explained by many factors, including cardiac risk and exposure to strong drugs over a number of years.

Cardiovascular risk

Although RA is associated with many extra-articular complications, including lung fibrosis, Sjögren’s syndrome, vasculitis, peripheral neuropathy and osteoporosis, the most common serious complication of the condition is an increased RR for cardiovascular disease.

Large epidemiological studies have consistently found that patients with RA have a 1.5- to threefold increased risk for cardiovascular events compared with non-RA controls.7,8

Although there is evidence of increased traditional cardiovascular risk factors,9 the increased rate of cardiovascular disease in patients with RA cannot be explained by these factors alone.

There is now increasing evidence that persistent inflammation is an independent risk factor for cardiovascular events, which may be reduced once disease activity is controlled.10

Section 5 Case study

A 45-year-old woman was referred to the rheumatology department with a six-week history of pain in her hands and feet. She had also noted morning stiffness that eased after about an hour.

Although she had no obvious joint swelling, she was particularly tender in her knuckles and wrists. Her GP had requested blood tests, which showed CRP 6mmol/L and ESR 32mm/hr.

She was negative for RhF and her serum urate was normal.

On her first consultation with the rheumatologist at week seven, her examination revealed tenderness in the small joints of her hands, particularly the metacarpophalangeal joints, but sparing of the distal interphalangeal joints.

There was no significant soft tissue swelling or erythema in her joints, although she could no longer remove her wedding ring and her joints felt tight. Further blood tests were requested, along with X-rays, and she was given an IM injection of corticosteroids.

She had complete resolution of her pain and morning stiffness 24 hours after her corticosteroid injection. A follow-up appointment was arranged for four weeks’ time.

During that time, she noticed the morning stiffness was slowly recurring. She was also found to be positive for anti-CCP antibodies. The X-rays of her hands and feet were normal.

A combination of methotrexate and hydroxychloroquine was discussed as a potential long-term treatment. The drugs were initiated by the rheumatologist and the patient was then followed up in outpatients by the rheumatology nurse practitioner and given a direct access contact if she needed extra advice or urgent review.

Section 6 Evidence base


  • NICE. Rheumatoid arthritis in over 16s. QS33. London, NICE, June 2013
  • NICE Pathways. Rheumatoid arthritis overview
  • NICE. Rheumatoid arthritis in adults: management. CG79. London, NICE, December 2015
  • NICE. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed. TA375. London, NICE, January 2016
  • NICE. Apremilast for treating active psoriatic arthritis. London, NICE, December 2015
  • Ding T, Ledingham J, Luqmani R et al. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies. Oxford, OUP, 2010
  • Luqmani R, Hennell S, Estrach C et al. BSR and BHPR guideline for the management of rheumatoid arthritis (after the first 2 years). Oxford, OUP, 2009
  • Chakravarty K, McDonald H, Pullar T et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Oxford, OUP, 2008

Key text

  • Hochberg MC, Silman AJ, Smolen JS et al. Rheumatology. Volume 1, third edition. Oxford, Mosby, 2003


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  10. Dixon WG, Watson KD, Lunt M et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumour necrosis factor alpha therapy: results from the BSR Biologics Register. Arthritis Rheum 2007; 56: 2905-12

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