Arthritic Disorders

I. II. III. IV.

Osteoarthiritis Management of Osteoarthiritis Rheumatoid Arthritis Management of Rheumatoid Arthritis

GOAL: To comprehend the pharmacotherapeutic management of rheumatoid arthritis(RA) and osteoarthritis(OA). OBJECTIVES: Upon completion of the coursework on arthritic disorders, the student will be able to: 1. Develop a treatment strategy for RA and OA, utilizing both pharmacologic and nonpharmacologic management. 2. Discuss the rationale, indications, dosage regimens, adverse reactions, monitoring parameters and therapeutic endpoints for the following agents in the treatment of RA and OA:

a. b. c. d. e. f. g. h. i.

simple analgesics (acetaminophen) topical analgesics NSAIDs, including aspirin gold penicillamine antimalTimes New Romans sulfasalazine immunosuppressives corticosteroids

3. Provide appropriate patient education for the therapeutic regimens used in the treatment of RA and OA.

Required Readings: DiPiro: Pharmacotherapy 3rd Edition--Chapter 84, Rheumatoid Arthritis and the Seronegative Spondyloarthropathies and Chapter 85, Osteoarthritis

ARTHRITIC DISORDERS

OSTEOARTHRITIS (DJD: Degenerative Joint Disease): I. Definition:

y

a localized joint disease characterized by progressive deterioration of articular cartilage and compensatory bony changes

II. Pathogenesis (Figure 1)

A. Initiating event unknown

y

possible initiating stimuli include trauma, normal aging or under-lying disease such as diabetes

B. Insult either kills chondrocyte or stimulates it to replicate C. Increased proteoglycan synthesis and lysosomal enzyme release leads to matrix
degeneration D. Matrix degeneration causes alterations in structural framework, leading to breakdown and erosion of cartilage E. With progressive disease, mechanical factors such as obesity can perpetuate and even accelerate the degenerative process, therefore weight loss is important for obese patients F. Secondary inflammation of the joint and inflammation in adjacent soft tissues, such as bursitis and tendonitis, may increase clinical symptoms, but inflammation is not a hallmark of OA Figure 1: Proposed Pathophysiology of Osteoarthritis

from: The Arthritis Foundation: Primer on the rheumatologic Diseases 1988

III. Epidemiology:

A. Radiographic evidence of osteoarthritis seen almost universally in persons over 65 years B. C. D. E.

of age however, radiologic findings do not correlate with symptoms Symptoms present in approximately 40% of persons over 65 years Onset begins in late 30's and peaks in 60's Below age 45, males outnumber females . Above age 55, females have OA more commonly than males Heredity plays a role

IV. Clinical Presentation: A. Symptoms localized to joints and surrounding soft tissue:
y y y y y y

swelling, pain, stiffness: early in disease pain seen primarily with joint use; as disease progresses, pain will also occur at rest morning stiffness of short duration, stiffness also occurs after periods of joint inactivity joints affected: hands (DIPs, PIPs, first CMC), knees, hips, first MTP, cervical and lumbar spines (See Figure 3) Heberden's nodes (DIP) and Bouchard's nodes (PIP): bony enlargement of interphalangeal joints chronic disease may lead to joint deformity bursitis and tendonitis commonly seen in surrounding soft tissues due to abnormal stress put on joints

Figure 2: Joints Affected in Osteoarthritis

 indicates joints most commonly affected in osteoarthritis from: Cooke and Dwosh. Clin Rheum Dis 12:155-172, 1986

V. Laboratory and Radiologic Findings:

A. ESR: usually normal for age B. Rheumatoid factor and ANA: negative (but remember: up to 5% of non-RA population
has +RF (rheumatoid factor)

C. Synovial fluid: clear, good viscosity, WBCs <2000 (non-inflammatory) D. X-Rays: "joint space narrowing" (evidence of cartilage loss), subchondral sclerosis and
marginal osteophyte formation VI. Prognosis:

A. Variable, symptoms do not always correlate with clinical and radiographic findings B. Involvement of spine and weight-bearing joints increases risk of disability C. Chronic, disabling disease occurs in 10% of elderly

MANAGEMENT OF OSTEOARTHRITIS

I. Treatment Goals:

A. Relief of pain

B. Preservation of joint form and function, minimized disability

II. Non-Pharmacologic Management: indicated for all patients

A. Muscle strengthening exercises: improved muscle tone stabilizes joints, can significantly
Improve joint symptoms

B. Local heat/cold therapy: use caution with either to avoid tissue damage C. Splints/braces: to maintain joint alignment and aid in function D. Achievement of ideal weight: minimizes stress on joints

Figure 3: Flow Chart for Management of Uncomplicated OA

III. Simple Analgesics (Acetaminophen)

A. Provide analgesic effect for non-inflammatory arthritic conditions B. Rationale for use in OA 1. Potentially less toxic than NSAIDs 2. Some studies demonstrate efficacy = NSAIDs C. Doses up to 3 or 4 grams daily can be used; PRN dosing is appropriate in many cases
especially early in the disease, as it progresses may need scheduled doses D. Avoid narcotic analgesics if at all possible--with chronic pain there is risk of dependence

IV. Topical Analgesics (Capsicum, Zostrix )

A. B. C. D. E.

Substance p depletor: diminishes pain sensation Adjunctive or monotherapy Apply to affected area tid-qid on scheduled (not prn) basis Takes 1-2 weeks before see benefit Adverse effects: localized irritation/burning

V. Nonsteroidal antiinflammatory drugs (NSAIDs)

A. Use analgesic doses prn initially, switch to scheduled dosing when needed B. Can often achieve pain relief with lower dosages than needed for antiinflammatory
effects C. See RA section for discussion of agent selection and adverse reactions D. Since many patients with OA are older and may have multiple disease states/be on multiple medications, it is important to monitor closely for NSAID ADRs, drug-drug and drug-disease interactions

VI. Intraarticular corticosteroids

A. Can be used as monotherapy for a single afflicted joint or as an adjunct to above therapy
when one or two joints are active/refractory despite systemic therapy B. See RA section for discussion of usage/dosage

VII. Sodium hyaluronate (Hyalgan )

A. B. C. D. E. F.

Viscous solution that mimics joint fluid Indicated for OA of the knee that has failed initial therapy 5 weekly injections into affected knee Pain relief comparable to NSAID in one study ADRs: primarily injection site pain Additional studies would be helpful RHEUMATOID ARTHRITIS:

I. Definition: -a chronic multisystem disease of unknown etiology characterized by persistent inflammation of the synovium, resulting in cartilage destruction, bone erosion and joint deformity. II. Pathogenesis: A. Etiology unknown: possibly triggered by an infectious or chemical agent in susceptible individuals B. Immunologically mediated inflammation (Figure 1) -leads to destruction of normal tissue

III. Epidemiology:

A. Affects approximately 1% of the U.S. population B. Females affected 3 times more frequently than males C. Onset of disease at any age but most common during 4th and 5th decades, second "peak" occurs in the elderly D. Genetic predisposition: positive association with histocompatibility alleles IV. Clinical Presentation: A. First symptoms often extra-articular: fatigue, weakness, may occur before onset of joint symptoms--may occur before onset of joint symptoms, diagnosis not usually made until joint symptoms occur B. Joint involvement: -bilateral: hands (MCPs, PIPs), wrists, elbows, shoulders, feet, ankles, knees, hips, cervical spine (dominant side may be more affected) -pain, swelling, tenderness, warmth: all markers of inflammation -significant morning stiffness: generally >1hr (useful as marker of disease activity) C. Extra-articular manifestations: -rheumatoid nodules (20-30%) -areas of central necrosis surrounded by inflammatory cells -found in periarticular subcutaneous tissue that is subject to mechanical pressures, e.g. around elbows, knuckles -may be found in deep connective tissues or viscera, e.g. lungs -associated with increased severity of disease -vasculitis: inflammation and necrosis of blood vessels -cardiac: pericarditis -pulmonary: pleuritis, fibrosis -osteoporosis: periarticular (secondary to inflammation) and generalized (secondary to chronic disease and immobilization)

V. Laboratory and Radiologic Findings: A. No laboratory test is diagnostic B. Rheumatoid Factor (autoantibodies reactive with the Fc region of human IgG) (Standard rheumatoid factor tests look for IgM antibodies, but can RF antibodies can also be IgG, IgA or IgE) presence of a + Rheumatoid factor is not diagnostic for RA
o o o

positive in approximately 70% of RA patients rheumatoid factor also found in 1-5% of normal population patients with RA but no RF have "seronegative rheumatoid arthritis"

C. ANA (antinuclear antibodies): positive in 25% (homogenous pattern) D. Erythrocyte Sedimentation Rate (ESR: non-specific measure of inflammation): usually elevated, in conjunction with clinical symptoms can be used as a disease marker E. Anemia: common, usually normochromic, normocytic anemia of chronic disease (may be compounded by concurrent iron or folate deficiency) F. Synovial fluid from tap of affected joint: cloudy, decreased viscosity, increased WBCs and protein, decreased complement (all characteristic of inflammation) G. X-Rays changes:
o o

early: soft tissue swelling, joint effusion, regional osteoporosis progressive/late: marginal joint erosions, decreased joint space and malalignment secondary to erosions of bone

VI. Diagnosis (Table 1) A. Made on basis of multiple factorsincludes clinical and laboratory findings

Table 1: Diagnostic Criteria for Rheumatoid Arthritis

1. 2. 3. 4. 5. 6. 7.

Morning joint stiffness of >1 hour a Swelling of > 3 jointsa Swelling of the PIPs, MCPs or wrist joints a Symmetrical joint swellinga Subcutaneous nodules Positive rheumatoid factor test X-Ray changes: erosions/periarticular osteoporosis in hand/wrist joints

: For criteria 1 through 4: symptoms must persist > 6 weeks and at least 3 other criteria must be positive

VII. Prognosis A. Characterized by exacerbations and remissions -possible exacerbating factors include emotional or physical stress and changes in weather conditions, especially increases in humidity B. 15% have no limitations or remit spontaneously within first year of illness (Class I) C. 10% develop severe, progressive disease resulting in marked joint deformities and disability (Class IV) D. Decreased life expectancy (by 3 to 7 years average) -death rate increased primarily due to respiratory disorders, infections, gastrointestinal disease and rheumatoid arthritis itself

MANAGEMENT OF RHEUMATOID ARTHRITIS I. Treatment Goals

A. Relief of pain B. Decrease inflammation C. Preservation of joint form and function, minimized disability
______________________________________________________________________________ __

Figure 5: Flow Chart for the Medication Management of RA

II. Non-Pharmacologic Management: indicated for all patients A. Rest: -systemic rest: encourage naps and 8 hours of sleep at night -joint rest: for acute inflamed joints via splints/braces B. Passive range of motion: to maintain joint function, prevent contractures, minimize muscle atrophy C. Exercise: need to maintain good muscle tone/joint alignment, however avoid active exercise during periods of active inflammation D. Local heat/cold therapy: use caution with either to avoid tissue damage E. Splints/braces: to maintain joint alignment and aid in function F. Achievement of ideal weight: minimizes stress on joints III. Non-Steroidal Anti-inflammatory Agents (NSAIDs) A. Analgesic and anti-inflammatory effects -used primarily for anti-inflammatory effectsfirst line therapy

B. Mechanism of action: -inhibition of prostaglandin synthesis through inhibition of cyclooxygenase enzyme inhibition of this enzyme may be permanent (e.g. aspirin) or reversible -other mechanisms implicated in effects of NSAIDs, e.g. inhibition of neutrophil activation, therapeutic benefits of these additional MOA are unclear C. Efficacy -decrease inflammation, pain and swelling -do not appear to slow progression of disease -no agent proven more efficacious than aspirin but others may be better tolerated D.Factors to consider when choosing an NSAID -large interpatient variability in efficacy and tolerance -some small differences in adverse reaction profiles between agents -compliance may or may not be an issue -try maximum dose of at least 2 weeks before measuring response -if a NSAID fails. Choose another agent from a different chemical "family" E. Aspirin (ASA-acetylsalicylic acid): -considered by some to be the drug of choice because of efficacy, low cost and availability -anti-inflammatory effect seen at salicylate levels of 15-30mg/dl -must stress compliance because analgesic dose << anti-inflammatory dose -may require doses of up to 5 grams per day (in 3-4 divided doses) to reach therapeutic level (average 65mg/kg/day) -avoid dosing to tinnitus because may lead to toxicity in some patients, rather, increase dose based on salicylate levels -at anti-inflammatory doses, aspirin exhibits saturation kinetics and half-life is approximately 20 hours: increase dose slowly and cautiously 1. Choice of product

-plain uncoated aspirin: low cost but high incidence of GI toxicity--generally not recommended for patients needing chronic therapy -buffered or antacid combinations: decrease GI symptoms but no significant decrease in GI blood loss over uncoated ASA -enteric-coated: increased cost over plain ASA, decreased GI toxicity both subjectively and objectively, bioavailability has been problem in past (most current brand-name products, e.g. Ecotrin(r), Easprin(r) are okay, they also come in larger doses for increased patient convenience: Ecotrin(r) 375mg, 500mg, Easprin(r) 975mg) -"sustained release" aspirin: larger dose in single tablet, increased cost over plain ASA, some products Rx only, often allow fewer numbers of tablets daily with less frequent dosing interval (e.g. ZORprin(r) 800mg-may be given BID) 2. Adverse reactions: Intolerance: -bronchoconstriction: not a true "allergy", probably mediated through prostaglandin inhibition, increased in patients with asthma and/or nasal polyps, cross reactivity often seen with other NSAIDs -urticaria, angioedema: frequently seen in patients with chronic urticaria, may be immunologically mediated Gastrointestinal: (also see section on non-salicylate NSAIDs) -MOA twofold: -local irritation (due to acidic nature of ASA) -systemic toxicity: mucosal resistance due to prostaglandin inhibition -symptoms: nausea, vomiting, dyspepsia, GI blood loss: symptoms do not correlate with degree of gastrointestinal damage -risk of GI ulceration/hemorrhage -risk decreased somewhat by using enteric-coated/sustained release products (minimizes local toxicity) but still a significant risk Dermatologic: -rash: urticTimes New Roman rash may suggest hypersensitivity

CNS: -tinnitus: dose related, usually occurs close to toxic level, although in some patients may occur at low levels, sometimes described as hearing loss, roaring in ears or sea shell sound, generally reversible with dose or stopping drug, may not occur in elderly even at high doses -HA, vertigo Hematologic: -platelet dysfunction: irreversible inhibition of platelet aggregation due to cycloxygenase inhibition, effect persists for life of platelet (approximately 7-10 days after last dose of ASA) results in increased bleeding time but no change in PT or PTT except at high doses -blood dyscrasias: rare Liver: -intrinsic hepatotoxin -hepatocellular toxicity: dose and concentration dependent -increased LFTs and hepatomegaly -increased risk in children on aspirin for Juvenile RA: monitor LFTs on regular basis Renal: -aspirin can decrease renal function (see NSAID section for mechanism) -less toxic to kidneys than other more potent NSAIDs F. Nonacetylated Salicylates: Drug of Choice in patients with ulcers, bleeding disorders and ASA-induced bronchospasm -Products available
o o o o o

Choline magnesium trisalicylate (Trilisate(r)): contains magnesium Salsalate (Disalcid(r)): two salicylate molecules joined together Choline salicylate (Arthropan(r)): liquid formulation Magnesium salicylate (Magan(r)): contains magnesium Sodium salicylate: contains sodium

(Salsalate and choline magnesium trisalicylate are the agents most commonly used)

-converted in vivo to salicylate which is active component of drug -initiate dosing at 1500mg bid (for anti-inflammatory effects), can use lower doses for analgesic effect -similar activity and kinetics to aspirin--monitor salicylate levels, as with ASA antiinflammatory levels are 15-30mg/dl -advantages over aspirin: -less gastrointestinal intolerance: felt to be non-ulcerogenic, can be used cautiously in patients with h/o PUD (note that patients may still complain of dyspepsia even if they don't have an ulcer.) -no antiplatelet effect: the nonacetylated salicylates do not affect platelet cyclooxygenase -may be used cautiously in aspirin intolerant patients (bronchospasm); in many patients these agents do not provoke similar symptoms, esp at lower dosages, patients should be aware of potential for bronchospasm -bid dosing, although at high doses, tid dosing is often used -disadvantages over aspirin -increased expense (generics are available for some of these agents) -salt load, use with caution in patients with renal impairment/CHF because of sodium or magnesium load with some of these agents G. Salicylate Drug Interactions: (occur with ASA and the non-acetylated salicylates) Warfarin: displacement from protein binding sites by salicylates -avoid aspirin in patients on warfarin for 3 reasons:
o o o

protein binding displacementincrease effect of warfarin GI irritation and blood lossincreased bleed risk antiplatelet effect can complicate warfarin-induced bleeding

-non-acetylated salicylates: will cause displacement from protein binding sites but do not increase risk of GI bleeding, nor do they cause platelet dysfunction, for patients who need chronic antiinflammatory therapy, these agents are good choices provided the patient understands the need for good compliance

Sulfonylureas (first generation agents): displacement from protein binding sites by salicylates, may precipitate hypoglycemia, does not occur with the second generation agents (glipizide, glyburide) Probenecid: inhibition of uricosuric effects by high doses of salicylates (>2gm/day) Antacids:
o o o

urinary alkalization enhances renal salicylate elimination chronic antacid use may lead to increased salicylate requirements salicylate intoxication may occur if chronic antacid use is stopped without a concomitant decrease in salicylate dose

Methotrexate: Salicylates diminish renal MTX elimination by blocking tubular secretion, may increase MTX toxicity H. Non-Salicylate NSAIDs: 1. Agents Available (Table 2):

Chemical Class Generic Name/Brand Name

Time to Peak Levels (hrs)1

Half-Life (hrs)

% Renally Eliminated Unchanged

Active Metabolite

SALICYLATES Aspirin Salicylate PROPIONIC ACIDS Fenoprofen (Nalfon(r)) Flurbiprofen (Ansaid(r)) Ibuprofen (Motrin(r), Rufen(r)) Ketoprofen (Orudis(r)) Naproxen (Naprosyn(r)) Naproxen Sodium (Anaprox(r)) 1 to 2 1.5 1 to 2 0.5-2 2 to 4 1 to 2 2 to 3 5.7 1.8-2.5 2 to 4 12 to 15 12 to 13 2-5% <15% 1% <1% <1% <1% none none none none none naproxen 1-2 1-2 0.29 2-302 <2% 2-303 Salicylate none

Oxaprozin (Daypro(r)) INDOLE ACETIC ACIDS Indomethacin (Indocin(r)) Indomethacin (Indocin SR(r)) Ketorolac (Toradol(r)) Sulindac (Clinoril(r))* Tolmetin (Tolectin(r)) FENAMATES Meclofenamate (Meclomen(r))

3-6

36-92

>90%

none

1 to 2 2 to 4 0.5 2 to 4 0.5 to 1

4.5 4.5 to 6 4 to 8.6 7.8/16.44 1 to 1.5

<15% <15% 56-60% 7% 15%

none none none sulindac sulfide none

0.5 to 1

2/3.35

2-4%

hydroxymethyl derivative

Mefenamic Acid (Ponstel(r)) OXICAMS Piroxicam (Feldene(r)) PHENYLACETIC ACIDS Diclofenac (Voltaren(r)) PYRANOCARBOXYLIC ACIDS Etodolac (Lodine(r)) NAPHTHYALKALONES Nabumetone (Relafen(r))* PYRAZOLES Phenylbutazone Oxyphenbutazone SALICYLATE DERIVATIVES Diflunisal (Dolobid(r))

2 to 4

2 to 4

<6%

none

3 to 5

30 to 86

10%

none

2 to 3

<1%

none

1 to 2

6-7

1%

none

3-66

246

<10%

6-MNA7

2 1 to 2

50-100 27-64

1% 1%

oxyphenbutazone none

2 to 3

8 to 122

<3%

none

* Prodrug 1 Food rate of absorption, peak may be delayed

2

Concentration dependent elimination kinetics 3 pH dependent renal elimination Half-life of active metabolite 5 Half-life after multiple doses

Time to peak/half-life of active metabolite 7 6-methoxy 2-naphthylacetic acid

Adapted from: Facts and Comparisons 1991, Clin Pharmacokinetics 8:297-331, 1983.

2. Adverse reactions "Hypersensitivity" (Intolerance): -high incidence of cross sensitivity with aspirin allergy due to inhibition of prostaglandin synthesis. NSAIDs should be avoided in patients with bronchoconstrictive reactions to salicylates Dermatologic: -rash: severe reactions (including Stevens-Johnson with phenylbutazone) have been reported -photosensitivity: encourage patients to use sunscreens Gastrointestinal: -generally less than seen with aspirin (due to less local mucosal toxicity) but still significant risk of PUD (primarily gastric ulcers) in patients at risk -high degree of patient variability in GI toxicity -risk groups for development of ulcers with NSAIDs -patients with h/o PUD -elderly -women -patients using high dose NSAIDs -patients using multiple NSAIDs -symptoms do not correlate with endoscopic findings: lack of symptoms does not indicate patient does not have an NSAID-induced ulcer. For some patients, the first symptom of ulceration may be an acute GI bleed -prevention and management: -in patients at risk, use less irritating agents first, such as the non-acetylated

salicylates or nabumetone -if these agents are not successful, use misoprostol (Cytotec(r)) in combination with an alternate NSAID for preventing ulcers -misoprostol: -dosage: 100-200mcg qid -adverse effects:
o o

diarrhea common, patients will develop tolerance abortifacient--do not use in pregnant women!

-H2 blockers or sucralfate may also provide some protection against NSAID-induced duodenal ulcers but do not appear to prevent gastric ulcers -Preventive therapy with misoprostol should also be considered in patients that aren't in risk categories listed above but who would not tolerate a major GI bleed, e.g. patients with significant pulmonary or cardiovascular disease CNS:
o o o o

tinnitus: incidence less than with salicylates drowsiness, dizziness and confusion: esp in elderly patients headaches: commonly seen with indomethacin aseptic meningitis (severe headache, nuchal rigidity): reported primarily with ibuprofen, but has also been seen with tolmetin and sulindac

Hematologic: -platelet dysfunction: inhibition as seen with ASA, but reversible, duration is related to t1/2 of drug, therefore, antiplatelet activity is of shortest duration with short-acting agents such as ibuprofen and tolmetin -blood dyscrasias (agranulocytosis, aplastic anemia): uncommon but reported with all agents, most significantly associated with phenylbutazone Nephrotoxicity: (2 types) 1. Hemodynamically-Induced Renal Failure -onset within days to weeks -related to antiprostaglandin effect

-mechanism of action: loss of renal vasodilation (Figure 6) -cause of decreased renal function is decreased blood flow to the kidney, not a direct toxic effect on the kidney ______________________________________________________________________________ _ Figure 6: Mechanism of NSAID-related Hemodynamically-Induced Renal

Failure

________________ from: Clive and Stoff. NEJM 310:563-572, 1984

-risk factors: (in patients with a risk factor, monitor renal function soon (within 1 to 3 weeks) after starting NSAID)
o o o o o o

compromised renal function e.g. secondary to age or disease such as long standing HTN or DM CHF hepatic cirrhosis with ascites volume contraction from any source dehydration concurrent medications: ACEI, diuretics

-presentation: edema, hyperkalemia, increased BUN/Scr decreased urine output, acute renal failure -generally reversible upon DC of NSAID (if caught in time) -appears that non-acetylated salicylates and sulindac areassociated with less risk of this type of nephrotoxicity 2. Nephrotic Syndrome -uncommon to rare -onset within weeks to months -presentation: proteinuria (>3gm/day) with severe renal impairment -most commonly reported with proprionic acid derivatives, esp fenoprofen (Nalfon(r)) -possibly represents an allergic reaction -generally reversible with DC of NSAID

Hepatotoxicity: -may be an idiosyncratic reaction or an intrinsic toxin -increased LFTs, GI symptoms, fever, rash, jaundice may be seen -15% of patients on NSAIDs develop transient increase in LFTs--no need to discontinue NSAID unless patient is symptomatic or LFTs are > 3x normal -cholestatic and/or hepatocellular toxicity may be seen -routine monitoring of LFTs not generally recommended other than for specific agents or patients with symptoms or underlying liver disease

3. Individual Agents Propionic Acids:

-Ibuprofen (Motrin(r), Rufen(r), others): generally well tolerated by GI tract, anti-inflammatory effect requires dose >1800mg/day pediatric formulation indicated for antipyresis only Dosage: 400-800mg tid-qid (max 3200mg/day) OTC dosage: 200mg tabs, 1200mg/day max

-Fenoprofen (Nalfon(r)): highest incidence of nephrotic syndrome Dosage: 300-600mg tid (max 3200mg/day)

-Naproxen (Naprosyn(r)): generally good GI tolerance, approved for pediatric use (suspension available) Dosage: 250-500mg bid-tid (max 1250mg/day) Pediatric dose: 10mg/kg/day in bid doses

-Naproxen Sodium (Anaprox(r)): only advantage over naproxen ismore rapid absorption/faster onset when taken on an empty stomach, not a significant benefit in patients on chronic dosing Dosage: 275-550mg bid-tid (max 1375mg/day) OTC dosage (Aleve(r)) 200mg q12hr

-Ketoprofen (Orudis(r), Oruvail(r)--SR) inhibits leukotriene and prostaglandin synthesis-clinical significance unknown Dosage:50-75mg bid-qid (max 300mg/day)

-Flurbiprofen (Ansaid(r)): short t1/2 but can be given bid Dosage: 50-100mg bid-qid (max 300mg/day)

-Oxaprozin (Daypro(r)): long half-life, can be dosed once daily Dosage: 1200mg/day

-Carprofen (Rimadyl(r)): may be less GI irritating (FDA approved but not currently being marketed by Roche)

Acetic Acids: -Indomethacin (Indocin(r), others): highly effective agent buthas higher incidence of ADR: headaches, sodium and fluid retention, GI toxicity. Avoid long term use in elderly. Also suppository and suspension Dosage: 25-50mg tid or 75mgSR bid (max 200mg/day)

-Tolmetin (Tolectin(r), others): approved for pediatric use short t1/2 requires frequent dosing Dosing:400-600mg tid (max 2000mg/day) Pediatric dose: 15-30mg/kg/day in tid-qid dosing

-Sulindac (Clinoril(r)): this agent is a prodrug which is metabolized to active agent in vivo. Associated with decreased risk of hemodynamically-induced nephrotoxicity but avoid in liver disease because of active metabolite Dosage: 150-200mg bid (max 400mg/day)

-Diclofenac (Voltaren(r), Cataflam(r)): short t1/2 but can be dosed bid Dosage: 25-50mg tid-qid or 75mg bid (max 200mg/day)

(Voltaren is "slow release", Cataflam is immediate release)

-Etodolac (Lodine(r)): good analgesic agent Dosage: 200-300mg bid-qid (max 1200mg/day)

-Ketorolac (Toradol(r)): injectable or oral NSAID used for pain management, not indicated for chronic use Dosage: IM: 30-60mg stat, 15-30mg q6hrs PO: 10mg q4-6hr, max 40mg/day

Fenamates: -Meclofenamate (Meclomen(r)): major adverse reaction is diarrhea Dosage: 50-100mg tid-qid (max 400mg/day)

-Mefenamic acid (Ponstel(r)): not FDA approved for RA or OA, only for pain/dysmenorrhea Dosage: 250mg tid-qid (max 1000mg/day)

Oxicams: -Piroxicam (Feldene(r)): long t1/2 allows qd dosing, use with caution in elderly because of long t1/2 Dosage: 10-20mg qd (max 20mg/day)

Naphthylalkalones:

-Nabumetone (Relafen(r)): prodrug, may be less toxic to GI tract, once a day dosing at initial dose Dosage: 1000mg qd, up to 2000mg/day in bid dosing

Others: -Diflunisal (Dolobid(r)): salicylate derivative but not converted to salicylate, cannot measure salicylate levels, good analgesic ?less tinnitus than other salicylates? Dosage: 250-500mg bid (max 1500mg/day)

Pyrazoles: -Phenylbutazone (Butazoladin(r), others): very effective agent but limit continuous use to <2 weeks because of hematologic toxicity, avoid in elderly, oxyphenbutazone is active metabolite Dosage: 100-200mg tid-qid (max 400mg/day) -Oxyphenbutazone (generic only-see comments/dosage for phenylbutazone)

4. Drug Interactions: Antihypertensives: NSAIDs may antihypertensive effect of many antihypertensiveincluding diuretics, beta-blockers, ACE-inhibitors, centrally acting agents such as clonidine, prazosin, monitor BP in patientson antihypertensive therapy and adjust antiHTN therapy accordingly (remember that ACEI and diuretics increase the risk of NSAID-induced renal dysfunction.) Warfarin:
o

protein binding displacement occurs with mefenamic acid & phenylbutazone o use other NSAIDs cautiously because of antiplatelet effect and risk of GI bleed

Methotrexate: decreased MTX renal elimination due to inhibition of tubular secretion (occurs with fenoprofen, naproxen, phenylbutazone and tolmetin)--probably not clinically important with the low doses of MTX used in RA and psoriasis, but is significant with chemotherapeutic doses of MTX Lithium:increased lithium levels from decreased renal blood flow (does not occur with salicylates)monitor patient for sx of lithium toxicity 5. Disease-Drug Interactions Limited data available on the effects of organ dysfunction on NSAIDs-USE ALL NSAIDS CAUTIOUSLY IN PATIENTS WITH ORGAN DYSFUNCTION Aging: altered metabolism V increased adverse reactions, start with low doses, increase cautiously, monitor labs more frequently, avoid phenylbutazone Cirrhosis: metabolism increased risk of renal dysfunction use caution with drugs that have active metabolites, effect may be decreased because of impaired conversion to active drug, active metabolite may also accumulate in patients with liver disease, e.g. sulindac, phenylbutazone o as most NSAIDs are highly protein bound, may see higher free drug levels in liver disease due to altered protein binding
o o o

Renal insufficiency: although NSAIDs primarily metabolized by liver, renal dysfunction may lead to free fraction and adverse effects Pregnancy: contraindicated after 32 weeks because may cause premature closure of ductus arteriosus, leading to pulmonary HTN in fetus o antiplatelet effect of NSAIDs given near term may risk of bleeding in mother and fetus (however, some studies suggest that low dose aspirin during pregnancy may decrease risk of preelampsia)risk versus benefit must be assessed for each patient
o

IV. Slow Acting Anti-Rheumatic Drugs (SAARDs):

o o o

also called Disease Modifying Anti-Rheumatic Drugs (DMARDs) or Remissive Agents used for progressive, erosive Rheumatoid Arthritis uncontrolled by NSAIDs have slow onset of action (up to 4 months) and are poor analgesics; therefore generally need to continue NSAID therapy for control of pain and inflammation until SAARD

"kicks in" or may need to use bridge prednisone therapy for symptom control when initiating SAARD A. Injectable Gold 1. Mechanism of action: -altered phagocytic activity of neutrophils and macrophages -interference with metabolic pathways of inflamed and normal tissue 2. Efficacy: -overall, approximately 25% of patients will have beneficial long-term response. Many (up to 50%) must discontinue therapy because of adverse reactions before benefits are seen -stated to prevent erosions but controversial 3. Agents (both 50% elemental gold): -Gold sodium thiomalate (Aurolate(r)): aqueous solution -Aurothioglucose (Solganol(r)): oil suspension 4. Dosing: Week #1: 10mg test dose IM Week #2: 25mg test dose IM Week #3 and every week thereafter: 50mg IM When cumulative dose of 1 gram has been reached, evaluate response: -if no response, discontinue gold treatment OR -if beneficial response, increase interval by weekly increments e.g. 50mg q2 weeks for several months, then to 50mg q3 weeks and then to 50mg q month indefinitely. Goal is to give the dose over the greatest interval that maintains benefit. May need to increase frequency of dosing if flare occurs 5. Adverse Reactions: -question patient carefully before each injection for adverse

reactions Mucocutaneous: -oral ulcers, stomatitis (gastrointestinal toxicity rare with injectable gold) -rash -monitoring: question patient before each dose -management:
o o o

hold gold until cleared, reinitiate cautiously, may be necessary to restart at lower dose, i.e. 25mg/week; if recurs on rechallenge generally must DC drug

Hematologic: -eosinophilia -thrombocytopenia (plt <150,000 -aplastic anemia/granulocytopenia (PMNs <3,000 -monitoring: complete CBC with differential before each injection -management: eosinophilia: no change in therapy needed unless associated with other toxicities o thrombocytopenia (plt <150,000): rare, discontinue drug do not restart o aplastic anemia/granulocytopenia (PMNs <3,000): discontinue drug, do not restart (may also need to discontinue gold therapy if blood count drops significantly, even if still above threshold)
o

Renal -glomerulonephritis, nephrotic syndrome -monitoring: urine dipstick for protein before each injection -management: proteinuria:
o

up to 2+ acceptable, if > 2+ on dipstick, do 24hr urine for protein

o o

if >1gram/24hr urine collection, stop drug and do not restart reversible upon DC of drug but may take months for complete resolution (average 11 months)

Pulmonary: -"gold lung" (fibrosis, pneumonitis): low incidence (<1%) usually seen within first 3 months of treatment, associated with eosinophilia -monitoring: patients should be questioned about shortness of breath/cough/fever before each dose of gold -management: discontinue gold

Nitritoid reaction: vasomotor reaction characterized by flushing and hypotension within 1/2-1 hr of injection, more common with aqueous solution (gold sodium thiomalate) -monitoring: question patient, if symptomaticmonitor BP after dose -management: switch to oil suspension

B. Oral Gold: Auranofin (Ridaura(r)) 1. Mechanism of action: modulatory effect on humoral and cellular immune systems 2. Efficacy: somewhat less effective than injectable gold but better tolerated 3. Dosing: Initiate at 3mg bid, may increase to 9mg/day 4. Adverse Reactions: Gastrointestinal
o o o

diarrhea, loose stools: seen in 50% of patients monitoring: question patient at regular intervals management: many patients develop tolerance, if severe, decrease dose or discontinue gold

Mucocutaneous:

o o o

rash, pruritis, stomatitis, conjunctivitis: monitoring: question patient at regular intervals management: decrease dose until resolved, then rechallenge or discontinue

Hematologic:
o o o

thrombocytopenia: low incidence (0.5% in one study) monitoring: CBC q 4-12weeks management: if platelets <150,000: discontinue drug and do not restart

Renal -glomerulonephritis, nephrotic syndrome: uncommon because drug is primarily eliminated through the feces (vs injectable gold which is 70% renally eliminated) -monitoring: urine dipstick for protein q 4-12 weeks -management: : proteinuria:
o o o

up to 2+ acceptable, if > 2+ on dipstick, do 24hr urine for protein if >1gram/24hr urine collection, stop drug and do not restart reversible upon DC of drug but may take months for complete resolution (average 11 months)

C. Penicillamine (Depen(r), Cuprimine(r)) 1. Mechanism of action (postulated): -inhibits T-lymphocytes, dissociates macrophages and rheumatoid factors 2. Efficacy -overall, about 25% of patients will have beneficial response, approximately equivalent to gold but less frequently used due to slow onset and adverse effect profile -secondary failures: after 3-5 years, may lose responsiveness 3. Dosing: "start low, go slow": -initiate at 125-250mg/day, increase at 1-3 month intervals to 1000mg/day if needed, once response occurs, attempt to taper to lowest effective dose

-must be taken on an empty stomach because metals in food can chelate with drug and decrease absorption 4. Adverse Reactions: Hypersensitivity: -penicillin allergy does not contraindicate penicillamine: incidence of cross sensitivity very low Mucocutaneous: -stomatitis, rash -monitoring: question patient regularly -management: -oral ulcers: hold drug until healed, rechallenge -rash: if early in therapy, discontinue or decrease dose later in therapy consider possibility of autoimmune disease Gastrointestinal: -nausea, vomiting, anorexia, diarrhea: tolerance develops with continued use, may give in split doses to decrease irritation Hematologic: -leukopenia, thrombocytopenia, microcytic anemia -monitoring: CBC every 2 weeks until dosage stabilized, then may decrease frequency -management: leukopenia (neutrophils <2000) or thrombocytopenia (platelets <100,000): DC drug and do not restart o microcytic anemia: may be due to copper or pyridoxine deficiency induced by penicillamine, does not require drug DC, if iron levels normal, supplement with copper or pyridoxine
o

Renal: nephrotoxicity: patients with a h/o gold-related proteinuria may have increased risk of proteinuria with penicillamine -monitoring: urine dipstick for protein/blood every 2 weeks until dose stable

-management: -proteinuria: up to 2+ on dipstick: decrease dose; if >2+, do 24 hr urine for protein: if >2gm/24hr discontinue drug, dont restart -hematuria: if >10 RBC/hpf discontinue drug, otherwise watch closely

Neurologic -peripheral neuropathy secondary to pyridoxine deficiency -monitoring: at each visit, question patient re: numbness/tingling in extremities -management: supplement with pyridoxine, monitor for resolution

Autoimmune Disorders -myasthenia gravies, Goodpasture's, thyroiditis -may induce positive ANA -if possible discontinue drug

Dysgeusia (altered taste sensation): -common, may subside without any alteration in therapy -if persists, may respond to short course of zinc -consider dysgeusia if patient losing weight without apparent cause D. AntimalTimes New Romans 1. Mechanism of action: -stabilization of lysosomal membrane-decreased enzyme release 2. Efficacy -? less effective than gold but better tolerated

3. Agents and Dosing Agent of Choice: (considered to have lower risk of retinopathy) -Hydroxychloroquine (Plaquenil(r)): 200-400mg/day or 2-6.5mg/kg/day May also use:
o o

Chloroquine (Aralen(r)): 250mg/day Quinacrine (Atabrine(r)): 100-200mg/day

4. Adverse Reactions Gastrointestinal: -bitter taste, cramps, pain, bloating, diarrhea: most common side effect, can be minimized by taking with food or nocturnal dosingnewer coated dosage form may minimize taste problem Dermatologic: -rash: hold until rash clears or discontinue therapy -pigmentation abnormalities: graying or bleaching of hair, blue-gray discoloration of skin; benign, do not require stopping drug Hematologic: -G6PD deficiency hemolytic anemia: rare except in overdose situations

Ocular: (retinal exam strongly recommended every 6 months) -3 types of problems--2 are benign, one is irreversible

1. accommodation defects: benign, patients will complain of blurred vision

or slowed ability to focus, reversible, doesn't require stopping drug unless a real problem for patient 2. corneal deposits: halos around lights, benign, reversible, doesn't require stopping drug 3. retinopathy: patchy irreversible visual loss associated with daily doses >6.5mg/kg/day, skin pigmentation may indicate increased risk, increased by UV light exposure; encourage patient to wear sunglasses that block UV light -monitoring: baseline exam in pts>40yo or with previous eye disease

-management:
o o

accommodation defects/corneal deposits: educate pt retinopathy: discontinue drug immediately

CNS: -irritability, nervousness Muscular: -skeletal muscle myopathy: patients may c/o weakness -neuropathy -cardiomyopathy E. Sulfasalazine (Azulfidine(r)) 1. Mechanism of action: -anti-inflammatory or immunosuppresive? -active moiety is probably sulfapyridine rather than the 5-aminosalicylic acid which is not systemically absorbed 2. Efficacy: -not FDA approved for this indication but frequently used; many studies indicate good response if patient can tolerate high doses needed for effect 3. Dosing: -2-4 grams per day in divided doses -to minimize GI toxicity, use enteric-coated product, start with low dose (500mg bid) and increase gradually to full dose over several weeks 4. Adverse Reactions: Hypersensitivity: -avoid in sulfa allergy -use cautiously in patients with salicylate allergy

Gastrointestinal: -nausea, vomiting very common, dose-related, patients develop tolerance if dose increased gradually, significantly decreased GI toxicity with enteric coated formulation Mucocutaneous: -rash, oral ulcers: consider possibility of allergic reaction Hematologic: -G6PD deficiency hemolytic anemia: -bone marrow depression: generally occurs within first year of therapy -megaloblastic anemia: long-term therapy complication--sulfasalazine inhibits folic acid absorption -monitoring: -baseline G6PD levels in patients at risk -CBC q 2-4 wks x 3 months, then q3 months -management: -G6PD deficiency: avoid drug -myelosuppression: DC drug -megaloblastic anemia: treat with folic acid supplementation, do not need to discontinue SSA CNS: -headache, dizziness Cardiovascular: -palpitations, tachycardia V. Immunosuppressives/Cytotoxic Agents -generally reserved until patient has failed other SAARDs--however, Methotrexate is gaining popularity as a first line SAARD -All these agents have dose-related hematologic toxicity

-monitoring: CBC q 1-4 weeks when dosage being escalated, then q2-3 months thereafter -management: if counts fall below the following baselines, hold drug until counts have rebounded, then restart drug at reduced dosage,
o o o

WBC <3500 neutrophils <1000 platelets <100,000

A. Azathioprine (Imuran(r)) 1. Mechanism of action: immunosuppression 2. Efficacy -known to be steroid-sparing, effect on disease progression unclear 3. Dosing: -initiate at 50mg-100mg/day, may increase to 2-5mg/kg/day -concurrent allopurinol requires decreasing azathioprine dose by 50-75% 4. Adverse Reactions: Hematologic: -bone marrow suppression: dose limiting toxicity -follow above guidelines Gastrointestinal: -nausea, vomiting, anorexia: dose related, -hepatitis: probably allergic reaction, monitor LFTs q6-8 weeks -pancreatitis: (severe abdominal pain) probably allergic reaction -monitoring: -question pt re GI sx

-LFTs q 6-12 weeks -if severe GI pain, check amylase to R/O pancreatitis -management: -minimized GI sx by split dosing, taking with food or milk, or giving dose at bedtime -hepatitis/pancreatitis: DC drug, rechallenge extremely cautiously Mucocutaneous -rash, oral ulcers: hold or decrease dose Oncogenesis/Non-Hodgkin's Lymphoma???: -increased incidence of malignancy in patients on azathioprine after renal transplant, effect in patients on drug for rheumatologic disorders less clear, some studies suggest risk is low

B. Methotrexate (Rheumatrex(r), others) 1. Mechanism of action: immunosuppression? 2. Efficacy -approximately 60% of patients will achieve at least partial remission or improvement in symptoms, onset may be quicker than other SAARDs, but once drug is discontinued, symptoms appear to return quickly 3. Dosing: -initiate at 7.5mg/wk in 3 divided doses, increase in 2.5mg increments to maximum of 20mg/wk -dosing schedules: **preferred: q12hrs x 3 doses/week, e.g. Monday 8am and 8pm, Tuesday 8am (**data suggests that the greater the drug free interval the lower the risk for liver toxicity.) alternate regimen: one dose Monday, Wednesday and Friday

4. Adverse reactions Some evidence that concurrent folic acid supplementation may toxicity but not routinely used by all practitioners Mucocutaneous -oral ulcers: -monitoring: question patient at each visit -management: hold drug until clear, may need to dose for rechallenge

Hematologic: -bone marrow suppression--dose related -megaloblastic anemia: due to folic acid deficiency -monitoring: follow above guidelines -management:
o o

bone marrow suppression: follow above guidelines megaloblastic anemia: supplement with folic acid

Gastrointestinal: -nausea, vomiting: take with food Hepatic: -transient increased liver function tests: seen in many patients, generally do not correlate with development of hepatotoxicity, -hepatic fibrosis and cirrhosis: may be increased once total dose exceeds 1.5gm, risk in diabetics, alcohol abusers, obese patients, age, and severe psoriasis -monitoring: -LFTs: q 4-8 weeks -some experts recommend liver biopsy when patient has received 1.5gm cumulative dosevery controversial for RA patients

-management: -hold drug if LFTs >3x normal -if LFTs do not resolve, consider further work-up Pulmonary -pulmonary infiltrates/fibrosis: uncommon: not dose or duration related, patients c/o shortness of breath, dry cough, possibly allergic reaction -monitoring: baseline chest X-Ray within 1 year of starting tx, question patient about sx -management:
o o o

discontinue methotrexate steroids may be required appears fully reversible

Teratogenicity: known teratogen, contraindicated in pregnancy 5. Drug Interactions: NSAIDs: decrease renal elimination, ? significance at RA doses -salicylates, fenoprofen, naproxen, phenylbutazone and tolmetin -NSAIDs should be avoided in patients receiving cancer chemotherapy with Methotrexate Alcohol: increases risk of hepatotoxicity, limited use on special occasions okay otherwise avoid C. Cyclophosphamide (Cytoxan(r)) 1. Mechanism of action: immunosuppression? 2. Efficacy -has been shown to prevent erosions, but use limited due to toxicity -pulse therapy effective in treating vasculitis related to rheumatoid arthritis 3. Dosing: -oral therapy: 1-2mg/kg/day in morning -intravenous pulse: 750-1000mg/m2/dose every 3 to 4 weeks for treatment of vasculitis

4. Adverse reactions: Hematologic: -bone marrow suppression: after pulse therapy nadir occurs at 7-10days, recovery at 21-25 days, cumulative toxicity may occur -monitoring: follow above guidelines, monitor CBC more frequently if using pulse dosing -management: follow above guidelines Gastrointestinal: -nausea, vomiting, anorexia: with oral therapy decrease by taking with food; after pulse IV therapy--delayed onset, premedicate with antiemetic Renal: -hemorrhagic cystitis: due to toxic metabolite, acrolein in contact with bladder wall, high fluid intake and frequent urination can minimize risks by decreasing contact time with bladder wall -bladder cancer -monitoring:
o o

UA for hematuria urine cytology q6-12 months, continuing after drug cessation

-management: -if hemorrhagic cystitis occurs, DC drug Dermatologic: -alopecia: associated with high dose pulse therapy, less common with daily po therapy Oncogenesis: -development of lymphomas 10-20years post-therapy -bladder cancer Fertility -may cause sterility (ovarian/testicular failure), risk appears to be greater in older patients

D. Chlorambucil: due to toxicities, use limited to severe progressive RA or life-threatening complications of RA E. Cyclosporin A--investigational for this indication, results look promising but as with cyclophosphamide, toxicity may limit usefulness VI. Combination of SAARDs -becoming more common for practitioners to use multiple SAARDs concurrently in an RA patient -limited studies available--some show some benefit over single drug therapy -combinations must be selected carefully to minimize toxicity--don't use two agents together that have very similar toxicities, e.g. gold and penicillamine -studies have been done looking at the following combinations:
o o o o

antimalTimes New Romans or sulfasalazine + gold or penicillamine antimalTimes New Romans or sulfasalazine + cytotoxic agents gold or penicillamine + cytotoxic agent two or more cytotoxic agents

VII. Corticosteroids -useful for anti-inflammatory effects -do not prevent erosive disease -systemic steroids can be used in RA but not indicated for OA -intraarticular steroids can be used in both RA and OA -euphoria and feeling of well-being may promote overcompliance and patient dependence, many patients flare upon withdrawal--need to taper off very slowly A. Dosing Regimens: 1. Acute Flare-ups: -used for flare-ups of several to multiple joints - moderate dose prednisone (20-40mg/day) po for short term use - taper quickly over 1-2 weeks

2. Bridge Therapy -low dose prednisone (5-10mg/day) po for intermediate-term use -useful during initiation therapy with DMARDs -alternate day therapy usually ineffective because of pain and stiffness recur on "off" day 3. Systemic manifestations: -high dose methylprednisolone (40-80mg q6hr) or hydrocortisone (1 gram q6hr) IV -used in treatment of systemic manifestations of RA such as vasculitis and pulmonary involvement 4. Intraarticular Injections -useful for management of one to several refractory joints -must rule out joint infection before steroid injection -maximum of 4 injections per joint per year -patient should be advised to rest joint after injection because overuse could lead to joint injury or destruction -minimal systemic adverse reactions -effect persists for 2 to 12 weeks -may give local anesthetic along with steroid, e.g. lidocaine in same syringe - gives immediate relief until steroid "kicks in" in 24-36 hrs -agents and doses (dose is dependent on the size of the joint to be injected)
o o

methylprednisolone acetate (Depomedrol(r)): 5-80mg triamcinolone hexocetonide (Aristospan(r)): 5-80mg

5. Adverse Reactions of Systemic Corticosteroids

GI -peptic ulcer disease?, pancreatitis Ophthalmologic -glaucoma, cataracts CNS -euphoria or depression, psychosis

Dermatologic Renal

-acne, thining of skin, striae, capillary fragility, decreased wound healing -sodium and fluid retention, hypokalemia -altered carbohydrate metabolism/glucose intolerance, HPA suppression, Endocrine growth retardation in Children Cardiovascular -hypertension, accelerated ASHD Musculoskeletal -osteoporosis, myopathy, muscle wasting, avascular necrosis of the long bones Immune System -anergy and increased susceptibility to infection Hematologic -demargination of white cells

ARTHRITIC DISORDERS: SUMMARY

RHEUMATOID ARTHRITIS OSTEOARTHRITIS

Prevalence

1% of the population

90-95% of >65 year olds

Age Group

All ages, but increasing with increasing age

Middle age to elderly

Gender

3 times more common in women than men

<45 years: males > females >55 years: males < females

Heredity

Yes

Yes

Joints Affected

Hands (PIP, MCP), Wrists

Hands (PIP, DIP) Knees

Elbows, Shoulders, Feet Ankles, Knees, Hips Cervical Spine

Hips, Feet (1st MTP) Cervical Spine, Lower Lumbar Spine

Morning Stiffness

> 1 hr

< 15 minutes

Fatigue, Anorexia Anemia (normochromic/cytic) Hypoalbuminemia Systemic Manifestations Skin (Rheumatoid) Nodules Vasculitis, Pleuropulmonary Disease, Pericarditis Sjogren's Syndrome None

ESR

Elevated

Usually normal

Rheumatoid Factor

Positive in 70%

Usually negative

Antinuclear Antibodies Positive

in 15%

Drug Treatment
y

Nonantiinflammatoryanalgesics (eg APAP)

Rarely

Yes

Antiinflammatory agents (eg

Yes

Yes

NSAIDS)

"Slow-acting" Agents (eg Gold)

Yes

No

Systemic steroids

Yes

No

Intraarticular steroids

Yes

Yes

ARTHRITIC DISORDERS - RECITATION CASES

RECITATION CASE I T.B. is a 43 year old white female who presents with a 2 month history of joint stiffness and swelling involving both wrists, elbows, knees and ankles. Several fingers are also involved. She also notes a decrease in her hearing acuity and a roaring-like sound in her ears. Aspirin was initially effective for her joint pains but has recently provided less relief. She also complains of significant fatigue and morning stiffness (lasting about 4 hours) which is interfering with her work as a gardener/landscaper. Past Medical History: Hypertension x20 years Migraine Headaches

Medications:

Propranolol 40mg bid HCTZ 50mg qam KCL 40mEq qam Aspirin 325mg 2tabs tid Cafergot prn migraine

Laboratory:

HCT/Hgb 33.2/10.3

Na 139 K 4.8 BUN 21 SCr 1.4 UA - glucose/blood Rheumatoid Factor (RF) 1:320 ESR 55 Salicylate Level 8mg/dl

Radiography:

Hand films show soft tissue swelling and joint space narrowing on all MCPs and first 3 PIPs of both hands. There is periarticular osteoporosis on both hands but no erosions are evident.

Physical Exam:

BP: 135/85 P 65 Wt 135lbs

Diagnosis:

Rheumatoid Arthritis

1. How is this patient's presentation consistent with a diagnosis of rheumatoid arthritis? 2. Should aspirin be continued in this patient? 3. Choose a treatment plan for this patient and justify your choice. 4. What parameters should be monitored in this patient? 5. How would you counsel this patient on the appropriate use of her NSAID? RECITATION CASE I - ANSWERS 1. How is this patient's presentation consistent with a diagnosis of rheumatoid arthritis?

Her presentation is typical for Rheumatoid Arthritis. She has joint stiffness and swelling bilaterally involving fingers, wrists, elbows, knees and ankles. Her history is positive for fatigue and morning stiffness. Her laboratory results are significant for an elevated ESR and

a + Rheumatoid Factor. Her X-rays show soft tissue swelling,joint space narrowing and periarticular osteoporosis which is consistent with RA. The characteristics which differentiate this patients arthritis from osteoarthritis include the systemic symptom of fatigue, the evidence of inflammation as noted by the increased ESR, the joints involved in the hand (MCPs and PIPs seen in RA, PIPs and DIPs seen in OA) and the positive Rheumatoid Factor.

2. Should aspirin be continued in this patient?

TB says that aspirin was initially helpful but no longer seems to work. Anti-inflammatory doses of ASA (salicylate levels of 15-30mg/dl) are recommended for the treatment of RA, but TBs salicylate level is only 8mg/dl, which would provide analgesic effect but minimal antiinflammatory benefit. In order for TB to get a therapeutic benefit from aspirin, she would need to be on a higher dose for 2 to 3 weeks. However, she is experiencing tinnitus and decreased hearing acuity even on this low dose of aspirin, so continuing aspirin in this particular patient is not a reasonable option.

3. Choose a treatment plan for this patient and justify your choice.

An anti-inflammatory dose of an NSAID is appropriate for TB at this time. There is no need to start her on a second line drug until assessment of her response to NSAIDs can be made. She has not had an adequate trial of NSAIDs and currently she has no erosions on her x-rays which would be a clear indication for treatment with a SAARD. As to choice of an NSAID, there is no one specific agent which would be best for her. However, I would avoid indomethacin because of her history of headaches. Also, because she is on HCTZ, she is at increased risk for nephrotoxicity from NSAIDs. A potentially less nephrotoxic NSAID would be desirable. Therefore, sulindac would be a good first choice for this patient. However, if sulindac was not effective, an alternate NSAID could be tried with close monitoring of her kidney function. (Although, they are relatively nontoxic to the kidney, the nonacetylated salicylates are not a good choice for this patient because, like aspirin, they require a salicylate level of 15-30mg/dl, and she had tinnitus at levels below this on aspirin.)

4. What parameters should be monitored in this patient?

y y y y

morning stiffness joint swelling and tenderness monitors of disease activity hand radiographs ESR (not very sensitive)

y y y

BUN/Cr (within 1-3 weeks of beginning NSAID) Blood pressure possible toxic effects of NSAIDs K+

5. How would you counsel this patient on the appropriate use of her NSAID?

y y y

She should be instructed to take NSAID with food/milk to minimize GI symptoms She should be cautioned to use a sunscreen since NSAIDs may cause photosensitivity reactions and she spends a lot of time outdoors She should be instructed on the importance of compliance with her prescribed regimen of NSAIDs since the anti-inflammatory effect, not the analgesic one is desired--PRN use is not appropriate for this patient It may take 2-3 weeks for her to achieve the full benefit from the NSAID

PMPR652: ARTHRITIC DISORDERS RECITATION CASE II

O.T. is a 55 year old white male with a history of RA for 5 years. He is currently taking Ibuprofen 600mg qid with moderate relief of his joint pain. (In the past he has taken ASA, tolectin, indomethacin and piroxicam, but did not tolerate these due to GI irritation.) He recently had to discontinue injectable gold therapy because of proteinuria. His morning stiffness lasts approximately 3 hours. Today he is complaining of significant pain in his left knee--he's having trouble walking due to the pain. His most recent hand x-rays show an erosion which is new since his last films 6 months ago.

Past Medical History:

Diabetes Mellitus, Type II x8yrs COPD, mild GI bleed due to PUD 10 yrs ago

Medications:

Ibuprofen 600mg qid Glipizide 5mg qam Theodur 200mg tid Antacids prn GI distress

Laboratory:

HCT/Hgb 41/12.3 MCV 90 WBC 3.0 FBS 180 BUN 25 SCr 1.3 (Was 0.9 on first visit 3 yrs ago) UA 1+ glucose - protein/blood ESR 48

Social History:

+ Tobacco (1/2 ppd) + EtOH (2-3 beers/day)

Allergies:

Penicillin (rash) Codeine

Physical Exam:

WNWD male in NAD mild tenderness and swelling in rt wrist, elbow and first three MCPs on right hand. Left knee is significantly swollen and tender BP 130/85 P 72 Wt 190lbs

1. Evaluate this patient's current regimen for rheumatoid arthritis. 2. Recommend a new regimen for this patient and justify your choice(s).

3. What parameters should be monitored in this patient based on the recommendations you made in #2? 4. Are corticosteroids indicated for this patient? PR652: ARTHRITIC DISORDERS RECITATION CASE II ANSWERS

1. Evaluate this patient's current regimen for rheumatoid arthritis.

This patient needs a new second line agent. The indications for SAARDs are lack of efficacy of an appropriate trial of NSAIDs (patient still has 3 hours of AM stiffness on a therapeutic dose of ibuprofen) and/or disease progression (patient has new erosion). May wish to consider misoprostol in this patient. Although tolerating ibuprofen well, he has a h/o a GI bleed and NSAID-induced ulcers may be asymptomatic.

2. Recommend a new regimen for this patient and justify your choice(s).

There in no single correct answer for this questionseveral SAARDs could be chosen: AntimalTimes New Romans-would be acceptable, well tolerated but long-term efficacy is unclear for patients with erosions Sulfasalazine-acceptable, but dose should be titrated up slowly to minimize adverse effects Azathioprine-acceptable, but patient has low baseline WBC, may not be able to give adequate dose of azathioprine without causing neutropenia Penicillamine: could be tried (no contraindication in patients with PCN allergy) however h/o proteinuria with gold increases risk of similar renal problems

with penicillamineif used must monitor very closely Combination therapy with two of the above might be usefulno clear cut guidelines for use as of yet

However, several SAARDs would not be appropriate for this patient: Oral gold: not appropriate-patient had proteinuria with injectable gold Methotrexate: poor choice, patient has diabetes and drinks ETOH regularly which increases risk of hepatotoxicity from MTX. Also has low baseline WBC. Use only if patient is willing to stop ETOH. Also need to watch pulmonary function because of h/o COPD Cyclophosphamide/Cyclosporin: too toxic to be used so early in disease, other drugs preferable

3. What parameters should be monitored in this patient based on the recommendations you made in #2?

Drug Efficacy: morning stiffness, joint pain, ESR, x-ray changes

Adverse Effects: NSAIDs: GI symptoms AntimalTimes New Romans: GI symptoms, ophthalmologic exam q6 months, muscle weakness Sulfasalazine: CBC esp WBC & MCV, GI symptoms, HA/dizziness Azathioprine: CBC esp WBC, LFTs, symptoms of pancreatitis Penicillamine: CBC, urinalysis, skin side effects For combination therapy, monitor as for each of the individual agents

4. Are corticosteroids indicated for this patient?

Corticosteroids in this situation could be used for active disease until the new second line drug "kicks in". However, steroids might decrease his diabetic control. If OT is not in severe discomfort, a preferable alternative to systemic steroids would be to increase his ibuprofen dose to 800mg qid until the SAARD became effective. (In this case, patient should also be Rx'd with misoprostol as indicated above.) He could also be given an intraarticular steroid injection into his left knee (his most troublesome joint) which would give local relief without the adverse effects of systemic steroids.