OH, MY ACHING JOINTS!
| RHEUMATOID ARTHRITIS — Howard R. Sawyer, MD, Assistant Clinical Professor of Medicine, David Geffen
School of Medicine at the University of California, Los Angeles
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| Clinical features: vague and nonspecific symptoms; ask, “is your pain in your joints or between your joints?”;
boggy joints (especially small joints; may be in hands or toes); American College of Rheumatology (ACR; formerly
American Rheumatism Association [ARA]) criteria — morning stiffness lasting ≥1 hr (present for ≥6 wk); swelling
in ≥3 joints; swelling in hand joints; symmetric joint swelling; joint erosion on x-ray; rheumatoid nodules (also can
exist in lungs, liver, and heart); positive serum rheumatoid factor (RF); most criteria clinical (laboratory studies
supportive); sedimentation rate or C-reactive protein (CRP) high; establish good relationship with patient; remain
sensitive to different presentations of rheumatoid arthritis (RA); educate patient
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| Clinical challenge: irreversible joint destruction occurs early (30% of patients have bone erosions at 1 yr, 60% at 2
yr); ≈25% of patients become disabled within 7 yr of diagnosis (50% become disabled eventually); patients have
increased mortality due to infections, heart disease, and renal disease; use aggressive preventive techniques (eg,
screen for hypertension; involve nephrologist as needed); treat low-density lipoprotein (LDL) and monitor hematologic
and renal complications
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| Pathophysiology: T and B lymphocytes target synovium; inflammatory residue in lining of joint; within short time,
synovium replaced with destructive abnormal tissue (pannus); T and B lymphocytes produce cascade of inflammation
and magnify inciting pathogen; metalloproteinases and collagenases destroy joint lining; rheumatoid processes
can occur in multiple organs of body; inflammation dissolves articular cartilage; joint erosion — early radiographic
sign; moth-eaten appearance; can become severe
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| Patient assessment: determine degree of joint pain; duration of morning stiffness correlates with amount of inflammation;
fatigue (nonspecific symptom); assess functional limitations on activities of daily living (eg, carrying
groceries, feeding oneself); look for signs of inflammation; decreased range of motion; crepitus (eg, knee); instability;
deformity; no single test confirms diagnosis; synovial fluid examination; check for RF; monitor complete
blood count (CBC; anemia problematic in RA); sedimentation rate or CRP; magnetic resonance imaging (MRI) —
for identifying early subtle signs of RA; identified erosions in 95% of patients in 78% of body locations, while
plain film radiography identified 60% of patients in 40% of body locations
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| Older therapies: gold compounds; penicillamine; steroids; sulfasalazine; cyclophosphamide (Cytoxan); acetaminophen
(Tylenol); nonsteroidal anti-inflammatory drugs (NSAIDs); hydroxychloroquine (Plaquenil); cyclosporine; doxycycline;
minocycline
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| Nonsteroidal anti-inflammatory drugs: useful for reducing pain; do not prevent destructive features of RA; use
in patients with polyarthritis; increase risk for upper and lower gastrointestinal (GI) bleeding
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| Corticosteroids: work on specific cell receptors; interrupt cell-to-cell communication in inflammatory cascade;
prednisone — rapid onset of action; potent; dosages of 1 to 60 mg daily frequently used but not for long duration;
maintenance dosage 5.0 to 7.5 mg daily; side effects —moon facies; type 2 diabetes; osteoporosis; bacterial, fungal,
and mycobacterial infections; steroid myopathy; injectable steroids — useful for flares; 5 to 10 mg of triamcinolone
in small joints, 10 to 20 mg for medium joints, and 30 to 40 mg for large joints
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| Disease-modifying antirheumatic drugs (DMARDs): affect rheumatologic destructive inflammation; methotrexate
—gold standard; easily given in office; monitor kidney function; decreases interleukin 1 (IL-1) and leukotriene production;
monitor CBC; can be given intravenously (IV) and orally; sulfasalazine — combination of salicylate and
sulfa moiety; contraindicated in patients with sulfa allergy; side effects similar to those of NSAIDs and include rash;
associated with severe allergic reactions; monitor CBC; azathioprine (Imuran) — depletes activated T and B cells,
resulting in decreased production of immunoglobulin and IL-2; consider consequences of suppressing immune system
(ie, opportunistic infections); document use; leflunomide — useful when methotrexate fails (can be used in combination);
used to reduce dose of steroids; liver toxicity most serious consequence; associated with induced
malignancy; teratogenic; use cautiously; biologic agents — attack tumor necrosis factor α (TNF-α); infliximab; etanercept
effective against inflammation; refer within first 3 mo of diagnosis; common combinations of agents —
methotrexate and prednisone; methotrexate and etanercept; methotrexate and leflunomide
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| Conclusion: make diagnosis early; start aggressively, then adjust dosages of 2 or 3 agents slowly and find maintenance
dosage; more objective data about therapy needed; early RA not mild disease; earlier treatment leads to
greater preservation of joint space and physical function; TNF-α inhibitors effective and can be used in combination;
involve rheumatologist early; treat hypertension; identify target organs aggressively
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| Additional Thoughts on Rheumatoid Arthritis —Christine H. Jones, MD, Clinical Assistant Professor of Medicine,
University of Vermont College of Medicine, Burlington
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| Patient history: determine whether process inflammatory; ask how long patient had symptoms and whether episodic
or always present; determine what improves stiffness and which joints involved; look for symmetry, inflammation
or soft tissue swelling, synovitis, and bony enlargement (more characteristic of osteoarthritis)
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| Characteristics of inflammatory arthritis: morning stiffness lasting >1 hr; improvement in symptoms with activity;
pain worse at rest; multiple joints affected bilaterally; constitutional symptoms include fatigue and malaise;
laboratory abnormalities (osteoarthritis does not usually cause elevated sedimentation rate and CRP); x-rays may
show bony erosions; RA — articular disease primary manifestation; systemic (extra-articular manifestations of skin
disease, hematologic disease, pulmonary disease, ocular disease, and vascular disease); most common inflammatory
arthritis; affects ≈1% of adults worldwide; direct annual cost, ≈$5.5 billion
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| Findings on joint examination: prominent metacarpophalangeal (MCP) and wrist involvement; thenar atrophy;
curled-up toes (cock-up toe deformities); examine feet and discuss walking; rheumatoid nodules may feel rubbery
rather than gritty like tophi; lupus, parvovirus, psoriatic arthritis, and gout may resemble RA
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| Predicting risk for RA: affects women 2 to 3 times more than men (1%-3% of women may develop RA; 75% of
Americans who have RA are women); risk increased during first 3 mo after pregnancy and in perimenopausal period;
hormones may be related to risk; risk lower during pregnancy; oral contraceptive use may decrease risk in
some women; breast-feeding may reduce risk, possibly due to anti-inflammatory role of progesterone; genetics —
certain genetic subtypes may increase risk; 80% of whites with RA have genetic sequence (“shared epitope”) in
HLA-D on chromosome 6 (carried by 20% of general population); genes different in other ethnicities; gene confers
increased susceptibility but only one part of process; genetic testing not practical; family members of patients with
RA at increased risk; dietary role and lifestyle factors — coffee does not appear to increase risk; tobacco smoking
may increase severity
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| Newly diagnosed RA: poor prognosis — associated with positive RF (especially high titers); presence of rheumatoid
nodules; erosions on x-ray; multiple joint involvement; extra-articular manifestations (eg, lung, eye); HLA-DR4 genotype;
male sex; young age; tobacco smoking; high sedimentation rate and CRP (not specific); thrombocytosis
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| Rheumatoid factor: antibody directed against Fc portion on immunoglobulin; not completely specific; present in
juvenile arthritis, 40% of lupus cases, nearly 100% of Sjögren’s syndrome cases, and cryoglobulinemia; 80% to
85% of RA patients have positive RF; RA patients who do not have positive RF have seronegative RA; some patients
negative initially and convert to positive RF after several years; once RF identified, testing again to determine
titer not helpful
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| Antibodies to cyclic citrullinated peptides: antibodies directed against antigens containing citrulline (rare
amino acid found in modified fibrin in rheumatoid joint); testing useful; sensitivity comparable to RF, but specificity
higher (95%-98%); when present with joint pain, swelling, or positive RF, likelihood of RA high
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| Imaging studies: early in disease, radiography of hands and feet to look for joint space narrowing, erosions, and
periarticular osteopenia; after 3 yr, 70% to 90% of patients may have radiographically evident bone erosions and
joint space narrowing; relationship between joint destruction and long-term consequences unclear; newer modalities
include MRI and ultrasonography
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| GOUT — Steven N. Berney, MD, Professor, Department of Medicine, and Chief, Section of Rheumatology, Temple
University School of Medicine, Philadelphia, PA
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| Hyperuricemia: serum uric acid concentration exceeds solubility (6.8 mg/dL); gout results from deposition of
monosodium urate crystals in tissue
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| Uric acid: weak acid (pH 7.4); sodium monourate ionizes to sodium biurate; extremely insoluble (increasing pH by
1 unit increases solubility ≈10-fold); sources include food (eg, organ meats and shellfish), salvaged breakdown
products of nucleoprotein materials, and production by body
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| Causes of elevated uric acid: overproduction — idiopathic; enzymes that increase synthesis of uric acid may be under
genetic control; myeloproliferative disorder; inadequate excretion — kidney at certain urate load does not excrete
adequate amounts; defects in tubular transport mechanisms responsible for secretion and excretion of uric acid; genetic
mechanisms in patients with family history of gout; secondary causes of kidney dysfunction — renal dysfunction;
drugs that inhibit tubular excretion of uric acid or enhance uric acid absorption; metabolic syndrome; drugs
interfere with kidney’s ability to handle uric acid; metabolic, endocrine, and blood dyscrasia problems enhance uric
acid synthesis
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| Difficulties: uric acid filtered through renal glomerulus; 99% of uric acid reabsorbed in proximal tubular mechanism; at
more proximal site, some uric acid resecreted into tubule, and at more distal site, high amount reabsorbed again; only
small amount of uric acid in urine; pharmacologic therapy —stimulates resecretion of uric acid; blocks reabsorption
of uric acid, resulting in greater output of uric acid in urine
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| Urate crystals: highly negatively charged; relatively insoluble; solubilized in water of proteoglycans that make up part
of cartilage; dissolved in joint cartilage; bound by positively charged protein (apolipoprotein E [apoE]) to become relatively
neutral; disturbance in joint proteoglycans (eg, injury to great toe) leads to water resorption, supersaturation of
urate crystals, and precipitation of urate crystals; crystals and noxious enzymes enter synovium; urate crystals initiate,
amplify, and sustain inflammatory reaction
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| Gouty attacks: self-limited (unlike RA); changes that inhibit ongoing inflammation — apoE recoats crystals; crystals
become neutralized and less “appealing” to macrophages and phagocytes; antichemotactic substances within
macrophage signal other phagocytes away from area; inflammatory reaction subsides; crystals may be present in
joints of asymptomatic patients; attack subsides within 7 to 14 days
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| Stages of gout: asymptomatic phase — lasts for decades; buildup of uric acid and deposition in tissues; begins in
men after puberty and continues until age 40 to 50 yr (when first attack usually occurs); acute flares — gouty attacks;
subside over 10 to 14 days; intercritical period — asymptomatic; recurrences — decades of recurring attacks;
attacks occur at shorter intervals and last longer; chronic or advanced tophaceous gout — end result of
decades of uric acid deposition; chronic inflammation; joint deformities; deposition of uric acid into soft tissues
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| Asymptomatic hyperuricemia: uric acid levels >6.8 mg/dL; increased risk for acute gouty attacks or kidney
stones; patients may be asymptomatic for decades; most patients do not develop attacks of gout; comorbidities
(metabolic syndrome) include hypertension, diabetes, obesity, and hyperlipidemia; initial Framingham study stated
no relationship between hyperuricemia, coronary artery disease, and uric acid levels (contradicted by Tecumseh
study); recent Framingham analysis agrees high uric acid levels associated with risk of developing comorbidities
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| First gouty attack: usually in men 30 to 50 yr of age; primary gout in women presents after menopause; monoarticular
(however, 10% of patients have >1 joint involved); great toe involved ≥50% of time; if untreated, podagra (involvement
of first metatarsophalangeal [MTP] joint) results
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| Precipitation of attacks: alcohol (especially beer [high yeast content]); trauma (physical, emotional, or medical);
using or discontinuing medications that alter urate metabolism; seasonal distribution (more attacks during spring
and fall); after first attack, intercritical period lasts ≈2 yr; patients continue to precipitate urate and develop chronic
polyarticular arthropathy with superimposed acute attacks and x-ray abnormalities; tophi typically found in elbow;
heart transplantation — atypical appearance of gout; course accelerated; usually attributed to hyperuricemia induced
by cyclosporine
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| Diagnosis: onset abrupt; attacks ongoing and recurrent; serum uric acid levels elevated; definitive diagnosis based
on isolation and identification of sodium biurate crystals from joint fluid or tophi; potential pitfalls — gout can be
polyarticular; serum uric acid levels may be normal; gout in women; atypical joint distribution in transplantation
patients; inability to obtain fluid; intralaboratory variation in identifying crystals
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| Management: weight reduction; alcohol reduction; try to deplete excess uric acid pools; lifelong treatment; terminate
attacks — NSAIDs; colchicine (do not use IV colchicine), but has narrow therapeutic window between effectiveness
and side effects (eg, diarrhea); quick course of corticosteroids; prevent attacks — lower doses of
colchicine or NSAID; wait 2 to 3 wk after attack subsides before starting therapy to lower uric acid stores; lowering
uric acid stores — goal 6.0 mg/dL; lifelong therapy; increase amount of uric acid excreted by kidney or block xanthine
oxidase (converts xanthine to uric acid); uricosuric agents (eg, probenecid [Benemid], losartan, fenofibrate);
block xanthine oxidase with allopurinol (oxypurinol for patients allergic to allopurinol); standard dosage of allopurinol
(300 mg daily) may be insufficient (increase dosage if indicated); monitor patients with kidney abnormalities;
high incidence of allergic reactions (eg, toxic epidermonecrolysis) to allopurinol; urate oxidase (uricase) — available
as pegylated recombinant; useful for hyperuricemia that occurs in malignancies treated with chemotherapy;
difficult to use; daily intramuscular injection; highly antigenic; febuxostat — selective xanthine oxidase inhibitor;
associated with liver toxicity; investigational
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Suggested Reading
Ali AA et al: Polymorphism of HLA-DR and HLA-DQ in rheumatoid arthritis patients and clinical response to methotrexate--a
hospital-based study. J Pak Med Assoc 56:452, 2006; Bernatsky S et al: Care pathways in early rheumatoid arthritis.
Can Fam Physician 52:1444, 2006; Chen LX et al: Gout: can we create an evidence-based systematic approach
to diagnosis and management? Best Pract Res Clin Rheumatol 20:673, 2006; Corrado A et al: Pathogenesis, clinical
findings and management of acute and chronic gout. Minerva Med 97:495, 2006; Gaffo A et al: Treatment of rheumatoid
arthritis. Am J Health Syst Pharm 63:2451, 2006; Hasan U: Tumour necrosis factor inhibitors--what we need to
know. N Z Med J 119:U2336, 2006; Hoskison KT et al: Management of gout in older adults: barriers to optimal control.
Drugs Aging 24:21, 2007; Pascual E et al: Therapeutic advances in gout. Curr Opin Rheumatol 19:122, 2007; Pincus
T: Advantages and limitations of quantitative measures to assess rheumatoid arthritis — joint counts, radiographs, laboratory
tests, and patient. Bull Hosp Jt Dis 64:32, 2006; Smolen JS et al: What should be our treatment goal in rheumatoid
arthritis today? Clin Exp Rheumatol 24:S007, 2006; Wortmann RL: The management of gout: it should be crystal clear.
J Rheumatol 33:1921, 2006; Zink A et al: Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an
observational cohort study: comparison of patients according to their eligibility for major randomized clinical trials. Arthritis
Rheum 54:3399, 2006.
Educational Objectives
| The goal of this program is to increase diagnosis and improve treatment standards for rheumatoid arthritis (RA) and
gout. After hearing and assimilating this program, the participant will be better able to:
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 | 1. Identify RA based on clinical and laboratory findings.
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| 2. Select appropriate drugs to treat RA.
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| 3. List risk factors for RA.
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| 4. Explain causes of hyperuricemia and gout.
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| 5. Choose effective therapy to terminate and prevent gouty attacks.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Jones is on the
Speakers’ Bureau for Pfizer US Pharmaceutical Group.
Acknowledgements
Dr. Sawyer spoke in Newport Beach, CA, at the 2006 Primary Update: Improving Patient Care, presented November 5-
8, 2006, by the Interstate Postgraduate Medical Association of America. Dr. Jones was recorded in Burlington, VT, on
June 15, 2006, at the University of Vermont College of Medicine’s 32nd Annual Vermont Family Medicine Review
Course. Dr. Berney spoke in Lancaster, PA, at the 30th Fall Family Practice Review, presented September 24-29, 2006,
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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