arthritic disorders

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Arthritic Disorders

I. Osteoarthiritis II. Management of Osteoarthiritis

III. R heumatoid Arthritis IV. Management of R heumatoid Arthritis

GOAL:

To comprehend the pharma cotherapeuti c management of rheumatoid arthritis( RA) and osteoarthritis(O A).

OBJEC TIV ES :

U pon completion of the coursework on arthriti c disorders, the student will be a ble to:

1. D evelop a treatment strategy for RA and OA, utilizing both pharma cologi c and non- pharma cologic management .

2. D iscuss the rationale, indications, dosage regimens, adverse reactions, monitoring parameters and therapeuti c endpoints for the following agents in the treatment of RA and OA:

a. simple analgesi cs (acetaminophen ) b. topical analgesi cs c. NSAID s, including aspirin d. gold

e. penicillamine f . antimal Times New R omans g. sulfasalazine h. immunosuppressives i. corticosteroids

3. P rovide appropriate patient education for the therapeuti c regimens used in the treatment of RAand OA.

R equired R eadings :

DiPiro: Pharma cotherapy 3rd Edition--Chapter 84, R heumatoid Arthritis and the Seronegative

Spondyloarthropathies and Chapter 85, Osteoarthritis

ARTHRITIC DISORDERS



from : The Arthritis Foundation : Primer on the rheumatologi c D iseases 1988

III. Epidemiology :

A. R adiographi c eviden ce of osteoarthritis seen almost universally in persons over 65 years of age however, radiologi c findings do not correlate with symptoms

B. Symptoms present in approximately 40% of persons over 65 years C. Onset begins in late 30's and peaks in 60's D. Below age 45, males outnum ber females . Ab ove age 55, females have OA more

commonly than males E. Heredity plays a role

IV. Clini cal Presentation :

A. Symptoms loca lized to joints and surrounding soft tissue :

y swelling, pain, stiffness : early in disease pain seen primarily with joint use; as disease progresses, pain will also occur at rest

y morning stiffness of short duration, stiffness also occurs after periods of joint inactivity y joints affe cted : hands (DIP s, PIP s, first CMC), knees, hips, first MTP , cervical and

lum bar spines (See Figure 3) y He berden 's nodes (DIP) and Bou chard 's nodes (PIP): b ony enlargement of

interphalangeal joints y chroni c disease may lead to joint deformity y bursitis and tendonitis commonly seen in surrounding soft tissues due to a bnormal stress

put on joints

Figure 2: Joints Affected in Osteoarthritis



indicates joints most commonly affe cted in osteoarthritis

from : Cooke and Dwosh . Clin R heum Dis 12:155 -172 , 1986

V. L a boratory and R adiologi c Findings :

A. ES R: usually normal for age B. R heumatoid factor and ANA: negative ( but remem ber : up to 5% of non- RA population

has +R F (rheumatoid factor ) C. Synovial fluid : c lear, good viscosity, WBCs <2000 (non-inflammatory )

D. X-R ays: "joint space narrowing " (eviden ce of cartilage loss ), su bchondral sclerosis and marginal osteophyte formation

VI. P rognosis :

A. Varia ble, symptoms do not always correlate with clinical and radiographi c findings B. Involvement of spine and weight- bearing joints increases risk of disa bility C. Chroni c, disa bling disease occurs in 10% of elderly

M ANAGE M ENT OF OSTEOARTHRITIS

I. T reatment Goals :

A. R elief of pain



B. Preservation of joint form and function, minimized disa bility

II. N on-Pharma cologic M anagement : indicated for a ll patients

A. Muscle strengthening exer cises : improved muscle tone sta bilizes joints, can signifi cantly 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 Uncompli cated OA



III. Simp le Ana lgesics (Acetaminophen)

A. Provide analgesi c effe ct for non-inflammatory arthriti c conditions B. R ationale for use in OA

1. Potentially less toxic than NSAID s 2. Some studies demonstrate effi cacy = N SAID s

C. Doses up to 3 or 4 grams daily can be used; PRN dosing is appropriate in many cases espe cially early in the disease, as it progresses may need scheduled doses

D. Avoid nar cotic analgesi cs if at all possi ble--with chroni c pain there is risk of dependen ce

IV. Topica l Ana lgesics (Capsicum, Zostrix ¿ )

A. Su bstan ce p depletor : diminishes pain sensation B. Ad junctive or monotherapy C. A pply to affe cted area tid-qid on scheduled (not prn) basis D. Takes 1-2 weeks before see benefit E. Adverse effe cts: localized irritation/ burning

V. Nonsteroida l antiinf lammatory dru gs (NSAIDs)

A. Use analgesi c doses prn initially, swit ch to scheduled dosing when needed B. Can often achieve pain relief with lower dosages than needed for antiinflammatory

effe cts 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 medi cations, it is important to monitor closely for NSAID ADR s, drug-drug and drug-disease intera ctions

VI. Intraarticu lar corticosteroids A. Can be used as monotherapy for a single affli cted joint or as an ad junct to a bove therapy

when one or two joints are active/refra ctory despite systemi c therapy B. See RA section for discussion of usage/dosage



VII. Sodium hya luronate (Hya lgan ¿ )

A. Viscous solution that mimi cs joint fluid B. Indicated for OA of the knee that has failed initial therapy C. 5 weekly in jections into affe cted knee D. Pain relief compara ble to NSAID in one study E. ADR s: primarily in jection site pain F. Additional studies would be helpful

RHEU M ATOID ARTHRITIS :

I. Definition:

-a chroni c multisystem disease of unknown etiology chara cterized by persistent inflammation of the synovium, resulting in cartilage destru ction, bone erosion and joint deformity .

II. Patho genesis:

A. Etiology unknown : possi bly triggered by an infe ctious or chemi cal agent in suscepti ble individuals

B. Immunologi cally mediated inflammation (Figure 1)

-leads to destru ction of normal tissue

III. Epidemio logy:



A. A ffects approximately 1% of the U.S. population

B. Females affe cted 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. G eneti c predisposition : positive asso ciation with histo compati bility alleles

IV. C linica l Presentation:

A. First symptoms often extra-arti cular : 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 invo lvement :

- bilateral : hands (MCPs, PIP s), wrists, el bows, shoulders, feet, ankles, knees, hips, cervical spine (dominant side may be more affe cted )

-pain, swelling, tenderness, warmth : all markers of inflammation

-signifi cant morning stiffness : generally >1hr (useful as marker of disease activity )

C. Extra-arti cular manifestations :

-rheumatoid nodules (20-30%)

-areas of central necrosis surrounded by inflammatory cells

-found in periarti cular su bcutaneous tissue that is su bject to mechanical pressures, e.g. around el bows, knuckles

-may be found in deep conne ctive tissues or viscera, e.g. lungs

-asso ciated with increased severity of disease

-vasculitis : inflammation and necrosis of blood vessels

-cardia c: pericarditis

-pulmonary : pleuritis, fi brosis

-osteoporosis : periarti cular (secondary to inflammation ) and generalized

(secondary to chroni c disease and immo bilization )



V. Laboratory and Radio logic Findin gs:

A. N o la boratory test is diagnosti c

B. R heumatoid Factor (autoanti bodies reactive with the Fc region of human IgG) (Standard

rheumatoid factor tests look for IgM anti bodies, but can R F anti bodies can also be IgG, IgA or IgE) ± presen ce of a + R heumatoid factor is not dia gnostic for RA

o positive in approximately 70% of RA patients o rheumatoid factor also found in 1-5 % of normal population o patients with RA b ut no R F have "seronegative rheumatoid arthritis "

C. ANA (antinu clear anti bodies ): positive in 25% (homogenous pattern )

D. Erythro cyte Sedimentation R ate (ES R: non-spe cific measure of inflammation ): usually elevated, in con junction with clinical symptoms can be used as a disease marker

E. Anemia : common, usually normo chromi c, normo cytic anemia of chroni c disease (may be compounded by concurrent iron or folate defi ciency)

F. Synovial fluid from tap of affe cted joint : cloudy, decreased viscosity, increased WBCs and protein, decreased complement (all chara cteristi c of inflammation )

G. X -R ays changes :

o early : soft tissue swelling, joint effusion, regional osteoporosis o progressive/late : marginal joint erosions, decreased joint space and malalignment

secondary to erosions of bone VI. Dia gnosis (Tab le 1 )

A. M ade on basis of multiple factors²in cludes clinical and la boratory findings

Ta ble 1: D iagnosti c Criteria for R heumatoid Arthritis

1. Morning joint stiffness of >1 hour a

2. Swelling of > 3 j ointsa

3. Swelling of the PIP s, MCPs or wrist joints a 4. Symmetri cal joint swelling a 5. Su bcutaneous nodules 6. Positive rheumatoid factor test 7. X-R ay changes : erosions/periarti cular osteoporosis in hand/wrist joints



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

VII. Pro gnosis

A. Chara cterized by exacer bations and remissions

-possi ble exacer bating factors include emotional or physical stress and changes in weather conditions, espe cially 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 disa bility (Class IV)

D. D ecreased life expe ctan cy ( by 3 to 7 years average )

-death rate increased primarily due to respiratory disorders, infections, gastrointestinal disease and rheumatoid arthritis itself

M ANAGE M ENT OF RHEU M ATOID ARTHRITIS

I. Treatment Goa ls

A. R elief of pain B. Decrease inflammation C. Preservation of joint form and function, minimized disa bility

______________________________________________________________________________ __



Figure 5: Flow Chart for the Medication Management of RA

II. Non - Pharmaco logic M ana gement: indicated for a ll patients

A. R est :

-systemi c rest : encourage naps and 8 hours of sleep at night

- joint rest : for acute inflamed joints via splints/ braces

B. P assive range of motion : to maintain joint function, prevent contra ctures, minimize muscle atrophy

C. Exer cise: need to maintain good muscle tone/ joint alignment, however avoid active exer cise during periods of active inflammation

D. L ocal heat/ cold therapy : use caution with either to avoid tissue damage

E. Splints/ braces: to maintain joint alignment and aid in function

F. Ac hievement of ideal weight : minimizes stress on joints

III. Non - Steroida l Anti - inf lammatory A gents (NSAIDs)

A. A nalgesi c and anti-inflammatory effe cts

-used primarily for anti-inflammatory effe cts²first line therapy



B. M echanism of action:

-inhi bition of prostaglandin synthesis through inhi bition of cyclooxygenase enzyme² inhi bition of this enzyme may be permanent (e.g. aspirin ) or reversi ble

-other mechanisms impli cated in effe cts of NSAID s, e.g. inhi bition of neutrophil activation, therapeuti c benefits of these additional MOA are unclear

C. Effi cacy

-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 varia bility in effi cacy and toleran ce

-some small differen ces in adverse reaction profiles between agents

-complian ce 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 chemi cal "family "

E. Aspirin (ASA - acety lsa licy lic acid):

-considered by some to be the drug of choice because of effi cacy, low cost and availa bility

-anti-inflammatory effe ct seen at sali cylate levels of 15-30mg/dl

-must stress complian ce because analgesi c dose << anti-inflammatory dose

-may require doses of up to 5 grams per day (in 3-4 divided doses ) to reach therapeuti c 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 exhi bits saturation kineti cs and half-life is approximately 20hours : 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 chroni c therapy

- buffered or anta cid com binations : decrease GI symptoms but no signifi cant decrease in GI blood loss over uncoated ASA

-enteric - coated : increased cost over plain ASA, decreased GI toxicity both su bjectively and o bjectively, bioavaila bility has been pro blem in past (most current brand-name products, e.g. Ecotrin(r ), Easprin(r ) are okay, they also come in larger doses for increased patient convenien ce: Ecotrin(r ) 375 mg, 500 mg, Easprin(r ) 975 mg)

-"sustained re lease" aspirin : larger dose in single ta blet, increased cost over plain ASA, some products R x only, often allow fewer num bers of ta blets daily with less frequent dosing interval (e.g. ZOR prin(r ) 800 mg-may be given BID)

2. Adverse reactions:

Into lerance:

- bronchoconstri ction: not a true "allergy ", pro ba bly mediated through prostaglandin inhi bition, increased in patients with asthma and/or nasal polyps, cross reactivity often seen with other

NSAID s

-urti caria, angioedema : frequently seen in patients with chroni c urticaria, may be immunologi cally mediated

Gastrointestina l: (also see section on non-sali cylate NSAID s)

-MOA twofold :

-local irritation (due to acidic nature of ASA)

-systemi c toxicity: ¿ mucosal resistan ce due to prostaglandin inhi bition

-symptoms : nausea, vomiting, dyspepsia, GI b lood loss : symptoms do not correlate with degree of gastrointestinal damage

-risk of GI ulceration/hemorrhage

-risk decreased somewhat by using enteri c-coated/sustained release produ cts (minimizes local toxicity) but still a signifi cant risk

Dermato logic:

-rash : urticT imes New R oman rash may suggest hypersensitivity



CNS:

-tinnitus : dose related, usually occurs close to toxic level, although in some patients may occur at low levels, sometimes descri bed as hearing loss, roaring in ears or sea shell sound, generally reversi ble with ¿ dose or stopping drug, may not occur in elderly even at high doses

-HA, vertigo

Hemato logic:

-platelet dysfun ction: irreversi ble inhi bition of platelet aggregation due to cycloxygenase inhi bition, effe ct 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: -intrinsi c hepatotoxin

-hepato cellular toxicity: dose and concentration dependent

-increased LFTs and hepatomegaly

-increased risk in children on aspirin for Juvenile RA: monitor LFTs on regular basis

Rena l:

-aspirin can decrease renal function (see NSAID section for mechanism )

-less toxic to kidneys than other more potent NSAID s

F. Nonacety lated Sa licy lates:

Drug of Choi ce in patients with ulcers, bleeding disorders and ASA-indu ced bronchospasm

-Produ cts availa ble

o Cho line ma gnesium trisa licy late (Trilisate(r )): c ontains magnesium o Sa lsa late (Disalcid(r )): two sali cylate mole cules joined together o Cho line sa licy late (Arthropan(r )): liquid formulation o M agnesium sa licy late (Magan(r )): c ontains magnesium o Sodium sa licy late : contains sodium

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



-converted in vivo to salicylate which is active component of drug

-initiate dosing at 1500 mg bid (for anti-inflammatory effe cts), can use lower doses for analgesi ceffe ct

-similar activity and kineti cs to aspirin--monitor salicylate levels, as with ASA antiinflammatory levels are 15-30mg/dl

-advantages over aspirin :

-less gastrointestinal intoleran ce: felt to be non-ul cerogeni c, 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 effe ct: the nona cetylated sali cylates do not affe ct platelet cyclooxygenase

-may be used cautiously in aspirin intolerant patients ( bron chospasm ); 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 (generi cs are availa ble for some of these agents )

-salt load, use with caution in patients with renal impairment/C HF because of sodium or

magnesium load with some of these agents G. Sa licy late Dru g Interactions : (occur with ASA and the non-a cetylated sali cylates )

Warfarin : displa cement from protein binding sites by salicylates

-avoid aspirin in patients on warfarin for 3 reasons :

o protein binding displa cement²in crease effe ct of warfarin o GI irritation and blood loss²in creased bleed risk o antiplatelet effe ct can compli cate warfarin-indu ced bleeding

-non-a cetylated sali cylates : will cause displa cement from protein binding sites but do not increase risk of GI b leeding, nor do they cause platelet dysfun ction, for patients who need chroni c antiinflammatory therapy, these agents are good choices provided the patient understands the need for good complian ce



Oxaprozin (Daypro(r )) 3-6 36 -92 >90% none

IND OLE ACE TIC ACIDS

Indometha cin (Indocin(r )) 1 to 2 4.5 <15% none

Indometha cin (Indocin SR (r )) 2 to 4 4.5 to 6 <15% none

K etorola c (Toradol(r )) 0.5 4 to 8.6 56-60% none

Sulinda c (Clinoril(r ))* 2 to 4 7.8 /16.4 4 7% sulinda c sulfide

Tolmetin (Tolectin(r )) 0.5 to 1 1 to 1.5 15% none

FE NAMAT ES

Meclofenamate (Meclomen(r )) 0.5 to 1 2 /3.3 5 2-4% hydroxymethyl

derivative

Mefenami c Ac id (Ponstel(r )) 2 to 4 2 to 4 <6% none

OXICAM S

Piroxi cam (Feldene(r )) 3 to 5 30 to 86 10% none

PH E NYLA CE TIC ACIDS

Diclofena c (Voltaren(r )) 2 to 3 2 <1% none

PYRAN OC AR BO XYLIC ACIDS

Etodola c (Lodine(r )) 1 to 2 6-7 1% none

NAPHTH YALKAL O NES

Na bumetone (R elafen(r ))* 3-66 24 6 <10% 6-MNA 7

PYRAZ OLES

Phenyl butazone 2 50 -100 1% oxyphen butazone

Oxyphen butazone 1 to 2 27 -64 1% none

SALI CY LAT E DERIVATIV ES

Diflunisal (Dolo bid(r )) 2 to 3 8 to 122 <3% none

* P rodrug 1 Food ¿ rate of a bsorption, peak may be delayed 2 Con centration dependent elimination kineti cs 3 pH dependent renal elimination 4 Half-life of active meta bolite 5 Half-life after multiple doses



6 Time to peak/half-life of active meta bolite 7 6-methoxy 2-naphthyla ceti c acid

Adapted from: Facts and Comparisons 1991 , Clin Pharma cokineti cs 8:297 -331 , 1983.

2. A dverse reactions

"Hypersensitivity" (Into lerance):

-high incidence of cross sensitivity with aspirin allergy due to inhi bition of prostaglandin synthesis . N SAID s should be avoided in patients with bron choconstri ctive reactions to sali cylates

Dermato logic:

-rash : severe reactions (including Stevens-Johnson with phenyl butazone ) have been reported

-photosensitivity : encourage patients to use suns creens

Gastrointestina l:

-generally less than seen with aspirin (due to less local mucosal toxicity) but still

signifi cant risk of PUD (primarily gastri c ulcers) in patients at risk

-high degree of patient varia bility in GI toxicity

-risk groups for development of ulcers with NSAID s

-patients with h/o PUD

-elderly

-women

-patients using high dose NSAID s

-patients using multiple NSAID s

-symptoms do not correlate with endos copic findings : lack of symptoms does not indicate patient does not have an NSAID -indu ced ulcer . For some patients, the first symptom of ulceration may be an acute GI b leed

-prevention and management :

-in patients at risk, use less irritating agents first, such as the non-a cetylated



sali cylates or na bumetone

-if these agents are not successful, use misoprostol (Cytote c(r )) in com bination

with an alternate NSAID for preventing ulcers

-misoprostol :

-dosage : 100 -200mcg qid

-adverse effe cts:

o diarrhea common, patients will develop toleran ce o a bortifa cient--do not use in pregnant women!

-H2 b lockers or sucralfate may also provide some prote ction against NSAID -indu ced duodenal

ulcers but do not appear to prevent gastri c ulcers -Preventive therapy with misoprostol should also be considered in patients that aren 't in risk categories listed a bove but who would not tolerate a ma jor GI b leed, e.g. patients with signifi cant pulmonary or cardiovas cular disease

CNS:

o tinnitus : incidence less than with salicylates o drowsiness, dizziness and confusion : esp in elderly patients o heada ches: commonly seen with indometha cin o

asepti c meningitis (severe heada che, nuchal rigidity ): reported primarily with i buprofen, but has also been seen with tolmetin and sulinda c

Hemato logic:

-platelet dysfun ction: inhi bition as seen with ASA, but reversi ble, duration is related to t1/2 of drug, therefore, antiplatelet activity is of shortest duration with short-a cting agents such as i buprofen and tolmetin

- blood dyscrasias (agranulo cytosis, aplasti c anemia ): uncommon but reported with all agents, most signifi cantly asso ciated with phenyl butazone

Nephrotoxicity: ( 2 types )

1. Hemodynamica lly- Induced Rena l Fai lure

-onset within days to weeks

-related to antiprostaglandin effe ct



-mechanism of action: loss of renal vasodilation (Figure 6)

-cause of decreased renal function is decreased blood flow to the kidney, not a

dire ct toxic effe ct on the kidney

______________________________________________________________________________ _

Figure 6: M echanism of NSAID -related Hemodynami cally- Indu ced R enal

Failure

________________

from : Clive and Stoff . N EJM 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 compromised renal function e.g. secondary to age or disease such as long standing HTN or DM

o CHF o hepati c c irrhosis with ascites o volume contra ction from any sour ce o dehydration o concurrent medi cations : A CEI, diureti cs



-presentation : edema, hyperkalemia, increased BUN /Scr decreased urine output, acute renal failure

-generally reversi ble upon DC of NSAID (if caught in time )

-appears that non-a cetylated sali cylates and sulinda c areasso ciated with less risk of this type of nephrotoxi city

2. Nephrotic Syndrome

-uncommon to rare

-onset within weeks to months

-presentation : proteinuria (>3gm/day ) with severe renal impairment

-most commonly reported with proprioni c acid derivatives, esp fenoprofen ( Nalfon(r )) -possi bly represents an allergi c reaction

-generally reversi ble with DC of NSAID

Hepatotoxicity:

-may be an idiosyn cratic reaction or an intrinsi c toxin

-increased LFTs, GI symptoms, fever, rash, jaundi ce may be seen

-15% of patients on NSAID s develop transient increase in LFTs--no need to

discontinue NSAID unless patient is symptomati c or LFTs are > 3x normal

-cholestati c and/or hepato cellular 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. Individua l Agents

Propionic Acids:



-Ibuprofen (Motrin(r ), R ufen(r ), others ): generally well tolerated by GI tract, anti-inflammatory effe ct requires dose >1800 mg/day

pediatri c formulation indicated for antipyresis only

Dosage : 400 -800 mg tid-qid (max 3200 mg/day ) OTC dosage : 200 mg ta bs, 1200 mg/day max

-Fenoprofen ( Nalfon(r )): highest inciden ce of nephroti c syndrome

Dosage : 300 -600mg tid (max 3200 mg/day )

-Naproxen ( Naprosyn(r )): generally good GI toleran ce, approved for pediatri c use (suspension availa ble)

Dosage : 250 -500mg bid-tid (max 1250 mg/day )

Pediatri c dose : 10 mg/kg/day in bid doses

-Naproxen Sodium (Anaprox(r )): only advantage over naproxen ismore rapid a bsorption/faster

onset when taken on an empty stoma ch, not a signifi cant benefit in patients on chroni c dosing

Dosage : 275 -550mg bid-tid (max 1375 mg/day )

OTC dosage (Aleve(r )) 200 mg q12hr

-Ketoprofen (Orudis(r ), Oruvail(r )--S R) inhi bits leukotriene and prostaglandin synthesis--clinical signifi cance unknown

Dosage :50-75mg bid-qid (max 300 mg/day )

-F lurbiprofen (Ansaid(r )): short t1/2 but can be given bid

Dosage : 50 -100mg bid-qid (max 300 mg/day )



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

-Etodo lac (Lodine(r )): good analgesi c agent

Dosage : 200 -300mg bid-qid (max 1200 mg/day )

-Ketoro lac (Toradol(r )): in jecta ble or oral NSAID used for pain management, not indicated for chroni c use

Dosage : IM: 30 -60mg stat, 15-30mg q6hrs

PO: 10 mg q4-6hr, max 40mg/day

Fenamates:

-M eclofenamate (Meclomen(r )): ma jor adverse reaction is diarrhea

Dosage : 50 -100mg tid-qid (max 400 mg/day )

-M efenamic acid (Ponstel(r )): not FDA approved for RA or OA, only for pain/dysmenorrhea

Dosage : 250 mg tid-qid (max 1000 mg/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 )

Naphthy la lka lones:



-Nabumetone (R elafen(r )): prodrug, may be less toxic to GI tract, once a day dosing at initial dose

Dosage : 1000 mg qd, up to 2000 mg/day in bid dosing

Others:

-Dif lunisa l (Dolo bid(r )): sali cylate derivative but not converted to salicylate, cannot measure sali cylate levels, good analgesi c

?less tinnitus than other salicylates ?

Dosage : 250 -500mg bid (max 1500 mg/day )

Pyrazo les:

-Pheny lbutazone (Butazoladin(r ), others ): very effe ctive agent but limit continuous use to <2weeks because of hematologi c toxicity, avoid in elderly, oxyphen butazone is active meta bolite

Dosage : 100 -200mg tid-qid (max 400 mg/day )

-Oxyphenbutazone (generi c only-see comments/dosage for

phenyl butazone )

4. Dru g Interactions:

Antihypertensives : N SAID s may ¿ antihypertensive effe ct of many antihypertensivein cluding diureti cs, beta- blockers, ACE-inhi bitors, centrally acting agents such as clonidine, prazosin, monitor BP in patientson antihypertensive therapy and ad just antiHTN therapy accordingly (remem ber that ACEI and diureti cs increase the risk of NSAID -indu ced renal dysfun ction .)

Wa rf a rin :

o protein binding displa cement occurs with mefenami c acid & phenyl butazone

o use other NSAID s cautiously because of antiplatelet effe ct and risk of GI bleed



M ethotrex a te: decreased MTX renal elimination due to inhi bition of tu bular secretion (occurs with fenoprofen, naproxen, phenyl butazone and tolmetin )--pro ba bly not clinically important with the low doses of MTX used in RA and psoriasis, but is signifi cant with chemotherapeuti c doses of MTX

Lithium :increased lithium levels from decreased renal blood flow (does not occur with sali cylates ) ²monitor patient for sx of lithium toxicity

5 . Disease - Dru g Interactions

Limited data availa ble on the effe cts of organ dysfun ction on NSAID s--

USE ALL NSAIDS CAUTIOUSLY IN PATIENTS WITH ORGAN DYSFUNCTION

Aging : altered meta bolism V increased adverse reactions, start with low doses, increase cautiously, monitor la bs more frequently, avoid phenyl butazone

C irrhosis :

o ¿ meta bolism o increased risk of renal dysfun ction o use caution with drugs that have active meta bolites, effe ct may be decreased

because of impaired conversion to active drug, active meta bolite may also accumulate in patients with liver disease, e.g. sulinda c, phenyl butazone

o as most NSAID s are highly protein bound, may see higher free drug levels in liver disease due to altered protein binding

R en al insufficiency : although NSAID s primarily meta bolized by liver, renal dysfun ction may lead to ¿ free fraction and ¿ adverse effe cts

P regn a ncy :

o contraindi cated after 32 weeks because may cause premature closure of ductus arteriosus, leading to pulmonary HTN in fetus

o antiplatelet effe ct of NSAID s given near term may ¿ risk of bleeding in mother and fetus (however, some studies suggest that low dose aspirin during pregnan cy may decrease risk of preelampsia ) ²risk versus benefit must be assessed for each patient

IV. S low Actin g Anti - Rheumatic Dru gs (SAARDs):

o also called Disease Modifying Anti- R heumati c D rugs (DMARD s) or R emissive Agents o used for progressive, erosive R heumatoid Arthritis uncontrolled by NSAID s o have slow onset of action (up to 4 months ) and are poor analgesi cs; therefore generally

need to continue NSAID therapy for control of pain and inflammation until SAARD



reactions

M ucocutaneous :

-oral ulcers, stomatitis (gastrointestinal toxicity rare with in jecta ble gold )

-rash

-monitorin g: question patient before each dose

-mana gement :

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

Hemato logic: -eosinophilia

-throm bocytopenia (plt <150 ,000

-aplasti c anemia/granulo cytopenia (PMN s <3,000

-monitorin g: complete CBC with differential before each in jection

-mana gement:

o eosinophilia : no change in therapy needed unless asso ciated with other toxicities

o throm bocytopenia (plt <150 ,000): rare, discontinue drug do not restart o aplasti c anemia/granulo cytopenia (PMN s <3,000): discontinue drug,

do not restart (may also need to discontinue gold therapy if blood count drops signifi cantly, even if still a bove threshold )

Rena l

-glomerulonephritis, nephroti c syndrome

-monitorin g: urine dipsti ck for protein before each in jection

-mana gement: proteinuria :

o up to 2+ accepta ble, if > 2+ on dipsti ck, do 24hr urine for protein



o if >1gram/ 24hr urine colle ction, stop drug and do not restart o reversi ble upon DC of drug but may take months for complete resolution

(average 11 months )

Pu lmonary :

-"gold lung " (fi brosis, pneumonitis ): low incidence (<1%) usually seen within first 3 months of treatment, asso ciated with eosinophilia

-monitorin g: patients should be questioned a bout shortness of breath/ cough/fever before each dose of gold

-mana gement: discontinue gold

Nitritoid reaction : vasomotor reaction characterized by flushing and hypotension within 1/2-1 hr of in jection, more common with aqueous solution (gold sodium thiomalate )

-monitorin g: question patient, if symptomati c ²monitor BP after dose

-mana gement: swit ch to oil suspension

B. Ora l Go ld: Auranofin (Ridaura(r))

1. M echanism of action: modulatory effe ct on humoral and cellular immune systems

2. Effi cacy: somewhat less effe ctive than in jecta ble gold but better tolerated

3. D osing : Initiate at 3mg bid, may increase to 9mg/day

4. A dverse R eactions :

Gastrointestina l

o diarrhea, loose stools : seen in 50% of patients o monitorin g: question patient at regular intervals o mana gement: many patients develop toleran ce, if severe, decrease dose

or discontinue gold

M ucocutaneous :



o rash, pruritis, stomatitis, con junctivitis : o monitorin g: question patient at regular intervals o mana gement: decrease dose until resolved, then rechallenge or

discontinue

Hemato logic: o throm bocytopenia : low inciden ce (0.5% in one study ) o monitorin g: CBC q 4-12weeks o mana gement: if platelets <150 ,000: discontinue drug and do not restart

Rena l

-glomerulonephritis, nephroti c syndrome : uncommon because drug is primarily eliminated through the feces (vs in jecta ble gold whi ch is 70% renally eliminated )

-monitorin g: urine dipsti ck for protein q 4-12 weeks

- mana gement: : proteinuria :

o up to 2+ accepta ble, if > 2+ on dipsti ck, do 24hr urine for protein o if >1gram/ 24hr urine colle ction, stop drug and do not restart o reversi ble upon DC of drug but may take months for complete

resolution (average 11 months )

C. Penici llamine (Depen(r), Cuprimine(r))

1. M echanism of action (postulated ): -inhi bits T-lympho cytes, disso ciates macrophages and rheumatoid factors

2. Effi cacy

-overall, a bout 25% of patients will have benefi cial response, approximately equivalent to gold but less frequently used due

to slow onset and adverse effe ct profile

-secondary failures : after 3-5 years, may lose responsiveness 3. D osing : "start low, go slow ":

-initiate at 125-250mg/day, increase at 1-3 month intervals to 1000 mg/day if needed, once response occurs, attempt to taper to lowest effe ctive dose



-must be taken on an empty stoma ch because metals in food can chelate with drug and decrease a bsorption


Hypersensitivity : -peni cillin allergy does not contraindi cate penicillamine : inciden ce of cross sensitivity very low

M ucocutaneous :

-stomatitis, rash

-monitorin g: question patient regularly

-mana gement:

-oral ulcers : hold drug until healed, rechallenge

-rash : if early in therapy, discontinue or decrease dose later in therapy consider possi bility of autoimmune disease

Gastrointestina l:

-nausea, vomiting, anorexia, diarrhea : toleran ce develops with continued use, may give in split doses to decrease irritation

Hemato logic: -leukopenia, throm bocytopenia, microcytic anemia

-monitorin g: CBC every 2 weeks until dosage sta bilized, then may decrease frequen cy

-mana gement:

o leukopenia (neutrophils <2000) or throm bocytopenia (platelets <100 ,000): D C drug and do not restart

o microcytic anemia : may be due to copper or pyridoxine defi ciency indu ced by

penicillamine, does not require drug DC, if iron levels normal, supplement with copper or pyridoxine

Rena l: nephrotoxi city: patients with a h/o gold-related proteinuria may have increased risk of proteinuria with penicillamine

-monitorin g: urine dipsti ck for protein/ blood every 2 weeks until dose sta ble



-mana gement:

-proteinuria : up to 2+ on dipsti ck : decrease dose; if >2+ , do 24 hr urine for protein : if >2gm/ 24hr discontinue drug, don¶t restart

-hematuria : if >10 R BC/hpf discontinue drug, otherwise wat ch closely

Neuro logic

-peripheral neuropathy secondary to pyridoxine deficiency

-monitorin g: at each visit, question patient re: num bness/tingling in extremities

-mana gement: supplement with pyridoxine, monitor for resolution

Autoimmune Disorders

-myasthenia gravies, Goodpasture 's, thyroiditis

-may indu ce positive ANA

-if possi ble discontinue drug

Dys geusia (altered taste sensation ):

-common, may su bside without any alteration in therapy

-if persists, may respond to short course of zinc

-consider dysgeusia if patient losing weight without apparent cause

D. Antima lTimes New Romans

1. M echanism of action:

-sta bilization of lysosomal mem brane-de creased enzyme release

2. Effi cacy

-? less effe ctive than gold but better tolerated



3. A gents and Dosing

Agent of Choice: (considered to have lower risk of retinopathy )

-Hydroxy chloroquine (Plaquenil(r )): 200 -400 mg/day or 2-6.5 mg/kg/day

May also use:

o Chloroquine (Aralen(r )): 250 mg/day o Quinacrine (Ata brine(r )): 100 -200 mg/day

4. A dverse R eactions

Gastrointestina l:

- bitter taste, cramps, pain, bloating, diarrhea : most common side effe ct, can be minimized by

taking with food or nocturnal dosingnewer coated dosage form may minimize taste pro blem Dermato logic:

-rash : hold until rash clears or discontinue therapy

-pigmentation a bnormalities : graying or bleaching of hair, blue-gray discoloration of skin; benign, do not require stopping drug

Hemato logic:

-G6PD deficiency hemolyti c anemia : rare except in overdose situations

Ocu lar : (retinal exam strongly recommended every 6 months )

-3 types of pro blems-- 2 are benign, one is irreversi ble

1. accommodation defe cts: benign, patients will complain of blurred vision or slowed a bility to focus, reversi ble, doesn 't require stopping drug unless a real pro blem for patient

2. corneal deposits : halos around lights, benign, reversi ble, doesn 't require stopping drug

3. retinopathy : patchy irreversi ble visual loss asso ciated with daily doses >6.5 mg/kg/day, skin pigmentation may indicate increased risk, increased

by UV light exposure; encourage patient to wear sunglasses that block UVlight

-monitorin g: baseline exam in pts>40 yo or with previous eye disease



-mana gement:

o accommodation defe cts/corneal deposits : edu cate pt o retinopathy : discontinue drug immediately

CNS : -irrita bility, nervousness

M uscu lar :

-skeletal muscle myopathy : patients may c/o weakness

-neuropathy

-cardiomyopathy

E. Su lfasa lazine (Azu lfidine(r))

1. M echanism of action:

-anti-inflammatory or immunosuppresive ?

-active moiety is pro ba bly sulfapyridine rather than the 5-aminosali cylic acid which is not systemi cally a bsor bed

2. Effi cacy:

-not FDA approved for this indication but frequently used; many studies indicate good response if patient can tolerate high doses needed for effe ct

3. D osing :

-2-4 grams per day in divided doses

-to minimize GI toxicity, use enteri c-coated produ ct, start with low dose (500 mg bid) and increase gradually to full dose over several weeks

4. A dverse R eactions : Hypersensitivity :

-avoid in sulfa allergy

-use cautiously in patients with salicylate allergy



Gastrointestina l:

-nausea, vomiting very common, dose-related, patients develop toleran ce if dose increased gradually, signifi cantly decreased GI toxicity with enteri c coated formulation

M ucocutaneous : -rash, oral ulcers : consider possi bility of allergi c reaction

Hemato logic:

-G6PD deficiency hemolyti c anemia :

- bone marrow depression : generally occurs within first year of therapy

-megalo blastic anemia : long-term therapy compli cation--sulfasalazine inhi bits foli c acid

a bsorption -monitorin g:

- baseline G6PD levels in patients at risk

-CBC q 2-4 wks x 3 months, then q3 months

-mana gement:

-G6PD deficiency: avoid drug

-myelosuppression : DC drug

-megalo blastic anemia : treat with foli c acid supplementation, do not need to discontinue SSA

CNS :

-heada che, dizziness

Cardiovascu lar :

-palpitations, tachycardia V. Immunosuppressives/Cytotoxic A gents

-generally reserved until patient has failed other SAARD s--however, Methotrexate is gaining popularity as a first line SAARD

-All these agents have dose-related hematologi c toxicity



-monitorin g: CBC q 1-4 weeks when dosage being escalated, then q2-3 months thereafter

-mana gement:

if counts fall below the following baselines, hold drug until

counts have re bounded, then restart drug at redu ced dosage,

o WBC <3500 o neutrophils <1000 o platelets <100 ,000

A. Azathioprine (Imuran(r))

1. M echanism of action: immunosuppression

2. Effi cacy -known to be steroid-sparing, effe ct on disease progression unclear

3. D osing :

-initiate at 50mg-100 mg/day, may increase to 2-5mg/kg/day

-concurrent allopurinol requires decreasing azathioprine dose by 50-75%


Hemato logic:

- bone marrow suppression : dose limiting toxicity

-follow a bove guidelines

Gastrointestina l:

-nausea, vomiting, anorexia : dose related,

-hepatitis : pro ba bly allergi c reaction, monitor LFTs q6-8 weeks -pan creatitis : (severe a bdominal pain) pro ba bly allergi c reaction

-monitorin g:

-question pt re GI sx



-LFTs q 6-12 weeks

-if severe GI pain, check amylase to R /O pancreatitis

-mana gement:

-minimized GI sx by split dosing, taking with food or milk, or giving dose at bedtime

-hepatitis/pan creatitis : DC drug, rechallenge extremely cautiously

M ucocutaneous

-rash, oral ulcers : hold or decrease dose

Onco genesis / Non-Hodgkin 's Lymphoma ???:

-increased incidence of malignan cy in patients on azathioprine after renal transplant, effe ct in patients on drug for rheumatologi c disorders less clear, some studies suggest risk is low

B. M ethotrexate (Rheumatrex(r), others)

1. M echanism of action: immunosuppression ?

2. Effi cacy

-approximately 60% of patients will achieve at least partial remission or improvement in symptoms, onset may be quicker than other SAARD s, but once drug is discontinued, symptoms appear to return quickly

3. D osing :

-initiate at 7.5mg/wk in 3 divided doses, increase in 2.5 mg increments to maximum of 20mg/wk

-dosing schedules :

**preferred : q12hrs x 3 doses/week, e.g. Monday 8am and 8 pm, 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



-mana gement:

-hold drug if LFTs >3x normal

-if ¿ LFTs do not resolve, consider further work-up

Pu lmonary

-pulmonary infiltrates/fi brosis : uncommon : not dose or duration related, patients c/o shortness of breath, dry cough, possi bly allergi c reaction

-monitorin g: baseline chest X-R ay within 1 year of starting tx, question patient a bout sx

-mana gement:

o discontinue methotrexate o steroids may be required o appears fully reversi ble

Terato genicity : known teratogen, contraindi cated in pregnan cy

5 . Dru g Interactions:

NSAIDs: decrease renal elimination, ? signifi cance at RA doses

-sali cylates, fenoprofen, naproxen, phenyl butazone and tolmetin

- NSAID s should be avoided in patients receiving cancer chemotherapy with Methotrexate Alcoho l: increases risk of hepatotoxi city, limited use on special occasions okay otherwise avoid

C. Cyc lophosphamide (Cytoxan(r))

1. M echanism of action: immunosuppression ?

2. Effi cacy

-has been shown to prevent erosions, but use limited due to toxicity

-pulse therapy effe ctive in treating vasculitis related to rheumatoid arthritis

3. D osing :

-oral therapy : 1-2mg/kg/day in morning

-intravenous pulse : 750 -1000 mg/m 2/dose every 3 to 4 weeks for treatment of vasculitis



4. A dverse reactions :

Hemato logic:

- bone marrow suppression : after pulse therapy nadir occurs at 7-10days, recovery at 21-25 days,

cumulative toxicity may occur -monitorin g: follow a bove guidelines, monitor CBC more frequently if using pulse dosing

-mana gement: follow a bove guidelines

Gastrointestina l:

-nausea, vomiting, anorexia : with oral therapy decrease by taking with food; after pulse IVtherapy--delayed onset, premedi cate with antiemeti c

Rena l: -hemorrhagi c c ystitis : due to toxic meta bolite, acrolein in contact with bladder wall, high fluid intake and frequent urination can minimize risks by decreasing contact time with bladder wall

- bladder cancer

-monitorin g:

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

cessation -mana gement: -if hemorrhagi c c ystitis occurs, DC drug

Dermato logic:

-alope cia: asso ciated with high dose pulse therapy, less common with daily po therapy

Onco genesis :

-development of lymphomas 10-20years post-therapy

- bladder cancer

Ferti lity

-may cause sterility (ovarian/testi cular failure ), risk appears to be greater in older patients



D. Ch lorambuci l: due to toxicities, use limited to severe progressive RA or life-threatening compli cations of RA

E. Cyc losporin 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 SAARD s concurrently in an RA patient

-limited studies availa ble--some show some benefit over single drug therapy

-com binations must be sele cted 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 com binations : o antimal Times New R omans or sulfasalazine + gold or penicillamine o antimal Times New R omans or sulfasalazine + c ytotoxi c agents o gold or penicillamine + c ytotoxi c agent o two or more cytotoxi c agents

VII. Corticosteroids

-useful for anti-inflammatory effe cts

-do not prevent erosive disease -systemi c steroids can be used in RA b ut not indicated for OA

-intraarti cular steroids can be used in both RA and OA

-euphoria and feeling of well- being may promote over complian ce and patient dependen ce, many patients flare upon withdrawal--need to taper off very slowly

A. D osing R egimens :

1. Ac ute 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 DMARD s

-alternate day therapy usually ineffe ctive because of pain and stiffness recur on "off " day

3. Systemi c manifestations :

-high dose methylprednisolone (40-80mg q6hr ) or hydro cortisone (1 gram q6hr ) IV

-used in treatment of systemi c manifestations of RA such as vasculitis and pulmonary involvement

4. I ntraarti cular In jections

-useful for management of one to several refra ctory joints

-must rule out joint infection before steroid in jection

-maximum of 4 in jections per joint per year

-patient should be advised to rest joint after in jection because overuse could lead to joint in jury or destru ction

-minimal systemi c adverse reactions

-effe ct persists for 2 to 12 weeks

-may give local anestheti c along with steroid, e.g. lido caine 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 in jected )

o methylprednisolone acetate (Depomedrol(r )): 5 -80mg o triam cinolone hexo cetonide (Aristospan(r )): 5 -80mg

5. A dverse R eactions of Systemi c Corti costeroids

GI -pepti c ulcer disease ?, pancreatitis Ophthalmologi c -glau coma, catara cts C NS -euphoria or depression, psychosis



Dermatologi c -acne, thining of skin, striae, capillary fragility, decreased wound healing R enal -sodium and fluid retention, hypokalemia

Endo crine -altered car bohydrate meta bolism/glu cose intoleran ce, HPA suppression, growth retardation in Children

Cardiovas cular -hypertension, accelerated ASHDMusculoskeletal -osteoporosis, myopathy, muscle wasting, avas cular necrosis of the long bones Immune System -anergy and increased suscepti bility to infe ction Hematologi c -demargination of white cells

ARTHRITIC DISORDERS: SU MM ARY

RHEUMAT OIDARTHRITI S

OSTEO ARTHRITI S

Prevalen ce 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)K nees



El bows, Shoulders, Feet

Ankles, K nees, Hips

Cervi cal Spine

Hips, Feet (1st MTP)

Cervi cal Spine, Lower

Lum bar Spine

Morning Stiffness > 1 hr < 15 minutes

Systemi c M anifestations

Fatigue, Anorexia

Anemia (normo chromi c/cytic)

Hypoal buminemia

Skin (R heumatoid ) N odules

Vasculitis, Pleuropulmonary

Disease, Pericarditis S jogren 's Syndrome

None

ESR Elevated Usually normal

R heumatoid Factor Positive in 70% U sually negative

Antinu clear Anti bodies Positive in 15%

Drug Treatment

y Non-antiinflammatoryanalgesi cs (eg APAP) R arely Yes

y Antiinflammatory agents (eg Yes Yes



NSAID S)

y "Slow-a cting " A gents (eg Gold)Yes No

y Systemi c steroids Yes No

y Intraarti cular 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, el bows, 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 . A spirin was initially effe ctive for her joint pains but has recently provided less relief . She also complains of signifi cant fatigue and morning stiffness (lasting a bout 4 hours ) which is interfering with her work as a gardener/lands caper .

Past Medical History :

Hypertension x20 years

Migraine Heada ches

Medications : Propranolol 40mg bid

HCTZ 50 mg qam

K CL 40 mEq qam

Aspirin 325 mg 2ta bs tid

Cafergot prn migraine

La boratory : HCT/Hg b 33.2 /10.3



Na 139 K 4.8

BUN 21 SCr 1.4

UA - glucose/ blood

R heumatoid Factor (R F) 1:320

ES R 55

Sali cylate Level 8mg/dl

R adiography : Hand films show soft tissue swelling and joint space narrowing on all MCPs and first 3 PIP s of both hands . T here is periarti cular osteoporosis on both

hands but no erosions are evident .

Physical Exam : BP: 135 /85 P 65 W t 135 l bs

Diagnosis : R heumatoid Arthritis

1. H ow 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. W hat parameters should be monitored in this patient ?

5. H ow 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 dia gnosis of rheumatoid arthritis ?

Her presentation is typical for R heumatoid Arthritis . She has joint stiffness and swelling bilaterally involving fingers, wrists, el bows, knees and ankles . H er history is positive for fatigue and morning stiffness . H er la boratory results are signifi cant for an elevated ESR and



a + R heumatoid Factor . H er X-rays show soft tissue swelling, joint space narrowing and periarti cular osteoporosis whi ch is consistent with RA.

The chara cteristi cs whi ch differentiate this patient¶s arthritis from osteoarthritis include the systemi c symptom of fatigue, the eviden ce of inflammation as noted by the increased ESR , the

joints involved in the hand (MCPs and PIP s seen in RA, PIP s and DIP s seen in OA) and the positive R heumatoid Factor .

2. Shou ld aspirin be continued in this patient?

TB says that aspirin was initially helpful but no longer seems to work . Anti-inflammatory doses of ASA (sali cylate levels of 15-30mg/dl ) are recommended for the treatment of RA, but TB¶s

sali cylate level is only 8mg/dl, which would provide analgesi c effe ct but minimal anti-inflammatory benefit . In order for TB to get a therapeuti c benefit from aspirin, she would need to

be on a higher dose for 2 to 3 weeks . However, she is experien cing tinnitus and decreased hearing acuity even on this low dose of aspirin, so continuing aspirin in this particular patient is not a reasona ble option .

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

An anti-inflammatory dose of an NSAID is appropriate for TB at this time . T here is no need to start her on a second line drug until assessment of her response to NSAID s can be made . She has not had an adequate trial of NSAID s 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 indometha cin because of her history of heada ches . A lso, because she is on HCTZ, she is at increased risk for nephrotoxi city from NSAID s. A potentially less nephrotoxi c N SAIDwould be desira ble. T herefore, sulinda c would be a good first choice for this patient . However, if sulinda c was not effe ctive, an alternate NSAID c ould be tried with close monitoring of her kidney function. (Although, they are relatively nontoxi c to the kidney, the nona cetylated sali cylates 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 shou ld be monitored in this patient?



Past Medical History :

Dia betes Mellitus, Type II x8yrs

COPD, mild

GI b leed due to PUD 10 yrs ago

Medications : Ibuprofen 600 mg qid

Glipizide 5mg qam

Theodur 200 mg tid

Antacids prn GI distress

La boratory : HCT/Hg b 41 /12.3 M CV 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

So cial History : + T o bacco (1/2 ppd)

+ EtO H (2-3 beers/day )

Allergies : Penicillin (rash )

Codeine

Physical Exam : WNWD male in NAD

mild tenderness and swelling in rt wrist, el bow and first three MCPs on right hand .

Left knee is signifi cantly swollen and tender

BP 130 /85 P 72 W t 190 l bs

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

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



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

4. A re corticosteroids indicated for this patient ?

PR652: ARTHRITIC DISORDERS RECITATION CASE II

ANSWER S

1 . Eva luate this patient's current re gimen for rheumatoid arthritis.

This patient needs a new second line agent . T he indications for SAARD s are lack of effi cacy of an appropriate trial of NSAID s (patient still has 3 hours of AM stiffness on a therapeuti c dose of i buprofen ) and/or disease progression (patient has new erosion ).

May wish to consider misoprostol in this patient . A lthough tolerating i buprofen well, he has a h/o a GI b leed and NSAID -indu ced ulcers may be asymptomati c.

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

There in no sin gle correct answer for this question²several SAARD s could be chosen :

Antimal Times New R omans-would be accepta ble, well tolerated but long-term effi cacy is unclear for patients with erosions

Sulfasalazine-a ccepta ble, but dose should be titrated up slowly to minimize adverse effe cts

Azathioprine-a ccepta ble, but patient has low baseline WBC, may not be a ble to give adequate

dose of azathioprine without causing neutropenia

Penicillamine : could be tried (no contraindi cation in patients with PC N allergy ) however

h/o proteinuria with gold increases risk of similar renal pro blems



with penicillamine²if used must monitor very closely

Com bination therapy with two of the a bove might be useful²no clear cut guidelines for use as of yet

However, several SAARD s would not be appropriate for this patient :

Oral gold : not appropriate-patient had proteinuria with in jecta ble gold

Methotrexate : poor choice, patient has dia betes and drinks ETOH regularly whi ch increases risk of hepatotoxi city from MTX. A lso has low baseline WBC. U se only if patient is willing to stop ETOH. A lso need to wat ch pulmonary function because of h/o COPD

Cyclophosphamide/Cy closporin : too toxic to be used so early in disease, other drugs prefera ble

3. What parameters shou ld be monitored in this patient based on the

recommendations you made in #2?

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

Adverse Effe cts:

NSAID s: GI symptoms

Antimal Times New R omans : GI symptoms, ophthalmologi c exam q6 months, muscle weakness

Sulfasalazine : CBC esp WBC & M CV, GI symptoms, HA /dizziness

Azathioprine : CBC esp WBC, LFTs, symptoms of pancreatitis

Penicillamine : CBC, urinalysis, skin side effe cts

For com bination therapy, monitor as for each of the individual agents

arthritic disorders

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