Rheumatoid Arthritis Lecture Notes PDF

RHEUMATOID ARTHRITIS (RA) Vanessa Lesneski, PharmD, BCPS, CPh 1 lecture hour https://images.app.goo.gl/9gqAjxwfBRANLRQF8 Objectives: The student shall ▪ Explain RA ▪ Appreciate the epidemiology of RA ▪ Define the pathophysiology and diagnosis of RA ▪ Identi...

RHEUMATOID ARTHRITIS (RA) Vanessa Lesneski, PharmD, BCPS, CPh 1 lecture hour https://images.app.goo.gl/9gqAjxwfBRANLRQF8 Objectives: The student shall ▪ Explain RA ▪ Appreciate the epidemiology of RA ▪ Define the pathophysiology and diagnosis of RA ▪ Identify the signs, symptoms, and complications of RA ▪ Recognize the extraarticular manifestations of RA ▪ List the treatments of RA (including place in therapy, side effects, and monitoring) ▪ Select an appropriate therapy for individual RA patients 2 RA definition A chronic, progressive autoimmune disease causing inflammation in the joints and other body systems. Which results in painful deformity and immobility. Most commonly seen in the fingers, wrists, feet, and ankles. Affects more than just joints. Can affect skin, eyes, lungs, heart and blood vessels. https://g.co/kgs/d4sBLZ 3 Epidemiology ▪ 1% prevalence of the population worldwide ▪ Prevalence increases with age up to 70s ▪ 3 times more common in women (6:1 in 15-45 age bracket) ▪ Cardiovascular disease is the leading cause of death in RA patients ▪ Increased risk of major cardio event ▪ RA is a predictor of Cardiovascular disease ▪ Life expectancy is 3-10 years less than the average 4 Epidemiology ▪ Genetic predisposition ▪ Dizygotic twins and siblings 6 X’s more common ▪ Monozygotic twins up to 30 X’s greater risk ▪ RA patients can have HLA-DR4, HLA-DR1, or both ▪ HLA-DR4 antigen presence=3.5 increase risk ▪ Environmental exposure ▪ Smoking (increases disease severity) ▪ Infectious mediators (e.g. Epstein-Barr virus, Escherichia coli), periodontal disease ▪ RA is considered an autoimmune disease ▪ Does not discriminate between self and non self https://images.app.goo.gl/eeWyWiEUbuHYZQey7 ▪ Mounts an attack resulting in inflammation, destruction, and cell proliferation 5  Rising rate of Autoimmunity by ANA prevalence ANA prevalence perecent million people Linear (ANA prevalence perecent) 45 41 40 35 30 27 25 22 20 15.9 15 11 11.5 10 5 0 1988-1991 1999-2004 2011-2012 ANA prevalence perecent 11 11.5 15.9 million people 22 27 41 Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. 2020. Increasing prevalence of antinuclear antibodies in the United States. Arthritis Rheum; doi: 6 10.1002/art.41214 [Online 8 April 2020]. Pathophysiology ▪ Inflammation of the synovial tissue lining the joint ▪ Immune system attacks the synovial and other connective tissues ▪ Chronic inflammation leads to proliferation of the tissue, results in a pannus ▪ A pannus is an abnormal layer tissue ▪ Eventually the pannus invades the cartilage then the bone, ultimately causing destruction of the joint https://images.app.goo.gl/YPGTGyGg7Hvp2GFQA 7  Pathophysiology: Inflammation of the joint Antigen- T-cells Macrophages presenting cells APCs present antigens to T T cells stimulate B-cells to Stimulate T cells and osteoclasts cells produce antibodies and to promote inflammation, as well as fibroblasts, to degrade the osteoclasts to destroy and bone matrix and produce remove bone proinflammatory cytokines TNF-alpha, Il-6 and Il-17 Histamine, Kinins, and prostaglandins T-cells and macrophages release agents that promote destruction, increase blood flow, and increase cellular invasion 8 Pathophysiology ▪ Many RA patients form antibodies to self called rheumatoid factors ▪ Does not correlate with level of disease activity ▪ But used to help make a diagnosis ▪ Seropositive patients tend to have a more aggressive disease ▪ Antibodies directed against the Fc portion of Immunoglobulin G (IgG) ▪ Also present in other autoimmune disorders, chronic and acute infection, and cancer ▪ Normal range : 72 IU/mL (>3X ULN) Humoral Antibodies Immune System Cell- mediated 9 Pathophysiology ▪ Anticitrullinated protein antibody (ACPA) is another antibody ▪ Produced in most RA patients ▪ Present during several types of inflammation ▪ Used as a diagnostic aid, not definitive ▪ ACPA may be present before symptoms of RA ▪ Positive antibodies = poorer prognosis ▪ Serology ▪ Normal value - < 20 EU/mL ▪ 20-39 EU/mL - Weakly positive ▪ 40-59 EU/mL - Moderately positive ▪ > 60 EU/mL - Strongly positive 10 11 https://www.google.com/url?sa=i&url=https%3A%2F%2Fcalgaryguide.ucalgary.ca%2F3044- 2%2F&psig=AOvVaw3RBtqkNWBUcoUMQGtdU02o&ust=1581541647623000&source=images&cd=vf e&ved=0CAIQjRxqFwoTCJCr2fOzyucCFQAAAAAdAAAAABAk Key inflammatory Mediators TNF Cytokines Il-1 Il-6 Soluble Prostaglandins Leukotrienes Mediators Matrix metalloproteinases 12 Patient Clinical Presentation ≥ 6 weeks of joint pain http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=133893255. Accessed February 03, 2020. and/or stiffness Fatigue, weakness, Symptoms (deformity not until low-grade fever, loss Wahl K, Schuna AA. Rheumatoid Arthritis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. later in disease of appetite progression) Tenderness, warmth, Signs and swelling in Rheumatoid nodules Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill;. Symmetrical joint affected joints (hands are possible and feet) Elevated ESR and CRP, Rheumatoid factor Normocytic Lab Tests (RF), Anticitrullinated protein antibodies (anti-CCP or ACPA) normochromic anemia, thrombocytosis Other Joint radiographs may Joint fluid aspiration show periarticular increased white blood osteoporosis, joint tests cell counts without space narrowing, or infection, crystals erosions 13  ▪ Eyes ▪ Vasculitis ▪ Neurological ▪ Blurred vision ▪ Asymptomatic ▪ Bumps on joints ▪ Can progress to ulcers Extraarticular Involvement ▪ Rheumatoid nodules-20% of RA patients ▪ Most common on the extensor surfaces of the elbows, forearms, and hands 14 Wahl K, Schuna AA. Rheumatoid Arthritis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill;. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=133893255. Accessed February 03, 2020.  ▪ Cardiac ▪ Swollen ▪ Pulmonary ▪ Splenomegaly ▪ Felty Syndrome ▪ Lymphadenopathy Extra-articular Involvement ▪ RA, splenomegaly and neutropenia, resulting in susceptibility to bacterial infections 15 Wahl K, Schuna AA. Rheumatoid Arthritis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill;. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=133893255. Accessed February 03, 2020. Joints affected ▪ Typically small joints ▪ Hands, feet, wrists ▪ Knees, hips, ankles, elbows and shoulders are all possible ▪ Progresses to more joints as inflammation continues (jaw, spine, etc.) ▪ Lasts 30 min – ALL day ▪ Persistent inflammation and proper exercise is diminished → Joint deformity 16 DIAGNOSIS RA 17 Diagnosis ▪ Synovitis of at least one joint and no other explanation ▪ Positive laboratory tests including RF, ACPA, CRP, and ESR ▪ Duration of symptoms more than or equal to 6 weeks ▪ Criteria: ≥ 6/10 18 19 Disease Activity Score 20 Prognostic Factors High tender Elevated anti- Radiographic and swollen Elevated RF CCP erosions joint counts antibodies Elevated ESR Elevated CRP Age Female Worsening Genetics Tobacco use physical function TREATMENT RA 22 Treatment Goals Achieve remission or lower disease activity (Treat to Target) Reduce QOL-pain progression of disease Maintain Reduce risk of function of joint damage joints 23 Non-Pharm-textbook ▪ Rest ▪ Appropriate amount ▪ After too much, risk of decreased range of motion, muscle atrophy, and contractures ▪ Occupational therapy/physical therapy ▪ Assistive devices ▪ Weight reduction ▪ Surgery ▪ Mental Health support 24 Pharm therapies ▪ Disease-modifying antirheumatic drug=DMARD ▪ Conventional synthetic DMARDs or just DMARDs ▪ Biologic DMARDs (biologics) including: ▪ TNF-α inhibitors ▪ Non-TNF biologics ▪ Tofacitinib ▪ NSAIDs ▪ Corticosteroids 25 DMARDs Disease-Modifying AntiRheumatic Drugs 26 Conventional (Non-biologic) DMARDs RA 27 Methotrexate (Rheumatrex, Trexall, MTX) ▪ Initial DMARD of choice ▪ Least expensive option ▪ Effective ▪ Anti-inflammatory action ▪ Inhibits cytokine production, inhibits purines, & stimulates adenosine release ▪ Relatively fast onset of action ▪ 2-3 weeks for initial effect ▪ Improvement up to 12 ▪ Pregnancy Cat X & NO in lactation ▪ Other CI’s: liver disease, immunodeficiency, pleural or peritoneal effusions, leukopenia, thrombocytopenia, preexisting blood disorders, and a creatinine clearance of less than 40 mL/min 28 Methotrexate Adverse Effects ▪ GI ▪ N/V/D, elevated liver enzymes ▪ Thrombocytopenia ▪ Leukopenia ▪ Pulmonary Fibrosis and pneumonitis – rare ▪ Folate depletion ▪ Folic acid antagonist 29 MTX: Dosing ▪ Routes: PO, SQ, IM ▪ PO dose ▪ Start 7.5 mg once weekly ▪ Typical 10 to 15 mg once weekly ▪ Increase by 5 mg every 2 to 4 weeks to a maximum of 20mg (30 mg) once weekly ▪ PO doses >15 mg, may want to switch routes d/t BA ▪ Alternate dosing: 2.5 mg PO q 12 hours for 3 doses every week ▪ Add folic acid 1mg PO daily ▪ Consider IM/SQ if GI side effects 30 MTX: Monitoring ▪ CBC with differential and platelets, serum creatinine, and LFTs ▪ Baseline and every 2 to 4 weeks for 3 months or if dose increases, then every 8 to 12 weeks until 6 months of therapy, then every 12 weeks or more frequently if clinically indicated ▪ Chest x-ray within 1 year prior to initiation ▪ Hepatitis B and C serology if at high risk ▪ Tuberculosis test annually for patients who have potential TB exposure ▪ Liver biopsy ▪ Baseline only for patients with persistent abnormal baseline LFTs, history of alcoholism, or chronic hepatitis B or C or during treatment if persistent LFT elevations (6 of 12 tests abnormal over 1 year or 5 of 9 results when LFTs performed at 6-week intervals) ▪ LFTs > 2x ULN = stop 31 Leflunomide (Arava) https://images.app.goo.gl/tLsJ5Mzg3ShHmcgT7 ▪ Inhibits pyrimidine ▪ Decreased lymphocyte proliferation, modulates inflammation ▪ Long half life; (18-19 days for active metabolite) onset about a month ▪ PRO-DRUG ▪ Without loading dose the steady state takes MONTHS to achieve ▪ Loading dose 100 mg daily for 3 days, then maintenance dose 20 mg daily ▪ Any disease duration ▪ Any disease severity ▪ Can decrease if SE 32 https://images.app.goo.gl/VVqz2aSrqyFVnfer9 Leflunomide: Adverse Effects ▪ Dose related ▪ N/V/D ▪ Alopecia ▪ Bone marrow suppression ▪ CBC monthly x 6 months, then q 6-8 weeks ▪ Contraindicated in liver disease ▪ LFTs >2x ULN = Stop ▪ Monitor LFTs monthly x 3 months then quarterly ▪ Pregnancy Category X 33 Leflunomide: Monitoring ▪ Pregnancy test prior to initiating therapy (in females of reproductive potential) ▪ TB test at baseline (annually for patients who have potential TB exposure) ▪ CBC with differential and platelets, at baseline and monthly during the initial 6 months of treatment; if stable, monitoring frequency may be decreased to every 6 to 8 weeks thereafter ▪ LFTs monthly for the first 6 months of treatment, then every 6 to 8 weeks thereafter 34 Leflunomide: Detox ▪ 6 months ▪ Place in therapy d/t NO myelosuppressive, NO hepatic and renal toxicities 36 Hydroxychloroquine – Adverse Effects ▪ GI effects are most common ▪ N/V/D, mitigated when taken with food ▪ Ocular toxicities– Monitor regularly ▪ Derm: rash, alopecia, and increased skin pigmentation ▪ Neuro: headache, vertigo, and insomnia usually are mild ▪ Pregnancy Category unranked ▪ Weigh risks and benefits 37 Hydroxychloroquine ▪ Indicated for all disease durations and severities ▪ Take with food ▪ Start: 200-300 PO mg BID ▪ After clinical response or 1-2 months, decrease to 200 mg daily or 200 mg BID 38 Sulfasalazine (Azulfidine) ▪ Prodrug ▪ Cleaved by gut bacteria in the colon to sulfapyradine and 5-ASA (IBD) ▪ What happens in SIBO or gut dysbiosis?? ▪ In this case the sulfapyradine is responsible for effect ▪ Response seen in < 2 months ▪ Binds Fe-limits absorption 39 Sulfasalazine – Adverse Effects ▪ GI: N/V/D/anorexia ▪ Start low, go slow titration ▪ Serum Sickness ▪ Flu like ▪ Rash ▪ Urticaria ▪ Hypersensitivity – contraindication ▪ Yellow-orange skin and urine*** 40 Sulfasalazine – Indication and dosage ▪ Indicated for all disease durations and severities ▪ Enteric coated ▪ 0.5 – 1 gm PO daily x 1 week ▪ Increase daily dose by 500 mg q week until 2 gm TDD (3 gm max) ▪ Can titrate more slowly or divide dose to minimize AE 41 Other DMARDs: Use limited by toxicities and LT benefits Gold salts Azathioprine D-penicillamine Cyclosporine Minocycline Cyclophosphamide 42 Treatment Strategies ▪ DMARD Monotherapy ▪ Combination therapy ▪ Dual ▪ Methotrexate plus hydroxychloroquine ▪ Methotrexate plus leflunomide ▪ Methotrexate plus sulfasalazine ▪ Triple DMARDs ▪ Sulfasalazine, hydroxychloroquine, and methotrexate 43 Biologic DMARDs RA 44 Biologic DMARDs ▪ Historically reserved for treatment failure ▪ NOW, carries indication for moderate to severe RA ▪ Effective ▪ Less toxicities, less monitoring ▪ Increase risk of infection ▪ Must test for TB prior to initiation of therapy ▪ If develop infection should discontinue infection is resolved ▪ No live vaccines should while taking biologics ▪ $$$ 45 Biologics: TNF-alpha Inhibitors Rheumatoid Arthritis 46 TNF Inhibitors ▪ Dysregulation of TNF-α production is associated with inflammation ▪ E.g. RA, IBD, ankylosing spondylitis, PsA, and psoriasis ▪ TNFα induces inflammatory cytokines (interleukins), enhances leukocyte migration, activates neutrophils and eosinophils, and induces acute phase reactants and tissue degrading enzymes Certolizumab Etanercept Infliximab Adalimumab Golimumab pegol (Enbrel), (Remicade) (Humira) (Simponi) (Cimizia) 47 TNF Inhibitors ▪ Warnings: ▪ CHF: increased risk of worsening and new-onset CHF ▪ Contraindicated in moderate-to-severe CHF (NYHA class III/IV) ▪ MS: development or worsening of autoimmune diseases such as peripheral and central demyelinating disorders (e.g. MS & drug-induced lupus-like syndromes) ▪ CA: increased risk of malignancies such as lymphoma, melanoma, & nonmelanoma skin cancer ▪ Cutaneous ADRs: e.g. vasculitis, granulomatous reactions, cutaneous infections, psoriasiform eruptions, & infusion or injection site reactions 48 Etanercept (Enbrel) ▪ Indicated for moderate to severe active RA ▪ Ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis ▪ Recombinant DNA-derived protein composed of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1 ▪ Binds tumor necrosis factor (TNF) and blocks its interaction with cell surface receptors ▪ Dose: 50 mg SQ once weekly (off-label 25 MG BIW) ▪ Typically self injection ▪ May continue methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics during etanercept therapy https://images.app.goo.gl/UN2zPVvpMqScGWt58 49 Etanercept (Enbrel) ▪ Adverse Effects ▪ Pruritic injection site reactions (up to 43%) ▪ lasts 3-5 days x 1st month, then better ▪ Other ADRs are similar to the TNF profile ▪ Headache (19%) ▪ Infection (up to 81%) ▪ URTI & LRTI Common: 65% and 54%, respectively ▪ Monitoring ▪ Baseline and Yearly ▪ PPD ▪ CBC ▪ LFTs 50 Infliximab (Remicade) ▪ Chimeric monoclonal antibody (mouse and human) ▪ Binds to TNFα, interfering with endogenous TNFα activity ▪ Indicated for adults with moderate to severe active rheumatoid arthritis with methotrexate ▪ AND severe psoriasis, PsA, Crohn’s disease, Ulcerative colitis, & Ankylosing spondylitis ▪ Dose: IV 3 mg/kg at 0, 2, and 6 weeks, followed by 3 mg/kg every 8 weeks thereafter ▪ Response seen in 4 weeks ▪ Infuse over 2 hours ▪ Begin infusion within 3 hours of reconstitution ▪ May lose efficacy due to antibody development (murine component) ▪ 14-40% of patients 51 Infliximab (Remicade) ADRs ▪ Infusion reactions: ▪ Flu-like symptoms ▪ Pruritus or urticaria ▪ Fever, chills, fatigue, diarrhea, ▪ Chest pain, hypotension, SOB pharyngitis ▪ Headaches, CNS complications ▪ How to minimize infusion reactions: ▪ Pre-medicate ▪ APAP and diphenhydramine 90 minutes prior to infusion ▪ Monitoring ▪ Corticosteroids ▪ Baseline & yearly ▪ Slow rate of infusion OR ▪ PPD ▪ CBC, ▪ Give with MTX or other immunosuppressants ▪ LFTs ▪ Infection ▪ Cases of hepatotoxicity ▪ CNS symptoms 52 Adalimumab (Humira) ▪ Anti-TNFα monoclonal antibody (IgG1) ▪ Binds to TNF-alpha, interfering with binding to TNFα receptors ▪ Indicated for adults with moderate to severe active rheumatoid arthritis ▪ AND Psoriasis & Psoriatic Arthritis. Juvenile idiopathic arthritis, Crohn’s disease, Ulcerative colitis, & Ankylosing spondylitis ▪ Great efficacy ▪ Noticeable improvement in only 1 week ▪ 75-100% improvement can be sustained x 3 years ▪ Dose: 40 mg SQ every other week (can continue methotrexate, other nonbiologic DMARDS, corticosteroids, NSAIDs, and/or analgesics); patients not taking concomitant methotrexate may increase dose to 40 mg every week ▪ Rebound unusual ▪ Lose efficacy if stopped and restarted ▪ ADRs similar to TNF profile (slightly more favorable) 53  Golimumab (Simponi) ▪ Human monoclonal antibody to TNF-alpha ▪ FDA Indx: moderate to severe active rheumatoid arthritis with methotrexate, Psoriatic Arthritis, UC, Ankylosing spondylitis ▪ Dose: 50 mg SQ once monthly with methotrexate ▪ IV: 2 mg/kg at weeks 0, 4, and then every 8 weeks thereafter with methotrexate ▪ AEs similar to TNF profile https://www.simponi.com/psoriatic- 54 arthritis/simponi-dosing/how-to-inject-simponi Certolizumab pegol (Cimzia) ▪ Indicated for moderate to severe active rheumatoid arthritis, Plaque psoriasis, Psoriatic Arthritis, Crohn’s, & Ankylosing spondylitis ▪ Pegylated humanized antibody fragment to TNF-alpha ▪ Dose: 400mg SQ at Week 0, 2, 4, then 200mg every other week ▪ Alternative maintenance dose: 400 mg SQ every 4 weeks ▪ Alone or with MTX ▪ AEs similar to TNF Profile ▪ Infections 38% ▪ URI 6-20% 55 Other biologics (non-TNFi) 56 Abatacept (Orencia) ▪ Inhibits interaction between APC and T-cells, prevents T-cell activation ▪ Binds CD80/CD86 receptors on antigen-presenting cells ▪ Indicated for moderate to severe RA as monotherapy or combo, typically in patients who fail to achieve an adequate response from other DMARDs ▪ Can combo with MTX ▪ AEs: headache, nasopharyngitis, dizziness, cough, back pain, hypertension, dyspepsia, urinary tract infection, rash, and extremity pain ▪ Infusion reactions ▪ Increase risk of infection and malignancy ▪ No live vaccines during and for 3 months after the completion of therapy ▪ Use with caution in COPD patients 57 Abatacept (Orencia) ▪ IV infusion over 30 minutes, Weight based ▪ Dose IV at weeks 0, 2, and 4, then q 4 weeks thereafter ▪ >100 kg – 1000 mg ▪ 60 – 100 kg – 750 mg ▪