UPDATE IN RHEUMATOLOGY
From Mayo Clinic College of Medicine’s 9th Annual Internal Medicine Update
Catherine E. Harmon, MD, Consultant in Rheumatology, Mayo Clinic College of Medicine, Scottsdale, AZ
| Case history 1: woman 34 yr of age; mother of 2; 2-mo history of additive arthritis; pain, swelling of metacarpophalangeal
(MCP) and metatarsophalangeal (MTP) joints, wrists, knees, and ankles; morning stiffness for ≈3 hr; 1+ to 2+
synovitis in multiple joints; high levels of inflammatory markers and rheumatoid factor (RF); anti-cyclic citrullinated
peptide (anti-CCP) antibodies >100 U/mL; diagnosis—rheumatoid arthritis (RA)
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| Treatment: disease-modifying antirheumatic drug (DMARD) methotrexate (MTX) recommended; rationale—patient’s
RA highly active with many tender swollen joints, high inflammatory markers, and high levels of RF and anti-CCP antibody,
all of which correlate with active, persistent, and progressive disease; 70% of erosions occur within first 2 yr of
RA; aggressive treatment critical at this time (aggresiveness of treatment should match aggressiveness of disease); hydroxycholorquine
or sulfasalazine alone “too little therapy”; MTX good drug to start with, but “not an end in itself”; if
patient does not improve, increase dose up to 20 mg/wk; if still no (or little) improvement, add tumor necrosis factor
(TNF) inhibitor; combination therapy currently norm for RA; TNF inhibitors—consider convenience (infusion or injection);
access to treatment if infusion chosen; cost ($17,000–$35,000/yr); patient’s preference and comorbidities (relative
contraindications include congestive heart failure, recurrent infection and recent neoplasm)
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 | Infliximab (Remicade): chimeric human/mouse monoclonal antibody; administered intravenously (IV; starting dose
3 mg/kg per infusion; can escalate to 5, and in rare cases, 10 mg/kg per infusion); not used as monotherapy because patients
can make antibodies to mouse component, decreasing efficacy; use in combination with MTX, leflunomide
(Arava), or mycophenolate mofetil (CellCept); adverse effects—infusion reactions (premedicate with diphenhydramine
[Benadryl] and acetaminophen [eg, Tylenol]); immune stimulation (eg, systemic lupus erythematosis [SLE],
unmasking of multiple sclerosis [MS]); increased risk for opportunistic infections
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| Etanercept (Enbrel): weekly subcutaneous injection of 50 mg as effective as twice-weekly injections; fully humanized
soluble receptor for TNF (not monoclonal antibody); can be administered as monotherapy, but works best with another
agent such as MTX; toxicities similar to those of infliximab, plus injection-site reaction (usually mild)
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| Adalimumab (Humira): fully humanized monoclonal anti-TNF antibody; can be used as monotherapy, but works better
in combination with another agent; toxicities similar to those of other TNF inhibitors
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| Contraindications to TNF inhibitors: current or recurrent infections; presence of tuberculosis, MS, or SLE (may worsen
it; unproven); active malignancy within previous 3 to 5 yr (except skin cancer); pregnancy or lactation (safety unknown);
uncompensated congestive heart failure; do not combine with another biologic agent (exacerbates adverse effects,
with no added benefit)
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| Other biologic agents: anakinra (Kineret)—use in RA limited; abatacept (Orencia)—fusion protein; prevents T-
cell activation; 10 mg/kg per infusion, in graduated induction and maintenance phases (0, 2, and 4 wk, and every 4 wk
thereafter); incidence of infusion reactions ≈9% (usually mild); do not administer with other biologics (unacceptably
high risk for infection); rituximab (Rituxan)—chimeric human/mouse monoclonal antibody against CD20 antigen
on B cells; in 2006, approved for treatment of RA when TNF inhibitors have failed; administered with MTX; given as
IV infusion starting with 1 g on day 1, repeated at day 15 with 100 mg methylprednisolone to prevent infusion reactions;
adverse effects include B-cell depletion lasting up to 6 mo (can repeat treatment then if depletion reversing); infusion
reactions; risk for infection
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| Case history 2: man’s RA well controlled with MTX until he develops lymphadenopathy; biopsy of node consistent with
MTX-related B-cell lymphoproliferation; MTX stopped; lymphadenopathy regressed and RA flared; rituximab and
levflunomide started, and patient doing well
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| Anti-CCP antibodies: patients with RA make antibodies against citrulline-containing proteins, which are abundant in
rheumatoid sera and synovia; presence has 66% sensitivity, 94% specificity for RA (compared to 65% sensitivity, 81%
specificity for RF); having both RF and anti-CCP more predictive of RA than either alone; anti-CCP better than RF for
predicting which patients with early synovitis will develop full-blown RA, and for predicting which ones with established
RA will develop progressive course; RF and anti-CCP antedate development of clinical RA by months to years;
Sjögren’s syndrome—≤ 50% of patients have RF, but only ≈5% have anti-CCP, underscoring specificity of anti-CCP
for RA
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| Pulmonary arterial hypertension (PAH) in scleroderma: estimated prevalence 10% to 15% in hospitalized series;
in limited scleroderma, PAH isolated arterial process; in diffuse, scleroderma, PAH secondary to advanced interstitial
lung disease; in either form, earliest symptom exertional dyspnea (reduced exercise capacity)
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| Evaluation: pulmonary function tests show reduced diffusion capacity with normal lung volume; indicators of PAH include
ratio of forced vital capacity (FVC) to diffusion capacity of carbon monoxide (DLCO) >1.4; resting pulmonary
arterial pressure (PAP) should be >25 mm Hg (>30 mm Hg with exercise); 6-min walk predictor of survival in PAH;
patients who can walk >332 m in 6 min have 92% 3-yr survival rate; those who can walk <332 m have 20% 3-yr
survival rate; right heart catheterization gold standard for diagnosis
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| Treatment: bosentan (oral endothelin receptor antagonist); epoprostenol given IV or subcutaneously; sildenafil
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| Case history 3: woman 78 yr of age with limited scleroderma >50 yr; has exertional dyspnea; resting PAP 51 mm Hg;
FVC 79%; DLCO 93% (ratio 0.85); mean PAP 18 mm Hg on heart catheterization; patient does not have PAH (diagnosis
recurrent pulmonary emboli)
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| Case history 4: Native American woman 52 yr of age with RA; taking MTX and infliximab; develops sudden dyspnea and
chest pain; large left pleural effusion on chest x ray; very high RF; positive for antinuclear antibody; anti-double-stranded
(ds) DNA 300 U (normal <24 U); diagnosis RA-lupus overlap (“rhupus”) or drug-induced lupus; today, main causes minocycline
and TNF inhibitors (responsible for elevated anti-dsDNA); infliximab stopped and patient treated with short
course of steroids; anti-dsDNA returned to normal in 6 mo
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| Case history 5: woman 20 yr of age; nephrotic syndrome due to membranous lupus nephritis; intolerant of or unresponsive
to azathioprine (Imuran), cyclosporine; requires unacceptably high doses of prednisone; evidence that after 7 to to
10 yr of sustained proteinuria, ≈25% of patients with lupus develop end-stage renal disease; chronic heavy proteinuria
also associated with hyperlipidemia, atherosclerosis, and hypercoagulability; study data show CellCept can reduce proteinuria
by ≈50%
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| Questions and answers: patient with arthralgias and anti-CCP—treat for arthralgias, starting with nonsteroidal
anti-inflammatory drugs (NSAIDs); if symptoms continue and inflammatory markers high, MRI of problematic joint
may help determine whether more aggressive treatment indicated; role of levflunomide—add to MTX in patient with
moderately aggressive RA who has failed MTX alone; patient with mildly active RA who shows intolerance to MTX
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| Case history 1: man 38 yr of age with 2-day history of increasingly painful red swollen left knee; overweight but no other
health problems; last examination 5 yr earlier for slightly painful big toe; at time patient told gout unlikely because of his
young age; has acute monoarticular inflamamtory arthritis (most likely causes infection, gout, or pseudogout; reactive arthritis
also possible in this age group)
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| Background: 40% to 50% of gout patients have normal serum urate at time of flare; but gout definitely associated with hyperuricemia;
main targets men and post-menopausal women
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| Approach to patient: most acute infectious monoarticular arthritides caused by staphylococci, streptococci, or gram-
negative organisms (hospitalization, IV antibiotics, and repeated aspiration required), so “shotgun” outpatient treatment
with antibiotics and indomethacin inadequate (definitive diagnosis necessary); patient’s knee fluid revealed 60,000 white
blood cells (WBCs), with 60% polymorphonuclear leukocytes; WBCs have negatively birefringent crystals (only definitive
way to diagnose gout); Gram stain and fluid culture recommended, as infection may coexist (negative in this case)
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| Gout facts: complication of hyperuricemia; 2% to 18% of normal population has hyperuricemia, and most never develop
gout; of people with persistent hyperuricemia >9 mg/dL, ≈20% develop gout within 5 yr; prevalence increased 2-fold
from late 1970s to late 1990s
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| Clinical stages of gout: asymptomatic hyperuricemia—develops in boys around puberty, in women around menopause;
uric acid level gradually rises over time; the higher the uric acid level, the greater the risk for gout; first manifestation
of hyperuricemia may be kidney stones; risk factors include— being middle-aged man or postmenopausal
woman; advancing age; use of certain drugs (eg, thiazide diuretics, cyclosporine); hypertension; posttransplant status;
high alcohol intake, especially beer (high guanosine content); obesity; diet rich in meat and seafood; acute gouty
attacks—majority initially monoarticular (first MTP joint in 65% to 75% of cases; ≈90% of cases involve that joint at
some time in disease course); initial polyarticular attacks rare, but seen in older women on diuretics or people who take
cyclosporine; after initial attack, 62% of patients have another within 1 yr; 7% never have another attack; after first attack,
tophi and x-ray changes take ≈5 yr to appear; pathogenesis—gout develops when urate crystals deposit in articular
areas and become coated with nonimmunologic immunoglobulin complement; leads to phagocytosis and acute
inflammatory cascade; intercritical period—time between attacks; later attacks characterized by increased frequency,
intensity, duration, and number of joints involved; chronic gouty arthritis—develops in minority of patients;
characterized by chronic low-grade arthritic pain punctuated by attacks of acute gout; tophi (accumulation of
urate crystals); x-ray changes; increasing dysfunction and disability; urate nephropathy; can be extremely disfiguring
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| Etiology of hyperuricemia: tubular defect results in inadequate urate excretion; seen in 90% of patients with primary gout
(only 10% of cases caused by urate overproduction); triggers for gout—hospitalization for surgery or significant
medical illness, eg, myocardial infarction
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| Case history 2: man 50 yr of age has tophaceous gout; takes only cardiac-dose aspirin; last attack 2 mo earlier; treat with
colchicine and allopurinol (indomethacin, steroids unnecessary because patient not having acute gouty attack; however,
patient already has advanced gout, so treatment indicated to decrease urate load and prevent further attacks; probenecid-
colchicine [colbenemid] poor choice because aspirin neutralizes activity of probenecid)
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| Principles of treatment: treat acute attacks quickly to protect against future attacks; treat hyperuricemia to prevent attacks
and disease progression
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| Treatment caveats: by time patients see rheumatologists, disease usually too far advanced for adequate control with colchicine;
IV colchicine used in hospitalized patients with healthy liver and kidneys; do not follow with oral colchicine (increases
risk for bone marrow suppression); do not start allopurinol or probenecid during acute gouty attack (ineffective;
may prolong attack); reduce allopurinol dose for patients with renal dysfunction, but adjust it to obtain serum uric acid <6
mg/dL; monitor allopurinol-azathioprine interaction; probenecid contraindicated if patient azotemic or taking aspirin
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| Basic recommendations: weight reduction “always a good idea,” but lowers serum urate by only 1 mg/dL; avoid low-
dose aspirin and extremes (too much alcohol, too little food); do not use drugs that raise serum urate, eg, thiazides; if
patient drinks, recommend wine over beer or hard liquor; avoid purines from meat and seafood (vegetable purines
fine); assess for comorbidities (uric acid independent risk factor for hypertension, coronary artery disease, and renal
disease); also assess for diabetes and hyperlipidemia
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| Acute attack: short-acting NSAIDs or corticosteroids; IV colchicine for inpatients
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| Long-term treatment: indications—frequent attacks not controlled by colchicine prophylaxis; presence of tophaceous
deposits or gouty joint damage; production of urinary uric acid >800 to 1000 mg/day; concurrent cancer treatment;
drugs—single dose of 300 to 400 mg/day allopurinol (100-200 mg/day for patients with renal impairment); colchicine
or low-dose NSAIDs used for 6 mo, or until attacks cease, or until serum urate ≤6 mg/dL; when prescribing allopurinol
to patient already taking azathioprine, reduce dose of azathioprine to 25% to 33% of original amount to
prevent severe bone marrow suppression; treatment should also include uricosuric agents; however, uricosurics (especially
probenecid) ineffective with concomitant aspirin use; helpful for patients who underexcrete uric acid, but not
useful in those who have renal impairment or overproduce uric acid
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| New or controversial issues: febuxostat—new agent; nonpurine selective xanthine oxidase inhibitor; superior to allopurinol
at achieving target serum urate levels <6 mg/dL; acceptable for people sensitive to allopurinol; people with renal insufficiency
can take full dose of 80 to 100 mg/day; on horizon—pegylated uricase in development (longer half-life and low
antigenicity); urate nephropathy—human and animal data have associated elevated uric acid with significant renal impairment,
independent of hypertension; Heberden’s nodes—consider gout when seen in elderly women (especially those
on thiazide diuretics) and nodes appear hot, red, and swollen
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| Case history 3: brother of previous patient; 42 yr of age; excellent health, but serum uric acid elevated; currently, no
treatment recommended, “but stay tuned” (impact of treating asymptomatic hyperuricemia on development of heart disease,
hypertension, and renal disease now under study)
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| Pseudogout (case history 4): man 68 yr of age with stiffness, achiness, and bony enlargement in multiple joints;
presents with 3-day history of red, painful, swollen, warm right knee; most likely diagnosis pseudogout; cause—
calcium pyrophosphate dihydrate (CPPD) deposition disease; pseudogout inflammatory reaction due to CPPD
crystal deposition in joint; crystals also often deposit in joint hyaline and fibrocartilage; sometimes resembles osteoarthritis,
but in unexpected joints; may also mimic RA, but patients negative for RF and anti-CPP; usually
seen in patients >65 yr of age (perform screening studies in patients <50 yr of age); knees and wrists most commonly
affected; chondrocalcinosis not always associated with clinical disease; elderly patient may present with
fever and delirium, as well as multiple joint involvement; intensity usually less than that of gout
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| Treatment of pseudogout: acute attacks—NSAIDs or corticosteroids; IV colchicine (for inpatients); recurrent
attacks—NSAIDs or prophylactic colchicine
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Suggested Reading
Cozzi F et al: Bosentan therapy of pulmonary arterial hypertension in connective tissue diseases. Eur J Clin Invest 36
Suppl 3:49, 2006; Denton CP, Nihtyanova SI: Therapy of pulmonary arterial hypertension in systemic sclerosis: an update.
Curr Rheumatol Rep 9:158, 2007; Johnson RJ et al: Essential hypertension, progressive renal disease, and uric
acid: a pathogenetic link? J Am Soc Nephrol 16:1909, 2005; Kavanaugh A: Current treatments for rheumatoid arthritis.
Am J Orthop 36(3 Suppl):4, 2007; Keith MP, Gilliland WR: Updates in the management of gout. Am J Med 123:221,
2007; Mathai SC et al: Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir
J 29:469, 2007; Mousa SA et al: Recent advances of TNF-alpha antagonists in rheumatoid arthritis and chronic heart
failure. Expert Opin Biol Ther 7:617, 2007; Plastiras SC et al: Determinants of pulmonary arterial hypertension in
scleroderma. Semin Arthritis Rheum 36:392, 2007; Rosenthal AK: Update in calcium deposition diseases. Curr Opin
Rheumatol 19:158, 2007; Schlesinger N: Management of acute and chronic gouty arthritis: present state-of-the-art.
Drugs 64:2399, 2004; Schneider M: Exploring new territory: considering the future. Lupus 16:221, 2007; Spillane AP
et al: Drug-induced lupus erythematosus in a patient treated with adalumimab. J Am Acad Dermatol 56(5 Suppl):S114,
2007; Strand V: Selective T-cell costimulation modulation: a new approach to treating rheumatoid arthritis. Am J Orthop
36(3 Suppl):13, 2007; Wise CM: Crystal-associated arthritis in the elderly. Rheum Dis Clin North AM 33:33,
2007.
Educational Objectives
| The goal of this program is to improve the diagnosis and treatment of arthritis, gout, and pseudogout. After hearing and assimilating
this program, the listener will be better able to:
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| 1. Recognize features of common rheumatic diseases, including rheumatoid arthritis and scleroderma.
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| 2. Develop a treatment approach that includes new therapies for rheumatoid arthritis, with emphasis on biologic agents.
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| 3. Discuss the evaluation and management of pulmonary arterial hypertension in scleroderma patients.
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| 4. List the clinical stages of gout and the basic principles of treatment.
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| 5. Explain the role of crystals in the diagnosis and management of gout and pseudogout.
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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 faculty reported nothing to disclose.
Acknowledgements
Dr. Harmon spoke at 9th Annual Mayo Clinic Internal Medicine Update, held October 19-22, 2006, in Sedona, AZ,
and sponsored by the Mayo Clinic College of Medicine, Scottsdale, AZ. The Audio-Digest Foundation thanks the
speaker and the sponsor for their cooperation in the production of this program.
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