Rheumatoid Arthritis Remittive Agent

Aka: Rheumatoid Arthritis Remittive Agent, Slow Acting Antirheumatic, Rheumatoid Arthritis Disease Modifying Drug, Rheumatoid Arthritis Remittive Medication, Disease Modifying Antirheumatic Drug, SAARDs, DMARDs, DMARD, csDMARD, bDMARD, tsDMARD

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II. Definitions

  1. Disease Modifying Antirheumatic Drug (DMARD)
    1. Immunosuppressive and immunomodulatory agents that slow progression of rheumatologic arthritic conditions
    2. Contrast with symptomatic, Analgesics (e.g. NSAIDs) which do not modify the disease course
  2. csDMARD (conventional synthetic DMARD)
    1. Conventional, original DMARDs (e.g. Methotrexate, Leflunomide, Hydroxychloroquine, Sulfasalazine)
  3. bDMARD (biological DMARD)
    1. Monoclonal Antibody
  4. tsDMARD (targeted synthetic - DMARD)
    1. Janus Kinase Inhibitor (JAK Inhibitors)

III. Background

  1. Most important agents in Rheumatoid Arthritis
  2. Start early (within 3 months of active disease onset) and treat to target (low disease activity or remission)
  3. Response to these agents is slow (over 1-6 months)
  4. Consider tapering DMARD if in remission for at least 6 months (esp. if anti-citrullinated Protein negative)
    1. In some cases DMARDs may be tapered off with maintained remission
    2. However, maintenance on at least one DMARD is recommended longterm
    3. Taper off doses and medications slowly
    4. If on triple therapy csDMARD (Methotrexate, Hydroxychloroquine, Sulfasalazine), taper off Sulfasalazine first
    5. If on Methotrexate and a bDMARD or tsDMARD, taper off Methotrexate first
    6. Haschka (2016) Ann Rheum Dis 75(1):45-51 [PubMed]
  5. Combination therapy may be optimal (often 3 agents, see below)
  6. Used with NSAIDs or COX2 Inhibitors for symptomatic pain relief
    1. Analgesics do not modify the disease course
    2. Systemic Corticosteroids are used for patients in whiom NSAIDs are contraindicated
  7. Screening before starting Biologic Agents and Immunosuppressants
    1. Tuberculosis Screening (PPD or IGRA)
    2. Hepatitis B Screening (HBsAg, HBcAb, HBsAb)
    3. Hepatitis C screening (anti-HCV)
    4. Skin Malignancy (increased risk of Squamous Cell Skin Cancer, Melanoma)
  8. Update Vaccines prior to starting DMARDs if possible
    1. Avoid Live Vaccines (e.g. Flumist or Zostavax) while on DMARDs
    2. Influenza Vaccine
    3. Pneumococcal Vaccine
    4. Hepatitis B Vaccine
    5. HPV Vaccine
    6. Herpes Zoster Vaccine
  9. Other factors affecting DMARD Selection
    1. Subcutaneous Rheumatoid Nodules
      1. Methotrexate is first-line therapy
    2. Lung Disease
      1. Risk of Methotrexate-Related Pneumonitis
      2. Methotrexate still considered first-line therapy, but monitor for respiratory adverse effects
    3. Nonalcoholic Fatty Liver Disease
      1. Limit Methotrexate to those with normal liver enzymes and no Hepatic Fibrosis
    4. Congestive Heart Failure
      1. Avoid TNF (Tumor Necrosis Factor) bDMARDs
    5. Serious Recent Infection in Last Year
      1. Avoid bDMARD, tsDMARD and Glucocorticoids

IV. Indications: Studies suggest starting DMARD early in Rheumatoid Arthritis

  1. Early DMARD start results in better longterm outcomes with less Disability, joint destruction and higher remission rate
    1. Randomized trial of n=238 over 1 year follow-up
    2. Less Functional Disability in DMARD and NSAID
    3. Placebo group was NSAID alone
    4. No XRAY differences
    5. Van der heide (1996) Ann Intern Med 124(8): 699-707 +PMID: 8633829 [PubMed]
  2. Randomized trial of n=102 over 2 years of follow-up
    1. Triple Therapy Combination Management
      1. Methotrexate 7.5 to 17.5 mg each week
      2. Sulfasalazine 500 mg PO bid
      3. Hydroxychloroquine sulfate (Plaquenil) 200 mg bid
    2. Good response (>50% improvement)
      1. Patients on triple therapy: 77% response
      2. Patients on 1 to 2 drugs: 33-40% response
      3. As effective as Methotrexate with biologic DMARD (Monoclonal Antibody or TNF agents)
    3. Drug toxicity
      1. Medications discontinued in 10% patients on 3 drugs
    4. References
      1. O'Dell JR (1996) N Engl J Med 334:1287-91 [PubMed]

V. Protocol: Starting Agents with Conventional Synthetic DMARDs

  1. Moderate to High Disease Activity
    1. First-line agent
      1. Methotrexate
    2. Other agents if higher risk of hepatotoxicity (e.g. pre-existing liver disease, Alcohol Abuse)
      1. Leflunomide (Arava)
      2. Hydroxychloroquine (Plaquenil)
      3. Sulfasalazine (Azulfidine)
  2. Low Disease Activity (listed in order of preference)
    1. Hydroxychloroquine (Plaquenil)
      1. Better tolerated and better adverse effect risk profile than other agents
      2. Preferred agent in low disease activity RA
    2. Sulfasalazine (Azulfidine)
      1. Less Immunosuppression than Methotrexate and Leflunomide
    3. Methotrexate
      1. Lower cost and better dosing flexibility than when compared with Leflunomide
    4. Leflunomide (Arava)

VI. Preparations: Conventional Synthetic DMARDs (csDMARD) - First Line in Moderate to Severe Disease

  1. Methotrexate
    1. Dosing
      1. Start: Methotrexate 7.5 to 10 mg orally once weekly
        1. Titrate to at least 15 mg/week in first 4-6 weeks
        2. Advance as needed up to 20-25 mg orally once weekly
      2. Coadminister with Folic Acid 1 mg orally daily (or 5 mg once weekly) to reduce side effects
      3. If gastrointestinal side effects limit use:
        1. Divide oral dose into 2 doses, 12 hours apart
        2. Methotrexate SQ/IM (vial $20/month or autoinjector $600/month)
    2. Efficacy
      1. Most effective single DMARD
      2. Good benefit to risk ratio
    3. Superior effect with Plaquenil or Sulfasalazine
      1. Methotrexate and
      2. Hydroxychloroquine sulfate (Plaquenil) and
      3. Sulfasalazine (may be used in place of Plaquenil)
    4. Combination with Etanercept reverses joint damage
      1. Klareskog (2004) Lancet 363:675-81 [PubMed]
  2. Leflunomide (Arava)
    1. Dose: 10-20 mg orally weekly
    2. Alternative to Methotrexate (and now generic)

VII. Preparations: Conventional Synthetic DMARDs (csDMARD) - Second Line (first line if mild disease)

  1. Hydroxychloroquine (Plaquenil) 100-200 mg orally twice daily
  2. Sulfasalazine (Azulfidine) 500 mg orally twice to three times daily
  3. Triple Combination Therapy: Methotrexate AND Hydroxychloroquine AND Sulfasalazine
    1. Indicated in moderate to severe disease refractory to single conventional synthetic DMARD
    2. Similar efficacy to adding a biologic DMARD (bDMARD) or Targeted Synthetic (tsDMARD)
    3. Triple therapy is very cost effective, but effects have slower onset and may not persist when compared to bDAMRD or tsDMARD
    4. ACR recommends bDAMRD or tsDMARD over triple therapy in refractory disease

VIII. Preparations: Third Line DMARDs - Biologics and Targeted Synthetics

  1. Precautions
    1. Do not start without an initial trial on Methotrexate (or similar csDMARD) first
    2. Biologic DMARDs (bDMARDs) are not universally effective (30-40% of patients do not respond)
    3. FDA considers approved Biosimilar Pharmaceuticals to be equivalent to the original Biologic Agents
  2. Background: Regarding Anti-Tumor Necrosis Factor Medications (may apply to other biologics)
    1. Advantages: Highly effective in refractory cases
    2. Disadvantages: Costs exceed $15,000 per year
    3. Containdicated in Congestive Heart Failure, Skin Malignancy
    4. Screen for Tuberculosis and Viral Hepatitis before starting (see above)
  3. Biologic DMARDs (bDMARDs)
    1. Anti-TNF Agents
      1. Adalimumab (Humira)
      2. Etanercept (Enbrel)
      3. Infliximab (Remicade)
      4. Certolizumab (Cimzia)
      5. Golimumab (Simponi)
    2. Interleukin-1 Receptor Antagonist
      1. Anakinra (Kineret)
    3. Interleukin-6 Receptor Antagonist
      1. Sarilumab (Kevzara)
      2. Toclizumab (Actemra)
    4. Anti-CD20
      1. Rituximab (Rituxan)
    5. Costimulator blocker (Cytotoxic T-CellAntigen 4)
      1. Abatacept (Orencia)
  4. Targeted Synthetic DMARD (tsDMARD)
    1. Janus Kinase Inhibitor (JAK Inhibitor)
      1. Background
        1. Increased risk of Thromboembolism
      2. Tofacitinib (Xeljanz)
      3. Baricitinib (Olumiant)
      4. Upadacitinib (Rinvoq)

IX. Preparations: Adjuncts - Corticosteroids

  1. Corticosteroid Indications
    1. Consider as adjunctive therapy for severe symptoms while starting DMARD (does NOT replace DMARDs)
    2. Symptoms refractory to above
    3. More cost-effective than NSAID with prophylaxis (PPI)
  2. Preparations
    1. Intra-articular Corticosteroid
    2. Prednisone 5-10 mg orally daily for 4-6 weeks
      1. See Corticosteroid Associated Osteoporosis

X. Preparations: Rarely used due to decreased efficacy (historical)

  1. Minocycline
    1. Dosing 100 mg orally twice daily
    2. Modest effect as an early use DMARD
  2. Parenteral Gold (Solganal)
    1. Slow onset
    2. Decreases progression but rarely remits
    3. Rarely used now
  3. Oral Gold (Auranofin)
    1. Rarely used now due to decreased efficacy
  4. Staphylococcal Protein A Column (Prosorba)
    1. No longer available as of 2006
    2. Plasma filtering device with immunomodulatory effect via IgG binding
    3. Had been used in refractory RA at $1000 per column, performed weekly
    4. Felson (1999) Arthritis Rheum 42:2153-59 [PubMed]
  5. Older agents used in refractory disease before bDMARDs and tsDMARDs were available
    1. D-Penicillamine
    2. Cyclophosphamide (Cytoxan)
      1. Effective for Vasculitis
    3. Azathioprine (Imuran) 50 to 150 mg PO qd
      1. Slow onset
      2. Reasonably effective

XI. Monitoring

  1. All agents above need careful monitoring
  2. Lab Tests every 4-8 weeks
    1. Liver Function Tests
    2. Complete Blood Count
    3. Serum Basic chemistry panel (Chem8)
  3. Physical Exam 3-6 times per year

XII. References

  1. (2014) Presc Lett 21(10): 56
  2. Arnold (2022) Am Fam Physician 106(3): 340-2 [PubMed]
  3. Boers (1997) Lancet 350: 309-18 [PubMed]
  4. Fraenkel (2021) Arthritis Care Res 73(7):924-9 +PMID: 34101387 [PubMed]
  5. Moreland (1998) Rheum Dis Clin North Am 24: 579-91 [PubMed]
  6. Pincus (1993) Rheum Dis Clin North Am 19:123-151 [PubMed]
  7. Rozman (1998) J Rheumatol 53:27-32 [PubMed]
  8. Scott (2010) Lancet 376(9746):1094-108 [PubMed]
  9. Stein (1997) Arthritis Rheum 40: 1721-3 [PubMed]
  10. Wasserman (2011) Am Fam Physician 84(11): 1245-52 [PubMed]
  11. Wasserman (2018) Am Fam Physician 97(7): 455-62 [PubMed]

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