ISSUES IN RHEUMATOLOGY
| INFLAMMATORY MYOPATHIES —Steven N. Berney, MD, Professor of Medicine, and Chief, Section of Rheumatology,
Temple University School of Medicine, Philadelphia
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| Introductory remarks: proximal muscle weakness most important clinical feature of polymyositis; muscle inflammation
main pathologic feature
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| Typical patient: woman 42 yr of age; several months of increasing, worsening weakness in proximal muscles of shoulders
and hips; has difficulty raising arms to brush hair and getting up from chair; stumbles when walking but has not fallen; denies
joint pain, shortness of breath, dysphonia, dysphagia, rash, or Raynaud’s phenomenon; notes no skin changes; takes no
medications; denies recent heavy alcohol intake
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| Physical examination: normal, with exception of muscle strength; neurologic examination fails to detect neuropathic
changes that would account for weakness
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| Medical history: may include pulmonary involvement (can be fleeting infiltrates or as severe as pulmonary fibrosis; patient
may complain of intermittent or constant shortness of breath); difficulty swallowing (due to upper esophageal function
abnormality); rash; joint pain; ask about symptoms that reflect Raynaud’s phenomenon; must get patient’s alcohol-,
substance-, and medication-use history
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| Muscle weakness can be associated with: rash; childhood; overlap syndrome (with features of several definable illnesses);
malignancy (lung cancer most common)
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| Dermatomyositis: term for inflammatory myositis when skin involved; typical skin changes—heliotrope rash on face;
“shawl sign” (v-shaped rash on anterior thorax); Gottron’s papules (pathognomonic for dermatomyositis); “mechanic’s
hands”
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| Etiology: unknown; often follows upper respiratory or other viral type of illness, with induction of muscle weakness several
weeks later; autoimmune disease; regardless of etiology, condition results in muscle injury with proximal and symmetric
muscle weakness (biochemical analysis shows elevations in muscle enzymes, eg, creatine phosphokinase [CPK])
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| Differential diagnosis: medications—lipid-lowering agents (probably most common drugs that can induce muscle weakness;
may or may not produce elevation in muscle enzymes); corticosteroids (can induce muscle atrophy and weakness;
muscle enzymes usually normal in persons on these drugs; dilemma in fact that corticosteroids used to treat inflammatory
myopathies; if patient shows initial improvement, then has recurrence of weakness, question whether relapse or steroid-induced
myopathy); substance abuse—alcohol abuse can induce rhabdomyolysis; cocaine abuse can also cause muscle
weakness and highly elevated enzymes; metabolic and endocrine abnormalities—hypothyroidism (probably most common
endocrine abnormality; associated with very high levels of CPK); adrenal dysfunction; metabolic abnormalities (eg,
hypokalemia); infections; trauma; myasthenia; amyotrophic lateral sclerosis (ALS) can occasionally present as muscle
weakness
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| Diagnosis: laboratory tests—muscle enzymes (usually CPK or aldolase, or both); autoantibodies (antinuclear antibody
[ANA] easiest test to obtain and to interpret); used to do electromyography (EMG) to demonstrate myopathic potential within
muscle; however, procedure fairly uncomfortable; magnetic resonance imaging (MRI) probably as reliable in identifying
muscles involved (patient with inflammatory myositis usually shows muscle edema on MRI; in appropriate context, should be
sufficient to indicate which muscle will give high yield on biopsy); if MRI not available or able to show muscle edema, EMG
more conventional standard (if ordered, should be done only unilaterally; if abnormality found, follow with contralateral biopsy);
remind surgeon performing biopsy that strip of muscle must be placed in preservative in stretched position
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| Treatment: mainstay is corticosteroids (therapy generally long-term [6 mo to 2 yr]), dose and method of administration frequently
determined by severity of illness and relative urgency of event); in cases where muscle strength and CPK level improve
with therapy, but lowering of initial dose appears to reexacerbate illness, addition of methotrexate (15-25 mg once
weekly) frequently enables successful tapering of steroids; if intolerance or adverse event forces discontinuation of methotrexate,
other immunosuppressants (eg, azathioprine, mycophenolate) substituted; if patient fails to respond to corticosteroid-
methotrexate combination therapy—intravenous immunoglobulin shown successful in isolated reports and small
series of patients; occasional reports of success with biologic-response modifiers (biologics)
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| STATUS OF COX-2 INHIBITORS —Arthur A.M. Bookman, MD, Associate Professor of Medicine, University of Toronto
Faculty of Medicine
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| Are cyclooxygenase (COX)-2 inhibitors safer than traditional nonsteroidal anti-inflammatory drugs (NSAIDs)
for gastrointestinal (GI) complications? Celecoxib Long-Term Arthritis Safety Study (CLASS) trial—8000 patients;
most had osteoarthritis; celecoxib compared to ibuprofen or diclofenac in maximal doses; primary study end point
incidence of complicated ulcers, secondary end point incidence of symptomatic and complicated ulcers; ≈21% patients
allowed to take prophylactic aspirin; Vioxx Gastrointestinal Outcomes Research (VIGOR) study—8000 patients; all
had rheumatoid arthritis; rofecoxib (Vioxx) compared to naproxen; primary end point incidence of symptomatic and
complicated ulcers, secondary end point incidence of complicated ulcers; patients not allowed to take prophylactic aspirin;
CLASS trial found celecoxib did not significantly reduce incidence of complicated ulcers, but significantly decreased
incidence of symptomatic and complicated ulcers; VIGOR study found rofecoxib highly effective in reducing symptomatic
and complicated ulcers and in decreasing complicated ulcers
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| Are COX-2 inhibitors better tolerated? CLASS trial found celecoxib better tolerated than traditional NSAIDs (lower
incidence of abdominal pain, nausea, and dyspepsia); however, equal incidence of diarrhea; rofecoxib not better tolerated
(associated with greater incidence of fluid retention, congestive heart failure [CHF], severe hypertension, and equal degree
of nausea, flatulence, diarrhea, and bloating when compared to traditional NSAIDs)
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| Are selective COX-2 inhibitors more effective? offer no advantage over traditional NSAIDs in renal side effects; necessitate
precautions in acute renal failure, hyperkalemia, edema, CHF, and hypertension; in several clinical trials using diclofenac,
naproxen, or ibuprofen as comparators, selective COX-2 inhibitors no more efficacious than traditional NSAIDs
for relief of pain or inflammation
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| Special considerations: absence of platelet antagonism allows COX-2 inhibitors to be used safely up to time of surgery; very
little, if any, interaction between them (particularly celecoxib) and warfarin (may be used concurrently with caution and careful
monitoring); probably produce less GI toxicity in elderly; may be given (with caution) to patients with aspirin-induced
asthma
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| Degree of cardiovascular risk associated with rofecoxib: VIGOR study found absolute risk 4 myocardial infarctions
(MIs) per 1000 patients (vs 1 MI per 1000 patients with naproxen); relative risk increased >100%; actual significance of risk
depends on how expressed to public (key point is that >2 billion prescriptions for rofecoxib worldwide; because of huge denominator,
risk for MI also large, and drug became concern); in VIGOR study, deaths from cardiovascular (CV) events did
not actually increase with rofecoxib, compared to naproxen; 2001 analysis of VIGOR study data found that increase in adverse
cardiac events with rofecoxib occurred after 6 to 8 mo
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| Adenomatous Polyp Prevention on VIOXX (APPROVe) study: compared rofecoxib and placebo in patients with recurrent
bowel polyps; study duration ≈3 yr; final analysis showed 26 thrombotic events in >1000 patients with placebo, 46 events
in >1000 patients with rofecoxib (≈100% increase in relative risk); interestingly, did not start to see increase in MIs and
thrombotic events until after 18 mo, and after 18 mo, rate progressively increased; trial halted 2 mo early and rofecoxib pulled
from market
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| Are increased cardiovascular complications seen with rofecoxib a class effect of all COX-2 inhibitors? in short-
term trial of patients who underwent cardiac surgery, paracoxib and valdecoxib given postoperatively associated with almost
4-fold increase in CV and cerebrovascular complication rate; study with celecoxib (Adenoma Prevention with Celecoxib
[APC] trial) also reported increase in CV and cerebrovascular complications and/or death rate
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| Can low-dose aspirin be used with COX-2 inhibitor to obviate CV complications? probably not; in study of 18,000
patients on lumiracoxib, drug very effective in reducing GI complication rates, but in ≈24% of patients who took prophylactic
aspirin, this benefit lost; thus, adding aspirin to COX-2 inhibitor appears to obviate improvement in incidence of ulcers
and ulcer complications
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| Comments: question of whether patients at risk for CV complications can be selected out; in APC trial, incidence of CV
events dose-dependent; in APPROVe and VIGOR trials, incidence of MIs increased with time
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| Conclusions: still special circumstances in which COX-2 inhibitors needed; patients must be selected judiciously; in appropriate
patients, these drugs offer increased tolerance with benefits similar to NSAIDs
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| RHEUMATOLOGY REVIEW —Barbara Abercrombie, MD, Assistant Professor of Medicine, Texas A & M College of
Medicine, and Director, Division of Rheumatology, Scott and White Clinic, Temple, Texas
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| Introductory remarks: patient history and physical examination (PE) cornerstones of evaluation; even though increasing
number of laboratory tests help to establish diagnosis, all interpreted within context of information obtained from history
and PE
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| Patient evaluation: helpful to ascertain amount of morning stiffness associated with joint complaints (patients with osteoarthritis
or noninflammatory processes typically have 15-30 min of morning stiffness; patients with inflammatory
diseases tend to have stiffness lasting 30-60 min, sometimes all morning; beware fibromyalgia patients); medical
history—look for other possible causes of joint pain (eg, hypothyroidism not uncommon in women); conditions that
might influence medical treatment of musculoskeletal complaint (eg, peptic ulcer disease, diabetes); surgical history
(particularly cancer surgery); medication history very important (anticonvulsants and birth control pills can be associated
with positive ANA tests); positive family history (puts patient at increased risk for connective tissue disorder or
other autoimmune diseases)
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 | Possible clues to diagnosis: skin rashes, sun sensitivity, increased hair loss (can indicate systemic lupus erythematosus
[SLE] or Sjogren’s syndrome); dry eyes and dry mouth; Raynaud’s phenomenon (seen in multiple connective tissue
diseases); history of gout (particularly in older men; can be difficult to distinguish, just on examination, between rheumatoid
arthritis [RA] and chronic gouty arthritis)
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| Comments: second step in patient evaluation is complete PE (example of patient who presented with 3-4 highly inflamed
joints; history unrevealing; most of PE also unrevealing; however, patient had psoriasis in belly button; ultimately, turned
out to have psoriatic arthritis)
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| Laboratory studies: complete blood count (CBC); renal and liver function tests; thyroid stimulating hormone (TSH); uric
acid (if gouty arthritis suspected); calcium; useful serologic tests include rheumatoid factor, cyclic citrullinnated peptide
antibodies, and ANA panel
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| Imaging studies: speaker does not often get x-rays early in patients who present with polyarthralgias and polyarthritis;
sometimes uses bone scans to help exclude disease in patients with highly symptomatic arthralgias
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| Factors that increase erythrocyte sedimentation rate (ESR): female sex; age; inflammatory diseases (not just rheumatologic
diseases); MI or stroke; pneumonia; sinusitis; also few factors that decrease ESR
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| Polymyalgia rheumatica: diagnosis of exclusion (must rule out other metabolic diseases, malignancy, or another connective
tissue disease); much debate about developing diagnostic criteria for this disorder (many tend to overlap with criteria
for conditions like early RA); need to evaluate patient’s ESR for age and other diseases and comorbidities
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| Empiric steroids: many disorders respond to steroids (not just polymyalgia rheumatica); cannot treat this disorder with
methylprednisolone (Medrol Dose Pack); ask about symptoms of temporal arteritis (50% of patients with temporal arteritis
have symptoms of polymyalgia rheumatica, and about 10%-15% of patients with polymyalgia have temporal arteritis);
if temporal arteritis not consideration, no need to start patient on high doses of steroids (15 mg/day usually
sufficient; if no response to medication, consider reevaluating diagnosis); if unsure of diagnosis, try patients on
NSAIDs before starting steroids
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| Case example 1: woman 70 yr of age; problem with right-sided chest pain; pain associated with fatigue, fever, and night
sweats; no history of neck, shoulder, or hip pain; denied morning stiffness; no symptoms of temporal arteritis; before presentation,
thought to possibly have splinter hemorrhages; hospitalized with question of bacterial endocarditis; ultimately determined
to have right lower lobe pneumonia and urinary tract infection; treated with IV and oral antibiotics; discharged from
hospital; at follow-up visit, ESR 89 mm/hr; diagnosis of polymyalgia rheumatica made; treated with prednisone 20 mg/day
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| In cases of suspected temporal arteritis: if considering diagnosis, need to order biopsy (if left untreated, patient may develop
irreversible blindness); have 2-wk window of opportunity (possibly longer) to obtain biopsy; higher doses of steroids
required for treatment (usually 45-60 mg/day; speaker usually gives 15-20 mg tid); cannot taper medication too quickly (duration
of disease usually 2 yr and can be longer [in some patients, ≤5 yr])
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| Rheumatoid factor: primarily associated with RA; however, positive in other connective tissue diseases (eg, SLE, scleroderma,
Sjogren’s syndrome); also associated with nonrheumatologic diseases (most commonly, subacute bacterial endocarditis)
and viral infections (eg, hepatitis B and C); positive in 80% to 88% of patients with RA (however, if patient
rheumatoid factor-negative, does not mean he or she will remain so, as frequency of positive result tends to increase within
first year)
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Educational Objectives
| The goal of this activity is to provide a better understanding of the diagnosis and treatment of inflammatory myopathies, an
update on the status of cyclooxygenase (COX)-2 inhibitors in the treatment of pain and inflammation, and a review of the
evaluation of a patient who presents with musculoskeletal complaints. After hearing and assimilating this program, the clinician
will be better able to:
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| Recognize signs and symptoms suggesting polymyositis in patients who present with complaints of muscle weakness.
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| Use the patient’s medical history, appropriate physical examination, and laboratory studies to diagnose inflammatory
myopathies.
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| Understand the mainstay of treatment for polymyositis and dermatomyositis, as well as alternative approaches to refractory
cases.
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| Cite the possible benefits and disadvantages of COX-2 inhibitors and describe the studies that have identified increased
cardiovascular (CV) complications with their use.
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| Evaluate the patient who presents with musculoskeletal complaints such as joint stiffness.
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Discussed on This Program
Acetaminophen (N -acetyl-P -aminophenol; APAP) [Tylenol, several formulations and trade names]
Aspirin (acetylsalicylic acid; ASA) [several formulations and trade names]
Azathioprine (AZA) [Imuran]
Celecoxib [Celebrex]
Cocaine [Cocaine HCl, Cocaine Viscous]
Diclofenac [Cataflam, Voltaren, Voltaren-XR] Etoricoxib [Arcoxia] (investigational)
Ibuprofen [Advil, other formulations and trade names]
Immune globulin intravenous (IGIV) [Gamunex]
Lumiracoxib [Prexige] (investigational)
Meloxicam [Mobic]
Methotrexate (amethopterin; MTX) [Methotrexate LPF, Rheumatrex Dose Pack, Trexall]
Methylprednisolone [Medrol]
Mycophenolate mofetil (MMF) [CellCept]
Naproxen [Aleve, Anaprox, Anaprox DS, EC-Naprosyn, Naprosyn, Naprelan]
Piroxicam [Feldene]
Prednisone [Deltasone, Liquid Pred, Meticorten, Orasone, Panasol-S, Prednicen-M, Prednisone Intensol Concentrate,
Strerapred DS]
Rofecoxib [Vioxx] (withdrawn from market 09/30/04)
Valdecoxib [Bextra]
Warfarin sodium [Coumadin]
Suggested Reading
Bombardier C: An evidence-based evaluation of the gastrointestinal safety of coxibs. Am J Cardiol 89:3D, 2002; Bombardier
C et al: Comparison of upper gastrointestina.toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.
VIGOR Study Group. N Engl J Med 343:1520, 2000; Bresalier RS et al: Cardiovascular events associated with
rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352:1092, 2005; Dalakas MC: Inflammatory disorders
of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis. Curr Opin Neurol 17:561, 2004;
Dalakas MC: The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-
based indications and safety profile. Pharmacol Ther 102:177, 2004; Dalakas MC, Hohlfeld R: Polymyositis and dermatomyositis.
Lancet 362:971, 2003; Drake LA et al: Guidelines of care for dermatomyositis. American Academy of
Dermatology. J Am Acad Dermatol 34:824, 1996; Farkouh ME et al: Comparison of lumiracoxib with naproxen and ibuprofen
in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised
controlled trial. Lancet 364:675, 2004; Kovacs SO, Kovacs SC: Dermatomyositis. J Am Acad Dermatol 39:899,
1998; Mukherjee D et al: Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954,
2001; Plotz PH et al: Myositis: immunologic contributions to understanding cause, pathogenesis, and therapy. Ann Intern
Med 122:715, 1995; Reimers CD, Finkenstaedt M: Muscle imaging in inflammatory myopathies. Curr Opin Rheumatol
9:475, 1997; Scheiman JM: Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors. Cleve Clin J
Med 69 Suppl 1:SI40, 2002; Silverstein FE et al: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory
drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-
term Arthritis Safety Study. JAMA 284:1247, 2000; Solomon DH et al: Evidence-based guidelines for the use of immunologic
tests: antinuclear antibody testing. Arthritis Rheum 47:434, 2002; Spektor G, Fuster V: Drug insight: cyclo-oxygenase
2 inhibitors and cardiovascular risk--where are we now? Nat Clin Pract Cardiovasc Med 2:290, 2005; Targoff IN:
Update on myositis-specific and myositis-associated autoantibodies. Curr Opin Rheumatol 12:475, 2000; Terkeltaub
RA: Clinical practice. Gout. N Engl J Med 349:1647, 2003; Zeng X et al: Diagnostic value of anti-cyclic citrullinated
Peptide antibody in patients with rheumatoid arthritis. J Rheumatol 30:1451, 2003; Zuckner J: Drug-related myopathies.
Rheum Dis Clin North Am 20:1017, 1994.
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. Berney spoke at the Family Practice Review, held September 25-30, 2005, in Lancaster, Pennsylvania, and sponsored
by the Temple University School of Medicine. Dr. Bookman was recorded at Musculoskeletal & Arthritis Day, held April
15, 2005, in Toronto, Canada, and sponsored by the University of Toronto Faculty of Medicine. Dr. Abercrombie was a
speaker at the 21st Family Medicine Review, held April 6-9, 2005, in Temple, Texas, and sponsored by the Scott and
White Clinic. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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