The Pharmacotherapy of Rheumatoid Arthritis

Rheumatoid Arthritis Rheumatoid Arthritis autoimmune Trtitumunosuppresent see to plathates exerts crohn'sdisease WBCIBRBC CoupsArthritis psoriasis • Autoimmune disorder that a ects the joints, leading to inflammation, pain, and sti ness. Key Clinical Features: Morning sti ness (especially in fingers) Symmetric joint involvement (a ects both sides of the body) Arthritis in three or more joints/areas at one time. Rheumatoid nodules (firm lumps under the skin) Serum Rheumatoid Factor (RF) t • Found in ~80% of patients Batfest • Negative RF does NOT rule out RA Radiographic changes (joint space narrowing, bone erosion) Exact etiology of RA is unknown 2 /1 6/ 20 2 5 Gosanbegeneticondenyimental cortisone Immunosuppressive med makeyourImmuresystem wead 3 inRIcytokineskeepsfighting orCauseindemation Pathogenesis of the inflammatory response whateverisinthe Teacher toattack 1. going a up Antigen-presenting cells (APCs) process and present antigens to T cells body 056s • Stimulate B cells to produce antibodies (rheumatoid factor - RF) • Positivity of RF is associated with more aggressive disease frominfection or UIhelpprotectbody 2. Macrophages • Stimulate osteoclasts to destroy and remove bone • Further stimulate T cells and osteoclasts to promote inflammation • Stimulate fibroblasts to release matrix metalloproteinases (MMPs) to degrade the bone matrix and produce inflammatory cytokines 3. T cells and macrophages also release factors that promote inflammation study • Tumor necrosis factor-α (TNF-α) and interleukin (IL-6, and IL-17) • Causes destruction, swelling, edema, redness, and pain that increases the severity of the illness • Results in cellular invasion of synovial tissue and joint injury 2/1 6/2 02 5 G.jo bricont I touseinflame Loo atkines firefight 6 In RI a JAIiscalling everyday Other mechanisms of pathogenesis • Overexpression of tumor suppressor gene p53 a CellDeath • Prevents normal DNA repair and interferes with cell apoptosis • Presence of anti-citrullinated protein antibodies (ACPA or Anti-CCP) is an important diagnostic tool for RA • Positivity is associated with a poorer prognosis in patients with RA • Signaling molecules that are important for activating and maintaining inflammation • Janus Kinase (JAK) promotes leukocyte activation –ex: Tofacitinib is an oral JAK inhibitor Go BE callingyourimmune systemsayingsomethingistrong 2 /1 6/ 20 2 5 7 Risk Factors so Pinflamation triggerimmuresystem • Cigarette smoking infection 474.1 • Stress (physical or emotional) • Gender: Women are twice as likely to develop RA • Genes: Patients with HLA-DR4 antigen are 3.5 times more likely to develop RA Mt • Infections: Epstein-Barr virus and E. coli 2/1 6/2 02 5 Ifyouhavethisgene youhave fetid Theninfegion 8 Joint Involvement no smallerjoints • Usually affecting: • Hands (PIP and mostly MCP joints) • Wrists • Knees • Ankles • Feet (MTP joints) • Often bilaterally • Tenderness, warmth, and swelling (feels soft and spongy) with or without pain • Rheumatoid nodules may be present • Symptoms present for 6 weeks or more • Deformities possible with advanced disease 2/1 6/2 02 5 10 2/1 6/2 02 5 11 C 2 /1 6/ 20 2 5 12 RAdiagnose severity monitoring Mia Laboratory tests/ Radiography Laboratory Tests • Rheumatoid Factor (RF). Present in 70-80% of RA patients. Higher titers may indicate more severe disease • Anti-Cyclic Citrullinated Peptide (ACPA/Anti-CCP) Antibodies. Highly specific (79-98%) for RA. Associated with more aggressive disease and worse prognosis • Erythrocyte Sedimentation Rate (ESR) & C-Reactive Protein (CRP). Markers of inflammation. Elevated levels correlate with disease activity and progression Radiographic Findings (X-Ray, MRI, Ultrasound) • Early RA: Soft tissue swelling, Joint space narrowing due to cartilage loss • Advanced RA: Joint erosions, subluxations, and deformities. Bone loss (osteopenia) around affected joints. Severe destruction 2/1 6/2 02 5 13 NImost fiber moreveg Nonpharmacologic Treatment Therapies to Improve Function: • Occupational therapy (OT) – Helps improve daily function and adapt to physical limitations • Physical therapy (PT) – Enhances mobility, strength, and reduces pain Lifestyle Modifications: • Weight reduction – Reduces stress on weight-bearing joints and improves overall health • Low-impact exercises: • Walking – Improves joint flexibility and cardiovascular health • Swimming – Reduces joint strain while promoting movement • Cycling – Enhances muscle strength with minimal joint impact Surgical Interventions (For Severe Cases): • Surgery – Considered in advanced cases for joint repair or replacement 2/1 6/2 02 5 15 Anti-Inflammatory Treatments for RA IbuprofenAdsit 1. a Provide symptomatic relief but do NOT prevent or slow joint destruction. Should ONLY be used in NSAIDsconjunction with DMARDs, not as monotherapy. asInsomngitatewifood 2. Corticosteroids • Potent anti-inflammatory agents that can help slow joint damage. • Not ideal for long-term use due to significant side e ects. • Used in low doses (5-10 mg prednisone) for short periods during active disease. • Often serves as “bridge therapy” until DMARDs take e ect. Rtfm mo gypped start cortisoneuntilDmardstartyouting 3. RA-PVOS (Prednisone) – Delayed-Release Option • Special formulation that releases prednisone ~4 hours after ingestion, enhancing absorption. • Recommended at night to reduce morning sti ness in RA patients. Takeatzight 2 /1 6/ 20 2 5 16 DMARDs (Disease-Modifying Anti-Rheumatic Drugs) Slow down RA progression and help prevent joint damage. • Non-Biologic DMARDs- Should be started within 3 months of diagnosis. • Biologic DMARDs- Reserved for patients who do not respond to non-biologic DMARDs. 2/1 6/2 02 5 17 med suppression marrow causeBone Allthese me Non-Biologic DMARDs 2/1 6/2 02 5 EMI 18 Eton Biologic DMARDs at Bell 2/1 6/2 02 5 as 19 Methotrexate (MTX) • Brand Names: Rheumatrex (PO tablet), Xatmep (PO solution), Otrexup, Rasuvo (SC) Mechanism of Action: I 2 3 a 5 EM Antimetabolite chemo agent (cell cycle-specific) S-phase toxin (Inhibits DNA synthesis during S phase) Folic Acid Structural Analog Competitively inhibits Dihydrofolate Reductase (DHFR) Inhibits de novo pyrimidine synthesis • Dosing: Once weekly – Max dose: 25 mg per week G Ifyouseedatythatsarongertoatment 2/1 6/2 02 5 higherdose forager 21 Methotrexate (MTX) fan • 5 Indications: 1. Rheumatoid Arthritis (RA) 2. Management of Psoriasis 3. Crohn’s Disease 4. Cancer therapy (Chemotherapeutic agent) 5. Termination of Ectopic Pregnancy (Pregnancy Category X) 2 /1 6/ 20 2 5 22 sulfaallergy coursephotosensitivity CRASHBgctnmtoonerg Methotrexate (MTX) Class Side Effects (SE) for ALL DMARDs noMucositis, Stomatitis061 flotation Bone Marrow Suppression Pulmonary Toxicity, Nephrotoxicity Photosensitivity (Avoid prolonged sun exposure) Crystallization in kidneys Methotrexate-Specific Side Effects Hepatotoxicity (Monitor LFTs) 2 3 Bone Marrow Suppression (Monitor CBC, neutrophils, lymphocytes, RBCs) Pulmonary Fibrosis (Monitor Chest X-ray, Pulmonary Function Test) 2/1 6/2 02 5 23 Is folatenhibitor mo Methotrexate (MTX) Bys experiencing Important Considerations pls reasonwhy no Supplement with Folic Acid (1 mg daily) to reduce toxicity (Except on the day of taking MTX) Exam AVOID Proton Pump Inhibitors (PPIs) – Can interfere with methotrexate absorption Oh AVOID Live Vaccines while on methotrexate MainaHoldtheBhim Trimethoprim-Sulfamethoxazole (Bactrim) interacts with MTX If patient must take Bactrim, HOLD methotrexate for 2 weeks, then restart Antidotes for Methotrexate Toxicity : Folinic Acid (Leucovorin), Glucarpidase Counseling Pt: Drink plenty of water/fluids (↓ crystallization in the kidneys to flush it out), use sunscreen 2 /1 6/ 20 2 5 24 Leflunomide (Arava) • Indication: Only for RA Washout procedure (t ½ life: 2 weeks) if: MOA: • Inhibits dihydroorotate dehydrogenase ->Pyrimidine inhibitor • Inhibitor of T-cell activation & proliferation • Similar to MTX in effects & efficacy Switching from leflunomide to another DMARD Hepatotoxicity PO ONLY Pregnancy (Cat X): Arava is contraindicated in premenopausal women or men who wish to father children. AtWashout Options: Eton Cholestyramine 8 grams TID for 11 days OR Activated charcoal 50 g made into suspension every 12 hours for 11 days 2/1 6/2 02 5 25 dng PI moo Azathioprine (Imuran) Ion 5 Indications: MOA: Purine analog / “antimetabolite” converts to 6-MP 1. RA 2. Chemotherapeutic agent warBoyddisafe PO ONLY 3. Ulcerative Colitis 4. Crohn’s Disease 5. Kidney transplant Pt 2 /1 6/ 20 2 5 26 Azathioprine (Imuran) SE: Myelosuppression Monitor: Hepatotoxic (monitor LFTs), Immunosuppressant (Monitor CBCs) DDI: Xanthine Oxidase Inhibitors (Allopurinol, Febuxostat) Metabolized via Xanthine Oxidase → ↓ dose of Azathioprine by 75% if administered with Allopurinol or Febuxostat If giving Azathioprine 100 mg w / Allopurinol then give Azathioprine 25 2/1 6/2 02 5 27 2 /1 6/ 20 2 5 28 D-penicillamine (Cuprimine) Indications: to logM • RA MOA: RA: Lowers IgM Rheumatoid factor. Wilson's Disease: Chelates with lead, copper, and mercury to form stable, water-soluble complexes that are excreted in urine • Wilson’s disease (Genetic disorder → Body can’t eliminate copper) Notes: Eon • Non-bio DMARD that is NOT hepatotoxic Special Instructions for Use: • Renally adjusted → Since it’s cleared by the kidneys, dose adjustments are needed in kidney disease. • Derived from Penicillin (PCN) → Avoid in patients with penicillin allergy. • Take on an empty stomach → Food can interfere with absorption. 2/1 6/2 02 5 29 Hydroxychloroquine (Plaquenil) Indications: • RA • Treatment + prevention of Malaria on • Lupus (SLE) PO ONLY SE / Monitoring: fam • Retinopathy (irreversible, monitor vision every 3 months) Trringingintlegy • Tinnitus (risk of toxicity) Agim MOA: An antimalarial agent used in RA suppresses the immune system by: • Reducing inflammatory cytokines involved in RA and lupus. • Immunosuppressant (monitor CBCs) • Hepatotoxicity (monitor LFTs) Key Clinical Relevance: • Unlike other DMARDs, Hydroxychloroquine does NOT cause myelosuppression (bone marrow suppression), making it safer in some patients. Eon Counseling Pt: Take on an empty stomach 2/1 6/2 02 5 30 Sulfasalazine (Azulfidine) SULFA allergy: SAL (Salicylate Allergy) ton Indications: usAspin MOA: 5-aminosalicylic acid (5-ASA) is the active component of sulfasalazine • RA → BID RA 2 • Ulcerative Colitis → TID Ues Renal Dose Adjustment (Regardless of indication): • CrCl 10 - 30 → BID only • CrCl < 10 → Once daily Gedney y z 2/1 6/2 02 5 s cabotead 31 Sulfasalazine (Azulfidine) SE: • Hepatotoxicity (monitor LFTs) • Bone Marrow suppression Contraindications: • Avoid in hepatic and renal failure • Sulfonamide or salicylate sensitivity • Urine Discoloration • Rash (Stevens-Johnson syndrome) Counseling Pt: • Take with Food (improves absorption) • Drink plenty of Water (won’t accumulate in the kidneys) 2/1 6/2 02 5 Monitoring: CBC, LFT, renal function, hypersensitivity reaction 32 JAK Inhibitors Indication: RA - ↓ response or intolerant to MTX. Used as monotherapy or in combination with MTX or other nonbiologic DMARDs. Don’t combine with biologics DMARDs ,azathioprine,or cyclosporine. MOA: Block Janus kinases (JAK) 1. Tofacitinib (Xeljanz) • Xeljanz XR → QD • Xeljanz → BID Indications: • RA • Juvenile idiopathic arthritis (JIA) • Psoriasis • Ulcerative colitis 2. Upadacitinib (Rinvoq) PO ONLY Indications: • RA • Juvenile idiopathic arthritis (JIA) • Psoriasis • Ulcerative colitis 3. Olumiant (Baricitinib) Indication: • RA only Class Monitoring: • Baseline TB test (latent TB will become Active TB) • No LIVE vaccine O 2 /1 6/ 20 2 5 bandits 33 Biologic DMARDs --SC/IV Exam • Monoclonal AB → Stored in the Fridge • Class SE: All cause immunosuppression (Monitor CBC) • Baseline TB test (PPD or IGRA) required! (Latent TB contraindicated) • Do not give Live vaccine 2/1 6/2 02 5 34 Anakinra (Kineret) Non-TNF biologics MOA: Interleukin-1 receptor antagonist • Only BIO DMARD dosed daily • All other DMARDs are dosed either weekly, bi-weekly, monthly, or bi-monthly Indications: • RA children no • Juvenile idiopathic arthritis (JIA) – Just like Xeljanz S/E: Infections: Neutropenia SC: Inject into the outer area of upper arms, abdomen (not within 2 inches of the belly button), front of middle thighs, or upper outer buttocks Do not use with: Active infection, TNF-blockers Monitoring: CBC for Neutrophil count, TB test at baseline 2/1 6/2 02 5 35 TNF-alpha blockers Class Indications: • RA • Psoriasis / Psoriatic arthritis (PsA) • Hydroxychloroquine Treats Lupus • Meds that cause Lupus: Loops, hydralazine, methyldopa, TNF-α • Ankylosing spondylitis (AS) (Autoimmune disorder) Contraindications & Risks: • Heart Failure (HF) , Hepatitis B (HBV) • Risk of Infections – they increase the risk of serious infections (e.g., TB, fungal infections). • Baseline TB test is required before starting therapy. • Live vaccines are contraindicated while on TNF-alpha blockers. • Drug-Induced Lupus (DILE) – TNF-alpha inhibitors can cause lupus-like symptoms in some patients. (SE): Hepatotoxicity – Monitor(LFTs), Increased lymphoma risk, Infections ANSA 2/1 6/2 02 5 ORPILE LUPUS 36 Etanercept (Enbrel) TNF-alpha blockers MOA: TNF receptor blocker • SC Weekly • Biosimilar: Erelzi injectable –Not interchangeable • Additional Indications: JIA (juvenile idiopathic arthritis) 2/1 6/2 02 5 37 Adalimumab (Humira) TNF-alpha blockers • SC- Inject: thighs & abdomen MOA: Monoclonal antibody - TNF alpha blocker • Weekly → Monotherapy • + MTX → SC QOW • Biosimilar: Amjevita Additional Indications: • Crohn’s disease (CD) • Ulcerative Colitis (UC) 2/1 6/2 02 5 38 Certolizumab (Cimzia) TNF-alpha blockers • SC QOW or SC Monthly MOA:TNF inhibitor Additional Indications: • Crohn’s disease • Ulcerative Colitis 2/1 6/2 02 5 39 Golimumab (Simponi) TNF-alpha blockers • + MTX SC Monthly for RA MOA: Targets and neutralizes TNF-α • Simponi Aria IV Q8W (Over 30 min infusion) Additional Indications: • Ulcerative Colitis (UC) 2/1 6/2 02 5 40 Infliximab (Remicade) TNF-alpha blockers moreeffective • + MTX IV Q8W for RA MOA: Anti-TNF alpha monoclonal antibody • Biosimilars: Inflectra, Renflexis • Compatible with NS only • Begin infusion within 3 hours of reconstitution (Over 2-hour infusion) • SE: Infusion-related rxn’s → Premedicate (APAP + CS ± Diphenhydramine) prior to infusion Additional Indications: • Crohn’s disease (CD) • Ulcerative Colitis(UC) 2/1 6/2 02 5 41 Abatacept (Orencia) Non-TNF biologics • SC weekly; IV Monthly MOA: A selective T cell co-stimulation modulator • Indications: RA only - An option for patients who do not respond to MTX, TNF blockers, or other DMARDs • Avoid in Pts with Asthma/COPD 2/1 6/2 02 5 42 Tocilizumab (Actemra) Non-TNF biologics • SC weekly; IV Monthly • RA only 1 MOA: Interleukin-6 (IL-6) inhibitor Sarilumab (Kevzara) Non-TNF biologics • SC QOW 2/1 6/2 02 5 MOA: Interleukin-6 (IL-6) inhibitor 43 Rituximab (Rituxan) Non-TNF biologics • + MTX IV QOW x 2 doses ONLY in RA Indications: • Non-Hodgkin’s Lymphoma MOA: Monoclonal Antibody to the CD20 antigen that depletes CD20 positive B Cells • Refractory RA (last line) S/E: • Infusion-related rxn’s → Premedicate (APAP ± CS ± Diphenhydramine) prior to infusion Bcall lastonlyfo zmonth • Hepatitis B reactivation → liver failure and death. Patients should be screened prior 2/1 6/2 02 5 44 Review of Biologic Agents IL-1 receptor antagonist: Anakinra (Kineret) SC QD The five TNF blockers: • Adalimumab (Humira) SC every other week • Etanercept (Enbrel) SC once weekly • Infliximab (Remicade) IV infusion every 8 weeks • Golimumab (Simponi) SC once a month / IV Q8 weeks • Certolizumab (Cimzia) SC once a month or twice a month Cell activation inhibitor: Abatacept (Orencia) IV / SQ CD20 monoclonal antibody: Rituximab (Rituxan) IV Interleukin-6 (IL-6) inhibitor: • Tocilizumab (Actemra) IV / SQ • Sarilumab (Kevzara) SQ 2/1 6/2 02 5 45 RA Treatment Review Methotrexate (MTX) is the first-line treatment due to its e ectiveness and long-term benefits. If additional therapy is needed, consider: • Sulfasalazine or Hydroxychloroquine for mild to moderate disease. A biologic DMARD if MTX response is inadequate. TNF inhibitors are the preferred first-line biologic DMARDs when conventional DMARDs fail, often used in combination with MTX for enhanced e icacy. Tofacitinib (Xeljanz) and other JAK inhibitors should be reserved for severe or refractory cases when TNF inhibitors are ine ective or contraindicated. Short-term corticosteroids may be used to manage acute flares or bridge therapy until DMARDs take e ect. Educate patients to promptly report signs of infection (e.g., fever, malaise, unusual fatigue) to prevent complications. 2 /1 6/ 20 2 5 46 2/1 6/2 02 5 47 Bone Marrow Suppression (BMS) / Myelosuppression WBClowainfection Reduced production of all blood cell lines (pancytopenia) thot Egon WarLower of platletsintleblood 45 body your Arabiling Bone Marrow Suppression (BMS) / Myelosuppression = • Anemia → ↓ RBCs → ↓ Hemoglobin (HGB) & Hematocrit (HCT) • Neutropenia → ↓ Neutrophils → ↑ Infection risk • Thrombocytopenia → ↓ Platelets → ↑ Bleeding risk 2 /1 6/ 20 2 5 48 Symptoms of Blood Cell Deficiencies Red Blood Cell (RBC) Decrease → Anemia • Symptoms: Fatigue, weakness, pale skin (pallor), shortness of breath, dizziness. White Blood Cell (WBC) Decrease → Leukopenia/Neutropenia • Symptoms: Increased risk of infections, fever, slow wound healing. Platelet (PLT) Decrease → Thrombocytopenia gum 2/1 6/2 02 5 • Symptoms: Easy bruising, prolonged bleeding, petechiae (small red spots on the skin), nosebleeds, bleeding. FridgeHastailure TBtest 49 Most frequently dosed to least frequently dosed: EAGGI Etanercept Mr Enbrell Bisimilar as tax ABV Adalimumab petrolizanab Hamina goin tpaglight EY Ettorser Bisimilar my 2/1 6/2 02 5 É Isimponil Crohn's cremisade pinflitimab Bisimilor inflection Renflexist Forty 50 ANA InducedLupus DME a somethingas Drug hecan'thave TNT frefency tumomereEncentration goingstragetttoBloodstream legs