Rheumatoid arthritis

Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease characterised by an inflammation of the synovial joints leading to joint and periarticular tissue destruction, as well as a wide variety of extra-articular features.

RA is associated with significant morbidity, including pain and disability. Suppression of inflammation in the early stages of the disease can result in substantial improvements in long-term outcomes. Improvements in the use of existing disease-modifying drugs, the development of new drugs and the better application of a range of therapeutic options including non-pharmacological treatments are important in reducing morbidity and mortality from RA.

About one third of people with RA remain seronegative¹. Despite awareness of the role of circulating autoantibodies in the development of 'seropositive' RA, the pathogenesis of seronegative RA is poorly understood. Evidence suggests that RA 'serotypes' reflect distinct disease entities that diverge with respect to genetic architecture, cellular pathology and even therapeutic responsiveness².

Epidemiology³

• The prevalence of confirmed RA is about 1% of the UK population.

• One study in the UK found the population minimum prevalence of RA to be 1.16% in women and 0.44% in men⁴.

• The incidence of the condition is low, with around 1.5 men and 3.6 women developing RA per 10,000 people per year in the UK.

• The overall occurrence of RA is two to four times greater in women than in men.

• The peak age of onset in the UK for both genders is 30-50 years, but people of all ages can develop the disease.

Risk factors

RA results from an interaction between genetic susceptibility and environmental factors, including high birth weight, smoking, silica exposure, alcohol abstention, obesity, diabetes mellitus, rheumatoid factor, and anti-citrullinated protein antibody⁵⁶.

• Smoking is an important risk factor⁷.

• HLA DR4 and DR1 are associated, especially in severe disease.

• There is possible infective aetiology, although no organism has been demonstrated.

• Onset is more common in winter.

Presentation

See also the separate Rheumatological History, Examination and Investigations and Aching Joints - Assessment, Investigations and Management in Primary Care articles.

National Institute for Health and Care Excellence (NICE) guidance emphasises the importance of early diagnosis and treatment⁸. There is evidence that the first 12-week period of the disease is immunologically distinct and represents a unique opportunity to influence the progress of the disease. The challenge for GPs is to recognise early symptoms and refer early. The presentation can be very variable. Constitutional symptoms (eg, profound fatigue, influenza-like symptoms, fever, sweats and weight loss) are common.

Palindromic rheumatism is a rare form of inflammatory arthritis. Attacks of joint pain and swelling are similar to rheumatoid arthritis, but the joints return to normal between attacks. Patients with palindromic rheumatism may later develop rheumatoid arthritis.

• Arthritis:
  

  • Usually starts as an insidious symmetrical polyarthritis, often with nonspecific systemic symptoms. RA can affect any synovial joint but typically affects the small joints of the hands and the feet. It is usually bilateral and symmetrical in distribution. More joints are affected with progression of the disease.

  • Joint inflammation produces characteristic changes: heat and sometimes redness, swelling, pain, stiffness (especially in the early morning or after inactivity), progressive joint destruction and loss of joint function. Pain, swelling, muscle wasting and damage to joints result in progressive deformity, disability and handicap.

  • Tendon sheaths have synovial linings and inflammation of these can result in tendon rupture.

• Signs of arthritis include:
  

  • Symmetrical, distal, small joint arthritis involving the proximal interphalangeal, metacarpophalangeal, wrist, metatarsophalangeal, ankle, knee and cervical spine joints.

  • Shoulders, elbows and hips are less commonly affected.

  • Hand deformities, including ulnar deviation, swan neck and Boutonnière's deformity of the fingers, Z deformities of thumbs and piano key deformity of the wrist.

  • Muscle wasting and tendon rupture.

  • Cervical complications (instability of the cervical spine).

Extra-articular features⁹

RA is a systemic disease and there are other manifestations of the disease.

• Eyes: secondary Sjögren's syndrome, scleritis and episcleritis.

• Skin: leg ulcers especially in Felty's syndrome (association of rheumatoid factor positive rheumatoid arthritis, neutropenia and splenomegaly). Rashes, nail fold infarcts.

• Rheumatoid nodules: these are common, and may occur in the eyes, may be subcutaneous, and may be in the lung, heart and occasionally the vocal cords.

• Neurological: peripheral nerve entrapment, atlanto-axial subluxation, polyneuropathy, mononeuritis multiplex.

• Respiratory system: pleural involvement, pulmonary nodules, pulmonary fibrosis, obliterative bronchiolitis, Caplan's syndrome.

• Cardiovascular system: cardiovascular disease, pericardial involvement, valvulitis and myocardial fibrosis, immune complex vasculitis.

• Kidneys: rare, including analgesic nephropathy, amyloidosis.

• Liver: mild hepatomegaly and abnormal transaminases are common.

• Other: thyroid disorders, osteoporosis, depression, splenomegaly and susceptibility to infections.

Differential diagnosis

See also the separate Acute Monoarthritis and Acute Polyarthritis articles.

• Viral arthritis (eg, parvovirus, rubella, hepatitis B).

• Reactive arthritis (eg, postinfective: throat, gut, sexually acquired).

• Seronegative spondyloarthropathy (eg, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease).

• Connective-tissue disease (eg, systemic lupus erythematosus (SLE), scleroderma).

• Polymyalgia rheumatica.

• Polyarticular gout.

• Osteoarthritis (eg, involvement of the proximal and distal interphalangeal joints, Heberden's or Bouchard's nodes).

• Septic arthritis (particularly if monoarthritis).

• Fibromyalgia.

• Lyme disease.

• Medical conditions presenting with arthropathy - eg, sarcoidosis, thyroid disease, infective endocarditis, haemochromatosis, diabetic cheiro-arthropathy, paraneoplastic syndromes, multiple myeloma.

Investigations

Diagnosis is essentially clinical; investigations are important in assessment and exclusion of other possible diagnoses.

Nonspecific investigations

• ESR, CRP and plasma viscosity: usually raised but may be normal.

• FBC: normochromic, normocytic anaemia and reactive thrombocytosis are common in active disease. Raised ferritin but low serum iron concentration and total iron binding capacity.

• LFTs: mild elevation of alkaline phosphatase and gamma GT.

• Antinuclear antibody: positive in SLE and related conditions; also in up to 30% of RA patients and weakly positive in up to 10% of the normal population.

• Uric acid/synovial fluid analysis: excludes polyarticular gout.

• Urinalysis: microscopic haematuria/proteinuria may suggest connective tissue disease.

Specific investigations

NICE recommends⁸:

• Rheumatoid factor in people with suspected RA who are found to have synovitis on clinical examination. Rheumatoid factor: positive in 60-70% of patients (and 5% of the normal population).

• Anti-cyclic citrullinated peptide (anti-CCP) antibodies in an individual with suspected RA, if the patient is negative for rheumatoid factor, and there is a need to decide about starting combination therapy. Anti-CCP has been found to be more specific than rheumatoid factor in RA and may be more sensitive in erosive disease.

• X-ray the hands and feet early in the course of the disease in people with persistent synovitis in these joints. X-rays may show soft tissue swelling, periarticular osteopenia, loss of joint space, erosions and deformity.

Referral⁸

Early involvement of secondary care is very important for establishing the diagnosis, early use of DMARDs and ensuring full access to all available resources.

NICE advises referral for specialist opinion any adult with suspected persistent synovitis of undetermined cause. Refer urgently if any of the following apply:

• The small joints of the hands or feet are affected.

• More than one joint is affected.

• There has been a delay of three months or longer between onset of symptoms and seeking medical advice.

Management

See the separate Management of Rheumatoid Arthritis and Disease-modifying Antirheumatic Drugs (DMARDs) articles.

NICE has published guidance on the standards of care for people with RA⁸.

Complications

• Adverse effects on work and social life are common¹⁰. Many people with RA have restricted mobility and difficulties with activities of daily living. Inability to work may occur early in the course of the disease, especially in someone with a manual occupation.

• Depression is common.

• Inflammatory conditions other than those involving joints and tendons.

• Vasculitis, vasculitic ulcers.

• Pleurisy, pleural effusions, pulmonary fibrosis.

• Pericarditis, pericardial effusions, myocardial infarction, myocardial dysfunction, myocarditis.

• Lymphadenopathy.

• Dry eye syndrome (keratoconjunctivitis sicca).

• Neuropathy.

• Felty's syndrome (enlarged spleen and low white cell count); can present with an infection or leg ulcer.

• Amyloidosis (rare).

• Anaemia.

• Orthopaedic complications: carpal tunnel syndrome, tendon rupture (particularly extensors of fingers or thumb), cervical myelopathy (usually after severe and long-standing RA), osteoporosis, articular deformities and functional impairment.

• Infectious complications: increased risk of infections. Pulmonary infection and generalised sepsis are particular risks. Septic arthritis is a rare but serious complication.

Complications associated with drug treatment, include³:

• Gastrointestinal: mainly due to the adverse effects of NSAIDs.

• Increased risk of infection: glucocorticoids and immunosuppressants.

• Liver toxicity: methotrexate-related.

• Malignancy: particularly TNF-alpha inhibitor-related (increased risk of skin cancer).

• Osteoporosis: low-dose glucocorticoid use. RA also increases the risk of osteoporosis in the absence of glucocorticoid use.

Prognosis

• The prognosis is variable. The clinical course is typically periods of exacerbations and remissions but may be mild self-limited disease or a chronic progressive illness. Approximately 40% of patients become disabled after ten years. The prognosis is worse when diagnosis and treatment are delayed.

• Approximately one third of people stop work because of RA within two years of its onset and this increases with time³.

• A worse prognosis for joint damage and disability is associated with:
  

  • Age younger than 30 years, male.

  • Insidious onset.

  • Extra-articular manifestations, a large number of involved joints, systemic symptoms, persistent anaemia of chronic disease.

  • HLA-DRB1*04/04 genotype, a high serum titre of autoantibodies (eg, rheumatoid factor, anti-CCP), raised levels of complement C1q.

  • Early X-ray evidence of bone erosions.

  • RA that remains persistently active for longer than one year.

• There is increased mortality, particularly due to cardiovascular disease, infection, vasculitis and poor nutrition.