Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a common chronic inflammatory disease affecting over 400,000 people in the United Kingdom. RA is associated with significant morbidity including pain and disability. It does not just affect synovial joints but is a systemic disease affecting other organs. It is also associated with increased mortality from, for example, an increased incidence of coronary artery disease. Suppression of inflammation in the early stages of the disease can result in substantial improvements in long-term outcomes. Identification and treatment of secondary and coexisting diseases can also greatly improve prognosis.

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. Recent NICE guidance emphasises the need for improvements in all these areas and outlines a clear way forward for all those with a contribution to make in the care of patients with RA.¹

RA is an autoimmune chronic inflammatory disorder. It is 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. See also Rheumatoid Arthritis and the Lung.

• 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.
• The initial trigger for RA is unknown but there are abnormalities of the immune system with abnormal immune and inflammatory reactions, particularly in joints. These changes can occur before symptomatic onset of RA.
• Inflammation produces characteristic changes:
  • Increase in blood flow to the joint (heat and sometimes redness).
  • Proliferation of the synovial membrane and increase in synovial fluid (swelling).
  • Pain (stretching of pain receptors in the soft tissues and bone around the joint).
  • Loss of muscle around an affected joint (contributes to further loss of joint function).
  • Increasing damage to the joint (caused by release of protein-degrading enzymes from inflammatory and other cells).
  • Conversion of parts of the synovial membrane into an inflammatory tissue called pannus (which can invade the bone and cartilage around the joint).
• The degree of progressive damage is related to the intensity and duration of the inflammation.
• 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.
• RA is a systemic disease and there are other manifestations of the disease:
  • Constitutional symptoms can result from the release of large concentrations of proteins that drive inflammatory processes (such as tumour necrosis factor-%u03B1 (TNF-%u03B1)) and include profound fatigue, influenza-like symptoms, fever, sweats and weight loss.
  • Symptoms from disease causing inflammation in other body organ systems (for example Sjögren's syndrome and rheumatoid nodules over extensor surfaces especially elbows) affecting up to a third of patients.
• Serious or life threatening inflammatory manifestations include:
  • Pulmonary fibrosis
  • Pericardial and pleural inflammation
  • Vasculitis (including peripheral neuropathies and scleritis)
  • Cervical complications (instability of cervical spine)
• Significant associated diseases and susceptibilities can further increase morbidity and mortality. For example:
  • Ischaemic heart disease and atherosclerosis
  • Osteoporosis
  • Susceptibility to infections

New NICE guidance emphasises the importance of early diagnosis and treatment.¹

The American College of Rheumatology classification of RA has proved useful.² However these criteria have come in for increasing criticism if used in diagnosis. For example one study highlighted that the these guidelines failed to diagnose early disease.³ These should not now be used as diagnostic criteria.¹ There is evidence that the first 12 weeks 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.

• Prevalence ranges from 0.5-1.5% of the population in industrialised countries.
• Peak incidence occurs between the ages of 40 and 50.
• The annual incidence in women was recently estimated at 36 per 100,000 and in men at 14 per 100,000 (ratio 2.5:1).

Risk factors

• The evidence suggests that the cause is multifactorial in people with genetic susceptibility.
• HLA DR4 and DR1 are associated, especially in severe disease.
• Possible infective aetiology, although no organism has been demonstrated.
• Onset is more common in winter.

Can be very variable.

Symptoms

• It usually starts as an insidious symmetrical polyarthritis, often with non-specific systemic symptoms.
• Pain - this may not be easy to detect in elderly patients with co-morbidities (e.g. dementia) which limit articulation.⁶
• Swelling.
• Stiffness, especially early morning or after inactivity.
• Fatigue, fever and weight loss are common.

Signs

Classically:

• Symmetrical, distal, small joint arthritis involving proximal interphalangeal, metacarpophalangeal, wrists, metatarsophalangeal, ankles, knees and cervical spine joints.
• Shoulders, elbows and hips are less commonly affected.
• Hand deformities, including ulnar deviation, swan neck and Boutonniere's of the fingers, Z deformities of thumbs and piano key deformity of wrist.
• Muscle wasting and tendon rupture.
• Occasionally may present atypically as a monoarthritis, sudden onset, or systemic illness with minimal joint problems at first (especially in men).This is known as Palindromic Rheumatoid Arthritis.

Systemic involvement

• 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: common, may occur in eyes, subcutaneous, lung, heart and occasionally vocal cords.
• Neurological: peripheral nerve entrapment, atlanto-axial subluxation, polyneuropathy, mononeuritis multiplex.
• Respiratory system: pleural involvement, pulmonary fibrosis, obliterative bronchiolitis, Caplan's syndrome.
• Cardiovascular system: pericardial involvement, valvulitis and myocardial fibrosis, immune complex vasculitis. A recent study concluded that there was an excess risk of fatal myocardial infarction compared to the general population.⁷ On the plus side, some rheumatoid arthritis treatments (e.g. methotrexate) have been found to have a protective effect against cardiovascular disease.⁸
• Kidneys: rare, including analgesic nephropathy, amyloidosis.
• Liver: mild hepatomegaly and abnormal transaminases common.
• Other: thyroid disorders, osteoporosis, depression, splenomegaly.

Differential Diagnosis includes:

• Viral arthritis (e.g. parvovirus, rubella, hepatitis B).
• Reactive arthritis (e.g. postinfective: throat, gut, sexually acquired).
• Seronegative spondyloarthropathy (e.g. psoriatic, ankylosing spondylitis, inflammatory bowel disease).
• Connective-tissue disease (e.g. systemic lupus erythematosus, scleroderma).
• Polymyalgia rheumatica.
• Polyarticular gout.
• Osteoarthritis (e.g. involvement of proximal and distal interphalangeal joints, Heberden or Bouchard nodes).
• Septic arthritis (particularly if monoarthritis).
• Fibromyalgia.
• Lyme disease.
• Medical conditions presenting with arthropathy, e.g. sarcoidosis, thyroid disease, infective endocarditis, haemochromatosis, diabetic cheiroarthropathy, paraneoplastic syndromes, multiple myeloma.

Diagnosis is essentially clinical and there is no diagnostic investigation. Investigations are important in assessment and exclusion of other possible diagnoses.

• ESR, CRP and plasma viscosity: usually raised but may be normal.
• Full blood count: normochromic, normocytic anaemia and reactive thrombocytosis common in active disease. Raised ferritin but low serum iron concentration and total iron binding capacity.
• Liver function tests: mild elevation of alkaline phosphatase and gamma GT.
• Uric acid/synovial fluid analysis: excludes polyarticular gout.
• Urinalysis: microscopic haematuria/proteinuria may suggest connective tissue disease.
• Rheumatoid factor: positive in 60-70% of patients (and 5% of normal population).
• An antibody to a substance called cyclic citrullinated peptide (CCP) has been found to be more specific than rheumatoid factor in rheumatoid arthritis and may be more sensitive in erosive disease.⁹
• Antinuclear antibody: positive in systemic lupus erythematosus (SLE) and related conditions; also in up to 30% of rheumatoid arthritis patients and weakly positive in up to 10% of the normal population.
• Radiology: X-rays may show soft tissue swelling, periarticular osteopenia, loss of joint space, erosions and deformity.

The British Society for Rheumatology has published guidance on the standards of care for people with rheumatoid arthritis.¹⁰ Early involvement of secondary care is very important for establishing the diagnosis, early use of disease modifying anti-rheumatic drugs (DMARDs) and ensuring full access to all available resources.
See Management of Rheumatoid Arthritis and Disease Modifying Antirheumatic Drugs.

• Adverse effects on work and social life are common.
• Many people with RA have restricted mobility and difficulties with activities of daily living.
• Depression is common.
• Inability to work may occur early in the course of the disease, especially in someone with a manual occupation.
• Inflammatory conditions other than those involving joint and tendon.
• Vasculitis, vasculitic ulcers.
• Pleurisy/pleural effusions, pulmonary fibrosis.
• Pericarditis.
• 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.
• Infectious complications: increased risk of infections. Pulmonary infection and generalised sepsis are particular risks. Septic arthritis is a rare but serious complication.

• Some people experience flares and remissions, and others a progressive course. Over the years, structural damage occurs, leading to articular deformities and functional impairment.
• The condition reduces life expectancy but prognosis is variable (20% one attack only, whereas nearly 90% of patients with severe disease will be clinically disabled in 20 years).
• About half of people will be unable to work within 10 years.
• Poorer prognosis associated with:
  • Insidious onset
  • Male sex
  • Extra-articular manifestations
  • Functional disability at 1 year after start of disease
  • High RF titres
  • HLA-DR4 present
  • X-ray evidence of erosions within 3 years

1. Rheumatoid arthritis, NICE Clinical Guideline (February 2009); Rheumatoid arthritis: the management of rheumatoid arthritis in adults
2. Arnett FC, Edworthy SM, Bloch DA, et al; The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315-24. [abstract]
3. Banal F, Dougados M, Combescure C, et al; Sensitivity and specificity of the American College of Rheumatology 1987 criteria for the diagnosis of rheumatoid arthritis according to disease duration: a systematic literature review and meta-analysis. Ann Rheum Dis. 2008 Sep 9. [abstract]
4. Management of early rheumatoid arthritis, SIGN (2004)
5. Rheumatoid arthritis, Clinical Knowledge Summaries (June 2009)
6. Royal College of Physicians, British Geriatrics Society and British Pain Society; The assessment of pain in older people: National guidelines 2007.
7. Levy L, Fautrel B, Barnetche T, et al; Incidence and risk of fatal myocardial infarction and stroke events in rheumatoid arthritis patients. A systematic review of the literature. Clin Exp Rheumatol. 2008 Jul-Aug;26(4):673-9. [abstract]
8. Pincus T, O'Dell JR, Kremer JM; Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy. Ann Intern Med. 1999 Nov 16;131(10):768-74. [abstract]
9. Nishimura K, Sugiyama D, Kogata Y, et al; Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007 Jun 5;146(11):797-808. [abstract]
10. British Society for Rheumatology Guidelines; BSR guideline for prescribing TNFalpha blockers in Adults with Ankylosing Spondylitis

• Management of early rheumatoid arthritis, SIGN (2004)
• Guidelines on standards of care for persons with Rheumatoid Arthritis, British Society for Rheumatology (2004)
• Guideline for disease-modifying anti-rheumatic drug (DMARD) therapy, British Society for Rheumatology and British Health Professionals in Rheumatology (2008)
• Disease-modifying anti-rheumatic drugs (DMARDs), Clinical Knowledge Summaries (2008)
• Guideline for the management of rheumatoid arthritis (after the first 2 years), British Society for Rheumatology and British Health Professionals in Rheumatology (January 2009)