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Rheumatoid arthritis

Last updated: October 15, 2021

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Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disorder that primarily affects the joints (e.g., causes pain, swelling, synovial destruction, deformities), but may also manifest with extraarticular features (e.g., rheumatoid nodules, pulmonary fibrosis). The risk of RA increases with age, and the disease predominantly affects women. The diagnosis is clinical and may be supported by laboratory tests (e.g., rheumatoid factor, anticitrullinated peptide antibodies) and imaging studies (e.g., the presence of synovitis on ultrasound and, later in the disease course, bone erosions and/or joint space narrowing on x-rays). There is no curative therapy for RA but early intervention with disease-modifying antirheumatic drugs (DMARDs) using a treat-to-target strategy can prevent disease progression and RA-related disability.

  • Prevalence
    • ∼ 0.24% worldwide [1]
    • 1% in northern Europe and US [2]
  • Sex: : > (3:1) [3]
  • Peak incidence: : > 65 years [4]

Epidemiological data refers to the US, unless otherwise specified.

“A DRone with 4 propellers and 1 camera:” rheumatoid arthritis is associated with HLA-DR4 and HLA-DR1.

Articular manifestations [11]

DIP joints are not typically affected in RA.

Extraarticular manifestations [14]

Rheumatoid arthritis of the cervical spine [12]

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.

Atlantoaxial subluxation

Before undergoing general anesthesia, an airway and neck assessment is crucial in patients with RA, as 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).

Felty syndrome [12]

Arthritis, splenomegaly, and neutropenia may suggest Felty syndrome.

Adult-onset Still disease

Undifferentiated arthritis [21][22][23]

  • Definition: symptoms of inflammatory arthritis that are not attributable to trauma or acute inflammatory events; often a transitional state preceding a definitive diagnosis [22][23]
  • Approach to management
    • Refer to a rheumatologist for periodical follow-up.
    • Management strategies are aimed at preventing progression and can be:
  • Prognosis [24]
    • Spontaneous remission in approx. 50% of patients
    • RA develops in approx. one-third of patients [21]

Other

Approach [22][25][26]

  • The diagnosis of RA is clinical.
    • Consider RA in patients with arthralgia, joint stiffness, and synovitis lasting ≥ 6 weeks (see “Clinical features”).
    • Consider alternative diagnoses in patients with atypical presentations (see “Differential diagnoses”).
  • Perform diagnostic studies to further support the diagnosis and help establish disease severity.
    • Routine laboratory tests. [22][26]
    • X-ray as the initial imaging study
  • Consult rheumatology, particularly if the diagnosis is uncertain and when choosing a treatment regimen.

RA is a clinical diagnosis. The 2010 ACR/EULAR classification criteria for RA can help identify RA, but the criteria do not need to be fulfilled in order to establish a diagnosis. [25]

Laboratory studies [22][26]

Routine studies

Up to 30% of patients with RA are negative for ACPA and RF. [26]

Additional studies

Additional studies should be considered on an individual basis.

ASCVD is the most common cause of premature death in patients with RA; therefore, an ASCVD risk assessment is recommended in all patients with RA.

Imaging studies [26][29][30]

While x-ray is recommended as the initial test, ultrasound and MRI might additionally be necessary to assess joint disease severity.

Typical RA findings on x-rays may be subtle or absent upon diagnosis in many patients with early RA; therefore, ultrasound or MRI may be more informative, as they have higher sensitivity for detecting early signs of inflammation and erosion.

Disease activity can be estimated by evaluating a combination of clinical and laboratory features. Disease activity scores may be used to assess RA activity and help guide a treat-to-target strategy (see “Treatment”). The ACR has recommended numerous disease activity scores for clinical practice, including the following: [32]

Clinical Disease Activity Index (CDAI) [22][32][33]
Parameter Score
28-joint physical examination: swollen joints 0–28
28-joint physical examination: tender joints 0–28
Patient global assessment 0–10 on a visual analog scale
Evaluator global assessment 0– 10 on a visual analog scale

Interpretation: add scores

  • ≤ 2.8: remission
  • > 2.8 to 10: low (minimal)
  • > 10.1 to 22: moderate
  • ≥ 22.1: severe

Consider the influence of concomitant conditions such as fibromyalgia or depression on subjective parameters (i.e., tender joint count and patient or evaluator global assessment) to help prevent patient misclassification.

Differential diagnoses of inflammatory arthritis
Condition Rheumatoid arthritis (RA)

Osteoarthritis

Psoriatic arthritis Gout Pseudogout

Epidemiology

  • Sex: >
  • Age (> 55 years)
  • Sex: =
  • Majority of people > 50 years
Risk factors
  • Family history of RA
  • History of joint injury or trauma
  • Obese patients
  • Family or personal history of psoriasis
  • May be triggered by trauma or infections (e.g., HIV infection)

Course of disease

  • Chronic course with varied patterns
    • Monocyclic
    • Polycyclic
    • Progressive
  • Chronic, progressive course
  • Chronic, progressive course
  • Chronic course with acute attacks

Clinical features

  • No constitutional symptoms
  • Morning stiffness < 30 minutes
  • Pain/stiffness worsens with increased activity and relieved by rest
  • Noninflammatory
  • Eventually development of tophi
Symmetry of joint involvement
  • Symmetrical
  • Usually asymmetrical
  • Asymmetrical oligoarticular type
  • Symmetrical polyarthritis type
  • Asymmetrical

Pattern of disease

Laboratory findings
  • No specific laboratory features
Imaging

The differential diagnoses listed here are not exhaustive.

Approach [22][26][34]

  • Initiate acute antiinflammatory treatment with glucocorticoids and NSAIDs for disease flares.
  • Long-term treatment
    • Initiate treatment with conventional DMARD monotherapy.
    • Consider short-term concomitant antiinflammatory treatment.
  • Initiate nonpharmacological management.
  • Consider surgical treatment in specific cases (e.g., patients with severe joint deformities).

Consult a rheumatologist before initiating treatment.

Acute antiinflammatory treatment [22][26][34]

Temporary (< 3 months) symptomatic treatment with glucocorticoids and/or NSAIDs is indicated for disease flares (i.e., episodes of increased disease activity and symptom worsening). [35]

Glucocorticoids should be used at the lowest effective dose and only for short periods of time to reduce the risk of their many adverse effects (e.g., hypertension, osteoporosis, infections). [26][34]

Long-term pharmacological treatment [22][26][30][34]

Initiation of treatment

  • All patients (regardless of baseline disease activity or disease duration): monotherapy with a conventional DMARD
  • Consider short-term concomitant use of acute antiinflammatory therapy (i.e., glucocorticoids and/or NSAIDs) for symptom control until the onset of action of DMARDs (e.g., ≥ 6 weeks). [34]

Early administration of DMARDs improves patients' outcomes.

Treat-to-target strategy [30][34]

Long-term treatment is guided by disease activity scoring systems for RA involving clinical and laboratory features, e.g., CDAI. The 2021 ACR guideline does not provide definitions for different stages of disease activity.

  • Target at 3 months: ≥ 50% improvement in the disease activity index
  • Target at 6 months: low disease activity (or remission)
  • Targets not reached: Consult rheumatology to adjust treatment.

A treat-to-target strategy can prevent RA-related disability. [22][30][34]

Do not discontinue all DMARDs in patients who achieve disease remission, as this may trigger a disease flare. [34]

Disease-modifying antirheumatic drugs (DMARDs) [26][30][34]

DMARDs are used as long-term therapy; . They interfere with the inflammatory mechanisms of RA, which can potentially lead to remission. DMARD therapy reduces RA mortality and morbidity by up to 30%. Prevention and monitoring of potential adverse effects are required (see also “Adverse effects” in “Immunosuppressants”). [12]

Synthetic DMARDs

Synthetic DMARDs for RA [22][30][34]
Drug class Agent Important considerations
Conventional DMARDs
  • Methotrexate (MTX) : first-line treatment in patients with moderate to high disease activity [30][34]
Targeted DMARDs (JAK inhibitors)
  • Adverse effects
    • Severe infections
    • TB reactivation
    • Anemia [30]

Methotrexate monotherapy is strongly recommended over all other synthetic and biologic DMARDs in patients with moderate to high disease activity. [34]

Biologic DMARDs [30]

All biologic DMARDs have similar efficacy when combined with MTX. When choosing a biologic DMARD, consider patient preferences, comorbidities, potential adverse effects, and drug availability. [22]

Prevention and monitoring of adverse effects [26][34][36][37]

Perform studies and vaccinations before the initiation of therapy based on the patient's individual risk and potential adverse effects of the prospective agent.

Nonpharmacological management [26]

  • ASCVD prevention measures are associated with improved outcomes in patients with RA.
  • Physical and occupational therapy can improve mobility.
  • Heat or cold packs for pain management.

Surgical treatment [26][38]

  • Indications
    • Consider in patients with extensive joint deformity.
    • Rarely, surgery may be used for symptom control in patients who do not respond to or cannot tolerate the recommended pharmacological regimen.
  • Procedures
    • Total joint replacement (e.g., hip joint replacement): Consider in patients with severe joint damage or concomitant osteoarthritis.
    • Synovectomy: surgical removal of the synovial tissue
    • Radiation synovectomy: ablation of inflamed synovia via injection of radioactive agents (beta particles) into the synovial cavity of affected joints [39]
      • Inhibits synovial growth and fibrosis of the synovia
      • May reduce inflammatory activity and pain
      • Also indicated in patients with other chronic inflammatory joint diseases (e.g., active arthrosis, psoriatic arthritis) who do not respond to pharmacological treatment

The ACR/EULAR classification criteria were developed for research purposes and should not be used as diagnostic criteria. These criteria are for targeted use in patients who have at least one joint with clinical synovitis that is not better explained by another cause, e.g. trauma or degenerative joint conditions. [25]

2010 ACR/EULAR criteria for the classification of RA [25]
Score Joint involvement (pain or swelling) Serology Acute-phase reactants Symptom duration
0 ≤ 1 large joint 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 (with or without large joint involvement) Low positive RF or ACPA
3 4–10 small joints (with or without large joint involvement) High positive RF or ACPA
5

> 10 joints (including at least one small joint)

Score: Obtained by adding together the points from each feature

Interpretation:

  • Patients with a score of ≥ 6 points fulfill the RA classification criteria.
  • Patients who do not fulfill the classification criteria can still be diagnosed with RA at the clinician's discretion. [25][26]

The ACR/EULAR classification criteria have high specificity but low sensitivity. Therefore, the purpose of these criteria is to standardize case definitions for enrollment in clinical studies, not to guide practice. [22][25][40]

Untreated and/or severe cases can result in permanent damage to the joints with stiffening and deformity.

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. [12]
    • Male sex [44]
    • Smoking
    • Social factors (e.g., low socioeconomic status, low level of education)
    • Presence of extraarticular disease
  • Elevated laboratory values associated with poor prognosis
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