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Rheumatoid Arthritis/Osteoarthritis

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1 Rheumatoid Arthritis/Osteoarthritis
Sarah Daoud Florida A&M University College of Pharmacy and Pharmaceutical Sciences 10/02/13 Seminar: Disease Presentation

2 Objectives Discuss the prevalence, epidemiology, risk factors, and pathophysiology of RA/OA. Discuss the signs and symptoms, diagnosis, and treatment of RA/OA. Assess treatment of disease states in special populations. Evaluate the role of the pharmacist in the overall approach of these conditions. Discuss key components of RA/OA which would serve as educational points for patients and healthcare practitioners.

3 RHEUMATOID ARTHRITIS The normal joint structure appears on the left. On the right is the joint with rheumatoid arthritis. RA causes synovitis, pain and swelling of the synovium (the tissue that lines the joint). This can make cartilage (the tissue that cushions between joints) and bone erode, or wear away. -a chronic progressive disease causing inflammation in the joints and resulting in painful deformity and immobility, esp. in the fingers, wrists, feet, and ankles.

4 Prevalence RA is the most common form of autoimmune arthritis affecting more than 1.3 million Americans. Women encompass 75% of individuals diagnosed with this disease. 1-3% of women may get RA in their lifetime. Usual occurrence is in individuals between years of age.

5 Epidemiology RA does not have any racial inclination and can occur at any age. Research has shown, this disease has a genetic predisposition and diagnosis may be necessitated by certain unknown environmental exposures. Major histocompatibility complex (MHC) molecules located on T-lymphocytes play a major role in patients with RA. Human lymphocyte antigen (HLA) typing can characterize these molecules and assess the risk of RA in those with presence of antigens on MHC molecules. -A majority of patients with RA have HLA-DR4, HLA-DR1, or both antigens found in the MHC region. -Patients with HLA-DR4 antigen are 3.5 times more likely to develop RA than those who have other HLA-DR antigens. -Although MHC region is important, it is not the sole determinant, because patients can have the disease without these HLA types.

6 Risk Factors Sex (Female) Family history Older age Silicate exposure
Smoking Consuming 3 or more cups of coffee/day (esp. decaffeinated coffee)

7 Pathophysiology Joint damage in rheumatoid arthritis begins with the proliferation of synovial macrophages and fibroblasts after a triggering incident, possibly autoimmune or infectious. Lymphocytes infiltrate perivascular regions, and endothelial cells proliferate. Neovascularization then occurs. Blood vessels in the affected joint become occluded with small clots or inflammatory cells. Over time, inflamed synovial tissue begins to grow irregularly, forming invasive pannus tissue. Pannus invades and destroys cartilage and bone. Multiple cytokines, interleukins, proteinases, and growth factors are released, causing further joint destruction and the development of systemic complications (vasculitis, pulmonary fibrosis, inflammation of the sclera, pericarditis, Felty’s syndrome)

8 Signs and Symptoms Morning stiffness lasting hours (sometimes whole day) Fatigue Weakness Low-grade fever Loss of appetite Joint pain Firm lumps ***Joint involvement tends to be symmetrical -Joints affected most frequently by RA are the small joints of the hands, wrists, and feet. In addition, elbows, shoulders, hips, knees, and ankles may be involved. -Chronic inflammation with lack of an adequate exercise program results in loss of range of motion, atrophy of muscles, weakness, and deformity.

9 Diagnosis According to the American College of Rheumatology Diagnostic Criteria

10 -Chronic inflammation of the synovial tissue lining the joint capsule results in the proliferation of this tissue. -The inflamed, proliferating synovium characteristic of rheumatoid arthritis is called pannus. -Pannus invades the cartilage and eventually the bone surface, producing erosions of bone and cartilage and leading to destruction of the joint. -Factors that initiate the inflammatory process are unknown.

11 Non-pharmacological Treatment
Rest Occupational therapy Physical therapy Use of assistive devices Weight reduction Surgery -rest alleviated pain and stress on the joints. -therapy provides pt with skills and exercises necessary to increase or maintain mobility. -wt reduction helps alleviate stress on the inflamed joints. -surgery options: tenosynovectomy, tendon repair, and joint replacement.

12 Pharmacological Treatment

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14 Pharmacological Treatment
Agents used for pain and inflammation Drug Dosage Adverse Effects Warnings/Contraindications Notes Ibuprofen (Motrin, Advil) -> mg Q6-8H (mild to moderate pain) -> mg Q6-8H; max 3.2g/d (moderate pain or inflammation) -Dyspepsia -Heartburn -Increase BP -GI bleeding -NSAIDS have BBW of increased risk of adverse CV thrombotic events; contraindicated for CABG perioperative pain; increased GI adverse events (ulceration, bleeding, perforation) -Contraindicated in pregnancy 3rd trimester. -Avoid use in advanced renal disease. Celecoxib (Celebrex) -> mg BID -Diarrhea -Nausea -Warnings are the same as NSAIDS. -Contraindicated with sulfa allergy. -Lower risk of GI complications. -Max 400mg Prednisone (Rayos, Prednisone Intenson) ->Initial 5-60mg daily indicated for acute inflammation ->Can use twice daily dose every other day to decrease adrenal suppression. -Fluid retention -Stomach upset -Increase appetite. -Hyperglycemia -Osteoporosis -Muscle wasting -Contraindicated with live vaccines, systemic lung infections. -Must assess bone density if used long-term. -Must taper dose off. -Rapidly acting antiinflammatory medications, including nonsteroidal antiinflammatory drugs (NSAIDs) and systemic and intraarticular glucocorticoids

15 Pharmacological Treatment
Non-biologic Disease-modifying anti-rheumatic drugs (DMARDS) Drug Dosage Adverse Effects Warnings/Contraindications Notes Methotrexate (Rheumatrex, Trexall) -folate antimetaboline that inhibits DNA synthesis -> mg/week -N&V -Diarrhea -GI upset -Anorexia -Reddening of skin -BBW: fetal death or congenital abn.; hepatotoxicity; BMS; malignant lymphomas; acute renal failure. -Contraindications: pregnancy; alcoholism; chronic liver disease; blood dyscrasias -Never dose daily for RA (dose can be split into smaller doses taken over hours) -Pregnancy category X Hydroxychloroquine (Plaquenil) ->Initial: mg/day ->Maintain: mg/day -Decreased visual acuity -Photophobia -Blurred vision -Corneal deposits -Can cause neuromyopathy with long-term use; SJS; alopecia; pigmentation of skin and hair (bleaching) -Used in mild RA -Take with food or milk -Mainly eliminated by the kidney Sulfasalazine (Azulfidine, Sulfazine) -5-aminosalicyclic acid derivative ->500-1,000mg BID; max 3g/day -Headache -Dyspepsia -Contraindications: pts with a sulfa or salicylate allergy, GI or GU obstruction -Can cause reversible oligospermia; folate deficiency d/t impaired folate absorption -Take with food and 8oz of water to prevent crytalluria -Can cause yellow-orange discoloration of skin/urine -May give 1mg/day folate supplement -Disease-modifying antirheumatic drugs (DMARDs), including nonbiologic (traditional small molecule or synthetic) and biologic DMARDs, and an orally-administered small molecule kinase inhibitor, which all have the potential to reduce or prevent joint damage and to preserve joint integrity and function

16 Pharmacological Treatment
Non-biologic DMARDS cont. Drug Dosage Adverse Effects Warnings/Contraindications Notes Minocycline (Dynacin, Minocin, Solodyn) ->100mg BID -GI upset -N&V -May cause SJS and decreased LFTs -Used in mild RA -Pregnancy Cat. D -Do not use in children 8 yoa or younger. Leflunomide (Arava) -> 100mg x3days, then 20mg daily -Diarrhea -URTIs -Rash -Alopecia -BBW: women of childbearing potential should not use age until pregnancy is excluded; hepatotoxicity -Must have negative pregnancy test before starting and use 2 forms of birth control. -If pregnancy wanted, must wait 2 yrs after discontinuation or give cholestyramine. -Can use with or without methotrexate -Pregnancy Cat. X

17 Pharmacological Treatment
Biologic agents- TNFalpha inhibitors BBW: serious infxs; lymphomas; malignancies; perform test for latent TB before initial therapy. Contraindication: sepsis Can cause worsening or new onset Heart Failure; hep. B reactivation; demyelinating disease. Do not give with other biologics or live vaccines SE: infections and injection site reactions Administration: do not shake; require refrigeration; allow to reach room temp. before injecting These agents are usually add-on therapy to methotrexate Biologics denature if hot.

18 Pharmacological Treatment
Biologic DMARD agents- TNFalpha inhibitors Drug Dosage Notes Etanercept (Enbrel) ->50mg SC once/week Adalimumab (Humira) ->40mg SC every other week -If not taking MTX, can increase dose to 40mg SC weekly Infliximab (Remicade) ->3mg/kg IV at weeks 0,2,6 and then Q8W can increase to 10mg/kg -Higher dose=increase infx risk -Infusion reaction: hypotension, fever, chills, pruritis (benefit from APAP/ antihistamine/ steroids as pre-treatment) -Delayed hypersensitivity rxn 3-10d after admin (fever, rash, myalgia, HA, sore throat) Certolizumab pegol (Cimzia) ->400mg SC at weeks 0,2,4 and then 400mg Q4W -Can maintain at 200mg every other week Golimumab (Simponi) ->50mg SC once/month -Give with MTX Biologics denature if hot.

19 Pharmacological Treatment
Biologic response modifiers Drug Dosage Adverse Effects Warnings/Contraindications Notes Rituximab (Rituxan) -depletes CD20+ B cells ->1g IV day 1 and 15 @50mg/hr (can increase to 400mg/hr if no rxn) -Fever -Chills -Angioedema -BMS -Abdominal pain -BBW: severe and fatal infusion related reactions; PML due to JC virus infection; tumor lysis syndrome leading to acute renal failure and dialysis; SJS, TEN can occur -Warnings: serious infxs -Pre-medicate with a steroid -Used with MTX -Do not give with live vaccines or other biologics -Screen for latent TB before initiating Anakinra (Kineret) -IL-1 receptor antagonist ->100mg SC daily -Headache -Infections -Injection site rxn Abatacept (Orencia) -Selective T cell costimulation blocker ->500mg-1,000mg IV based on body wt; given over 30min PML- progressive multifocal leukoencephalopathy John cunningham virus

20 Pharmacological Treatment
Kinase Inhibitors Drug Dosage Adverse Effects Warnings/ Contraindications Notes Tofacitinib (Xeljanz) -inhibitor of Janus kinase (JAKs) ->5mg PO BID -URTIs -Diarrhea -Headache -BBW: can cause serious infections, lymphomas and other malignancies; screen for latent TB -Can cause GI perforation -Not recommended in severe hepatic impairment -Do not give with live vaccines -Do not use with potent 450 inducers; reduce dose to 5mg daily w/ potent 3A4 and 2C19 inhibitor. -Do not use with biological DMARDs or potent immunosuppressants -Monitor neutrophil count, hemoglobin, and lymphocyte count -Janus kinase inihibitors block cytokine signaling

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24 OSTEOARTHRITIS (AKA: Degenerative Joint Disease)
-degeneration of joint cartilage and the underlying bone, most common from middle age onward. It causes pain and stiffness, esp. in the hip, knee, and thumb joints.

25 Prevalence An estimated 15.8 million adults display symptoms of OA
Prevalence increased with age E.g. Those aged years, 85% have OA of the hands, whereas those 45 year and younger, only 1/5th have OA of the hands. Severity also increases with age Women are more affected Knee OA twice as prevalent in black opposed to white women -Older women twice as likely as men to have OA of hands and knees

26 Epidemiology Most prevalent of the rheumatic diseases
Responsible for disability and loss of productivity OA at some skeletal sites occurs in nearly everyone 75 years and older ½ million symptomatic cases of idiopathic OA occur yearly in the US white population

27 Risk Factors Obesity Repetitive motion (constant stress on hand, knee, etc.) Joint injury Genetics Type and intensity of physical activity -Obesity: increased body weight is strongly associated with hip, knee, and hand OA. The risk of developing OA increases by about 10% with each additional kilogram of weight, and in obese persons without OA, weight loss of even 5kg decreases the risk of future knee OA by ½. -Genetics: heberden’s nodes (hard or bony swellings that can develop in the distal interphalangeal joints (DIP))->higher risk if a woman’s mother had them [2fold increase]. Premature development of OA is associated with a defect in type 2 procollagen.

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29 Pathophysiology Initial thickening of articular cartilage as ECM is damaged and water content increases (from pressure on proteoglycan[component in cartilage matrix]). Decline in response of chondrocytes (only cells found in healthy cartilage) to stabilize or restore tissue, resulting in progressive cartilage loss. Increased turnover of adjacent subchondral bone (the layer of bone right below the cartilage), leading to release of vasoactive peptides and enzymes, causing cartilage degradation. Inc leakiness of adj cartilage. Loss of cartilage exposes the underlying subchondral bone and may lead to microfractures. Microfractures lead to callus and osteoid production. New bone formations at the joint margins distant from cartilage destruction are referred to as osteophytes (an attempt to stabilize the joint) Pain arises from the activation of nociceptive nerve endings within the joint by mechanical or chemical irritants. Osteophytes can have a significant clinical impact and can be a source of pain and loss of function. The latter mainly through nerve compression, limitation of joint mobility and obstruction of tissues and organs.

30 Signs and Symptoms Pain with motion
Joint stiffness lasting <30min (usually in the morning) Joint: Tenderness Crepitus Enlargement Crepitus- a crackling or grating sound heard with joint movement (caused by irregularity of joint surfaces)

31 Diagnosis 3 Goals: Differentiate between primary or secondary OA
Clarify joints involved Assess prior therapies Diagnostic Parameters: OA of knee- Refer to signs and symptoms Age >50yo OA of hand- Heberden’s node (2 or more out of 10) OA of hip- Normal ESR Osteophytes and joint space narrowing on on X-ray Heberden’s node- distal interphalangeal joints (osteocytes or bony enlargement) ESR-erythrocyte sedimentation rate

32 Non-pharmacological Treatment
Exercise programs (aquatic) Weight loss Patient education for self-management Wedged shoe insoles Rest Braces (symptomatic relief) -The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint injury.

33 Pharmacological Treatment
Pain Relief (primary indication for pharmacological treatment) Drug Dosage Adverse Effects Warnings/ Contraindications Notes Acetaminophen (Tylenol) -> mg PO Q6H -Constipation -Headache -Vomiting -Contraindications; hepatic impairment -Alcoholism can increase hepatic injury -For mild to moderate pain -Max 4g/day Tramadol (Ultram) ->initial: 25mg/day, increase by 25mg increments in separate doses every 3 days ->maintain: mg PO Q4-6H -Flushing -Nausea -Xerostomia -Contraindications: hypercapnia, severe bronchial asthma, acute intoxication with alcohol, narcotics, etc. -For moderate to severe pain -Max 400mg/day -Adjust dose for renal impairment -Tx strategies include approaches directed at achieving remission or low disease activity by more rapid and sustained control of inflammation and by the institution of disease-modifying antirheumatic drug (DMARD) therapy early in the disease course.

34 Pharmacological Treatment
Opioid Analgesics Drug Dosage Adverse Effects Warnings/ Contraindications Notes Codeine sulfate ->15-60mg PO Q4H -Somnolence -Dyspnea -Hypotension -Bowel obstruction -Pancreatitis -Contraindications: bronchial asthma, hypercarbia -Has potential for abuse -May cause diminished biliary and pancreatic secretions -May prolong GI obstruction -For mild to moderate pain -Max dose: 360mg/day Oxycodone hydrochloride ->5-15mg PO Q4-6H -Constipation -Nausea -BBW: fatal respiratory depression -For moderate to severe pain

35 Pharmacological Treatment
NSAIDS Drug Dosage Adverse Effects Warnings/ Contraindications Notes Aspirin ->Up to 3g/day in divided doses -GI upset -Bleeding -GI ulcer -Caution with bleeding disorders, renal or hepatic disease -May take with food or milk Ibuprofen (Advil) ->1200 to 3200 mg/day PO in 3-4 divided doses -Dyspepsia -Heartburn -Increase BP -GI bleeding -NSAIDS have BBW of increased risk of adverse CV thrombotic events; contraindicated for CABG perioperative pain; increased GI adverse events (ulceration, bleeding, perforation) -Contraindicated in pregnancy 3rd trimester. -Avoid use in advanced renal disease Naproxen (Aleve) -> mg PO BID -Edema -Abdominal pain -Tinnitus -Dyspnea --NSAIDS have BBW of increased risk of adverse CV thrombotic events; contraindicated for CABG perioperative pain; increased GI adverse events (ulceration, bleeding, perforation) -Max 1500mg/day for up to 6 mo Celecoxib (Celebrex) ->100mg BID or 200mg daily -Diarrhea -Nausea -Warnings are the same as NSAIDS. -Contraindicated with sulfa allergy. -Max 200mg

36 Pharmacological Treatment
Topical NSAIDS (preferred over oral NSAIDs for pts >75 yoa) Topical Analgesics Drug Dosage Adverse Effects Warnings/ Contraindications Notes Diclofenac sodium 1% gel (Voltaren) ->4g topically to lower extremities 4x/day ->2g to upper extremities 4x/day -Application site rxn -Burning sens. in eye -Raised IOP -Same as NSAIDs BBWs -NSAID oral therapy not recommended concomitantly -Can cause anaphylaxis -Max 8g/day to any single joint of upper extremity; 16g/day for lower extremity; 32g/day total over all affected joints Trolamine salicylate 10% cream (Arthricream) ->Apply topically 3-4x/day -Erythema -Skin irritation -Contraindications: hypersensitivity to salicylates, severe renal insufficiency -May cause tinnitus -Beware of toxicity with over use -Do not cover area with occlusive material Drug Dosage Adverse Effects Warnings/ Contraindications Notes Capsaisin 0.025% or 0.075% ->Apply to affected joints 3-4x/day -Application site erythema -Pruritus -Nausea -Hypertension -May increase risk of cardiovascular adverse effects -Use nitrile gloves for handling

37 Pharmacological Treatment
Intra-acrticular Glucocorticoids (knee or hip) Drug Dosage Adverse Effects Warnings/ Contraindications Notes Triamcinolone acetonide (Kenalog, Aristocrat A, Nasacort) ->initial mg as single injection ->Additional doses can be adjusted to 20mg or more -Cushing’s syndrome -Headache -Pharyngitis -Flu-like symptoms -Contraindications: administration with live vaccines; idiopathic thrombocytopenic purpura -Increased risk of infections -Impaired skin healing -Weight gain -Hyperglycemia Triamcinolone hexacetonide (Aristospan) ->up to 0.5mg/square inch of affected skin -Hypertension -Osteoporosis -Same as above -Total daily dose may vary from 2-48mg/day Used if condition has progressed to pure inflammation

38 Pharmacist Role Be aware of certain labs to order for particular agents Understand patient populations, which certain medications should be avoided in Counsel patients on the disease state , SE, possible treatments Assess progression of disease and appropriate measures to take Make recommendations to physicians regarding drug regimen *RA-We obtain a baseline complete blood count, serum creatinine, aminotransferases (AST/ALT), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in all patients. -Serologic testing for hepatitis w/ MTX, biologic DMARDs, leflunomide -Opthalmology consult with hydroxychloroquine

39 Clinical Pearls- Based on Guidelines
RA Etanercept recommended for use in patients with hepatitis C. No biologics for hepatitis B Rituxibam recommended for pts with malignancy <5yrs, treated skin melanoma, treated lymphoproliferative disease TNF inhibitor recommended for patients with CHF OA Knee Acetaminophen Oral NSAIDs Topical NSAIDs Tramadol Intraarticular corticosteroid injections Hip Same as above without topical NSAIDs Hand Topical capsaicin

40 Reference American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee. American College of Rheumatology. vol. 64, No. 4, April 2012, pp 465–474 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid ArthritisAmerican College of Rheumatology. vol. 64, No. 5, May 2012, pp 625–639 Kenneth C Kalunian, MD. Patient information: Osteoarthritis symptoms and diagnosis (Beyond the Basics). UpToDate August 2013. Peter H. Schur, MD. General principles of management of rheumatoid arthritis in adults. UpToDate August 2013 Micromedex


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