02. Rheumatoid Arthritis

Resident Editor: Megan Lockwood MD

Faculty Editor: Sarah Goglin, MD

BOTTOM LINE

✔ Regardless of disease activity level, a treat-to-target strategy should be employed

✔ Early use of DMARD therapy is crucial for all patients with RA

✔ All patients should be referred to a rheumatologist, which is associated with better disease outcomes

Background/Epidemiology

  • U.S. prevalence of 1-2%
    • Increases to 5% of F >70 y/o
  • Peak onset in 4th-5th decade of life
  • F:M predominance 2.5:1
  • Risk factors: cigarette smoking; HLA-DRB1 haplotype (“shared epitope”), infections

 

Signs and Symptoms

  • Typical presentation: 
    • Subacute development (weeks to months) of symmetric pain and swelling of the small joints (wrists, MCPs, PIPs, MTPs), may have associated fatigue, low-grade fever and weight loss.
  • Other involved joints: 
    • Knees, elbows, ankles, hips, shoulders, TMJ, upper C-spine (C1–C2 transverse ligament tenosynovitis à atlantoaxial instability)
  • Joints usually spared: 
    • DIPs, T/L-spine (however, patients may have concurrent DJD and/ or osteoporotic fractures that can affect the spine)
  • Palindromic rheumatism:
    • Self-limited mono- or polyarthritis lasting days to weeks, with 50% progressing to typical RA

 

Diagnostic Criteria

  • According to 2010 American College of Rheumatology/European League Against Rheumatism Criteria, definite RA is defined as score of at least 6 (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:

 

Joints

1 large joint (shoulder, elbow, hip, knee, ankle)

0

2–10 large joints 

1

1–3 small joints (MCP, PIP, 2nd–5th MTP, thumb IP, wrist; excludes DIP, 1st CMC, 1st MTP), with or without large-joint involvement

2

4–10 small joints, with or without large-joint involvement

3

> 10 joints, including at least 1 small joint

5

Serology

RF neg, anti-CCP neg

0

RF or CCP weakly pos (> ULN; if RF available as pos/neg only, consider pos result weakly pos)

2

RF or CCP strongly pos (> 3x ULN)

3

Acute-Phase Reactants

 

ESR and CRP normal

0

ESR or CRP elevated

1

Duration of Symptoms

< 6 weeks

0

≥ 6 weeks

1
 

 

Differential Diagnosis

  • Viral Infection: Parvovirus B19, HCV (positive RF, usually joint pain > synovitis)
  • Other inflammatory syndromes: SLE, systemic sclerosis, mixed connective tissue disease (MCTD) or Sjögren’s, overlap (such as with SLE)
    • May see positive RF in all of these conditions
    • Features not present in RA- Raynaud’s, rash and other positive auto-antibodies
  • Other inflammatory arthritides: 
    • Psoriatic arthritis + Spondyloarthritides (involve DIP, less commonly symmetrical & look for involvement of SI joint)
    • CPPD can have a “pseudo-RA” presentation
    • Rarely inflammatory OA

 

Evaluation

 Clinical joint exam

  • Synovitis in affected joints (joint swelling and tenderness on exam)
  • Deformities (seen in long-standing disease)
    • Hands: Ulnar deviation at MCPs, swan-neck and Boutonniere deformities 
    • Wrists: Volar subluxation, radial deviation
    • Feet: MTP subluxation (deformity can lead to ulcers of the toe)

 

Clinical exam for extra-articular manifestations

  • Neurologic: Entrapment neuropathies, cervical myelopathy due to atlantoaxial instability
  • Ophthalmologic: Secondary Sjogren’s, episcleritis / scleritis, peripheral ulcerative keratitis (“corneal melt”)
  • Cardiac: Pericarditis and pericardial effusions, valvulitis and accelerated atherosclerosis
  • Pulmonary: Pleural effusions (lymphocyte predominate, exudative effusions with low glucose), pulmonary nodules, interstitial lung disease (NSIP, UIP, and organizing pneumonia), pulmonary arterial hypertension, arteritis, shrinking lung
  • Renal: SAA Amyloid, membranous nephropathy
  • Hematologic: Normocytic normochromic anemia, thrombocytosis, lymphadenopathy, Felty syndrome (severe neutropenia, thrombocytopenia and splenomegaly that occurs in longstanding, untreated RA).
  • Skin: Rheumatoid nodules, pyoderma gangrenosa, pallisaded neutrophilic granulomatous dermatitis
  • MSK: In addition to arthritis may see inflammatory myositis and muscle atrophy
  • Vascular: Small periungual infarcts (non- fatal), medium vessel arteritis resulting in LE ulceration (can be fatal)

 

Recommended initial labs:

  • Serologies - If suspicious for RA then order both tests together (improves overall sensitivity)
    • Rheumatoid Factor:       
      • Sensitivity 70%, Specificity 50-70%
    • CCP Ab:           
    •             Sensitivity 70%, Specificity >90%
  • Acute Phase Reactants: CRP, ESR
  • Infectious: HBV, HCV, HIV, TB testing
  • Basic Labs: CBC with diff, LFTs, Chemistry

 

X-rays: to assess for erosions

  • Bilateral Hands – 3 views (includes the wrist so no need to order separately)
  • Bilateral Feet – 3 views including weight bearing lateral views

 

Ongoing assessment:

  • No need to recheck RF/CCP once positive. 
  • ESR & CRP correlate with disease activity

 

Treatment

  • General considerations:
    • Early initiation of therapy can slow disease progression and prevent disability. Goal is to start treatment within first 3-6 mo of disease onset.
    • Therapy is changed based on clinical disease activity scores with the goal of inducing and maintaining remission.
  • Preventive care:
    • Monitor for and prevent osteoporosis (particularly those on steroids)
    • Address cardiac risk factors - increased incidence of CAD in these patients
  • Vaccinations:
    • For all patients: Influenza annually, Pneumococcal (both PCV 13 and PPSV 23), HBV if risk factors present
    • Patients on biologics: Avoid live vaccine preparations however new inactivated Zoster vaccine (Shingrix) appears safe and efficacious even in patients on anti-TNFs
  • Basics for early disease:
    • Use a treat-to-target strategy
    • All patients:
      • Start with DMARD monotherapy (preferably MTX)
    • If disease activity remains moderate or high despite DMARD monotherapy:
      • Use combination DMARDs or TNFi or non-TNF biologic, rather than DMARD monotherapy
    • If disease flares:
      • Add short-term glucocorticoids at the lowest possible dose for the shortest possible duration
  • Basics for patients with established disease:
    • Always use a treat-to-target strategy
    • If disease activity remains low:
      • Used DMARD monotherapy
    • If disease activity remains moderate or high despite DMARD monotherapy:
      • Use combination DMARDs or TNFi or non-TNF biologic, rather than DMARD monotherapy
    • If disease activity remains moderate or high despite TNFi therapy:
      • Add one to two DMARDs to TNFi therapy, rather than TNFi therapy alone
    • If disease is in remission, do not discontinue all therapies

 

 

Drug Classes

Drug class

 

Medications

Non-disease-modifying agents
  • NSAIDs (symptomatic relief)

Nonbiologic disease modifying anti-rheumatic drugs (DMARDs)

**Can take up to 3 months for effect
  • Prednisone
  • Methotrexate (preferable first-line agent)
  • Leflunomide
  • Sulfasalazine
  • Hydroxychloroquine

Biologic DMARDs

**Can take up to 3 months for effect
  • Anti-TNF alpha agents (etanercept, infliximab, adalimumab, certolizumab, golimumab)
  • Abatacept (CTLA4 Ig)
  • Rituximab (anti-CD20)
  • Tocilizumab (anti-IL6)

Small molecule drugs
  • Tofacitinib (JAK-STAT inhibitor)
  • Baricitinib (JAK-STAT inhibitor)

 

  • 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, max dose 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, pneumonitis (fever, cough, dyspnea)
    • Contraindications: pregnancy, HBV, 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.
      • Monitoring labs and: CBC and LFTs 1 month after initiation and q6months thereafter, TB screening at baseline
  • Other biologics:
    • Abatacept – CTLA4 Ig, prevents T-Cell activation by disrupting Ag presentation.
      • Contraindications: TB, COPD (due to infections), live vaccinations
    • Rituximab – anti CD20, depletes B-cells.
      • Contraindications: HBV; high risk of HBV reactivation – if isolated HBcAb positive, still need HBV prophylaxis
    • Tocilizumab – anti IL6
      • Contraindications: TB 
  • Small molecule medications (Tofacitinib and baricitinib - JAK/STAT inhibitors)
    • Adverse effects: infection, cytopenias, hepatitis, hyperlipidemia

 

 

When to refer

  • As the choice and management of immunosuppressive regimens is highly complex, all patients with a diagnosis of RA (or in whom diagnosis is in doubt) should be referred to rheumatology 
  • 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

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.

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.

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.

Singh JA, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care and Res. 2016 Jan;68(1):1-26.