Rheumatoid arthritis (RA) is a chronic autoimmune multisystemic inflammatory disease that affects many organs but predominantly attacks the synovial tissues and joints.

The paediatric condition, juvenile rheumatoid arthritis, is discussed separately.

Epidemiology

The overall prevalence is 0.5-1% and the disease is 2-3 times more common in women ¹. Onset is generally in adulthood, peaking in the 4^th and 5^th decades ^ref.

Risk factors

• smoking (seropositive RA) ¹²

• obesity ^ref

• low socioeconomic status ^ref

Clinical presentation

The clinical features can be broadly categorised as articular and extra-articular. Generally, the onset of the condition may be insidious or abrupt, and early features commonly include tiredness, malaise, and generalised aches ^ref. Articular features generally develop prior to extra-articular features ^ref.

Articular features include a symmetrical deforming peripheral polyarthropathy that classically affects the fingers and hands, but also commonly involves the feet and can involve multiple other joints. The arthropathy has a classic inflammatory phenotype, with joint stiffness, reduced range of motion, reduce functionality, and a 'boggy' feel to palpation. For further details, please refer to musculoskeletal manifestations of rheumatoid arthritis.

Extra-articular features include ^ref:

• pulmonary involvement

  • interstitial lung disease

  • pulmonary nodules

  • pleural effusion

  • Caplan syndrome ⁷: rheumatoid arthritis and pneumoconiosis

• cardiovascular involvement

  • accelerated/premature coronary artery atherosclerosis ⁸, contributing significantly to the excess mortality of RA

  • pericarditis

• cutaneous involvement

  • rheumatoid nodules: usually seen in pressure areas (e.g. elbows, occiput, lumbosacral) ³ in RF-positive patients ⁹

  • rheumatoid vasculitis: classically deep cutaneous ulcers in the lower limbs, may have associated nailfold lesions

• haematological involvement

  • anaemia of chronic disease

  • Felty syndrome: syndrome characterised by the triad of rheumatoid arthritis, splenomegaly, and neutropenia

  • large granular lymphocyte leukaemia

• ocular involvement

  • keratoconjunctivitis sicca

  • episcleritis

• neurological involvement

  • rheumatoid meningitis

Pathology

Aetiology is unknown but is probably multifactorial. It is generally considered that a genetic predisposition (e.g. HLA-DR B1 which is the most common allele of HLA-DR4 involved in rheumatoid arthritis) and an environmental trigger (e.g. Epstein-Barr virus postulated as a possible antigen, but not proven) lead to an autoimmune response that is directed against synovial structures and other organs ^ref.

Activation and accumulation of CD4 T cells in the synovium start a cascade of inflammatory responses which result in ^ref:

• activation of the macrophages and synovial cells and production of cytokines such as IL4 and TNF, which in turn cause proliferation of the synovial cells and increase the production of destructive enzymes such as elastase and collagenase by macrophages

• activating B cell lymphocytes to produce various antibodies including rheumatoid factor (RF-IgM antibodies against Fc portion of the IgG) which makes immune complexes that deposit in different tissues and contribute to further injury 

• directly activate endothelial cells via increased production of VCAM1, which increases the adhesion and accumulation of inflammatory cells

• producing RANKL which in turn activate osteoclasts causing subchondral bone destruction 

The inflammatory response leads to pannus formation. Pannus is an oedematous thickened hyperplastic synovium infiltrated by lymphocytes T and B, plasmocytes, macrophages, and osteoclasts. Pannus will gradually erode bare areas initially, followed by the articular cartilage. It causes fibrous ankylosis which eventually ossifies ^2,3.

Other associated antigen subtypes include ¹⁴

• HLA-B54

• HLA-DQB1*0601

• HLA-B40

Diagnostic criteria

Diagnosis is based on a combination of clinical, radiographic, and serological criteria. The 2010 ACR - EULAR classification criteria for Rheumatoid Arthritis ⁴ has a maximal score of 10 and requires a score of >6 for a diagnosis of rheumatoid arthritis to be made:

• joint involvement

  • 0: 1 large joint

  • 1: 2-10 large joints

  • 2: 1-3 small joints (with or without the involvement of large joints)

  • 3: 4-10 small joints (with or without the involvement of large joints)

  • 5: >10 joints (at least 1 small joint)

• serology

  • 0: negative RF and negative anti-CCP

  • 2: low-positive RF or low-positive anti-CCP

  • 3: high-positive RF or high-positive anti-CCP

• acute phase reactants

  • 0: normal CRP and normal ESR

  • 1: abnormal CRP and abnormal ESR

• duration of symptoms

  • 0: <6 weeks

  • 1: >6 weeks

Markers

There are several serological markers for rheumatoid arthritis ^ref:

• rheumatoid factor (RF): is an IgM antibody against FC portion of the IgG antibodies, and is a traditional marker but is non-specific; associated with several autoimmune and chronic infectious diseases

• anti-cyclic citrullinated peptide (anti-CCP)/anti-citrullinated plasma antibody (ACPA): it is more than 80% sensitive and more than 95% specific

• elevated CRP and/or ESR

Radiographic features

Musculoskeletal

Musculoskeletal manifestations are the earliest and dominant features of rheumatoid arthritis ^ref.

For further details, please refer to musculoskeletal manifestations of rheumatoid arthritis.

Respiratory

Pulmonary rheumatoid disease may involve the airway, interstitium, and/or pleura; a full description is available in respiratory manifestations of rheumatoid arthritis ^ref.

Abdominal

Splenomegaly may be seen as part of Felty syndrome, usually in long-standing rheumatoid arthritis ^ref.

Treatment and prognosis

Treatment of rheumatoid arthritis is aimed at improving the symptoms and slowing disease progression. Medications used in treatment include:

• non-steroidal anti-inflammatory drugs (NSAIDs)

• disease-modifying anti-rheumatic drugs (DMARDs)

  • conventional synthetic DMARDs (csDMARDs): e.g. methotrexate, leflunomide, prednisolone

  • biological DMARDs (bDMARDs): e.g. TNF-α inhibitors (e.g. infliximab), tocilizumab, abatacept, rituxumab

  • targeted synthetic DMARDs (tsDMARDs): e.g. tofacitinib

The disease carries a significant burden of disability. There is also a reduction in life expectancy, with excess mortality usually related to its non-articular manifestations ^5,6.

History and etymology

Rheumatoid arthritis was a term first coined by British physician Sir Alfred Baring Garrod (1819-1907) in 1859 ¹¹.

Differential diagnosis

• psoriatic arthritis: distal distribution, new bone formation, enthesitis ^ref

• erosive osteoarthritis: distal distribution, central erosions, and 'gull wing' appearance ^ref

• systemic lupus erythematosus: non-erosive metacarpophalangeal joint subluxation ^ref

• scleroderma ¹³

  • can have similar erosions and be CCP-positive

  • soft tissue calcifications and acro-osteolysis are characteristic findings

• robust rheumatoid arthritis ^ref