D&D- OA, RA, Gout Therapeutics PDF

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D&D: Skin, Connective Tissue, etc 1Osteoarthritis Facts & Figures  Most common form of arthritis (Knee> hand > hip)  15% of the population is affected by OA o 60-70% OF those over 70 years  Risk Factors o Increasing age o Women > men o Excess body weight o Rep...

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D&D: Skin, Connective Tissue, etc Osteoarthritis Facts & Figures  Most common form of arthritis (Knee> hand > hip)  15% of the population is affected by OA o 60-70% OF those over 70 years  Risk Factors o Increasing age o Women > men o Excess body weight o Repetitive joint use (occupation, sports) o Trauma Signs and Symptoms of OA  Knees, hips, distal interphalangeal joints more affected o Pain which worsens with movement o Stiffness lasting less then 30 mins usually in the morning or after period of prolonged immbolility o Crepitus in affected joint  Crepitus is cracking of the joint upon movement  Joints asymmetrically  X-ray finding – decreased joint space  Decrease in activity of daily living  ESR normal (rule out gout or other inflammatory cdts) o Fluid withdrawn from joint = no infection  Wont see elevated WBC  ESR= erythrocyte sedimentation rate not changed  Low time to deposit = inflammation not present in osteoarthritis  Inflammation is mild and localized: synovial fluid WBC < 2,000 cells/mm3  Calcium pyrophosphate deposition (CPPD): present in 30-60% of cases  Assessment tools for pain, stiffness, and physical function  Deposition of osteophytes o Distal = Heberden’s o Proximal = bouchard’s Goals of Therapy  Educate the patient, caregiver, and relatives o Arthritis self-management program – Arthritis Foundation  Relieve of symptoms such as pain & stiffness o Provide analgesia o Support activity of daily living (ADL)  Preserve joint motion & function by limiting disease progression  Minimize disability Approach to Treatment  Physical and occupational therapy o Assistive devices o Hold or cold treatment o Regular exercise o Aquatic exercise programs o Tai-Chi programs o TENS: transcutaneous electrical nerve stimulation  Weight reduction  Drug Therapy o Acetaminophen o NSAIDs o COX2 inhibitors o Topical therapies  NSAIDs, capsaicin o Tramadol/ opioids o Intraarticular therapies o Duloxetine o Glucosamine/ chondroitin o Natural medicines  Surgery o Cleaning out the joint o Joint replacement  Patient education Acetaminophen  Role in therapy: o First choice for the treatment of mild to moderate OA o Based on cost, efficacy & toxicity profile, it should be given a trial as initial therapy  Efficacy o In mild to moderate pain, APAP is comparable to ibuprofen o For severe pain, ibuprofen was better  Dosing

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o Regular schedule dosing NOT PRN for 2 to 3 weeks o Initial 650 mg QID or 1000 mg TID Concerns o Hepatotoxicity  Use with caution in patients with liver disease  Avoid in patients with chronic alcohol abuse  o Prolong the half life of warfarin  Increases INR o Make sure patients are not taking other APAP containing medications o Renal failure: specially in combination with NSAIDs Role in therapy o Use in patients who fail to obtain relief with APAP and can tolerate the GI and renal effects o Generally use lower analgesic doses Factors in choice of agent o Previous experience of patient o Cost o Schedule o Size of tab/cap GI adverse events: o Nausea, dyspepsia, abdomical pain, flatulence, diarrhea (take with food or milk) o Gastric and duodenal ulcers  History of upper GI problems (PUD, GERD)  Provide gastro protection (misprostol, PPI) Renal function = creatinine clearance goes down o Renal impairment (CrCl < 30 ml/min) o o ACE inhibitors by the themselves cause them to already have renal impairment but given with NSAID can escalate it CV toxicity: CHF, MI, stroke Other SE: CNS, bleeding, HTN Ketorolac is only approved for short term management of moderate to severe acute pain requiring analgesia at the opioid level NSAIDs with long half life and extended release formulations cause more GI events Risk factors for GI complications with NSAIDs o 65 yrs old and older o NSAID dose o Previous GI adverse event o Concomitant use of steroids o Oral antiplatelet and anticoagulants o Presence of co-morbid conditons  PUD  Upper GI bleed  GI hospitalization  Dyspepsia  CV disease o Possible- smoking and alcohol abuse o H.pylori infection

Treatment Options for Patients at risk for Upper GI Adverse Event  Acetaminophen  COX-2 inhibitors  NSAID + misoprostol or PPI  Nonacetylayed saliculate  Tramadol  Opioid  IA steroids, hyaluronate  Topical capsaicin or methylsaliylate  Topical NSAIDs 

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Salicylates Aspirin  GI symptoms  Dec plt aggregation  Therapeutic level = 15-25 mg/ dL  > 30 mg/ dL, tinnitus  Allergy  Cheap

Non- acetylated salicylates Choline magnesium trisalicylate  Less GI symptoms  No effect on plts  No renal toxicity  Some risk of salicylate toxicity  More expensive

FDA warning: o NSAIDs increase the chance of a heart attack or stroke (first weeks of taking an NSAID)  Increase risk with prolong use  Risk is greater with an increase of dose  Newest information doesn’t show which NSAID has higher or lower risk  A large number of studies support the finding that NSAIDs increase risk of heart attacks with or without heart disease  In general patients with heart disease have a greater likelihood of heart attack or stroke o Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first attack  Increase risk of heart failure with NSAID use o Recommendation  Patients and health care professionals should remain alert for heart related side effects the entire time that NSAIDs are being taken  Patients should seek medical attention immediately when they experience chest pain, shortness of breath or trouble breathing, weakness in one part or side of their body or slurred speech. All NSAIDs have a boxed warning about increased CV events o Chronic NSAIDs in high-CV-risk patients, celecoxib, naproxen and ibuprofen have similar risk of heart attack and stroke.

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Consider celecoxib in CV patients with GI risk factors, age over 65, previous ulcer or taking antithrombotics or corticosteroids  Causes fewer serious GI events than naproxen Recommend adding a PPI I patients in high GI risk Suggest low-dose aspirin for CV protection when appropriate

NSAIDs ASA Interactions  NSAIDs block the antiplatelet effects of aspirin if taken prior to ASA o NSAIDs have reversible and variab;e antiplatelet effect o NSAIDs bloc ASA access to COX-1 (TxA2)  Take ibuprofen at least 30 minutes or longer after aspirin ingestion or more than 8 hours before aspirin ingestion to avoid attenuation of aspiring effect COX-2 inhibitors  Some COX-2 selective seem to cause less GI SE o Meloxicam o Nabumetone o Etodolac o Celecoxib  Safety issues o Removal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the US market following an increased risk of CV events) o FDA: revised labeling for all prescription? OTC NSAID o Avoid COX-2 inhibitors, especially in patients with CV disease or who are at risk for CV disease o Exception- if COX-2 inhibitor is the only medication that provides relief for the patient an dthey understand and accept the risks  Celecoxib o Concerns  Questionable whether less GI side effects  Some patients may still need GI protection  CYP inhibitors  Do not use in patients with allergy to ASA or NSAIDs  Contraindicated in sulfa allergy  Reports of inc INR with warfarin  Cost may be an issue ( > $100/ month)  Concern about inc CV risk  Bottom line o Avoid COX-2 inhibitors, especially in patients with CV disease or who are at high risk for CV disease o Exception: if COX-2 inhibitor is the only medication that provides relief for the patient and they understand and accept the risks How to monitor patients  BMP: basic metabolic panel o BUN, SrCr, K  BUN= blood urea nitrogen up to 20 mg/dL  CBC: complete blood count (with differential) o Hematocrit = Hct, Hgb= hemoglobin  LFT: Liver function tests o AST, ALT Opioids 

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Tramadol 50-100 mg q 4-6 hrs (max 400 mg/d) o Similar side effects as opioids, but lower abuse potential o It is contraindicated during or within 14 days following MAO inhibitor therapy or other medication with serotonin activity  Risk of serotonin syndrome o Requires dose adjustment in renal failure  CrCL < 30 mL/ min 50-100 mg q 12 hours (max 200 mg/day) APAP with hydrocodone or oxycodone o Start low and increase as needed Adverse effects: CNS depression, constipation, tolerance, dependence, resp depression, addiction

Duloxetine  SNRI: selecetive serotonin and norepinephrine reuptake inhibitor  Indicated: GAD, MDD, fibromyalgia, neuropathic pain and chronic musculoskeletal pain  Oral : 30 mg QD for 1 week then inc to 60 mg QD as tolerated  Not recommended for use in ClCR < 30 mL/min  CNS: headache, somnolence, fatigue  GI: nausea, xerostomia  May enhance the adverse/ toxic effect of other serotonin modulators, the development of serotonin syndrome may occur Topical Therapy  Capsaicin  Diclofenac  May be used alone or in combination with other pharmacologic therapies for OA  Advantages over oral therapy o Unable to tolerate oral NSAIDs because of GI, renal and cardiac side effect same warning o Avoid topical and oral NSAID combo o May combine with APAP Capsaicin  Substance P

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Most effective for knee or hands. Not very effective for the hip Apply 3-4 times/ day May tae several weeks for max effect Patient education o May burn upon application o Wash hands very well after applixcation o Do not get in eyes or mucus membranes

Diclofenac Topical  Indicated for upper extremities: hands, elbows, wrists  Lower extremities: ankles, feet, knee  Dosing o Gel is applied according to a doing card  LE: 4 gm QID  UE: 2 gm BID o Solution = 40 drops QID or 50 drops TID to each affected knee  Patch o Acute pain due to minor strains, sprains, and contusions Intra-articular Therapy  Role in therapy o Only for OA of the knee in patients who have not responded to non-pharmacologic therapy and APAP or NSAIDs or COX-2 inhibitors  Sodium Hyaluronate o Viscosupplementation; reconstitute synovial fluid and reduce symtpms o Efficacy  Pain relief is comparable or greater than IA steroids but last longer  Only approved for one course  May be useful until patients can go to surgery ( 1 yr delay) o Adverse effects  Local pain, joint swelling, ecchymoses, pruritis, rare cases of anaphylactoid reaction  Steroids o Dose depends on size of joint o Cant only inject specific joint 2-3 times per year o Avoid strenuous activities on joint for a few weeks after injection (triamcinolone, methylprednisolone) o Show effective for app 4-8 weeks o Side effects  Localized inflammatory reaction Glucosamine/ Chondroitin  Stimulate proteoglycan synthesis from articular cartilage in vitro  Dietary supplements- regulations  Dose o Glucosamine = 1500  SO4 shows better efficacy than HCl o Chrodrontin = 1200  Adverse effects mild GI discomfort o Glucosamine: avoid shellfish allergy o Chondroitin: avoid in shark, cattle, pig  If effective will see effect in 4-8 weeks  Study designs may exaggerate response, most only measured symptoms, not changes in pathology  Glucosamine/ Chondoitin Arthritis Interventio Trial (GAIT) o NIH-supported study o Objective: study whether the dietary supplements could diminish the structural damage of osteoarthritis and relied pain o Result  No treatment showed a clinically important reduction in joint space width loss  In patients with moderate to severe pain the combo was sig. better than placebo American College of Rheumatology- OA Guideline 2012  Separate recommendation for knee, hip, hand  Nonpharmacologic modalities  Acteaminophen 4g/ day  Oral NSAIDs except CrCL < 30 ml/min  Topical NSAIDs  Capsaicin (hand)  Tramadol  Intraarticular therapies (knee, hip)  > 75 yrs use topical NSAIDs  Opioids  Glucosamine and chondroitin Rheumatoid Arthritis Epidemiology  Chronic systemic inflammatory disorder o Polyarthritis o Spectrum of extra-articular manifestations  Prevalence: 1& worldwide, 1.5 million patients in USA, ration female:male 3/2:1  Onset 3-4th decade up to 7th

D&D: Skin, Connective Tissue, etc Increase incidence in premature death Risk factors/causes o Genetic o Environment (food groups) o Affects of advancing age o Changes in muscoskeletal and immune system  The course o Polycyclic (On and off) o Monocyclic (Sudden onset followed by prolonged) o Progressive (Uninterrupted) Clinical Features  Morning stiffness for at least one hour and present for at least six weeks  Swelling of three or more joints, wrist, metacarpophalangeal or proximal interphalangeal joints for at least 6 weeks o Joints with a higher ratio of synovium to cartilage are more likely to be affected  Joints are tender and warm but not erythematous  Symmetric joint swelling  Hand x-ray changes typical to RA: erosions or bony decalcification  Rheumatoid subcutaneous nodules  

Diagnosis  Clinical, no single lab test is diagnostic  Lab finding associated with RA: o Rheumatoid factor o C-reactive protein (CRP) o Erythrocyte sedimentation rate (ESR) o Anticyclic citrllinated peptide antibody (ACPC)  Citrullinated peptide (anti-CCP) antibodies  Mutated citrullinated vimentin (MCV)  Life long disease although remission is possible Extra-articular manifestations  Rheumatoid nodules  Vasculitis  Pulmonary complications: lung nodules  Ocular manifestation: Sjogren’s syndrome (keratoconjunctivitis sicca) episcleritis, scleritis  Cardiac involvement: pericarditis, myocarditis, AV block  Felty’s syndrome: thrombocytopenia, splenomegaly  Cancer  Others: renal disease anemia, fatigue, neuropathy, anemia Goals of Therapy  Low disease activity if remission is not possible  Improve/ maintain functional status to increase QOL  Control of disease activity and joint pain  Slow progression of disease activity and reduce deformities  Improve extra-articular manifestations  Treatment involves shared decisions between the patient and their healthcare providers  Treatment should include measure disease activity and adjust therapy as appropriate Poor Predictors of outcome  Young ate at time of diagnosis  Elevated ESR = more inflammation  High titer of rheumatoid factor  Swelling found in > 20 joints  Female  Extra-articular manifestations Non-Pharmacologic Therapy  Rest  OT/PT  Assistive devices  Weight reduction  Surgical procedures  Emotional support and education Non-biologic DMARDs  ACR recommendation o Methotrexate (Rhematrex, Trexall) o Sulfasalazine (Azulfidine) o Leflunomide (Arava) o Hydroxychloroquine (Plaquenil)  Not included in the ACR recommendation o Gold o Penicillamine o Azathrioprine o Cyclophosphamide

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Biologic Agents  TNFa antagonists- all equally effective o Etanercept (Enbrel) o Infliximab (Remicade) o Adalimumab (Humira) o Golimumab (Simponi) o Certolizumab pegol (Cimzia)  Non TNF o Abatacept (Orencia)- T lymphocyte inhibito o Rituximab (Rituxan)- B cell inhibitor o Tocilizumab (Acterma)- IL-6 blocker o Tofacitibin (xeljanz): Janus kinase inhibitor class o Sarilumab (Kevzara): IL-6 antagonist  Anakinra (Kineret): IL-1 antagonist (no longer included in the ACR guidelines) NSAIDs, COX-2 Inhibitors, Salicylates  Role in therpy o Adjunct role o Does not alter the course of the disease o Can be used with DMARDS to help manage symptoms until DMARD takes effect  Efficacy o If no effect after 2-4 weeks increase dose or switch to another agent  Toxicity o GI, renal, CV, CNS, antiplatelet affect  Monitoring o Scr, CBC q 2-4 weeks then q 6-12 months o BP, wt, electrolytes, stool guaiac  Patient Information o Take with food, report GI symptoms, blood stools, SOB, edema or weight gain dizziness o Salicylates- ringing in the ears Corticosteroids  Role in Therapy o Used for acute flare-ups o Used to limit inflammation and prevent disease progression o Addition with DMARD may slow joint erosion and inflammation o To control symptoms while waiting for DMARDs to take effect o IA for particularly painful joints o Last resort in refractory patients  Dosage: o PO: lowest dose possible (10 mg or less prednisone or eq), short term (< 3 months) o IA- no more than 2-3 shots/ joint/ yr (provides days to months of relief)  Toxicity o HPA suppression (outside source of cortisol) o Myopathies o Osteoporosis o Glaucoma/ cataracts o Gastritis  PUD- NSAID and corticosteroids o Hypertension o Hyperlipidemia o Weight gain o Cushing’s syndrome o Hirsutism o E-lyte abnormalities o Glucose intolerance o Skin atrophy o Infections o Psychosis  Monitoring o BP, blood glucose, electrolytes, IOP, BMD  Patient Education o Report signs and symptoms of infection o Take calcium and vitamin D (MD should consider starting bisphosphonate) o Regular ophthalmologic exams Methotrexate  Role in therapy o Consider the gold standard of DMARDs o Slows disease progression  Efficacy o Most predictable log term benefit o Onset of effect is 2-4 weeks  Dose: Weekly

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o 2.5 mg po or IMq12 hoyr x 3 doses per week or 2.7-20 mg once weekly o increase by 2.5 mg per week every 6-8 weeks max of 20-25 mg/wk o can give as one dose per week when tolerated o if CrCL 60 yrs q 1 yr  Elderly  Renal impairment  Cumulative dose > 300 g  Daily dose > 6.5 mg/kg LBW  Ask patients about visual changes o Patient Education  Wear sunglasses in bright light ( dec. accommodation)  Caution driving at night (dec. night vision)  Report vision changes  Take with food or milk Sulfasalazine  Role in therapy o All dx activity , without poor prognosis; woman who plan to have children  Efficacy o Effects seen in 1-2 months  Dosing

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o 500 mg bid, then inc to 1 g bid or 1 g tid Toxcitiy o Myelosuppresion, rash, inc LFTs, GI Monitoring o CBC w pltls and LFTs at baseline and every other week x 3 months, then q 1-2 months, Sr Cr q 2-4 weeks x 3 months then q 12 weeks; UA periodically o Cl: Pltls < 50,000/ mm3 Can cause the urine to turn orange

Leflunomide  Role in therapy o Alternative in patient who fail or do not tolerate MTX  Efficacy o See effect by 1 month, stabilized by 3-6 months  Dosing o Loading dose: 100 mg po qd x 3 days o Maintenance dose: 20 mg po qd; may dec to 10 mg qd o Long ½ life with an active metabolite (15 hrs)  Adverse Effects o Diarrhea, headache, rash, alopecia, nausea o Increase LFTs (rare reports of hepatotoxicity, liver failure & death) o Contraindicated in impaired liver fxn o Contraindicated in pregnancy (category X)  Highly teratogenic, even after discontinuation  Cholestyramine may be used to remove o Myelosuppression (most often with combo tx)  Monitoring o LFTs at baseline and montly x 6 months, then q 6-8 weeks thereafter o If 2-3 x ULN, dec dose to 10 mg/ day; if > 3 X ULN d/c drug o CBC & Plt at baseline and monthly x 6 months then q 6-8 weeks thereafter  Patient Education o Maintain adequate hydration o Report GI symptoms (NV) or jaundice immediately o Report signs/ symptoms of infection Biologics  TNFa antagonists- all equally effective o Etanercept (Enbrel) o Infliximab (Remicade) o Adalimumad (humira) o Golimumab (Simponi) o Certolizumab pegol (Cimzia)  Non TNF o Abatacept (Orencia): T-lymphocyte inhibitor o Rituximab (Rituxan): B cell inhibitor o Tocilizumab (Acterma): IL-6 blocker o Tofacitinib (xelijanz) janus kinase inhibitor class o Sarilumab (Kevzara): IL-6 blocker  Anakinra (Kineret): IL-1 blocker (No longer included in the ACR guidelines)  Warnings o TNFa blockers: risk of infection from legionella and listeria o TNFa blockers Azathioprine, Mercaptopurine reports of hepatosplenic T-cell Lymphoma o Black box warming of anti-TNF therapies  Malignancy  Fatal infections  Tuberculosis  Anti-TNF agent can be used first line in patient o Early disease of high activity with poor prognostic feature  +/- MTX ( add if biologic is used as monotherapy)  Infliximab combo w MTX  Combinations of biologics are not recommended  Etanercept (Enbrel)  Role in therapy TNFa antagonist o ...