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A. Types of Agents navigator

  1. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
  2. Glucocorticoids (steroidal anti-inflammatory drugs)
  3. Sulfasalazine and it's derivatives
  4. Anti-malarials (antigen processing inhibitors)
  5. Tetracyclines
  6. Chemotherapeutic Agents
    1. Methotrexate (MTX)
    2. Cyclophosphamide
    3. Chlorambucil
  7. Azathioprine
  8. Gold
  9. Calcineurin and Related Inhibitors
    1. Cyclosporine A (CsA)
    2. Tacrolimus (FK506)
    3. Sirolimus
  10. Mycophenolate
  11. Intravenous Immune Globulin (IVIg)
  12. Tumor Necrosis Factor alpha (TNFa) Blockade
  13. Interleukin 1 (IL-1) Blockade
  14. Leflunomide
  15. Thalidomide
  16. Protein A Column (Prosorba®) Plasmapheresis

B. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) [1] navigator

  1. Inhibit cyclooxygenases (COX, prostaglandin synthetases)
  2. Older agents have nearly equal activity against COX-1 and COX-2 enzymes
  3. Newer selective and specific NSAIDs against COX-2 [2]
    1. Reduced gastrointestinal side effects
    2. Good anti-inflammatory activity
    3. Unclear effects on renal function
  4. Generally no disease modifying effects
  5. Relative Risk of Ulceration
    1. In increasing order of risk:
    2. Ibuprofen and diclofenac low risk
    3. Piroxicam, indomethacin
    4. Ketorolac has highest risk [3]
    5. COX2 specific inhibitors celecoxib and rofecoxib appear to have lowest risks [1,]
    6. Rofecoxib has been withdrawn from market due to cardiovascular toxicity [24]
  6. Gastritis and ulceration can be prevented [4]
    1. Misoprostol is the only agent approved for prophylaxis
    2. Diclofenac + misoprostal (Arthrotec®) is now available for chronic use
    3. H-2 blockers may be used in patients intolerant to misoprostol, but are less effective
    4. High dose famotidine (40mg bid) reduces gastric and duodenal ulcers from NSAIDS [5]
    5. COX-2 specific inhibitors probably do NOT require any prophylaxis [2]
  7. Renal Insufficiency
    1. Renal problems are especially prevalent in patients with underlying renal disease
    2. Avoid chronic NSAID use in patients on ACE inhibitors, especially elderly
    3. Relative contraindications: diabetes, dehydration, myeloma, renal artery stenosis
  8. NSAIDs and Blood Pressure (BP) [7]
    1. NSAIDs may also raise BP
    2. May be independent of renal effects
    3. COX2 selective agents do not appear to affect BP

C. Glucocorticoids navigator

  1. Broadly effective, rapidly acting anti-inflammatory agents
  2. Inhibit both Prostaglandin and Leukotriene Synthesis
    1. Block late (but not early) inflammatory responses
    2. Especially potent at suppressing eosinophil and lymphocyte function
    3. Decreased peripheral blood eosinophilia
    4. Increased Synthesis of lipocortin (37K protein)
    5. This enzyme blocks production of PLA2 (phospholipase)
      1. Thus preventing synthesis of arachidonic acid
      2. This leads to decreased synthesis of prostaglandins, leukotrienes, thromboxanes
  3. Inhibit lymphocyte and macrophage cytokine production
    1. Reduce production of major inflammatory cytokines IL-1, IL-6, TNFa, IFNg
    2. Induce lymphocyte apoptosis (causing lymphopenia)
  4. Reduce integrin expression on endothelium and inhibit leukocyte migration
  5. Relative anti-inflammatory activities of commonly used glucocorticoid agents
    1. Cortisol, Hydrocortisone 1X
    2. Prednisone (Deltasone®, others) 5X
    3. Prednisolone 5.5X
    4. Methylprednisolone (SoluMedrol®) 6X
    5. Dexamethasone (Decadron®) 25X
  6. Acute and Subacute Complications
    1. Gastrointestinal Problems
    2. Steroids often lead to worsening of gastritis and gastric ulcers
      1. Prevent duodenal ulcer healing
      2. Glucocorticoids do not appear to cause peptic ulcers of any type
    3. Hyperglycemia - Glucose Intolerance ± Diabetes (treatment may be indicated)
    4. Osteonecrosis (Aseptic Necrosis) - usually femoral head
    5. Fluid retention, with facial puffiness
    6. Hirsutism, especially facial
    7. Pituitary and Adrenal insufficiency (see below)
    8. Infection - risk strongly related to dose and duration; mainly atypical organisms
  7. Chronic Complications
    1. Osteoporosis (even on low doses) [9,10]
    2. Cardiovascular
    3. Hypertension
      1. Accelerated atheroscerlosis
      2. Dilative cardiomyopathy (related to skeletal muscle atrophy)
    4. Skin - atrophy, easy bruising
    5. Muscle - atrophy, glucocorticoid myopathy
    6. Buffalo hump (fat deposition) and truncal obesity
    7. Neuropathy - nerve atrophy
    8. Cataract Formation
    9. Pituitary and Adrenal Insufficiency
  8. Even chronic low dose prednisone (<12mg/d) is associated with increased adverse effects

D. Sulfasalazine (Azulfidine®) navigator

  1. Moderately slow onset of action (3-8 weeks) for arthritis syndromes
  2. May be more effective than hydroxychloroquine for rheumatoid arthritis (RA)
  3. Some use in spondyloarthropathy
    1. Weak activity in ankylosing spondylitis; may have some activity in peripheral disease
    2. Active in Reiter's Syndrome and Reactive Arthritis
    3. Some activity in psoriatic arthritis
    4. Appears most effective in patients with IBD-associated arthritis
  4. Dosing
    1. Initiate at 500mg po qd for 1 weeks
    2. Increase dose by 500mg qd for 3 to 7 days
    3. Dose maximum is 2-3gm/d in divided doses (1gm bid or tid)
  5. Side Effects
    1. Sulfa allergies (not found with olsalazine)
    2. Gastrointestinal intolerance, including pancreatitis (monitoring not usually required)
    3. Bone marrow suppression - monitoring complete blood count (CBC) monthly recommended
    4. Reduction in sperm counts (oligospermia), reduced motility, abnormal sperm [21]
    5. Male fertility effects reversible on discontinuation of drug
    6. No problems in women who continue on drug; no effect on fetus [21]
    7. Avoid or reduce dose during lactation

E. Hydroxychloroquine (Plaquenil®) [6]navigator

  1. Second line agent for mild to moderate RA
  2. First line agent for cutaneous lupus and SLE
  3. Effective in Sjogren's Syndrome
  4. May take 3-6 months to observe results but good studies do show effects
  5. Dose is 200mg bid or 400mg qd po (usually begin 600-800mg/d x 1-2 weeks then lower)
  6. Retinopathy and retinal disease may develop, but are very uncommon at RA doses
  7. Other side effects include nausea and headache
  8. Advocate use as second line agent in patients who fail or are still symptomatic on NSAIDs
  9. Ophthalmological examinations should be done q6 (or q12) months

F. Minocycline (Minocin®) [7] navigator

  1. Some activity in RA over 6-12 months
  2. Dose 100mg po bid
  3. Generally well tolerated; some episodes of dizziness, especially in elderly persons
  4. Persons with pre-existing liver disease should probably by monitored with LFTs
  5. Hypersensitivity pneumonitis on second exposure to agent has been reported [14]

G. Methotrexate (MTX, Rheumatrex®) [1,8,9] navigator

  1. Increasing utility in rheumatologic diseases
  2. Current Uses [10]
    1. RA - remitting agent of choice in moderate to severe disease in adults
    2. Juvenile RA - superior to leflunomide for polyarticular JRA [25]
    3. Psoriatic Arthritis - doses higher than RA usually needed for good response
    4. Excellent agent for severe psoriasis (usually 7.5-10mg/week)
    5. Systemic Lupus Erythematosus - some effect on joint inflammation, some skin disease
    6. ANCA Associated Disease and other Vasculitides
    7. Wegener's Granulomatosus and Polyarteritis Nodosa
      1. Alternative long term to cyclosphosphamide; under investigation
    8. Polymyositis and Dermatomyositis - patients who cannot be weaned off glucocorticoids
    9. Polymyalgia Rheumatica - glucocorticoid sparing activity; appears effective and safe [22]
    10. Giant Cell Arteritis - no apparent benefit on disease relapse, glucocorticoid dose [23]
    11. Consider use in patients with severe sarcoidosis on high dose glucocorticoids
  3. Used in low doses has few side effects
    1. Generally well tolerated even combined with other agents [9]
    2. Giving Folate, 1-2mg po qd, significantly decreased hepatitis and stomatitis from MTX
    3. Folinic acid (Leukovorin®) 2.5mg-5mg with each MTX dose also reduces MTX symptoms
    4. Low dose folic acid or folinic acid does not affect the efficacy of MTX in RA
    5. MTX associated with reduced risk of overall and cardiovascular death in RA patients [11]
  4. Tests required prior to starting MTX
    1. Liver function tests including albumin, Hepatitis B and C serologies
    2. Baseline chest radiograph (CXR) - see below
    3. Complete blood counti (CBC)
    4. Stop all EtOH - continued EtOH ingestion is an absolute contraindication to MTX
    5. Smoking is relatively contraindicated
    6. HIV tests should be done on any patients with risk factors
    7. Liver biopsy within 3 months of starting therapy in patients with liver disease history
    8. Note that biopsy should only be done on responding patients (if no response, stop drug)
    9. Liver biopsy for monitoring in absence of hepatitis or albumin decrease not indicated
  5. Dosing
    1. Initially as 7.5mg po q week, usually in 2.5mg q12 hours divided doses once per week
    2. Elderly or smaller patients may begin at 5.0mg q week
    3. May be increased to 15-20mg q week orally, up to 40-50mg sc q week
  6. Laboratory Monitoring
    1. Liver functions (LFT) monthly
    2. CBC monthly
    3. Chest Radiography baseline in all patients is recommended (questionable utility)
    4. Consider pulmonary function tests (PFTs) in patients with abnormal CXR
    5. PFTs probably useful in patients with underlying lung disease
    6. Pregnancy must be ruled out before initiating agent; contraception must be used
  7. Side Effects [8]
    1. Rash - ~5%
    2. GI - Nausea (~15%), Vomiting (~4%), Diarrhea (~8%); folate may reduce these symptoms
    3. Stomatitis (~5%) - try 1mg folic acid per day
    4. Headache, Hair Loss, Dizziness, may increase rheumatoid nodules
    5. Macrocytosis - may have MCV up to 115 fL, neutrophil polylobulated nuclei
    6. Overall excellent tolerance by patients, better than most other agents
    7. >2X increased in transaminases - temporarily discontinue, then reinitiate at lower dose
    8. Patients with liver or lung disease are at increased risk for severe side effects
  8. Severe Side Effects
    1. Cirrhosis / Fibrosis - up to 10% with total of 1.5-2gm
    2. Hematologic - leukopenia (discontinue drug if WBC < 1K), thrombocytopenia
    3. Gastric Ulcers - rare
    4. Infection - ~4% of patients (varicella, herpes simplex, pneumocystis, fungi)
    5. Hypersensitivity Pneumonitis - acute
    6. Agent is not carcinogenic but is highly teratogenic
    7. No increase in hematologic malignancies in patients with RA treated with MTX
  9. MTX Pneumonitis [13]
    1. Allergic, idiopathic reaction in up to 5% of patients
    2. Risk factors include diabetes, hypoalbuminemia, rheumatoid pleuropulmonary disease
    3. Increased incidence of MTX-lung disease in patients with abnormal CXR
    4. Pulmonary function tests should be done at baseline in patients with abnormal CXR
    5. DLCO is reduced, usually <70%, and histopathology shows hypersensitivty pneumonitis
    6. Stop agent, treat with prednisone, may require intubation
  10. Liver Biopsy
    1. Generally indicated around initiation of therapy in patients with history of liver disease
    2. Also may be useful in patients with long alcohol history
    3. MTX should be used cautiously in patients with hepatitis of any cause
    4. Some patients with hepatitis C and autoimmune markers tolerate MTX well
    5. Biopsy may also be indicated in patients receiving >1.5gm cumulative dose

H. Cyclophosphamide [14,15] navigator

  1. Mechanism
    1. Chemotherapeutic alkylating agent
    2. Potent anti-lymphocyte activity
    3. Causes generalized bone marrow suppression (including neutropenia)
    4. Effects appear to be greater on B lymphocytes than on T lymphocytes
  2. Current Utility [10]
    1. Severe lupus organ dysfunction: nephritis (clear benefit), CNS disease and vasculitis
    2. Inflammatory Myopathies: may be effective in progressive interstitial pneumonitis
    3. Systemic Sclerosis: effective in progressive interstitial pneumonitis
    4. RA: reserved for refractory, severe cases and rheumatoid vasculitis
    5. Systemic Vasculitides: primarily for ANCA related diseases
    6. Inflammatory Renal Diseases: Goodpasture's, ANCA related renal disease
    7. Membranous Nephropathy and Minimal Change Nephropathy: usually for recurrent disease
  3. Dosing
    1. Oral (2-4mg/kg/day) is used in most vasculitides
    2. Intravenous bolus usually 500-1000mg/square meter per month is used in other diseases
    3. Immunoablative (high dose) IV 50mg/kg/day x 4 days for severe disease [16]
  4. Immunoablative Dosing [16]
    1. Has been used with some success for aplastic anemia and severe autoimmune disease
    2. Requires growth factor (G-CSF) and blood product support
    3. Does not require stem cell reinfusion/rescue (avoids autoaggressive lymphocytes)
    4. Alopecia is the major side effect
    5. Neutropenia generally not a major problem with G-CSF and antibiotics
    6. Gonadal failure is very uncommon
    7. Autoimmune hemolytic anemia, thrombocytopenia, lupus, Felty Syndrome, CIPD
  5. Side effects somewhat dependent on mode of administration
    1. Main concern is 2.4X risk increased long term risk of acute leuekmia, other cancers
    2. Increase 33X in bladder cancer in 158 patients treated >20 years with oral drug
    3. Transitional cell cancers of bladder usually preceded by hematuria [17]
    4. Oral cyclophosphamide has increased hemorrhagic cystitis (~43%), hair loss, leukopenia versus IV cyclophosphamide
    5. IV pulse q month has higher risk of gonadal failure than oral [18]
    6. All immumosuppressive agnets carry high risk of infection, including zoster and sepsis
  6. Drug is metabolized to active 4-hydroxycyclophosphamide and acrolein
    1. Acrolein is a severe bladder irritant (highly reactive vinyl aldehyde)
    2. Mesna 400mg iv or po taken with cyclophosphamide can neutralize bladder acrolein

I. Chlorambucil [10,15] navigator

  1. Alkylating agent with potent anti-lymphocyte activity
  2. Rare used in Rheumatologic Conditions
    1. Has been recommended in Behcet's Syndrome in patients resistant to glucocorticoids
    2. Also used in idiopathic membranous and minimal change nephropathies
  3. Dose is 0.1mg/kg/day to 0.2mg/kg/day
  4. High risk of leukopenia, thrombocytopenia
  5. Unclear benefits over cyclophosphamide (but does not cause bladder toxicity)

J. Azathioprine (Imuran®) [1,15]navigator

  1. Nucleotide analog with anti-lymphocyte activity, primarily on T cells
  2. Used for "glucocorticoid" sparing effects in many diseases
    1. Use in resistant RA when MTX is not tolerated or ineffective
    2. Polymyalgia rheumatica and giant cell arteritis in patients on long term glucocorticoids
    3. Use in SLE in patients who will require long term glucocorticoids
    4. Maintenance therapy after cyclophosphamide induction in ANCA related vasculitis [20]
    5. Also used in SLE for renal disease, skin disease, cytopenias
    6. Oral azathioprine, dosed to white blood cell thiopurine methyltransferase activity, is safe and beneficial in moderate to severe atopic dermatitis [12]
    7. Effective in 50-70% of patients with IBD
  3. Dosing
    1. Usually begin with 50mg po qd (~1mg/kg)
    2. Follow CBC and LFTs and Amylase for 1-2 weeks
    3. Increase dose to 50-150mg po qd, max 3-4mg/kg/day
    4. Usually well tolerated when begun at low dose
  4. Side Effects
    1. Common side effects include cytopenias, rash; must monitor CBC
    2. Uncommon: pancreatitis, hepatotoxicity, infection (~2%), alopecia (mild)
    3. Very small increased incidence of cancers (? relevance), usually lymphomas

K. Gold (Auranofin®, others) [19]navigator

  1. Gold is no longer recommended since leflunomide and TNFa blockers became available
  2. The efficacy of injectable gold compounds in adult RA has been questioned
  3. Common side effects: rash, stomatitis, metallic taste, proteinuria

References navigator

  1. Drugs for Rheumatoid Arthritis. 2000. Med Let. 42(1082):57 abstract
  2. Hawkey CJ. 1999. Lancet. 353(9149):307 abstract
  3. Rodriguez LAG, Cattaruzzi C, Troncon MG, Agostinis L. 1998. Arch Intern Med. 158(1):33 abstract
  4. Roth SH. 1996. Arch Intern Med. 156(15):1623 abstract
  5. Taha AS, Hudson N, Hawkey CH, et al. 1996. NEJM. 334(22):1435 abstract
  6. Clark P, Casas E, Tugwell P, et al. 1993. Ann Intern Med. 119(11):1067 abstract
  7. Tilley BC, Alarcon GS, Heyse SP, et al. 1995. Ann Intern Med. 122(2):81 abstract
  8. Methotrexate. 1994. Med Let. 36(935):103
  9. O'Dell JR, Haire CE, Erikson N, et al. 1996. NEJM. 334(20):1287 abstract
  10. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 128(12):1021 abstract
  11. Choi HK, Hernan MA, Seeger JD, et al. 2002. Lancet. 359(9313):1173 abstract
  12. Meggitt SJ, Gray JC, Reynolds NJ. 2006. Lancet. 367(9513):839 abstract
  13. Alarcon GS, Kremer JM, Macaluso M, et al. 1997. Ann Intern Med. 127(5):356 abstract
  14. Boumpas DT, Austin HA III, Fessler BJ, et al. 1995. Ann Intern Med. 122(12):940 abstract
  15. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 129(1):49 abstract
  16. Brodsky RA, Petri M, Smith BD, et al. 1998. Ann Intern Med. 129(12):1031 abstract
  17. Talar-Williams C, Hijazi YM, Walther MM, et al. 1996. Ann Intern Med. 124(5):477 abstract
  18. Boumpas DT, Austin HA III, Vaghan EM, et al. 1993. Ann Intern Med. 119:366 abstract
  19. Kremer JM. 2001. Ann Intern Med. 134(8):695 abstract
  20. Jayne D, Rasmussen N, Andrassy K, et al. 2003. NEJM. 349(1):36 abstract
  21. Janssen NJM and Genta MS. 2000. Arch Intern Med. 160(5):610 abstract
  22. Caporali R, Cimmino MA, Ferraccioli G, et al. 2004. Ann Intern Med. 141(7):493 abstract
  23. Hoffman GS, Cid MC, Hellmann DB, et al. 2002. Arthritis Rheum. 46(5):1309 abstract
  24. Celecoxib and Rofecoxib. 2004. Med Let. 46(1194):87 abstract
  25. Silverman E, Mouy R, Spiegel L, et al. 2005. NEJM. 352(16):1655 abstract