creation date: 2025-07-09 18:42
tags: Pathologies
Rheumatoid Arthritis
Background
Definitions
Rheumatoid arthritis (RA) is a systemic autoimmune disease and the most common chronic form of inflammatory arthritis.
This is referred to as early RA if symptoms have been present for <6 months and established RA if symptoms are present for ≥6 months.
Joint inflammation and destruction of the joint cartilage and bone is progressive if left untreated.
Etiology
The underlying cause of RA is primarily genetic along with its interaction with environmental factors.
Numerous alleles have been associated with an increased risk in developing RA including HLA-DRB1.
Environmental risk factors that play a role in triggering RA include:
- Cigarette smoking (strongest factor)
- Silica
- Asbestos
- Textile dust
- P. gingivalis
Pathogenesis
The exact pathogenesis of RA can be multifaceted and uncertain. Initial steps likely involve environmental triggers inducing peptidyl arginine deiminases into modifying peptide (converting arginine to citrulline). The modified proteins are presented to T-cells which leads to production of antibodies directed at citrullinated proteins (anti-citrullinated protein antibodies).
In the years leading up to symptomatic RA, anti-citrullinated protein antibodies (ACPAs) and cytokines increase in circulation. It is likely a second event occurs that leads to synovitis, such as the formation of immune complexes resulting in the activation of synovial cells.
The initiation and perpetuation of arthritis is then mediated by inflammatory molecules including autoantibodies. Inflammation further activates mesenchymal cells in the joints which destroy cartilage and osteoclasts damages subchondral bone.
Clinical Presentation
Signs & Symptoms
Clinical features of RA are diverse but most patients will have the following.
Constitutional symptoms
Associated with inflammatory process:
- Unintentional weight loss
- Asthenia
- Fatigue
- Myalgias
Morning stiffness
- Lasting longer than one hour suggests inflammatory joint disease (nonspecific to RA).
Joint manifestations
- Joint pain and swelling that predominantly affects the metacarpophalangeal (MCP), metatarsophalangeal (MTP), and/or proximal interphalangeal (PIP) joints
- Cervical spine may be involved (only part of spine with synovial joints)
- Synovial thickening
Extraarticular manifestations
- Nodules may be found on pressure points (eg. olecranon) or over joints of the hands and feet, patella, and Achilles tendons.
- Interstitial lung disease may be present
- Sjogen syndrome resulting in dry eyes and dry mouth
- Vasculitis involving medium and small vessels
Classic signs of RA are present in advanced, chronic disease:
- Ulner deviation
- MCP joint subluxation
- Swan neck deformity
- Boutonniere deformity
- Bowstring sign
Additional findings of late stage RA include: - Decreased shoulder, elbow, and knee ROM
- Hallux valgus (aka bunion) of the foot
History & Physical Exam
History should elicit the details of manifestation of symptoms. Rheumatoid arthritis typically have gradual, insidious onset over a period of weeks to months.
Physical exam on affected joint may find:
- Pain if pressure is applied, on movement
- Absence of joint erythema and warmth
- Boggy feel on palpation (due to synovial thickening)
- Reduced grip strength
Diagnosis
Criteria
Diagnosis generally requires:
- Confirmation of synovitis and thus presence of inflammatory arthritis (eg. soft tissue swelling, warmth over joint, joint line tenderness to palpation, joint effusion, loss of motion) in characteristic joint distribution.
- Confirmatory serology
- Elevated rheumatoid factor (high sn and sp inpatient’s with high pretest probability)
- Elevated ACPA (high sp)
However, a clinical diagnosis of seronegative RA can be made based on negative RF and ACPA. Approximately 10% of patients are seronegative.
The ACR/EULAR classification criteria for RA is often used as a guidelines but many patients will not satisfy these criteria, especially in earlier stages of the disease.
Work-up
Plain film radiograph is typically done regardless of usefulness to diagnosis as it may provide insight on the progression of joint damage. Characteristic findings include:
- Soft tissue swelling
- Periarticular osteopenia
- Erosions (severe)
In cases where synovitis isn’t evident from physical exam, ultrasonography is sensitive for inflammation.
A number of investigations are also done to establish a baseline prior to initiation of management. This includes:
- Routine lab work including CBC, serum creatinine, aminotransferases, ESR, CRP
- Hepatitis virus screening
- Cardiovascular risk assessment
- Fracture risk assessment
- Immunization history
Differential
Joint pain is a common clinical presentation. A number of inflammatory and noninflammatory diagnoses exist. This is discussed separately as part of the joint pain workup.
Briefly, these include:
- Alternative forms of inflammatory polyarthritis (eg. infectious)
- Lyme disease
- Other rheumatic diseases (eg. lupus, Sjorgren’s disease)
- Polymyalgia rheumatica
- Noninflammatory disease (eg. osteoarthritis)
Red Flags / Complications
Untreated RA can result in irreversible damage as the disease progresses. This typically leads to joint destruction (erosion of cartilage and bone), resulting in loss of physical function, inability to carry out daily tasks of living, and more.
Uncontrolled inflammation can also increase other health risk such as cardiovascular disease, osteoporosis, and certain cancers.
Management
Non-pharmacological
A number of non-pharmacological interventions should be used in conjunction with pharmacological therapy.
Patients should receive education the nature of arthritis and cause. A plan should be developed so the patient is aware of the prognosis and treatment option. Therapy may be necessary, especially in the context of managing chronic illness.
Physical activity and exercise, including aerobic and resistance training, should be a part of treatment programs. Exercise has been shown to reduce disease activity, fatigue, and pain. Coordination with physiotherapy and/or occupational therapy may be beneficial.
This should be balanced with rest for an inflamed joint without resorting to sedentary behaviour which can exacerbating joint immobility.
Pharmacological
The basis of drug therapy for rheumatoid arthritis is disease-modifying antirheumatic drugs (DMARDs). This should be started as soon as possible as early use has been shown to improve outcomes.
The first-line option is typically methotrexate (MTX), which is preferred for its efficacy, cost, and favourable adverse effect profile.
Some nonbiologic alternatives, should methotrexate be contraindicated, include:
- Leflunomide
- Hydroxychloroquine
Biologic and targeted synthetic DMARDs are also available such as tumour necrosis factor (TNF) inhibitors and Janus kinase (JAK) inhibitors, respectively. These, however, are not preferred as first-line due to their side effects and/or safety concerns, except in the presence of specific comorbidities.
In highly active RA, combination therapy may be effective.
Symptom management is an important adjunct to DMARDs, especially for rapid control of disease activity prior to DMARD action. In most patients, NSAIDs are sufficient. Recommended, due to their lower GI toxicity, are:
- Meloxicam 7.5-15 mg tab daily or 5-10 mg cap daily
- Celecoxib 200 mg daily or 100 mg q12h, up to a daily maximum of 400 mg
In patients with moderate to severe disease and NSAID therapy is inadequate or contraindicated, glucocorticoids can be considered.
- Prednisone 5-10 mg daily until DMARD control achieved (usually after 4-6 months)
- Intraarticular glucocorticoids if synovitis is limited to 1-2 accessible joints
Follow-up of drug response and activity should occur every 3 months following change in regimen until disease is controlled.
References
Tools / Guidelines
MDCalc - ACR/EULAR classification criteria