Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Systemic inflammation can lead to extraarticular manifestations such as rheumatoid nodules, interstitial lung disease, Felty syndrome, and pericarditis. Prolonged and severe disease can lead to irreversible joint deformities. Diagnosis is based on strong clinical suspicion and confirmed by the presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, and characteristic imaging. Management involves long-term disease-modifying antirheumatic drugs (DMARDs), biologic agents, and physical therapy. Glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) are the treatment of choice for acute exacerbation.

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Epidemiology and Risk Factors

Epidemiology

  • Worldwide incidence: 3 per 10,000 people per year
  • More prevalent in:
    • Native Americans
    • North America
    • Northern Europe
  • 2–3 times more common in women
  • Peak age of presentation is 30–50-years-old.

Risk factors

The cause of rheumatoid arthritis (RA) is unknown, but several risk factors play a role.

  • Genetic predisposition:
    • 2–3 times more likely in those with a 1st-degree relative with RA
    • Associated with:
      • HLA-DR1
      • HLA-DR4
  • Environmental factors:
    • Lifestyle:
      • Cigarette smoking 
      • Obesity 
    • Hormonal
    • Infectious:
      • Epstein-Barr virus (EBV)
      • Parvovirus B19
      • Hepatitis B and C 
      • Rubella
      • Mycoplasma
      • Recurrent dental infections

Pathophysiology

  • Not completely understood
  • An external trigger sets off the autoimmune response and ↑ expression of enzymes that convert arginine to citrulline → creation of antigens
  • B cells produce antibodies to citrullinated proteins → bind to fibrinogen and collagen → complement activation
  • Synovium is infiltrated by immune cells (e.g., macrophages, mast cells, B cells, CD4 T cells) → cytokine and chemokine production → synovial membrane thickening and villus formation
  • Hyperplastic synovial tissue (pannus) releases: 
    • Collagenase
    • Stromelysin
    • Interleukins (IL)
    • Tumor necrosis factor (TNF)-alpha
  • Leads to:
    • Continued synovial inflammation
    • Cartilage destruction
    • Osteoclasts-mediated bone destruction

Clinical Presentation

Articular manifestations

  • Symptoms:
    • Joint pain
    • Joint swelling
    • Early morning stiffness ( > 1 hour)
  • Characteristics:
    • Gradual onset
    • Polyarticular
    • Symmetric
  • Commonly affected joints:
    • Wrists
    • 2nd and 3rd metacarpophalangeal (MCP) joints
    • Proximal interphalangeal (PIP) joints
    • Metatarsophalangeal (MTP) joints
    • Wrists
    • Shoulders
    • Elbows
    • Hips
    • Knees
    • Ankles
  • Atlantoaxial subluxation can occur in 20%–50% of patients:
    • Neck and shoulder stiffness and pain
    • Radiculopathy
  • Note: Distal interphalangeal (DIP) and carpometacarpal (CMC) joints are typically spared.

Physical exam

  • General:
    • Synovitis:
      • Joint tenderness
      • Swelling
      • Effusions may be noted in larger joints.
    • Interosseous muscle atrophy
    • Joint deformities
    • ↓ Range of motion
  • Common hand findings:
    • ↓ Grip strength
    • Ulnar deviation of MCP joints
    • Boutonniere deformity:
      • PIP flexion
      • DIP hyperextension
    • Swan neck deformity:
      • PIP hyperextension
      • DIP flexion
    • Hitchhiker thumb (“Z” deformity): 
      • MCP flexion
      • Interphalangeal joint (IP) hyperextension
    • Bowstring sign: prominence of the tendons in the extensor compartment of the hand
  • Common lower extremity findings:
    • Restricted hip movement
    • Baker’s cyst:
      • Caused by large knee effusions
      • Cyst caused by entrapment of the synovium between articular structures.
      • Swelling or fullness will be noted behind the knee.
      • Also seen in osteoarthritis, trauma, gout, and meniscal tears
    • Hammertoe: MTP joint hyperextension

Extraarticular manifestations

  • General:
    • Fatigue
    • Fever
    • Weight loss
    • Myalgias
  • Cutaneous:
    • Rheumatoid nodules:
      • Not painful
      • Seen on extensor surface of the elbow, heel, ischial tuberosities, and fingers
      • Can also occur in the viscera 
    • Skin ulcers
    • Neutrophilic dermatosis:
      • Sterile neutrophil infiltration 
      • Symmetric, erythematous papules
  • Ocular: 
    • Sjögren syndrome (keratoconjunctivitis sicca)
    • Episcleritis
    • Uveitis
  • Neurologic:
    • Myelopathy and radiculopathy
    • Mononeuritis multiplex or polyneuropathy
    • Carpal tunnel syndrome
    • Depression
  • Respiratory:
    • Interstitial lung disease
    • Upper airway obstruction due to:
      • Cricoarytenoid arthritis
      • Rheumatoid nodules of the vocal cords
    • Pleuritis
    • Pleural effusion
    • Pulmonary nodules
  • Cardiac:
    • Myocardial infarction
    • Pericarditis
    • Myocarditis
    • Pericardial effusion
    • Valvular insufficiency (from rheumatoid nodules)
    • Conduction abnormalities (from rheumatoid nodules) 
  • Vascular:
    • Vasculitis
    • Peripheral vascular disease
    • Deep vein thrombosis 
  • Hematologic:
    • Felty syndrome:
      • RA
      • Neutropenia
      • Splenomegaly
    • Anemia of chronic disease

Rheumatoid nodules in RA:
Firm, non-tender, subcutaneous swelling on the extensor surface of the elbow in a RA patient

Image: “Right elbow” by Department of Medicine, Woodhull Medical Center, Brooklyn, NY 11206, USA. License: CC BY 3.0

Diagnosis

Rheumatoid arthritis (RA) diagnosis is based on high clinical suspicion and confirmed by serology and imaging.

Laboratory testing

  • General:
    • Complete blood count (CBC):
      • ↓ Hemoglobin → anemia of chronic disease
      • ↑ Platelets
      • Neutropenia → Felty syndrome
      • Mild leukocytosis may be present.
    • Inflammatory markers:
      • ↑ Erythrocyte sedimentation rate (ESR) 
      • ↑ C-reactive protein (CRP)
      • ↑ Ferritin
  • Serology:
    • Rheumatoid factor (RF):
      • Present in 70%–80% of patients
      • RF is present in 15% of patients without RA.
    • Anti-cyclic citrullinated peptide (anti-CCP) antibodies: highly specific
    • Antinuclear antibody (ANA): 
      • Nonspecific
      • Positive in 30% of patients
  • Synovial fluid analysis:
    • Leukocytosis (5,000–50,000 cells/microliter) with neutrophil predominance
    • ↓ Glucose
    • Gram stain and gram culture both negative
    • Negative for crystals

Imaging

  • Radiographs:
    • May be normal in early disease
    • Soft tissue swelling
    • Periarticular osteopenia
    • Bony erosion
    • Joint-space narrowing
    • Joint subluxation
  • Ultrasonography:
    • Erosion
    • Joint-space narrowing
    • Synovitis
  • Magnetic resonance imaging (MRI): 
    • More sensitive than radiographs
    • Detects erosion earlier
    • Evaluates hypertrophic and inflamed synovial tissue

Management and Prognosis

Management

The goal is to prevent deformity and permanent damage. Patients should be referred to a rheumatologist.

Nonpharmacological therapies:

  • Physical and occupational therapy
  • Smoking cessation

Acute exacerbation management:

  • Nonsteroidal antiinflammatory drugs (NSAIDs)
  • Glucocorticoids:
    • Can be used as a bridge to disease-modifying antirheumatic drug (DMARD) therapy or for acute flares
    • Options: systemic or intraarticular injection

Long-term pharmacological therapy:

  • DMARDs:
    • Should be initiated in all patients upon diagnosis
    • Methotrexate is usually the 1st choice.
    • Additional options: sulfasalazine, hydroxychloroquine, azathioprine, leflunomide
  • TNF-alpha inhibitors:
    • May be added if DMARD therapy is not effective
    • Options: etanercept, adalimumab, infliximab, golimumab, certolizumab
  • Other biologic therapy options:
    • IL-6 inhibitors (tocilizumab)
    • CD20 monoclonal antibody (rituximab)
    • Selective T cell costimulation blocker (abatacept)

Surgery:

  • Indicated for severe damage and limited function
  • Can be considered if pharmacologic therapy is unsuccessful
  • Options:
    • Joint replacement
    • Joint fusion
    • Synovectomy

Additional considerations:

  • While on glucocorticoid treatment, patients should be monitored for:
    • Osteoporosis
    • Diabetes
    • Hypertension
  • Appropriate vaccinations should be given to prevent infectious complications of immunosuppressive medications.
  • All patients should be screened for tuberculosis and hepatitis.
  • Patients require ongoing laboratory monitoring for drug toxicity:
    • CBC
    • Liver function
    • Creatinine
  • Cervical spine imaging prior to surgical procedures:
    • Evaluate for cervical subluxation (most often at the atlantoaxial joint).
    • Intubation can be fatal in those with cervical instability.

Prognosis

  • RA is a chronic, progressive disease:
    • The majority of patients relapse.
    • 10% will be severely disabled despite adequate management.
  • Associated with an increased risk of:
    • Cardiovascular disease
    • Infection
    • Respiratory disease
    • Gastrointestinal bleeding
    • Lymphoma (especially with Felty syndrome)
  • 2–3 times higher risk of death than the general population
  • Risk factors for a poor prognosis:
    • Extraarticular manifestations
    • Advanced age
    • Women
    • Caucasians
    • Early erosion on imaging
    • Cigarette smoking
    • High inflammatory markers and/or antibody titers
    • ≥ 20 affected joints

Differential Diagnosis

  • Osteoarthritis (OA): a “wear and tear” form of arthritis due to cartilage destruction and changes of the subchondral bone. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. The PIP, DIP, and CMC joints are frequently affected. Diagnosis is clinical and supported with radiographic joint findings. Inflammatory markers, RF, and anti-CCP are negative. Management includes analgesics, intraarticular steroid injections, and surgery for advanced disease.
  • Gout: a disease caused by hyperuricemia, which leads to arthritis from the precipitation of monosodium urate crystals in the joints. Gout is often monoarticular, and usually involves pain, tenderness, swelling, erythema, and warmth of the 1st MTP joint. Diagnosis is confirmed by the identification of negatively birefringent, needle-shaped crystals in the synovial fluid. Management includes NSAIDs, colchicine, corticosteroids, and uric acid reduction with allopurinol.
  • Pseudogout: intraarticular calcium pyrophosphate deposition with unclear etiology. Patients present with acute flares of joint swelling, warmth, and pain. Pseudogout usually affects larger joints, such as the knee. Diagnosis is confirmed by the identification of positively birefringent, rhomboid crystals in the synovial fluid. Management includes NSAIDs, corticosteroids, and colchicine.
  • Psoriatic arthritis: a spondyloarthropathy occurring in patients with psoriasis. Psoriatic arthritis is inflammatory, frequently asymmetric, and involves both small and large joints, including DIP joints and the sacroiliac spine. Symptoms may also include enthesopathy and dactylitis. Diagnosis is clinical and should be suspected in patients with psoriasis. Management includes DMARDs and biologic agents.
  • Reactive arthritis: a spondyloarthropathy often precipitated by a gastrointestinal or genitourinary infection. Patients may present with asymmetric arthritis, typically of the lower extremities. Reactive arthritis can be associated with fever, tendinitis, enthesitis, mucocutaneous ulcers, and conjunctivitis. Diagnosis is clinical and management includes NSAIDs, DMARDs, and treatment of the infection.

References

  1. Firestein, G.S., and Guma, M. (2020). Pathogenesis of rheumatoid arthritis. In Romain, P.L. (Ed.), Uptodate. Retrieved February 5, 2021, from https://www.uptodate.com/contents/pathogenesis-of-rheumatoid-arthritis
  2. Venables, P.W.J., and Bchir, M.B. (2019). Clinical manifestations of rheumatoid arthritis. In Romain, P.L. (Ed.), Uptodate. Retrieved February 5, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-rheumatoid-arthritis
  3. Matteson, E.L., and Davis, J.M. (2021). Overview of the systemic and nonarticular manifestations of rheumatoid arthritis. In Romain, P.L. (Ed.), Uptodate. Retrieved February 5, 2021, from https://www.uptodate.com/contents/overview-of-the-systemic-and-nonarticular-manifestations-of-rheumatoid-arthritis
  4. Cohen, S., and Mikulus, T.R. (2020). Initial treatment of rheumatoid arthritis in adults. In Romain, P.L. (Ed.), Uptodate. Retrieved February 5, 2021, from https://www.uptodate.com/contents/initial-treatment-of-rheumatoid-arthritis-in-adults
  5. Kontzias, A. (2020). Rheumatoid arthritis (RA). [online] MSD Manual Professional Version. Retrieved February 5, 2021, from https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/rheumatoid-arthritis-ra
  6. Smith, H.R., and Brown, A. (2020). Rheumatoid arthritis (RA). In Diamond. H.S. (Ed.), Medscape. Retrieved February 5, 2021, from https://emedicine.medscape.com/article/331715-overview
  7. Chauhan, K., Jandu, J.S., Goyal, A., Bansal, P., and Al-Dhahir, M.A. Rheumatoid arthritis. [online] StatPearls. Retrieved February 5, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK441999/

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