RHEUMATOLOGY UPDATE
Educational Objectives
| The goal of this program is to improve diagnosis and management of rheumatoid arthritis (RA) and other
rheumatologic diseases. After hearing and assimilating this program, the clinician will be better able to:
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 | Institute combination therapy in patients with RA.
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| Explain the role of the new biologic therapies in the treatment of RA.
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| Manage patients on anti-tumor necrosis factor (TNF) medications for RA.
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| Evaluate the hot swollen joint.
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| Diagnose and manage acute monoarticular joints of infectious and rheumatologic etiologies.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee 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 faculty and planning committee reported nothing to disclose.
Acknowledgements
Dr. Graf was recorded at 36th Annual Advances in Internal Medicine, sponsored by the University of California, San
Francisco, School of Medicine in San Francisco, CA, May 19-23, 2008; Dr. Harmon, at Clinical Reviews 2008: Primary
Care and Internal Medicine Update, sponsored by Mayo Medical School in Scottsdale, AZ, March 26-29,
2008. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
| ADVANCES IN BIOLOGIC THERAPIES IN RHEUMATOLOGY—Jonathan Graf, MD, Assistant Professor of
Medicine, University of California, San Francisco, School of Medicine, San Francisco
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| Burden of disability: rheumatoid arthritis (RA) chronic inflammatory, predominantly small-joint, polyarticular
arthritis; affects ≤1% of US population; affects more women than men, often women of childbearing age; increased
mortality from cardiovascular disease (leading cause of death in RA patients); significant morbidity, ie,
35% of patients work-disabled within 10 yr of diagnosis (represents decline from ≈50% in 1967); RA destroys
ability to use hands and wrists
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| Traditional treatment paradigm: pyramid of therapy, starting with conservative approach and gradually progressing
to disease-modifying antirheumatic drugs (DMARDs)
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| Early diagnosis and treatment: at speaker’s institution, patients seen within 1 wk of referral; therapy with
DMARDs begins within 2 wk; narrow window of opportunity before initial changes progress to severe erosions
and loss of anatomic alignment
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| Once window closes, permanent joint deformity, destruction, and disability ensue
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| RA becomes different disease the longer it goes poorly controlled, and standard therapies cease being as effective
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| Current treatment paradigm: rapid evaluation; treatment even before standard 6 wk required to establish diagnosis;
initiation of DMARD therapy within 3 mo of diagnosis; goals—prevent or control joint damage and
loss of function, decrease pain, and improve quality of life
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| DMARD therapies: methotrexate; leflunomide (Arava); sulfasalazine; mycophenolate (Imuran; CellCept); corticosteroids;
hydroxychloroquine (Plaquenil); minocycline
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| Combination therapies: begin early to achieve rapid control; step-up approach—begin with, eg, methotrexate,
and add other DMARDs and biologics; step-down approach—begin with multiple medicines, followed by
withdrawals; possible combinations—sulfasalazine plus leflunomide; methotrexate plus hydroxychloroquine;
caveat—do not combine methotrexate with leflunomide because of liver toxicity
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| Benefits of combination therapies: American College of Rheumatology (ACR) composite score—combines 5 or 6
disease activity measures; ACR 20 (20% improvement) achieved by more patients on combination therapy
than those on one therapy alone; on combination therapy, ACR score of 50 attained by ≈60% of patients, vs
35% to 40% of patients on biologic or DMARD therapy alone; Sharp score—based on composite of erosions
and joint-space narrowing on x-ray; on methotrexate, score increases over 6 to 12 mo; on biologic alone, score
increases more slowly; on combination therapy (methotrexate plus biologic), score “almost negative” (possible
healing)
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| British approach: disease activity score (DAS) calculated based on joint count, erythrocyte sedimentation rate, patient
symptoms, and physician assessment; begin DMARD and titrate dose upward; if significant disease activity
continues, add biologic agent; cannot use biologic until DAS >5
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| Biologic therapy: two meanings; first, drug made by process in living cell that makes proteins; second, modifies
biologic response within body
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| Families of biologic therapies
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| Anti-tumor necrosis factor (TNF) medications: etanercept; infliximab; adalimumab
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| B cell-depleting antibody: rituximab
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| T cell stimulation inhibitor: abatacept
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| About TNF: primarily derived from macrophages and monocytes (effector cells of immune system); 2 forms of
TNF—TNF-α TNF- β TNF-α culprit in RA; 2 forms of TNF-α—membrane-bound and free (soluble)
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| How free TNF-α made: cleaved by enzyme from membrane TNF-α on macrophages and released into serum;
free TNF-α drives inflammation in RA
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| Where TNF-α acts: binds to membrane-bound receptors on cells and activates inflammatory response; soluble
TNF-α receptors (cleaved from membrane) act as decoys (like sponge) to remove free TNF-α from body
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| TNF-α effects: good—required for normal biologic and immune function; essential for granulomatous host defenses
against intracellular bacteria, eg, tuberculosis (TB), fungal infections; bad—TNF-α binds to membrane-bound
TNF-α receptors, mediating proinflammatory processes in RA and other rheumatic diseases;
ratio—of soluble TNF-α receptors to membrane-bound TNF-α receptors determines balance between anti-inflammatory
and proinflammatory effects; balance shifts to anti-inflammatory effects when free (soluble)
TNF-α receptors outnumber membrane-bound TNF-α receptors
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| Advances in anti-TNF therapies: etanercept (Enbrel); infliximab (Remicade); adalimumab (Humira)
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| Etanercept: man-made decoy TNF-α receptor; acts as sponge, removing TNF-α from body; as soluble fusion receptor,
also removes TNF- β does not work for inflammatory bowel disease
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| Infliximab: partially humanized antibody; binds only to TNF-α chimeric molecule that incorporates small
amount of mouse components
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| Adalimumab: fully humanized antibody; binds to TNF-α alone
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| Possible benefit of antibody therapies: able to bind to both membrane-bound and free (soluble) TNF-α probably
also able to clear TNF-producing cells, although unproven; have longer half-lives than receptor therapy
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| Therapeutic considerations
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| Pharmacokinetics: half-life—etanercept ≈4 days; infliximab and adalimumab ≈2 wk; point of caution—6 wk after
infliximab infusion, patient may present to emergency department with immunity still suppressed
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| Food and Drug Administration (FDA)-approved uses: all approved for RA, psoriatic arthritis, and ankylosing
spondylitis; etanercept and adalimumab approved for juvenile RA
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| Off-label uses: inflammatory bowel disease; Behçet’s syndrome, especially its ocular manifestations
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| Dosing: etanercept and adalimumab—40 mg from self-administered injection pen; infliximab—3- to 4-hr infusion
in physician’s office; 3 loading doses over 6 wk; maintenance dose (3 mg/kg) at 2-mo intervals; allows
dosing flexibility
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| Before starting therapy: assess risk of activating latent TB (baseline purified protein derivative [PPD; tuberculin]
and chest x-ray); consider risk for latent histoplasmosis and coccidiomycosis infections; no other baseline or
routine laboratory testing recommended; speaker recommends age-appropriate cancer screening; live-vaccine
immunizations not recommended after initiating therapy
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| Contraindications: history of TB without adequate treatment; active or chronic infection (hepatitis C possible exception);
active or suspected malignancy; hypersensitivity to anti-TNF agent; severe hepatic or renal disease;
moderate-to-severe congestive heart failure (CHF); history of demyelinating disease
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| Potential complications: increased risk for infection; possible increased risk for malignancy; worsening of CHF;
development of lupus-like features, eg, antinuclear antibody; hepatitis; injection-site reaction; temporary infusion
reaction and serum sickness with infliximab
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| Risk for TB: 4-fold greater incidence of TB with anti-TNF therapy (atypical presentations); recommendations—
counsel patients about risk for TB; screening tests for TB; treat latent disease for ≈6 mo; be alert for atypical
presentations
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| Hepatitis: hepatitis B—speaker does serology on all RA patients before treating with anti-TNF-α agent, and
avoids use in RA patients with chronic hepatitis B; emerging literature suggests RA patients on therapy for
hepatitis B do well on anti-TNF-a agents; hepatitis C—some literature suggesting that RA patients treated
with high doses of anti-TNF-α agents have lower incidence of progression to cirrhosis
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| Malignancy: patients with RA have elevated risk for lymphoma; meta-analysis—indicated 3.3 times greater risk
in patients on anti-TNF therapy (more likely with antibodies [infliximab and adalimumab], especially at highest
doses); number needed to harm 1 in 154; experienced investigator—reported no increased risk for lymphoma
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| CHF: anti-TNF-α agents shown to exacerbate heart failure; speaker obtains echocardiography on patients with
mild compensated CHF for use as baseline; if ejection fraction normal discuss risks of therapy and follow
closely; if EF abnormal, speaker does not treat; therapy discontinued in patients who develop CHF if cause
unidentified
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| Question and answer: in patients started on anti-TNF therapy without apparent swollen joints, is RA present?
joints may be no longer swollen after therapy begins; may have mild form of RA; since infliximab infused
in physician’s office, some rheumatologists “quick to pull the trigger”; rheumatologists may have detected
inflammation missed by others; also, focus now on early therapy
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| THE HOT SWOLLEN JOINT—Catherine E. Harmon, MD, Assistant Professor, Department of Medicine, Mayo
Clinic, Scottsdale, AZ
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| Approach to diagnosis: determine if—within joint or periarticular (eg, bursitis, tendinitis); inflammatory or
noninflammatory; warm and red as well as painful and swollen; history of trauma; happened before (if recurrent,
infection unlikely)
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| Acute monoarticular arthritis: hot, red, painful swollen joint potential rheumatologic emergency; acute—
present ≤6 wk; monoarticular (single joint) and pauciarticular (4 to 5 joints or fewer) have same differential
diagnosis
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| Major causes: gout; pseudogout; infection
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| Additional causes: Reiter’s syndrome (reactive arthritis); colitic arthritis; palindromic rheumatism; RA; trauma
(must be temporally related)
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| Gout: commonly in middle-aged men and postmenopausal women; pseudogout—usually in patients >60 yr of
age, more commonly older than 65 to 70 yr of age; in patient <55 yr of age, consider comorbid conditions, eg,
hemachromatosis (check iron) and hyperparathyroidism (check parathyroid hormone [PTH]); crystals—4 times
more likely to be cause of acute monoarticular arthritis than infection
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| Infection: responsible for only 20% of cases of acute monoarticular arthritis, but represents rheumatologic emergency;
valley fever (coccidiomycosis) usually presents as polyarthritis but may present as monoarticular arthritis;
gonorrhea—major cause of monoarticular arthritis in otherwise healthy patient
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| Synovial fluid: tap joint and analyze fluid; diagnose gout or pseudogout with crystals; diagnose infection with
Gram stain and culture
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| Normal: clear; low white blood cell (WBC) count (≤200/µL)
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| Abnormal: WBC count 200/µL to 2000/µL, and <25% polymorphonuclear leukocytes (PMNs); seen in trauma
and degenerative joint disease
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| Inflammatory: hazy; cloudy; may be turbid; WBC count 2000/µL to ≥100,000/µL; ≥50% PMNs
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| Septic: purulent fluid; WBC >80,000/µL; >75% PMNs; diagnostic of infection
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| Hospitalization: treatment of presumed bacterial arthritis requires intravenous antibiotic therapy and removal of
pus
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| Acute bacterial arthritis
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| Gonococcal (GC) arthritis: usually seen in young women; 80% presents as migratory arthralgia, 20% as acute
monoarticular arthritis; ≈50% with skin pustules and/or tenosynovitis (low rate of culture positivity);
diagnosis—commonly made with history and culture from typical site, eg, genital
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| Nongonococcal bacterial arthritis: eg, resulting from Staphylococcus, Streptococcus, gram-negative organism; affects
men and women equally; usually older age group, often with underlying health issues; ≈80% present as
monoarticular arthritis; ≈15% of septic arthritis presents with polyarticular involvement (usually in patients with
comorbid conditions, eg, RA, cancer, diabetes); tendons and skin usually normal; synovial fluid positive in ≈66%
of cases; blood culture positivity possible
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Suggested Reading
Bathon JM et al: The 2008 American College of Rheumatology. Recommendations for the use of nonbiologic
and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis: where the rubber meets the road. Arthritis
Rheum 59:757, 2008; Campbell SM: Gout: how presentation, diagnosis, and treatment differ in the elderly.
Geriatrics 43:71, 1988; Castro-Rueda H et al: Biologic therapy for early rheumatoid arthritis: the latest
evidence. Curr Opin Rheumatol 20:314, 2008; Cornelius R et al: Gouty arthritis in the adult. Radiol Clin North
Am 26:1267, 1988; Danila MI et al: Biologics and heart failure in rheumatoid arthritis: are we any wiser? Curr
Opin Rheumatol 20:327, 2008; Finckh A et al: At the horizon of innovative therapy in rheumatology: new biologic
agents. Curr Opin Rheumatol 20:269, 2008; Gerlag DM et al: Novel approaches for the treatment of rheumatoid
arthritis: lessons from the evaluation of synovial biomarkers in clinical trials. Best Pract Res Clin
Rheumatol 22:311, 2008; Glück T et al: Vaccination in patients with chronic rheumatic or autoimmune diseases.
Clin Infect Dis 46:1459, 2008; Greenberg JD et al: Tumor necrosis factor antagonist responsiveness in a United
States rheumatoid arthritis cohort. Am J Med 121:532, 2008; Ho G Jr et al: Gout and pseudogout in hospitalized
patients. Arch Intern Med 153:2787, 1993; Laas K et al: Clinical impact of switching from infliximab to etanercept
in patients with rheumatoid arthritis. Clin Rheumatol 27:927, 2008; Lally EV et al: The clinical spectrum of
gouty arthritis in women. Arch Intern Med 146:2221, 1986; Lawry GV 2nd et al: Polyarticular versus monoarticular
gout: a prospective, comparative analysis of clinical features. Medicine (Baltimore) 67:335, 1988; Saag
KG et al: American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic
disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 59:762, 2008.
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