Definition: A chronic inflammatory disorder that primarily involves the joints but can also involve other organ systems.

Etiology / Risk Factors

• U.S. prevalence of 1-2%, increases to 5% in females >70. Peak onset 4th-5th decade of life
• Female:Male 2.5:1
• Risk factors: cigarette smoking, HLA-DRB1 haplotype, periodontitis. Altered oral, lung and gut microbiome may also contribute.

Evaluation

• Differential diagnosis: viral infection (e.g. parvovirus B19, HCV, HBV, HIV, EBV), other connective tissue diseases (SLE, MCTD, systemic sclerosis, Sjogren’s, overlap syndromes), other inflammatory arthritides (psoriatic arthritis, spondyloarthritides, CPPD, polyarticular gout, rarely inflammatory OA), paraneoplastic polyarthritis
• Typical presentation: subacute development (weeks to months) of symmetric pain and swelling of the small joints (wrists, MCPs, PIPs, MTPs). May have associated fatigue, fever and weight loss
• Deformities (seen in long-standing disease)
  • Hands: ulnar deviation at MCPs, swan-neck and Boutonniere deformity
  • Wrists: volar subluxation, radial deviation
  • Feet: MTP subluxation (deformity can lead to ulcers of the toe)

• According to 2010 American College of Rheumatology/European League Against Rheumatism Criteria (ACR/EULAR), definite RA is defined as score of at least 6 from the individual scores in 4 domains (see table below) in a patient with synovitis (pain and swelling) in at least 1 joint and no alternative diagnosis that better explains his or her symptoms

Extra-articular involvement (more likely if RF+):

• Neurologic: entrapment neuropathies, cervical myelopathy due to atlantoaxial instability
• Ophthalmologic: secondary Sjogren’s, episcleritis/scleritis, peripheral ulcerative keratitis (“corneal melt”)
• Pulmonary: pleural effusion (exudative effusion with low glucose and low pH (similar to empyema, must r/o infection; often lymphocyte predominate), pulmonary nodules, ILD (UIP>NSIP, organizing PNA), PAH, trapped lung
• Airway: vocal cord nodulosis, cricoarytenoid arthritis, bronchiolitis, and bronchiectasis
• Cardiovascular: pericarditis, valvular RA nodules, accelerated atherosclerosisvasculitis (rarely seen in modern treatment era)
• Renal: SAA amyloid, rare membranous nephropathy (related to RA meds)
• Skin: rheumatoid nodules, pyoderma gangrenosum, pallisading neutrophillic granulomatous dermatitis, vasculitis resulting in cutaneous ulceration or digital nailfold infarcts
• Hematologic: normocytic normochromic anemia, thrombocytosis, leukocytosis, lymphadenopathy, Felty’s syndrome (splenomegaly, neutropenia, thrombocytopenia seen in longstanding, untreated RA)
• MSK: in addition to arthritis may see muscle atrophy

Management

Labs/imaging

• Diagnosis: once positive no need to recheck
  • Rheumatoid Factor: sensitivity 70%, specificity 50-70%
  • CCP Ab: sensitivity 70%, specificity >90%
• Disease activity: ESR & CRP
• Other labs: CBC with diff, LFTs, chemistry, HepB, HepC, HIV, TB testing
• Plain films show erosions in >70% of patients within 2 years of symptom onset if untreated
  • Order bilateral hands (3 views including the wrist), bilateral feet (3 views including weight bearing) to assess for erosions and juxta-articular osteopenia

Treatment

• Early initiation of DMARD therapy can slow progression and prevent disability. Start within 3-6 months of disease onset
• Pre-treatment screening: For methotrexate and leflunomide check Hepatitis B & C; for biologic and small molecule DMARDs check for Hep B, Hep C, and latent TB
• Consider patient comorbidities when selecting DMARD: history of CHF, COPD or other chronic lung disease, CKD, zoster, malignancy, diverticulosis, VTE 
• Use a treat-to-target strategy
• Start with conventional DMARD monotherapy (1^st line MTX, if contraindicated can consider leflunomide, plaquenil, sulfasalazine) +/- glucocorticoids (usually <10 mg daily controls symptoms, wean when controlled)
• If disease activity remains moderate or high despite DMARD monotherapy after 3-6 months:
  • Use combination conventional DMARDs (if prognostically favorable course) or add TNFi or non-TNF biologic (if prognostically unfavorable factors are present e.g., RF/ACPA at high levels, high disease activity, early joint damage, failure of >2 csDMARDs), rather than DMARD monotherapy
  • Triple therapy (MTX, sulfasalazine, and hydroxychloroquine) has been shown to be non-inferior to methotrexate plus TNFi in clinical trials, though compliance may be an issue
  • If disease flares: add short-term glucocorticoids at the lowest possible dose for the shortest possible duration

Drug Classes

• Methotrexate: non-biologic DMARD, first line agent that can be used as monotherapy or in combination with SSZ and HCQ as part of “triple therapy”
  • Dosed weekly either orally or as IM injection
  • Initiate at low dose 7.5-15mg weekly, up to 20 mg weekly
  • Patients should also receive folic acid 1mg daily to reduce risk of side effects
  • Common side effects: mucositis, nausea, diarrhea, fatigue, alopecia
  • Severe adverse effect: hepatotoxicity, myelosuppression, rare acute pneumonitis (fever, cough, dyspnea)
  • Contraindications: pregnancy, untreated HBV or HCV, other underlying liver disease
  • Caution in CKD due to reduced excretion and increased risk of toxicity
  • Monitoring:
    • Following initiation or dose changes: CBC, AST/ALT, and Cr every month
    • On maintenance dose: CBC, AST/ALT, and Cr every 3 months

• Biologic DMARDs:
  • Anti-TNFα agents (etanercept, infliximab, adalimumab, certolizumab, golimumab)
    • Adverse effects: Infection (particularly TB), CHF exacerbations (do not use in NYHA stage III/IV CHF), increased risk of lymphoma and melanoma, drug-induced lupus, demyelination; infliximab - serum sickness reaction, others - injection site reactions.
• Other biologics:
• Abatacept. CTLA4 Ig, prevents t-cell activation by disrupting second signal for Ag presentation.
  • Contraindications: TB, COPD (due to infections)
• Rituximab. Anti-CD20, depletes B-cells.
  • Contraindications: HBV; high risk of HBV reactivation, if isolated HBcAb positive, need HBV prophylaxis
  • Tocilizumab. Anti-IL6
    • Adverse effects: infection, hepatitis, hyperlipidemia, increased risk for GI perforation (avoid if history of diverticulitis)
• Small molecule medications (Tofacitinib and baricitinib - JAK/STAT inhibitors)
  • Adverse effects: infection, cytopenias, hepatitis, hyperlipidemia, increased risk for VTE, increased risk for GI perforation (avoid if history of diverticulitis)

Key Points 

• Anti-CCP is more specific than RF and predicts erosive disease.
• Extra-articular manifestations of RA are varied and are usually seen in seropositive patients with poorly controlled, erosive, destructive arthritis.
• Early initiation of DMARDs is the cornerstone of treatment.
• All patients should be referred to a rheumatologist, which is associated with better disease outcomes.
• Initial studies to obtain with referral to rheum: CBC with differential, creatinine and a liver panel (to guide therapy), ESR, CRP, RF & CCP Abs, HBV (HBcAb, HBsAb, HBsAg) & HCV Ab, quantiferon or PPD; plain films of bilateral hands and feet.

References

Imboden JB et al. Current Diagnosis and Treatment in Rheumatology. 3rd ed. New York: McGraw-Hill, 2013.

Klippel JH et al. Primer on the Rheumatic Diseases. 13th ed. New York: Springer, 2008.

Aletaha D et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569–81.

Singh JA et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care and Res. 2012 May;64(5):625–39.

Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.

Content adapted from 2018 UCSF Outpatient Handbook, Agile MD