Table of contents
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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- Robenacoxib and Valdecoxib Increase cardiac risk, withdrawn from market (by thrombosis mechanism)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 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:
- High dose 3-10mg/kg
- Give with methotrexate
- 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!!) |
| 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 |
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) |
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 |
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) |
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 |
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) |
|
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)
- Infections
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