PAINFUL JOINTS
| ADVANCES IN RHEUMATOLOGY —Kenneth H. Fye, MD, Clinical Professor of Medicine, University of California,
San Francisco, School of Medicine
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| History of treatment for osteoarthritis: 1975—analgesic agents with physical therapy and corticosteroids; nonsteroidal
anti-inflammatory drugs (NSAIDs; eg, indomethacin [Indocin], phenylbutazone, ibuprofen) as effective as
acetaminophen (Tylenol), but associated with unacceptable side-effect profiles; use of Tylenol standard of practice;
antacids used for gastrointestinal (GI) toxicity
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 | Development of new NSAIDs: carboxylic acid derivatives—aspirin; aromatic acetic acid derivatives (eg, Indocin,
sulindac [Clinoril]); phenylacetic acids (eg, diclofenac [Voltaren]); propionic acids (eg, naproxen); pyranocarboxylic
acids (eg, etodolac [Lodine]); fenamic acids (eg, meclofenamate [Meclomen]); enolic acid derivatives—pyrazolones
(eg, phenylbutazone); oxicams (eg, piroxicam [Feldene], meloxicam [Mobic]); naphthylalkanones—eg, nabumetone
(Relafen); new NSAIDs more effective than Tylenol; GI toxicity—10% of patients developed GI symptoms
(20%-40% had endoscopic damage); caused 16 500 deaths per year; use of prostaglandin E2 (PGE-2; eg, misoprostol
[200 µg qid; side effects include diarrhea]) with NSAID shown effective in decreasing symptoms and endoscopic
damage; H2 -blockers (eg, ranitidine [Zantac], cimetidine [Tagamet]) effective in decreasing symptoms and peptic ulcer
disease in duodenum, but no effect on development of gastritis; proton pump inhibitors (PPIs) decreased symptoms,
peptic ulcer disease, and gastritis; analgesic agents, physical therapy, and corticosteroid injections adjunctive
therapy
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| Cyclooxygenase (COX) inhibitors—COX-1 protects GI tract and platelet, endothelial, and renal function; COX-2 largely
found in areas of inflammation; 2002—COX-2 inhibitors (eg, rofecoxib [Vioxx], celecoxib [Celebrex], valdecoxib
[Bextra; removed from market], Mobic) used with fewer GI symptoms; use of COX-2 inhibitor (add Tylenol if COX-2
inhibitor alone ineffective), physical therapy, and corticosteroid injections standard of care; advantages of COX-2 inhibitors
include fewer GI complaints and abnormalities, with no platelet inhibition; disadvantages include increased occlusive
vascular disease due to normal platelet aggregation and prostacyclin inhibition; Vioxx removed from market
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| Modern use of NSAIDs: better-tolerated nonselective NSAID (eg, Lodine or Relafen]) used with GI-protective agent
(eg, PPI); adjunctive analgesic therapy if indicated; physical therapy and corticosteroid injections; selective COX-2
inhibitors used on patients taking warfarin (Coumadin) and patients intolerant to other NSAIDs (reduce risk by giving
aspirin 81 mg daily)
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| Diagnosis of rheumatoid arthritis (RA): history and physical examination; positive rheumatoid factor; elevated
erythrocyte sedimentation rate (ESR); x-ray changes; diagnostic criteria—≥4 criteria required for diagnosis of RA; inflammatory
polyarthritis >6-wk duration; symmetric arthritis affects small proximal joints of upper extremities; morning
stiffness >1-hr duration; positive rheumatoid factor; abnormal x-ray; subcutaneous nodules
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| History of treatment of RA: 1975—aspirin 3 g daily; hydroxychloroquine (Plaquenil); gold injections standard of
care; penicillamine; prednisone; corticosteroid injections; physical therapy; surgery; 1990—NSAIDs, Plaquenil, sulfasalazine,
methotrexate, prednisone, and corticosteroid injections; disease-modifying antirheumatic drugs
(DMARDs)—developed during 1990s; slow erosions and development of deformities; methotrexate; leflunomide
(Arava); mycophenolate mofetil (CellCept); tetracycline; Prosorba column (expensive; response rate lower)
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| Leflunomide: decreases production of pyrimidines, resulting in decreased nucleic acid production and decreased B- and
T-cell function; half-life long; breaks down to active metabolite; tightly protein-bound; enterohepatic circulation long-
lived; side effects—diarrhea; alopecia; hepatotoxicity; marrow suppression; infection; carcinogenesis; teratogenicity; give
regular dose and perform laboratory tests (eg, complete blood count [CBC] and liver function tests after 2 wk, then every
1-3 mo); if patient develops significant side effects and/or patient decides to become pregnant, give 8 to 9 g of
cholestyramine tid for 11 days (teratogenic levels in blood remain 2 yr)
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| Etanercept (Enbrel): soluble recombinant genetically engineered fusion protein of 2 p75 tumor necrosis factor
(TNF)-α surface receptors attached to Fc component of human IgG1; receptors bind to circulating TNF-α before TNF-
α can attach to cell surfaces and become eliminated by reticuloendothelial system, rendering TNF-α biologically inactive;
side effects—infection (eg, inactive TNF-α can lead to reactivation of tuberculosis [TB], Staphylococcus aureus,
sepsis); local injection-site reactions; demyelinating neuropathy rare; marrow suppression; increased risk for non-
Hodgkin’s lymphoma; autoantibodies rare; congestive heart failure (CHF; contraindicated in patients with class III or
IV CHF); dosing—50 mg/wk subcutaneously (subQ); rotate injection sites; keep drug refrigerated; perform chest x-ray
and give purified protein derivative (PPD; tuberculin) before initiating therapy; no routine monitoring laboratory tests
required (baseline antinuclear antibody [ANA] and CBC recommended)
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| Infliximab (Remicade): chimeric monoclonal anti-TNF-α antibody; binds tightly to TNF-α which becomes biologically
unavailable; half-life long; side effects identical to those of etanercept; give 3 mg/kg baseline and repeat after 2 wk, 6
wk, and every 2 mo; give simultaneous low-dose methotrexate (or other antimetabolite [eg, Arava, azathioprine]) to prevent
production of anti-idiotypic antibodies which decrease efficacy of drug; check for TB; no routine monitoring laboratory
tests required, but usually performed when patient on antimetabolite
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| Adalimumab (Humira): humanized monoclonal anti-TNF-α antibody; give subQ every other week; use antimetabolite
to decrease possibility of anti-idiotypic antibodies; check for TB; no monitoring laboratory tests required, but usually
performed when patient on antimetabolite
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| Paradigm shift in view of RA: 30 yr ago—RA considered chronic painful debilitating disorder but not life-threatening;
drugs thought to be more dangerous than disease; present—RA systemic inflammatory disorder with significant
effect on survival; disease more dangerous than modern therapy; therapeutic approach no longer “go slow, use as little
or as few medicines as possible”; treat early to prevent erosions and deformities; treat aggressively; use combination
therapy; 80% of seropositive RA patients on low-dose prednisone
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| Modern tools for RA: positive anticyclic citrullinated peptide (more specific and sensitive than rheumatoid factor; not
needed with known positive rheumatoid factor); ultrasonography for soft tissue inflammation; magnetic resonance imaging
(MRI); therapy—modern NSAID, Plaquenil (or sulfasalazine), methotrexate (or other antimetabolite), and low-
dose prednisone; add TNF-α antagonist if patient does not show dramatic response; local corticosteroids, physical therapy,
and surgery cornerstones of therapy; goals—improve articular disease in 70% of patients (incidence of extra-articular
manifestations decreased over past 20 yr); slow progression of erosions; normalize life span
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| Seronegative spondylitis: includes ankylosing spondylitis, chronic inflammatory bowel disease (CIBD), reactive arthritis,
and psoriatic arthritis (characterized by scaling rash and asymmetric sacroiliitis)
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| History of diagnosis and treatment of seronegative spondylitis:
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| 1975: diagnosis—history and physical examination; x-ray changes; ESR; biopsy; treatment—only for symptomatic
benefit; Indocin; phenylbutazone; adjunct analgesic therapy; physical therapy to maintain integrity of periarticular
supporting structures in musculature; steroids not particularly effective; treat extra-articular manifestations; surgery
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| 1990: diagnosis—HLA-B27; colonoscopy for CIBD; treatment—sulfasalazine and methotrexate for peripheral manifestations
(no effect on axial disease or long-term outcome)
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| 2005: diagnosis—computed tomography (CT) and MRI for patients with negative sacroiliac joint films; treatment—
NSAIDs; DMARDs; switch to TNF-α antagonist if dramatic results not obtained
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| GOUT —Steven Berney, MD, Professor of Medicine and Chief, Section of Rheumatology, Temple University Hospital,
Philadelphia
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| Introduction: associated with uric acid metabolism and hyperuricemia (>6.8 mg/dL implies risk for development of
acute gout); uric acid breakdown product of purine in primates; gout occurs because uric acid (in form of sodium
monourate) precipitates in joint and causes inflammatory reaction
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| Uric acid: lower in women than in men; pH 7.4; ionizes as sodium biurate; extremely insoluble (solubility can be increased
by increasing pH; increasing urinary pH by 1 unit difficult in patients on high-protein diets); uric acid increased
by dietary purines (eg, lobster, shrimp; ask about dietary intake and alcohol consumption); product of tissue breakdown;
in situ production by amino acids; xanthine oxidase inhibition lowers uric acid levels
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| Causes of elevated uric acid levels: overproduction—idiopathic; genetic; may be caused by defect in feedback inhibition,
excess purine production, dietary indiscretion, rapid cell turnover (as in, eg, patients with myelo- and lymphoproliferative
disorders or psoriasis), and other illnesses (eg, glycogen storage diseases); inadequate excretion—
may be due to tubular defect, kidney disease, inhibition of tubular excretion, enhanced reabsorption by medication, and
hypertension
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| Uric acid elimination: uric acid goes through glomerulus and enters proximal tubule; ≈99% of uric acid reabsorbed
by proximal tubule and resecreted into distal tubule; 10% of total filtered load goes through most proximal tubule and
into distant site for reabsorption; pharmacologic intervention used to increase output
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| Causes of secondary hyperuricemia: kidney problems; drugs; endocrinopathic, metabolic, and blood dyscrasia
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| Urate crystals: highly negatively charged; dissolved within joint proteoglycans and bound by apolipoprotein E (apoE);
great toe—perturbation of proteoglycans leads to loss of water, supersaturation of urate, and loss of solubility; precipitation
of urate crystals initiates and amplifies inflammatory response, resulting in acute attack; self-limited course
(shape, size, and quality of crystal changes during inflammatory response, allowing crystal to be recoded by apoE; inhibitory
cytokines secreted and inflammation subsides)
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| Asymptomatic hyperuricemia: long prodrome; uric acid elevated in individuals with no history of gouty attack; hyperuricemia
does not diagnose gout; as uric acid levels continue to rise, likelihood of acute gout attack rises, resulting in
repeated gouty flares; after decades of no intervention, patients develop advanced or chronic tophaceous gout (ie, large
lumps of uric acid hanging out of skin; easily identified in laboratory); >6.8 mg/dL represents hyperuricemia; patients
at risk for developing urate kidney stones; patients may be asymptomatic for decades and never develop gout;
comorbidities—hypertension; diabetes; obesity; hyperlipidemia; cardiovascular disease; metabolic syndrome; Framingham
study showed no association between hyperuricemia and metabolic syndrome or cardiovascular disease
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| General presentation of gout: men 35 to 50 yr of age; women rarely have attacks before menopause; monoarticular
in ≈90% of patients; diagnosis of gout unlikely in patients with no history of altered uric acid metabolism or podagra
(pain in first metatarsophalangeal joint); typical patient—man 55 yr of age with hypertension and on thiazide diuretic
wakes up during night with severe pain, swelling, redness, and heat in great toe; patient says he drank beer and ate sausage
sandwiches night before; patient may have low-grade fever; intercritical period after first attack may last several
years, but periods between attacks shorten and chronic tophaceous gout develops
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| Chronic tophaceous gout: polyarticular; patients may have superimposed acute flares; identifiable on x-ray; high incidence
in heart transplantation patients (patients atypical in presentation and accelerate rapidly into chronic course;
usually result of cyclosporine use)
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| Diagnosis: history and physical examination; serum uric acid; differential diagnosis; isolate and identify sodium biurate
crystals in synovial fluid or tophi; confusions in diagnosis—gout can be polyarticular; serum urate levels can be normal
during acute attack; affects women (especially if on hyperuricemic drugs and after menopause); gouty attacks in unusual
joints; not every laboratory skilled in identifying sodium biurate crystals
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| Treatment: reduce alcohol intake in heavy drinkers; modification of high-purine diets; weight control; approach—stop
attack; prevent next episode; eliminate excess uric acid; continue pharmacologic intervention; NSAIDs; colchicine may
be too toxic; corticosteroids (especially for patients with chronic tophaceous gout or when underlying condition precludes
use of NSAIDs or colchicine); prevention—colchicine (0.6 mg or 1.2 mg daily in divided doses); NSAIDs; try
for several weeks before turning to agents that lower uric acid levels; lifelong therapy—reduce uric acid levels to <6.0
mg/dL; force kidney to excrete more uric acid or inhibit xanthine oxidase; uricosuric drugs (eg, probenecid [Benemid]
most commonly used); losartan may be useful in hyperuricemic patients on angiotensin-receptor blocker;
allopurinol—300 or 400 mg daily (start low and raise by 100 mg every 2 wk until full dose reached); problems include
insufficiency of standard dose, build up in patients with kidney dysfunction, high rate of allergic reaction (including
rash), contraindicated in patients on azathioprine (Imuran), effectiveness reduced by cyclosporine, blocks other enzymes
in uric acid pathway; uricase available in Europe; febuxostat (xanthine oxidase inhibitor) undergoing development
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Educational Objectives
| The goal of this program is to educate the listener about the management of arthritis and gout. After hearing and assimilating
this program, the participant will be better able to:
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| 1. Describe the development of modern nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of osteoarthritis.
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| 2. List side effects and contraindications of drugs used to treat rheumatoid arthritis.
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| 3. Explain the history of the diagnosis and treatment of seronegative spondylitis.
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| 4. Describe the common presentation of patients with hyperuricemia.
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| 5. Counsel patients about treatment and prevention of gout.
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Discussed on This Program
Acetaminophen (N -acetyl-P -aminophenol; APAP) (several trade names)
Adalimumab [Humira]
Allopurinol [Aloprim, Zyloprim]
Aspirin (acetylsalicylic acid; ASA) [several trade names]
Auranofin (29% gold) [Ridaura]
Aurothioglucose (50% gold) [Solganal]
Azathioprine (AZA) [Imuran]
Celecoxib [Celebrex]
Cholestyramine (several trade names)
Cimetidine [Cimetidine Oral Solution, Tagamet, Tagamet HB]
Colchicine Diclofenac [Cataflam, Solaraze, Voltaren, Voltaren-XR]
Etanercept [Enbrel]
Etodolac [Lodine, Lodine XL]
Febuxostat (investigational)
Hydroxychloroquine sulfate [Plaquenil, Plaquenil Sulfate]
Ibuprofen (several trade names)
Indomethacin [Indocin, Indocin SR, Indomethacin Extended-Release]
Infliximab [Remicade]
Leflunomide [Arava]
Losartan potassium [Cozaar]
Meclofenamate sodium [Meclomen]
Meloxicam [Mobic]
Methotrexate (amethopterin; MTX) [Methotrexate LPF, Rheumatrex Dose Pack, Trexall]
Misoprostol [Cytotec]
Mycophenolate mofetil (MMF) [CellCept]
Nabumetone [Relafen]
Naproxen [Aleve, Anaprox, Anaprox DS, EC-Naprosyn, Naprosyn, Naprelan]
Penicillamine [Cuprimine, Depen]
Phenylbutazone [Azolid, Butazolidin]
Piroxicam [Feldene]
Prednisone (several trade names)
Probenecid
Ranitidine HCl [Zantac, Zantac 75, Zantac EFFERdose, Zantac GELdose]
Rofecoxib [Vioxx] (withdrawn from market 09/30/04)
Sulfasalazine [Azulfidine, Azulfidine EN-tabs]
Sulindac [Clinoril]
Tetracycline HCl (several trade names)
Urate oxidase [Uricase-PEG 20] (investigational)
Valdecoxib [Bextra] (withdrawn from market 04/07/05)
Warfarin sodium [Coumadin]
Suggested Reading
Amor B: HLA-B27 antigen and seronegative arthritis. Acta Rhumatol 3:164, 1979; Chen Q et al: New therapeutic
approaches for rheumatoid arthritis. Assay Drug Dev Technol 3:329, 2005; Dubey S et al: Management of early rheumatoid
arthritis. Clin Med 5:211, 2005; Dzielak DJ et al: Emerging concepts in cardiovascular disease should elevated
serum uric acid be considered a risk factor? Expert Opin Investig Drugs 7:85, 1998; Ene-Stroescu D et al: Gouty arthritis
a primer on late-onset gout. Geriatrics 60:24, 2005; Fautrel B et al: Impact of medical practices on the costs of
management of rheumatoid arthritis by anti-TNFalpha biological therapy in France. Joint Bone Spine, 2005; Florentinus
SR et al: The trade-off between cardiovascular and gastrointestinal effects of rofecoxib. Pharmacoepidemiol Drug
Saf 14:437, 2005; Hochberg MC: COX-2 selective inhibitors in the treatment of arthritis a rheumatologist perspective.
Curr Top Med Chem 5:443, 2005; Olivieri I et al: Seronegative spondyloarthritides. Best Pract Res Clin Rheumatol
16:723, 2002; Ramey DR et al: The incidence of upper gastrointestinal adverse events in clinical trials of etoricoxib
vs. non-selective NSAIDs an updated combined analysis. Curr Med Res Opin 21:715, 2005; Ritchlin CT et al: Recent
advances in the treatment of the seronegative spondyloarthropathies. Curr Rheumatol Rep 3:399, 2001; Saag KG et al:
Recent advances in the epidemiology of gout. Curr Rheumatol Rep 7:235, 2005; Schumacher HR Jr: Febuxostat a
non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. Expert
Opin Investig Drugs 14:893, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Fye spoke in San Francisco on March 22, 2005, at the Annual Review in Family Medicine, presented by the University
of California, San Francisco, School of Medicine. Dr. Berney was recorded in Lancaster, Pennsylvania at the 29th Annual
Spring Family Practice Review, presented March 14-18, 2005, by Temple University School of Medicine and Lancaster
General Hospital. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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