Anti Rheumatic Drugs

    .

     

     

     

    Non-DMARD Anti-Inflammatories

    • Anti-inflammatory agents
    • Reduce heat, redness, swelling, improve function
    • They improve signs and symptoms but NOT disease modifying (do not change the outcome/progress of disease)
    • High risk of gastric ulcers with non-selective NSAIDs, if using for prolongued period of time, consider PPI (NOT H2 blockers, they improve symptoms, but do not decrease risk of ulcers)

     

    Drug Mechanism Uses NOTES Toxicities/Adverse Events

    NSAIDs

    - ASA

    - Ibuprophen

    - Naproxen

    - Indomethacin

     

    - Anti-inflammatory

    analgesic

     

    - Block prostaglandin generation,

    reduces prostaglandin E2

    - Prostaglandin E2 also

    maintains renal blood

    flow and acid

     

    - Occasionally ASA

    can cause asthma

    (Pulmonary constriction)

    shunts arachidonic acid

    increasing leukotriene

    - Inflammation/Pain

     

     

    - Naproxen REDUCES

    cardiovascular risk

    - Reduces renal function

     (decreases

     renal blood flow by

    prostaglandin E2)

     

    - ASA can cause asthma

      exacerbation

     

    - Gastric Ulcers 

     (Use PPI, not H2 blockers)

     

    - MANY OTHERS!

    COX-2 inhibitors

    - Celecoxib

    - Robenacoxib

     (removed from market)

    - Valdecoxib

     (removed from market)

    - Cox-1- homeostatic function

    - Cox-2- inflammation

    selective Cox-2 inhibition

    and less toxicity

    COX-2 ARE NOT safer for 

    kidneys, still have renal 

    activity

       

    - Still reduces renal

    function

     

    - Robenacoxib and Valdecoxib

    Increase cardiac risk, 

    withdrawn from market

    (by thrombosis mechanism)

     

    - Celecoxib still on market

    (avoid in cardiac patients)

    Colchicine

    - Impairs microtubular

    assembly

    - Inhibits inflammasome

     (molecules producing IL-1)

    - Pericarditis

    - Pleuritis

    - Gout, Pseudogout

    - Familiar Mediterranean

      Fever

    - NEJM paper: evidence

     for use in recurrent 

     unexplained pericarditis

    - Diarrhea (dose-related)

    - Chronic Use - bone marrow

      suppression

    - Chronic Use - neuromyopathy

    - Renal Excretion (pts with AKI

      present with pancytopenia, 

      neuropathy, myopathy)

     

    (not recommended chronically)

    Corticosteroids

    - Poorly understood

    - Alter expression of 

     anti-inflammatory genes

    - Almost any

      rheumatologic 

      condition

    - In RA may modify

      disease progression

      (controversial)

    - Analgesic effects also

    - always minimize risks

    - Must be given Ca++

     and VitD

    - If > 7.5mg daily for 

      ≥3mo -

       ADD bisphosphanate

    - Preferred local 

     (i.e. intraarticular)

    MANY!!!

    - HTN, obesity, DM, avascular

    necrosis, weight gain, gastric

    ulcers, anxiety, insomnia, 

    psychosis, myopathy, cataracts

    cataracts, emema, glaucoma

    dyslipidemia, atherosclerosis

    immune suppression, seizures

    etc etc. ... 

    - IF unable to taper off, can add

    steroid sparing agents

    (I.e. azathioprine, etc..)


     

     

    DMARDs

     

    • Slow disease progression

     

    Drug Mechanism Uses NOTES Toxicities

    Methotrexate

    - Once Weekly dosing

     

    - Must also prescribe

     daily 5mg folic acid

    - Raises extracellular

      adenosine levels

    - Inhibits folate

      acid synthesis

    - Gold standard

      in RA

    - PsA

    - Polymyositis,

    - systemic vasculitis

    - Dosed Weekly

    - Must take folic acid

    to avoid S/E

      daily  (avoid taking

    on day of methotrexate

    to not inhibit MTX action)

     

     

    - Marrow Suppression

    - Liver Toxicity

      Abstain from EtOH

    - Allergic pneumonitis (RARE)

    - folic acid avoids oral ulcers, GI sx

     

    MONITORING:

    - CBC and Liver chemistry monthly

     once stable do q3-4mo

     

    - Stop 3mo prior to pregnancy

    Hydroxychloroquine

    (Plaquenil)

    - 200-300mg/day

    - Decreases 

      acidification

      of inflammatory 

      granules

    - Prevents T-cell

      activation

    - SLE

    - Mild RA

     

     

    FEW!!

    - Retinal Pigment Deposition

     

    MONITORING:

    - Retinal Exam q1y (first few yrs

      may not need to, cumulative)

     

    - Category C pregnancy, but

      many continue in pregnancy 

      (expert consensus: probably safe)

    Sulfasalazine

    - Salicilate and

      sulfapyridine

    (initially thought 

     antibiotic and anti-

     inflammatory)

    - Used for IBD to 

      deliver to distal colon

    - RA

    - IBD (gets to distal 

       colon) 

     

    - GI upset, headache common

    - Agranulocytosis / Hepatitis (HOLD)

    - Reversible aspermia (hold if 

      trying to get pregnant)

    - Considered safe in pregnancy

     

    MONITORING

    - Labs 2-3w after starting, 

      first few mo in first year

      (if toxicity happens, happens early)

    Leflunomide

    - Pyrimidine inhibitor

    Targets lymphocytes

    (Lack salvage pathway)

    - RA (excellent!)

    [as effective as MTX]

    - Used in MTX failures

    (came out same time as

    TNF inhibitors)

    - Can use with MTX

     but lower both doses.

     (similar toxicities)

    Same as MTX

    - Liver, Immunologic toxicity, etc..

     

    VERY teratogenic, do not use 

    in pregnancy.  VERY long half-life

    upwards of 3-4mo

    - If want to get pregnant or S/E, give

     cholestyramine TID x11 day to 

     pull drug into gut. 

    Azathioprine

    - inhibits thiopurine

    methyltransferase

    (TPMT)

    - Metabolites degraded

     by xanthine oxidase

    (allopurinol and

     foboxustat inhibit it)

    Connective Tissue

    Diseases:

    - Lupus

    - Vasculitis

    - Polymyositis

    (steroid sparing or

    maintenance)

     

    - Pts with TPMT deficiency

     have toxciity (some 

    rheumatologists check TPMT activity

    level)  or follow counts carefully!

     

    - DO NOT USE WITH ALLOPURINOL

      OR FOBOXUSTAT (inhibit xanthine

      oxidase)

    - If have to use them, lower doses!

    Cyclosphophamide

    - Potent alkylating

    agent

    - Life threatening

    SLE and vasculitis

    (ANCA vasculitidies)

     

    MANY S/E
    - Leukopenia, Anemia, opportunistic

    infections, hemorrhagic cytisits, 

    bladder Ca, infection

     

    - Secondary malignancy (lymphoma)

     

    MONITORING

    - Urinalysis, Blood counts, LFTs

     

    NEVER use in pregnancy (unless

    life threatening)

    Mycophenylate 

    Mofetil

    (Cellcept)

    - Inosine purine

    pathway inhibitor

    (antimetabolite)

    - Inhibits T & B cells

     

    - SLE

    - In lupus nephritis

    similar to 

    cyclophosphamide

    with fewer S/E

    - Vasculitis

    - Polymyositis

    - initially used for 

    transnplant rejection

    - think of it as "safer

    azathioprine"

     
    Cyclosporin  

    - Transplant

    3rd Line for many

     rheumatic diseases 

    - Psoriasis, 

    inflammatory myositis

    - Ocassionally in RA

    SLE, and IBD

     

    Common!

    HTN, Nephrotoxicity, tremor

    Hirsutism


    Biologics

    Introduction to Antibodies

    •    

     

    History

    • Dr. Lloyd Old demonstrated endotoxin-induced serum factor that caused tumor cell necrosis.
      • Tumor Necrosis Factor (TNF)
      • Cachetin
    • Bruce Beutler
      • Investigated inhibition of TNF to improve sepsis outcomes
      • Found anti-TNF (rabbit anti-serum) improved septic mice
      • Protected mice from bacterial lipopolysaccharide
      • Tried to brand Anti-TNF antibody as Centoxin
      • Could not use in humans --> Gets rejected
      • Developed chimeric antibody
      • (FAB + human Fc) = cA2
      • 25% mouse, 75% human
    • Initial Anti-TNF antibody did not help sepsis patients.  
    • Eventually TNF discovered as part of inflammatory cascade for RA
    • The group who developed the antibody were contacted, and tried on RA patients.
      • Results were DRAMATIC
      • Tiredness + Fatigue gone in HOURS
      • Reduction in joint stiffness in DAYS
      • All patients responded, ESR decreased.
      • BUT! After 8-26w relapsed due to few mechanisms (i.e. neutralizing antibodies)
        • Found 3 ways to maintain response:
    1. High dose 3-10mg/kg
    2. Give with methotrexate
    3. Humanize antibody (reduce mouse component, increase human components)

     

    Anti-TNF Agents

    • Used mostly in RA and spondyloarthropathies
    • Before Starting TNF Inhibitor:
      • TB Surveillance  (IGRA or skin test - IGRA more specific)
      • HepB surveillance (can reactivate HepB)
      • Ensure vaccines up to date (cannot administer live vaccines after, and may not mount a response to vaccines on TNF inhibitors - especially Rituximab).
    • Cautions:
      • If develops infection --> HOLD TNF AGENT until infection resolves!
      • Cannot receive live vaccines (i.e. MMR, nasal flu vaccine, Zostavax)
        • (Same with high dose prednisone >20mg prednisone equivalent/day or >15mg/week of MTX)
    • Side Effects:
      • Can cause psoriasis (also treats psoriasis)
      • Drug-induced lupus (rare)
      • Multiple Sclerosis & demyelinating conditions
      • Unclear relationship with cancers (lymphoma and melanoma), but hold if develops
    • NOTES:
      • NEVER combine two biologics (trials show unacceptably high infection rate)
      • Can combine methotrexate and biologics (improves response and duration of response to biologics)
      • HepC and HIV patients can be treated with TNF inhibitors (but not HepB)

     

     

    Drug Administration

    Structure (Red = mouse, blue = human)

    and Function

    Indications

    Infliximab (Remicade)

    xi = chimeric

    (part mouse

    part human)

    mab = monoclonal

             antibody

     

    (FIRST ONE!!)

     

    chermicc.png

    IBD

    Adalimumab (Humira)

    = Completely Human

    2002

    Every other week

    SC (0.8mL vials, preloaded syringes

    pen devices)

     

    "World's Best Selling Drug"

    - Very effective, but expensive,

    can be used for IBD

    $20,025/mo

    human.jpg

    Similar response rate to TMX monotherapy, 

     

     

    and in combination doubles response rate

    Rheumatoid Arthritis

    Psoriatic Arthritis

    Ankylosing Spondylitis,

    IBD

    Psoriasis,

    Idiopathic Juvenile Arthritis

    Golimumab(Simponi)

    = Completely Human

     

    Centocor(Johnson&Johnson)  /

    Merck in Europe

    Human MAB (CNTO 148)  -  

     

    Advantage:  Dosed qMonthly,

    Can be self-administered at home

    (SC)

    human.jpg

    Validated: Golimumab+ MTX better than

    MTX alone

     

    Also in 2013: mod-severe UC (better than placebo)

    Rheumatoid Arthritis

    Psoriatic Arthritis

    Ankylosing Spondylitis

    Ulcerative Colitis

    Etanercept (Embrel)

    cept = receptor

    qWeekly SC

    Injection

     

    Immunexacquired by Amgen

     in 2002 (Powder form)

    Pfizer (Pre-mixed liquid)

    $20,025/yr

    cept.png

    TNF receptor attached to 

    Fc portion of immunoglobulin

     

    Used as 3rd line (after TNF inhibitors)

     

    Ankylosing Spondylitis

    Juvenile Rheumatoid Arthritis

    Psoriasis

    Psoriatic Arthritis

    Rheumatoid Arthritis

    NOT Effective in IBD

    Abatacept (Orencia)

    - Monthly IV infusion

    - SC injections weekly available

    CTLA4 Receptor mounted to the Fc portion of 
    a human antibody. Blocks antigen presenting 
    cells from activating T-cells. 
    Prevents T-Cell Costimulation (Activation)
    - Takes 5-6mo to see response (LONG time!)
    - Risk of lymphoma and lung disease higher.
    - Caution with COPD.

    For Mod-to-High RA activity

    If failed to response to

    non-biologic DMARDs

    or MTX + biologics. 

     

    Certolizumabpegol
    (Cimzia)
     
     

    FAB.jpg

    Humanized Fab of antibody mounted

    on a PEG molecule

    (PEG is chemically inert, causes less 

    resistance to drug).

     

    Ustekinumab

    (STELARA)

     

    Binds P40 component of IL12, IL23

    - More prone to mycobacterial, fungal, 

    salmonella infection

    Psoriasis

    Psoriatic Arthritis

    IBD

    PEGylatedTNFR1

    (Not released yet?)

    Amgen

    PEGTNFR.jpg

    PEGylatedTNFR1 p55 monomer
     
    Tocilizumab
    (Actemra)

    Monthly IV infusion

     

    Chmeric mab targets IL6 receptor

    Prevents Leukocyte activation. 

     

    Toxicities:

    - Can reactivate TB

    - Causes hyperlipidemia, cytopenias, LFT 

      abnormalities not seen in TNF-inhibitors

    - Case reports of gastric/intestinal rupture

    (avoid in diverticulosis and PUD)

    Rheumatoid Arthritis

    (if no response to TNFi)

     

    Hyperlipidemia

    Cytopnenias

    LFT abnormalities

    (These are not seen with

    other TNF inhibitors)

    Rituximab (Rituxan)

     

    chermicc.png

    Chimeric Monoclonal Antibody

    CD20 B-cell depleting

     

    Anti-CD20 mab, Inhibits B-cells

    (Watch IgG levels to monitor 

    toxicity), depletes B-cells

    - No risk of infection, but can get infusion

    rxns

    Rheumatoid Arthritis

    (if no response to TNFi)

    ANCA-ass'd vasculitis

    - as effective as cyclophos.

    Risk SLE Manifestations?

    (i.e. thrombocytopenia, 

      hemolytic anemia of SLE)

     

    Monitor IgG levels

    (hypogammaglobulinemia)  for toxciity

    Anakinra (Kineret) 

    Rilonacept

     - IL-1 Trap

    Canakinumab

     

      Block IL-1

    Developed for RA, but found

    ineffective

    Works for:

    - Periodic Fever Syndromes

    "Cryopyrin-Associated

    Syndromes" - genetic

     

    - Juvenile Inflammatory arthritis

    (i.e. Stills)

    Belimumab  

    Mab targets B-cell Activating Factor (BAF)

    aka BLSS

    - SLE

    OTHERS:

    • tofacitinib - Janus Kinase (JAK) inhibitor - used to Tx of RA

    Side Effects of Anti-TNF Therapy

    • Biggest S/E:
      • Infections
        • Atypical: Legionella, Listeria.
        • Fungal: (histoplasmosis, coccidiodomycosis, blastomycosis).  Empiric antifungals until identified.
      • TB Reactivation (Screen for Latent TB!!!)
      • CHF exacerbations
      • Demyelinating disease
      • Auto-Antibody Formation / Lupus-like Syndrome
      • Lymphoma (Hepatosplenic T-Cell Lymphoma – HSTCL)

     

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