Rheumatoid Arthritis Treatment

Hydroxychloroquine (Plaquenil)

Antimalarial Inhibit prostaglandin synthesis - anti-inflammatory Dose: 200-300 mg twice daily Onset of action delayed up to 6 weeks Therapeutic failure if no response after 6 months of therapy Adverse Effects:Nausea, epigastric pain, retinopathy

Leflunomide

Arava

NSAIDs are used as what in RA?

As a bridge for symptomatic relief in patients who are just starting a new DMARD Do not slow the progression of the disease; anti-inflammatory properties Anti-inflammatory doses: - ibu 3200 MG/DAY - Naproxen 1100mg

Gold salts

Auranofin (Ridaura)

Corticosteroids

Bridging therapy Continuous low-dose therapy - 5-10mg/daily Short-term high-dose bursts to control flares May also be delivered by injection - IM route preferred for patients with compliance (2-8 weeks of symptom control) - IV route - provide large amounts of drug during a steroid burst - Intra-articular - fewest number of side effects; repeat every 3 months - triamcinolone (Aristopan)

Azathioprine (Imuran®)

Immunosuppressant Used for refractory RA or systemic involvement such as rheumatoid vasculitis Side Effects: Hepatitis, GI intolerance, bone marrow suppression, pancreatitis

Azathioprine

Imuran

Corticosteroids

Inhibit prostaglandin and leukotriene synthesis Inhibit neutorphil and monocyte superoxide radical generation Absorbed rapidly from the GI tract Elimination half-life is long - once daily dosing

Cyclosporine(Restasis, Sandimmune)

Inhibits T-cell activation Inhibitor of interleukin-2 and interferon-gamma Dose: 2.5mg/kg/day and may increase to 5mg/kg/day at 2-4 week intervals Substrate of 3A4 Very nephrotoxic, may increase BP, HA, hypertrichosis, gingival hyperplasia

Leflunomide (Arava®)

Inhibits pyrimidine synthesis: decrease in lymphocyte proliferation and modulation of inflammation Dose: after a loading dose of 100mg daily for 3 days, maintenance is 20mg/d Adverse Effects: diarrhea occurs frequently, alopecia, rash, myelosuppression and hepatotoxicity may occur Pregnancy Category X Peripheral neuropathy - 6 months after beginning of the drug

Averse effects of TNF-alpha

Injection site reactions (erythema, pruritis, rash) - etanercept, golimumab, certolizumab, adalimumab Infusion reactions - infliximab (fever, urticaria, dyspnea, hypotension) Cytopenia - monitor CBC Infections including active tuberculosis and fungal infections; Legionella and Listeria - Tuberculin skin testing and chest x-rays Hepatotoxicity; reactivation of hepatitis B virus Lymphomas - do not use in patients with recent history of malignancy Congestive heart failure has been reported during the postmarketing use of etanercept. Demyelinating conditions - MS Infliximab black box warning - hepatotoxicity

Anakinra (Kineret)

Interleukin-1 receptor antagonist Less effective than TNF-inhibitors May provide an alternative for patients at risk for TB Dose: 100 mg/day SC Adverse effects:Injection site reactions, upper respiratory tract infections

Rheumatoid arthritis is a systemic disease and its inflammation can affect organs and areas of the body other than the joints.

It can cause dry eyes, pericardial sac of the heart can be affected, much more prone to wounds because you are immune suppressed.

What NSAID has the highest GI risk

Ketorolac and Indocin

Diueretics

Loop diuretics: Lasix(furosemide), bumetanide, demadex (torsemide), and edectrin (ethacrynic acid) Thiazide diuretics: microzide(hyudrochlorothiazide), chlorthalidon, Zaroxolyn

What is the drug of choice for RA?

Methotrexate

Non-Biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Methotrexate (Rheumatrex Trexall®) Hydroxychloroquin (Plaquenil®) Sulfsalazine (Azulfidine®) Leflunomide (Arava®) Gold Salts - Auranofin (Ridaura®) Azathioprine (Imuran®) Cyclosporine (Sandimmune®, Neoral®) Cyclophosphamide (Cytoxan®)

Golimumab (Simponi)

Moderately to severely active rheumatoid arthritis in combination with methotrexate Also FDA-approved for psoriatic arthritis Golimumab is for subcutaneous administration. Each single-use prefilled syringe and single-use prefilled autoinjector contains 50 mg/0.5 ml of golimumab Dose: 50mg once monthly SC in combination with MTX OR 2mg/kg IV at 0 and 4 wks and maintain at 2mg/kg IV every 8 wks Keep refrigerated

Infliximab (Remicade)

Monoclonal antibody - half human, half murine Inhibits the activity of TNF-α FDA-approved for Crohn's Disease Almost removed from market due to hepatotoxicity, but black box warning issued Dose: 3 mg/kg IV over at least 2 hours given at weeks 0, 2, and 6 then every 8 weeks in combination to methotrexate

DMARDS

Use three or 4 then we go to biologic NSAIDs are first line as long as there is no cont. Hepatotoxic, alchol abuse, don't start with methotrexate.

Sulfsalazine

(Azulfidine®)

Etanercept

(Enbrel)

Hydroxychloroquin

(Plaquenil®)

Side effects of methotrexate

- Bone marrow suppression (all should be on folic acid supplementation) - Hepatotoxicity - Oral ulcers/stomatitis.Malaise, HA, Ulcerative Stomatitis, Pulmonary Fibrosis, Bone Marrow Suppression Most serious long-term toxicity: HEPATOXICITY Contraindications: Hepatitis, frequent alcohol usage Pregnancy Category X

Drug Interactions of NSAIDS

- Diuretics - Beta-blockers: - ACE Inhibitors - Lithium - Methotrexate - Warfarin

NSAIDs

- Piroxicam and ketorolac (highest risk) - Naproxen, indomethacin, ibuprofen (lower risk) - Co-administration with a PPI Increased cardiovascular risk - increase blood pressure (naproxen - least risk) Risk of renal disease

Anticyclic citrullinated peptide antibody

- Useful in the diagnosis of pts with unexplained joint inflammation, especially when RF is negative. -Present in 50% to 85% of patients with the disease Detectable very early in the disease Indicator of more potentially aggressive form of the disease

F.A. is a 55-year-old woman with rheumatoid arthritis. On diagnosis 1 year ago, F.A. had an RF titer of 1:64, signs and symptoms of inflammation in the joints of both hands, and about 45 minutes of morning stiffness. She began therapy with methotrexate, and she is presently receiving 15mg every week, folic acid 2 mg/day, ibuprofen 800 mg 3 times/day, and omeprazole 20 mg/day. At today's clinic visit, F.A. reports a recurrence of her symptoms. Radiographic evaluation of her hand joints shows progression of joint space narrowing and bone erosion. Which one of the following is the next step in therapy for F.A.? A. Administer etanercept. B. Administer hydroxychloroquine. C. Add prednisone bridge therapy. D. Change to leflunomide.

A. Administer etanercept.

Biological agents and Janus kinase inhibitors

Abatacept prevents full T-cell activation. Ritixumab targets B cells. Anakinra block action of IL-1. Etanercep, Adalimumab and Infliximab block the action of TNF-alpha

Hydroxychloroquine (Plaquenil) side effects

Abdominal cramps, retinopathy, diarrhea, reduced appetite, headache, nausea and vomiting, vision difficulties, tinnitus, hearing loss diminished reflexes, hives, itching, rash, loss of hair, weakness and anemia. Patients with G6PD enzyme deficiency who take Hydroxychloroquine can develop a severe anemia and should be closely monitored if the drug is not stopped.

Ace inhibitors

Accupril (quinapril) Aceon (perindopril) Altace (ramipril) Capoten (captopril) Lotensin (benazepril) Mavik (trandolapril) Monopril (fosinopril) Prinivil, Zestril (lisinopril)

Beta blockers

Acebutolol (Sectral) Atenolol (Tenormin) Bisoprolol (Zebeta) Metoprolol (Lopressor, Toprol-XL) Nadolol (Corgard) Nebivolol (Bystolic) Propranolol (Inderal LA, InnoPran XL)

Which of the following is a reason that DMARDs are preferred over non-DMARD for RA management?

C. DMARD agents may reduce or prevent joint damage and preserve joint function.

Certolizumab Pegol (Cimzia)

Chemically attached to polyethylene glycol. Potent neutralizer of TNF-alpha.

Certolizumab Pegol

Cimzia

Sulfsalazine (Azulfidine®)

Cleaved by bacteria in the colon into sulfapyridine and 5-aminosalicylic acid Anti-inflammatory/immunomodulatory properties Dose: 500mg twice a day; may increase to 1g twice a day Benefits seen in 2-3 months Adverse Effects: GI side effects, leukopenia, stomatitis, alopecia, lupus-like syndrome, PHOTOSENSITIVITY May bind to iron in the GI tract: decreased absorption of sulfsalazine

Methotrexate(RHEUMATREX)

Concomitant administration of folic acid 1-5mg/day Adverse effects: Malaise, HA, Ulcerative Stomatitis, Pulmonary Fibrosis, Bone Marrow Suppression Most serious long-term toxicity: HEPATOXICITY Contraindications: Hepatitis, frequent alcohol usage Pregnancy Category X

What do you use for acute flare ups

Corticosteroids

Pharmacologic Therapy

Corticosteroids - Flare-ups Nonsteroidal Anti-Inflammatory Drugs Disease-Modifying Antirheumatic Drugs Non-Biologic Agents Biologics and Janus Kinase Inhibitors

Hydroxycholoroquin (Plaquenil)

Cuses retinopathy-drug can crystallize in the eye. does not cause immunosuppression.

Cyclophosphamide

Cytoxan

Diagnostic Criteria for RA (ACR/EULAR) ≥ 4 criteria present > 6 wks

Morning stiffness > 1 hour Arthritis of ≥ 3 joints areas (PIP, MCP, wrist, elbow, knee, ankle, and MTP) Arthritis of hand joints (wrist, MCP, PIP) Symmetric arthritis Rheumatoid nodules RF+ Radiographic changes Erosions Unequivocal periarticular osteopenia Rheumatoid nodules-bumps on elbow hot and usually painful osteopenia-some brittle bones but not full osteoporosis. You must supplement with Calcium and Vitamin D.

TNF-α Inhibitoros

Etanercept (Enbrel)-1996 Infliximab (Remicade) - 1999 Adalimumab (Humira) - 2002 Golimumab (Simponi) - 2009 Certolizumab Pegol (Cimzia) - 2009

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

First line of therapy Mechanism of Action: - Inhibition of COX-1 and COX-2 - Inhibition of COX-2 is responsible for the anti-inflammatory effect of NSAIDs Gastrointestinal Adverse Effects - All NSAIDs can cause dyspepsia and gastric and duodenal ulcers Effects on bleeding - Interfere with platelet function and prolong bleeding time

Adalimumab

Humira

Cyclophosphamide (Cytoxan®)

Immunosuppressant Suppresses T-cell function Limited for most severe cases of RA Long-term use can increase risk of infection and malignancy Myelosuppression

What is the drug of choice for someone with MI

Naproxen

Azathiopurine

Not used in RA that often used more in IBD.

Hydroxychloroquin

Onset of action delayed up to 6 - 12 weeks Therapeutic failure if no response after 6 months of therapy Useful and safe in women who may become pregnant and during pregnancy

Penicillamine (Cuprimine)

Oral chelating agent for Wilson's disease Resistant RA Penicillamine also appears to depress circulating levels of IgM rheumatoid factor; depresses T-cell activity Initial dose: 125-250 mg/day; increase dose at 1-3 months intervals by 125-250 mg/day; Maintenance: 500-1500 mg/day SE: Rash, epigastric pain, loss of appetite, n/v, myelosuppression

Major Limitation to use of corticosteroids

Osteoporosis, HTN, Diabetes, Infections, Weight gain.

Biologics (ACR Guidelines)

Patients who fail at least 2 non-biologic DMARDs, alone or in combination Can be used earlier in patients with high disease activity and poor prognosis Anti-TNF - third step for patients who failed 3 months of nonbiologic DMARD combination therapy after a trial of monotherapy Anti-TNF and MTX - moderate active RA with partial response to MTX alone for 4-12 weeks Greater symptom relief and better remission rates If fail two anti-TNF agents, try a non-TNF agent

NSAIDS

Prostacycline causes vasodilation (inhibits platelet aggregation) Thromboxane causes vasoconstriction (promotes platelet aggregation) Nsaids cause sodium and water retention Celebrex and Meloxicam-COX 2 inhibitor

Etanercept(Enbrel)

Recombinant human fusion protein FDA-approved as monotherapy Self-administered injection Dose: 50 mg SC weekly given as one 50 mg injection or two 25 mg injections in one day, or one 25 mg injection given twice weekly, 72-96 hours apart Auto-injector

Adalimumab (Humira)

Recombinant human monoclonal antibody May cause hypertension Dose: 40mg SC every other week; 40mg SC every week in patients not receiving concomitant methotrexate SC administration:

Infliximab

Remicade

NSAIDs toxicity

Renal toxicity - Inhibition of renal prostaglandins ________ decrease renal blood flow, fluid retention, hypertension and renal failure

Non-Pharmacologic Therapy

Rest Occupational Therapy Physical Therapy Weight reduction Use of assistive devices Surgery

NSAIDs MOA

Reversibly inhibit COX-1 & COX-2 Block prostaglandin synthesis

Diagnosis

Review history of symptoms Examination of joints for inflammation and deformity X-Rays, Ultrasound, MRI Laboratory Findings: Anemia Thrombocystosis Leukopenia Erythrocyte Sedimentation Rate Rheumatoid Factor Antinuclear Antibodies Anticyclic citrullinated peptide antibody

Methotrexate

Rheumatrex Trexall®)

Cyclosporine

Sandimmune, Neoral

Golimumab

Simponi

Rheumatoid Arthritis and Inflammation of the organs

Sjogren's Syndrome: autoimmune dry eyes and mouth Pleuritis - causes chest pain Pericarditis Anemia-anemia of chronic disease Felty's Syndrome Vasculitis

Methotrexate (Rheumatrex®)

Standard of care for initial DMARD therapy of RA Immunosuppressant Antirheumatic Effect - 4-6 Weeks Folate antimetabolite/Antineoplastic agent Interferes with cell reproduction and induces a suppressive effect on rapidly proliferating cells and secretion of cytokines Dose: 7.5-15mg weekly

Disease Modifying Anti-Rheumatic Drugs (DMARDs)

Symptom Control Control current inflammatory features Modify the course of disease Reduce joint damage and deformity Reduce radiographic progression Reduce long-term disability

Biological DMARDs

TNF Blockers IL-1 Receptor Antagonist Selective Costimulation Modulator B-cell/CD20 Antigen Blocker Interleukin-6 Receptor Antagonist

Gold Salts

Used infrequently Injectable gold more effective than oral gold Dosage: 6mg daily or 3mg bid; if response inadequate after 6 months, increase to 9mg and if response inadequate after 3 months, DC therapy Adverse Effects: - Gold toxicity Not recommended for use during pregnancy

Gold salts(Auronofin (Ridaura)

decrease hemoglobin severe toxicity

Diclofenac

high cardiovascular risk

Flurbiprofen(Ansaid)

high gi risk

Ketorolac (Toradol )

high gi risk

Meclofenamate

high gi risk

Ibuprofen

mod to high cardiovascular risk

How is methotrexate excreted

renally. NSAIDs are going to get excreted instead of methotrexate which causes methotrexate toxicity.