- Clinical science
Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder characterized by joint pain, swelling, and synovial destruction. RA predominantly affects women and middle-aged individuals. The condition can also cause various extra-articular manifestations such as rheumatoid nodules and pulmonary fibrosis. Diagnosis is mainly based on clinical features (e.g., morning stiffness, symmetrical joint swelling) and laboratory tests (e.g., anti-CCP). X-ray findings (e.g., soft tissue swelling or joint space narrowing) occur late in the disease and are therefore not typically used for diagnosis. Early intervention with disease-modifying antirheumatic drugs (DMARDs) plays a decisive role in successful treatment. RA is not curable, but early effective treatment may help offset severe complications (e.g., permanent damage to the affected joints).
- Prevalence: ∼ 1% of the population
- Sex: ♀ > ♂ (3:1)
- Peak incidence: 50–75 years
Epidemiological data refers to the US, unless otherwise specified.
- Chronic inflammatory autoimmune disorder of unknown etiology
- Hypotheses suggest the etiology is multifactorial, with the following factors playing a role:
- Initially, non-specific inflammation affects the synovial tissue, which is later amplified by activation of T cells (autoimmune response).
- With time, it may lead to inflammatory joint effusion and synovial hypertrophy, as well as progressive destruction and deterioration of cartilage and bone.
- Patients with positive rheumatoid factor (RF) are more likely to develop extra-articular manifestations of rheumatoid arthritis. 
- Morning stiffness > 30 min; often improves with activity
- "Rheumatoid hand" is characteristic, and can include 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 distal interphalangeal joint (DIP) with fixed flexion of the MCP joint
- Ulnar deviation of the fingers
- Hammer toe
- "Rheumatoid hand" is characteristic, and can include the following deformities:
Compression test (Gaenslen squeeze test)
- Painful compression of hands (or feet) at the level of the metacarpophalangeal joint (metatarsophalangeal joint)
- Painful handshake = early sign of arthritis
DIP joints are not typically affected in RA!
- Constitutional symptoms: low-grade fever, myalgia, malaise, night sweats
- Skin: rheumatoid nodules (common); non-tender, firm, subcutaneous swellings (2 mm–5 cm)
- Lungs: : causing fibrosis, nodules; , pleuritis, and pleural effusions
- Eye: keratoconjunctivitis sicca, scleritis, and episcleritis
- Endocrine and exocrine glands: secondary
- Hematological: anemia of chronic disease
- Other musculoskeletal
- Heart: pericarditis and myocarditis; higher risk of myocardial infarction, stroke, and CHF
- Vascular: peripheral vasculitis; manifesting as , , purpura, necrosing fingertips or rheumatoid neuropathy
Complication: atlanto-axial subluxation
- Life-threatening complication!
- Pain and stiffness of the neck
- Neurological deficits, e.g., cervical radiculopathy with peripheral paresthesias
- Deformity, e.g., stiffness and scoliosis
- In some cases, symptoms of high spinal cord compression (see also )
- Extension and flexion x-rays of the cervical spine
- Treatment: surgery if instability or myelopathy are present
- Definition: Felty syndrome is a severe subtype of seropositive RA.
- Clinical triad consisting of arthritis, splenomegaly, and neutropenia (leads to ↑ risk of recurrent bacterial infections)
- Other symptoms: skin ulcers of the lower limbs (indicating vasculitis), hepatomegaly, fever, and chest pain (indicating pleuritis or pericarditis)
- Associated with increased risk of developing non-Hodgkin lymphoma
- Very rare and with symptoms similar to juvenile idiopathic arthritis) (systemic onset
- Main symptoms
- Laboratory tests
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.
ACR criteria for RA (ACR/EULAR classification criteria (2010) 
Rheumatoid arthritis = score of ≥ 6 points + confirmed presence of synovitis in at least one typical joint without an alternative, more probable diagnosis (e.g., trauma or degenerative joint conditions)
- For every column, the highest score is taken into account.
|Points||Joint involvement (pain/swelling)||Serology||Acute phase reactants||Duration of symptoms*|
|0||≤ 1 large joints**||Negative RF and ACPA||Normal CRP and ESR||< 6 weeks|
|1||2–10 large joints||↑ CRP or ESR||≥ 6 weeks|
|2||1–3 small joints||Low positive RF or ACPA|
|3||4–10 small joints||High positive RF or ACPA (> three times higher than normal)|
> 10 joints (at least one small joint)
- Non‑specific parameters
- Serology (specific parameters)
- Synovial fluid analysis
- Conventional x-ray
Even if radiographic findings are normal, RA is still possible!
Radiological changes classified by Steinbrocker
|Stade||Radiological changes||Joint mobility|
|0||Clinical signs, normal x-ray||Fully maintained|
|I||Periarticular osteoporosis and changes in soft tissue||Fully maintained|
|II||Additional lesions of cartilage and bones||Slightly impaired|
|III||Additional subluxations/malposition||Significantly impaired|
|IV||Destructive joints, total luxation, ankylosis||Completely restricted|
- MRI: (with or without contrast), especially if cervical spine involvement is suspected or in early stages
- Ultrasound: joint effusion, formation of
- Further diagnostic measures: contrast-enhanced ultrasound, scintigraphy
Before undergoing general anesthesia, airway and neck assessment is crucial in patients with rheumatoid arthritis. Atlanto-axial 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).
- Synovial pannus formation and bone invasion; : proliferative granulation tissue with mononuclear inflammatory cells
- Synovial lining hyperplasia with mononuclear cell infiltrate
- Perivascular inflammatory infiltrates
- Fibrin deposition on synovial surfaces
- Characteristic histology of rheumatoid nodules: central fibrinoid necrosis with histiocytes and surrounding epithelioid cells
|Rheumatoid Arthritis (RA)|
| || || || |
Course of disease
| || || || |
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|Symmetry of joint involvement|| || || || || |
Pattern of disease
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Other differential diagnoses:
- Autoimmune-related arthritis (e.g., sarcoidosis, SLE, rheumatic fever, mixed connective tissue disease, polymyalgia rheumatica)
- Arthritis associated with Inflammatory bowel disease
- Viral arthritis (e.g., parvovirus B19, hepatitis viruses)
- Lyme arthritis
- Reactive arthritis (post-urethritis, post-enteritis)
The differential diagnoses listed here are not exhaustive.
- For acute episodes of inflammation: cryotherapy
- Physical and occupational therapy
- Physical activity
Acute anti-inflammatory therapy
- Indication: acute attack
- Glucocorticoids; : given until DMARD's onset of action or as long-term therapy for highly active RA.
- NSAIDs and COX-2 inhibitors: symptomatic relief without improving prognosis
Long-term anti-inflammatory therapy with disease-modifying antirheumatic drugs (DMARDs)
- Induce immunosuppression, leading to potential remission of RA
Reduce mortality and morbidity by up to 30%
- Slow progression of disease
- Preserve joint function
- Limit complications
- Slow onset of action (≥ 6 weeks), so symptomatic treatment with glucocorticoids and NSAIDs is often required
Drug of choice: (MTX)
- First-line treatment for moderate to severe RA
- Benefits: highly effective, relatively well-tolerated, low cost, possibly life-prolonging
- Gastrointestinal side effects; , rash, hepatotoxicity; (abnormal liver chemistry), interstitial pneumonitis; and pulmonary fibrosis, bone marrow suppression , nephrotoxicity, increased risk of lymphoproliferative disorders, teratogenicity, alopecia 
- 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 .
- Alternative drugs:
- Drug of choice: (MTX)
- Indication: moderate or severe disease activity remaining after three months of DMARD therapy
- Should be combined with non-biologic DMARDs
Tumor necrosis factor (TNF) α inhibitors: e.g., adalimumab, infliximab, etanercept
- See .
- Others: anti-CD20) and anakinra (interleukin-1 receptor antagonist, particularly for ) (
Early administration of DMARDs is crucial for a better outcome!
Surgical intervention may contribute to pain relief, deformity correction, and functional improvement. However, indications evolve individually. Sometimes early intervention may help to maintain quality of life.
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 findings” above)
Complications in the lower limbs
- Baker cyst due to inflammatory joint effusion
- Foot impairment: pes plano‑valgus
Other complications 
- See "Subtypes and variants" above.
- Muscle weakness
- Lung disease: pleural and parenchymal lung diseases
- Cardiovascular disease: increased risk of pericarditis, coronary artery disease, heart failure, atrial fibrillation, and stroke
- Vasculitis involving the kidneys and skin
- Amyloid A (AA)
- Septic arthritis
- Osteopenia, , and bone fractures
- Sjögren syndrome (secondary form)
We list the most important complications. The selection is not exhaustive.
Factors associated with poor prognosis
- Prolonged disease progression without initiation of treatment
- Late onset (> 60 years of age)
- Sex: ♀
- Social factors (e.g., low socioeconomic status, low level of education)
- Laboratory tests associated with worsened prognosis if abnormally elevated