Rheumatoid Arthritis Remittive Agents

Aka: Rheumatoid Arthritis Remittive Agents, Slow Acting Antirheumatics, Rheumatoid Arthritis Disease Modifying Drugs, Disease Modifying Antirheumatic Drug, SAARDs, DMARDs, DMARD

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II. 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. 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
  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

III. Indications: Studies suggest starting DMARD early

  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]

IV. Protocol: Choice of intial agent

  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)

V. Preparations: 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)

VI. Preparations: Second line (First line if mild disease)

  1. Hydroxychloroquine (Plaquenil) 100-200 mg orally twice daily
  2. Sulfasalazine (Azulfidine) 500 mg orally bid to tid
  3. Minocycline 100 mg PO bid
    1. Modest effect
    2. May work best early

VII. Preparations: Third Line Agents (biologics in refractory cases)

  1. Precautions
    1. Do not start without an initial trial on Methotrexate (or similar DMARD) first
  2. Anti-Tumor Necrosis Factor Medications (see below)
    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)
    5. Anti-TNF Agents
      1. Adalimumab (Humira)
      2. Etanercept (Enbrel)
      3. Infliximab (Remicade)
      4. Certolizumab (Cimzia)
      5. Golimumab (Simponi)
  3. Other biologic agents
    1. Interleukin-1 Receptor Antagonist
      1. Anakinra (Kineret)
    2. Interleukin-6 Receptor Antagonist
      1. Sarilumab (Kevzara)
      2. Toclizumab (Actemra)
    3. Anti-CD20
      1. Rituximab (Rituxan)
    4. Costimulator blocker (Cytotoxic T-CellAntigen 4)
      1. Abatacept (Orencia)
    5. Janus Kinase Inhibitor (JAK Inhibitor)
      1. Tofacitinib (Xeljanz)
      2. Increased risk of Thromboembolism

VIII. Preparations: Corticosteroids

  1. Indications
    1. Consider for severe symptoms when starting DMARD
    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

IX. Preparations: Last ditch effort (more serious adverse effects)

  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

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

  1. Parenteral Gold (Solganal)
    1. Slow onset
    2. Decreases progression but rarely remits
    3. Rarely used now
  2. Oral Gold (Auranofin)
    1. Rarely used now due to decreased efficacy
  3. 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]

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 chemistry panel (Chem7)
  3. Physical Exam 3-6 times per year

XII. References

  1. (2014) Presc Lett 21(10): 56
  2. Boers (1997) Lancet 350: 309-18 [PubMed]
  3. Stein (1997) Arthritis Rheum 40: 1721-3 [PubMed]
  4. Rozman (1998) J Rheumatol 53:27-32 [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. Scott (2010) Lancet 376(9746):1094-108 [PubMed]
  8. Wasserman (2011) Am Fam Physician 84(11): 1245-52 [PubMed]
  9. Wasserman (2018) Am Fam Physician 97(7): 455-62 [PubMed]

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Related Studies

Ontology: Antirheumatic Agents (C0003191)

Definition (CSP) agent that relieves or prevents rheumatic disease, especially rheumatoid arthritis.
Definition (MSH) Drugs that are used to treat RHEUMATOID ARTHRITIS.
Concepts Pharmacologic Substance (T121)
MSH D018501
SnomedCT 88279005, 372888006
English Agents, Anti-Rheumatic, Anti-Rheumatic Agents, antirheumatic agent, Agents, Antirheumatic, Anti Rheumatic Drugs, Anti-Rheumatic Drugs, Antirheumatic Agents, Antirheumatic Drugs, Drugs, Anti-Rheumatic, Drugs, Antirheumatic, ANTIRHEUMATICS, Antirheumatic Agent, Antirheumatic, Antirheumatic Agent [TC], [MS100] ANTIRHEUMATICS, antirheumatic agents, antirheumatic, anti rheumatic drug, anti-rheumatic drugs, anti rheumatic drugs, antirheumatic drugs, antirheumatic drug, antirheumatics, Anti Rheumatic Agents, Antirheumatic agents, Anti-rheumatic agent (product), Anti-rheumatic agent (substance), Anti-rheumatic agent, Anti-rheumatic agent, NOS
Swedish Antireumatiska medel
Czech antirevmatika
Finnish Reumalääkkeet
Italian Farmaci antireumatici, Antireumatici
Russian PROTIVOVOSPALITEL'NYE SREDSTVA ZOLOTOSODERZHASHCHIE, PROTIVOREVMATICHESKIE SREDSTVA, ANTIREVMATICHESKIE SREDSTVA ZOLOTOSODERZHASHCHIE, BOLEZN'-SMIAGCHAIUSHCHIE ANTIREVMATICHESKIE LEKARSTVENNYE SREDSTVA, ANTIREVMATICHESKIE SREDSTVA, KHRIZOTERAPEVTICHESKIE SREDSTVA, ANTIREVMATICHESKIE LEKARSTVA, SMIAGCHAIUSHCHIE TECHENIE BOLEZNI, PROTIVOREVMATICHESKIE SREDSTVA ZOLOTOSODERZHASHCHIE, ZOLOTOSODERZHASHCHIE PROTIVOVOSPALITEL'NYE SREDSTVA, DMARD, АНТИРЕВМАТИЧЕСКИЕ ЛЕКАРСТВА, СМЯГЧАЮЩИЕ ТЕЧЕНИЕ БОЛЕЗНИ, АНТИРЕВМАТИЧЕСКИЕ СРЕДСТВА, БОЛЕЗНЬ-СМЯГЧАЮЩИЕ АНТИРЕВМАТИЧЕСКИЕ ЛЕКАРСТВЕННЫЕ СРЕДСТВА, ПРОТИВОРЕВМАТИЧЕСКИЕ СРЕДСТВА, АНТИРЕВМАТИЧЕСКИЕ СРЕДСТВА ЗОЛОТОСОДЕРЖАЩИЕ, ЗОЛОТОСОДЕРЖАЩИЕ ПРОТИВОВОСПАЛИТЕЛЬНЫЕ СРЕДСТВА, ПРОТИВОВОСПАЛИТЕЛЬНЫЕ СРЕДСТВА ЗОЛОТОСОДЕРЖАЩИЕ, ПРОТИВОРЕВМАТИЧЕСКИЕ СРЕДСТВА ЗОЛОТОСОДЕРЖАЩИЕ, ХРИЗОТЕРАПЕВТИЧЕСКИЕ СРЕДСТВА
Japanese 疾病-修飾抗リウマチ薬, 抗リウマチ剤, 疾病-修飾第二線薬, 抗リウマチ薬
Croatian Not Translated[Antirheumatic Agents]
Polish Leki przeciwreumatyczne, Leki przeciwreumatyczne modyfikujące chorobę, Leki zmieniające przebieg choroby
Spanish Antirreumáticos, Drogas Antirreumáticas Modificadoras de la Enfermedad, Agentes Antirreumáticos, agente antirreumático (producto), agente antirreumático (sustancia), agente antirreumático, antirreumático
Norwegian Antirevmatiske midler, DMARD, Antirevmatika
Portuguese Antirreumáticos, Drogas Modificadoras da Evolução de Doenças Reumáticas, Agentes Antirreumáticos
French Agents antirhumatismaux, Antirhumatismaux, Agent antirhumatismal, Antirhumatismal, Médicaments antirhumatismaux
German Antirheumatika, Rheumamittel
Derived from the NIH UMLS (Unified Medical Language System)

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