Rheumatoid arthritis (RA) is a chronic, systemic inflammatory autoimmune disorder that primarily affects the joints (e.g., pain, swelling, synovial destruction, deformities) but may also manifest with extraarticular features (e.g., rheumatoid nodules, pulmonary fibrosis). Incidence is highest in women over 65 years of age. The condition is chronic and systemic, since it can also cause various extraarticular manifestations such as rheumatoid nodules and pulmonary fibrosis. Diagnosis is mainly clinical but may also involve laboratory tests (e.g., anti-CCP) and, later in the disease course, x-ray findings (e.g., soft tissue swelling or joint space narrowing). There is no curative therapy, but early intervention with disease-modifying antirheumatic drugs (DMARDs) can reduce the risk of complications (e.g., permanent damage to the affected joints).
- ∼ 0.24% worldwide 
- 1% in northern Europe and US 
- Sex: ♀ > ♂ (3:1) 
- Peak incidence: > 65 years 
Epidemiological data refers to the US, unless otherwise specified.
- Idiopathic inflammatory autoimmune disorder of unknown etiology
- Risk factors include: 
- Certain interstitial tissue proteins (e.g. intracellular filament protein vimentin, filaggrin, type II collagen) undergo a posttranslational modification that involves the conversion of arginine to citrulline (citrullination). 
- Citrullinated proteins are recognized as foreign by the antigen-presenting cells that present them to CD4+ T cells.
- Activation of CD4+ T cells leads to the following sequences of events: 
- IL-4 production → B-cell proliferation and differentiation → production of anticitrullinated peptide antibodies → and
- Migration of CD4+ T cells to synovial joints → secretion of cytokines (IFN-γ, IL-17) → recruitment of macrophages → secretion of cytokines (TNF-α, IL-1, IL-6) → inflammation and proliferation
- Bouts of inflammation, angiogenesis, and proliferation → proliferative granulation tissue with mononuclear inflammatory cells → pannus and synovial hypertrophy → invasion, progressive destruction, and deterioration of cartilage and bone
- Antibodies against Fc portion of IgG (rheumatoid factor, RF) are produced to aid in removing autoantibodies and immune complexes.
Articular manifestations 
- Symmetrical pain and swelling of affected joints (also at rest)
- Frequently affected joints 
- Rarely affected: distal interphalangeal (DIP) joints, first carpometacarpal (CMC) joint, and the axial skeleton (except for the cervical spine)
- Morning stiffness (often > 30 min) that usually improves with activity
Rheumatoid hand is characteristic and typically manifests with one or more of the following deformities:
- Deepening of the interosseous spaces of the dorsum of hand
- Swan neck deformity: PIP hyperextension and DIP flexion
- Boutonniere deformity: PIP flexion and DIP hyperextension.
- Hitchhiker thumb deformity (Z deformity of the thumb): hyperextension of the interphalangeal joint with fixed flexion of the MCP joint 
- Ulnar deviation of the fingers
- Piano key sign: dorsal subluxation of the ulna
- Hammer toe or claw toe
- (see “ ” below)
- Rheumatoid hand is characteristic and typically manifests with one or more of the following deformities:
- Physical examination: compression test (Gaenslen squeeze test)
Extraarticular manifestations 
- Constitutional symptoms
- Rheumatoid nodules
- Eye: keratoconjunctivitis sicca, scleritis, and episcleritis 
- Endocrine and exocrine glands: secondary
Subtypes and variants
Rheumatoid arthritis of the cervical spine 
RA typically affects the cervical spine early in the course of the disease, while normally sparing the thoracic and lumbar spine. RA of the cervical spine most commonly manifests with atlantoaxial subluxation. Other patterns of instability are atlantoaxial impaction and subaxial subluxation.
- Definition: a potentially life-threatening complication caused by the inflammatory destruction of the ligaments affecting the atlantoaxial joint and the intervertebral joints
- Pain and stiffness of the neck (typically early-morning neck pain at rest)
- Head tilt
- Neurological deficits
- Treatment: surgery if instability or myelopathy are present
Felty syndrome 
- Definition: a severe subtype of RA characterized by neutropenia and splenomegaly .
- Epidemiology: rare (1–3 % of patients with RA) 
- Clinical features
- Complications: Neutropenia increases risk of recurrent bacterial infections.
Adult-onset Still disease
- Epidemiology: 1.6:10,000 general population in France 
- Symptoms similar to juvenile idiopathic arthritis) (systemic onset
- Intermittent high fever
Salmon-pink maculopapular rash
- Affects the proximal limbs and torso
- Associated with pyrexial episodes (mostly evenings)
- Other symptoms: symmetrical polyarthritis, splenomegaly, polyserositis (pleura and pericardium)
- Laboratory studies
The diagnosis of RA is based on diagnostic criteria that include laboratory testing. Imaging may support the diagnosis, but radiological joint findings are no longer included in the criteria, as they often become evident only in late stages of disease.
- Rheumatoid arthritis = score of ≥ 6 points + confirmed presence of synovitis in at least one typical joint in the absence of a more probable cause (e.g., trauma or degenerative joint conditions)
- The total score is obtained by adding the points from each feature.
|Points||Joint involvement (pain/swelling)*||Serology||Acute phase reactants||Duration of symptoms|
|0||≤ 1 large joint||Negative RF and ACPA||Normal CRP and ESR||< 6 weeks|
|1||2–10 large joints||N/A||↑ CRP or ESR||≥ 6 weeks|
|2||1–3 small joints||Low positive RF or ACPA||N/A||N/A|
|3||4–10 small joints||High positive RF or ACPA (> three times higher than normal)||N/A||N/A|
*Large joints comprise the shoulder, elbow, hip, knee, and ankle. Small joints comprise the wrist, metacarpophalangeal joint (MCP), metatarsophalangeal joint (MTP), and proximal interphalangeal joint (PIP) of the hand and the foot.
- Nonspecific parameters
Serology (specific parameters)
- Anticitrullinated peptide antibodies (ACPA) 
- Rheumatoid factor (RF)
- Antinuclear antibodies (ANA): elevated in 30% of patients 
Synovial fluid analysis
- Synovial fluid is collected by joint aspiration.
|Radiological changes classified by Steinbrocker |
|Stage||Radiological changes||Joint mobility|
|0|| || |
|II|| || |
|IV|| || |
- MRI (with or without contrast): especially if cervical spine involvement is suspected or in early stages
- Further diagnostic measures: contrast-enhanced ultrasound and bone scintigraphy are very sensitive to inflammatory arthritis, providing further evaluation of disease activity and therapeutic monitoring of the disease.
Even if radiographic findings are normal, RA is still possible.
Before undergoing general anesthesia, airway and neck assessment is crucial in patients with rheumatoid arthritis. Atlantoaxial subluxation may be present, which increases the risk for spinal cord injury. Preoperative flexion-extension radiographs can help to evaluate the position of the cervical vertebra atlas (C1) with regard to the axis (C2).
Assessment of the disease activity
Typically, periods of minimal or no symptoms alternate with periods of increased disease activity (flares).
|Criteria to assess disease activity|
|Disease activity||Joints||Fever||Extraarticular symptoms||Functional impairment|
|Mild|| || || |
|Moderate|| || || |
|Severe|| || || |
- Synovial pannus formation and bone invasion: pathological layer of proliferative granulation tissue, mononuclear inflammatory cells, and fibroblast-like mesenchymal cells, releasing cytokines and enzymes, which, in turn, damage and invade the surrounding connective tissue 
- Synovial lining hyperplasia with mononuclear cell infiltrate
- Perivascular inflammatory infiltrates
- Fibrin deposition on synovial surfaces
- Rheumatoid nodules: central fibrinoid necrosis with palisading histiocytes (epithelioid cells)
|Differential diagnoses of inflammatory arthritis|
|Condition||Rheumatoid arthritis (RA)|| |
|Risk factors|| |
Course of disease
| || || || |
|Symmetry of joint involvement|| || || || |
Pattern of disease
|Laboratory findings|| |
Other differential diagnoses
- Autoimmune-related arthritis (e.g., sarcoidosis, SLE, rheumatic fever, mixed connective tissue disease, polymyalgia rheumatica)
- Enteropathic arthritis
- Viral arthritis (e.g., parvovirus B19, hepatitis viruses)
- Lyme arthritis
- Reactive arthritis (post-urethritis, post-enteritis)
- Soft tissue rheumatic disorders: a group of common nonsystemic focal syndromes characterized by nonarticular pain
- Hypertrophic osteoarthropathy: typically characterized by periosteal reaction in the metaphyses and diaphyses of long bones and associated with lung disease (e.g., lung cancer)
The differential diagnoses listed here are not exhaustive.
- Physical and occupational therapy
- Physical activity
- Application of heat or cold packs as needed
Acute antiinflammatory therapy
- Indication: acute attack
- Glucocorticoids: given until the onset of action of DMARD or as long-term therapy for highly active RA
NSAIDs and selective COX-2 inhibitors: symptomatic relief without improving prognosis
- Comedication with PPI is recommended because combining glucocorticoids with NSAIDs substantially increases the risk of GI ulcers.
- Not recommended in patients with the following:
Long-term antiinflammatory therapy with disease-modifying antirheumatic drugs (DMARDs) 
- Induces immunosuppression, leading to potential remission of RA
- Should be initiated regardless of the disease activity
- DMARD monotherapy is preferred for any level of disease activity
- Treat-to-target strategy should be used
- DMARD therapy reduces mortality and morbidity by up to 30% 
- Slow onset of action (≥ 6 weeks); symptomatic treatment with glucocorticoids and/or NSAIDs is often required
Drug of choice: (MTX)
- First-line treatment
- Benefits: highly effective, relatively well-tolerated, low cost, possibly life-prolonging
- Before initiation, check CBC and liver function tests
- To minimize side effects, folic acid is recommended 24–48 hours after taking MTX.
- Do not give NSAIDs on the same day as MTX, as they can worsen the side effects of MTX by inhibiting its renal excretion.
- Sulfasalazine: especially used in pregnancy
- Others: azathioprine, cyclophosphamide, cyclosporine A
- Rarely used: D-penicillamine, parenteral gold (many side effects, e.g., stomatitis, proteinuria)
Biologic agents 
- Indication: moderate or severe disease activity remaining after three months of DMARD therapy
- Should be combined with nonbiologic DMARDs
- Test for latent TB and hepatitis B and hepatitis C prior to initiation of treatment
- TNF-α inhibitors: e.g., adalimumab, infliximab, etanercept (see also “”)
- Others: anti-CD20), anakinra (interleukin-1 receptor antagonist, particularly for ), tocilizumab (IL-6 receptor antagonist) (
Early administration of DMARDs is crucial for a better outcome.
Surgical intervention may help relieve pain, correct deformity, and improve function. However, indication should be considered on an individual basis. Sometimes early surgical intervention may help to maintain quality of life.
- Radiation synovectomy: ablation of inflamed synovia via injection of radioactive agents (beta particles) into the synovial cavity of the affected joint
- Synovectomy: surgical removal of the synovial tissue
Untreated and/or severe cases can result in permanent damage to the joints with stiffening and deformity.
- Complications in the upper limbs: rheumatoid hand deformities (see “Clinical features” above)
- Complications in the lower limbs
- Other complications
We list the most important complications. The selection is not exhaustive.
Factors associated with poor prognosis
- Cardiovascular disease and infections are the most common causes of death. 
- Male sex 
- Social factors (e.g., low socioeconomic status, low level of education)
- Presence of extraarticular disease
- Elevated laboratory values associated with poor prognosis