PAINFUL AND INFLAMED JOINTS
Educational Objectives
| The goal of this program is to improve the management of rheumatoid arthritis (RA) and other causes of painful and
inflamed joints. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Identify common clinical manifestations of RA.
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| 2. Use laboratory and clinical findings to help diagnose and predict prognosis of RA.
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| 3. List contraindications of agents commonly used to treat RA.
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| 4. Describe common presentations of osteoarthritis.
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| 5. Recognize spondyloarthropathies and gout based on joint involvement and other clinical findings.
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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 following has been
disclosed: Dr. Brown is on the Speakers’ Bureau for Abbott Laboratories. Dr. Sack and the planning committee reported
nothing to disclose.
Acknowledgements
Dr. Brown spoke in Kiawah Island, SC, at An Intensive Review of Family Medicine, presented June 18-23, 2007, by the
Medical University of South Carolina. Dr. Sack was recorded on July 12, 2007, in San Francisco, CA, at the University
of California, San Francisco, School of Medicine’s Family Medicine Board Review Course. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
| RHEUMATOID ARTHRITIS —Alan N. Brown, MD, Associate Professor of Medicine, and Associate Vice Chair for Education,
Medical University of South Carolina, Charleston
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| Introduction: rheumatoid arthritis (RA) aggressive disease with devastating consequences; early aggressive management
leads to successful disease control and remission; types of arthritis—inflammatory; degenerative (eg, osteoarthritis
[OA]); infectious
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| Inflammatory arthritis: RA; arthritis associated with seronegative spondyloarthropathies (eg, ankylosing spondylitis,
Reiter’s syndrome, enteropathic arthritis); arthritis associated with systemic lupus erythematosus (SLE) or other connective
tissue diseases; crystalline-induced arthropathies (eg, gout); sarcoidosis; arthritis associated with hepatitis C; infectious
or postinfectious arthritis (associated with, eg, Lyme disease)
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| Rheumatoid arthritis: multisystem disease that affects every organ system with cartilage and bone destruction; morning
stiffness lasting ≥1 hr (<1 hr in OA); consider testing for hepatitis C; 2 to 3 times more common in women; primarily
affects premenopausal women; average age of onset 20 to 45 yr; 3 million Americans affected; reduces life expectancy by
5 to 15 yr; genetic predisposition; most theories implicate external stimulus (eg, virus)
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| Drugs: abatacept; rituximab (Rituxan) reduces B cells; tumor necrosis factor (TNF) antagonists include adalimumab, infliximab,
and etanercept; anakinra (Kineret) interrupts interleukin-1 (IL-1); minocycline or doxycycline work on production of
neutral proteases and collagenases; efalizumab—monoclonal antibody; “not ready for prime time”; does not work well in
RA; denosumab—to be approved for treatment of osteoporosis; monoclonal antibody that inhibits receptor activator of nuclear
factor ê B (RANK) ligand; in clinical trials for RA
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| Morbidity and mortality of RA: patients with RA twice as likely to have myocardial infarction; coronary artery disease
leading cause of death in patients with RA; 70% more likely to suffer stroke or develop infection; risk for lymphoma 3 times
that in general population (may be as high as 28 times with highly active RA); rate of progression in first 2 yr predicts long-
term course; early remission important; moderate loss of function may occur in first 2 yr, severe loss of function in 5 yr;
≤85% of patients unable to work 8 to 10 yr after onset of disease
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| Clinical manifestations: fever not common in RA (consider infection, especially in patients taking immunosuppressive
medications); musculoskeletal—symmetric soft tissue swelling; prolonged morning stiffness; involvement of wrists and
metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of second and third digits; late manifestations—
synovial swelling of soft tissues (perform squeeze test; when PIP joint squeezed, tissue pulls back); ulnar drift; rheumatoid
nodules; extraarticular manifestations; if RA suspected, squeeze MCP and metatarsophalangeal (MTP) joints (tenderness
indicates synovitis and RA); bony changes seen as early as 4 mo after onset of symptoms; on x-ray, marginal erosions seen
in bare area (not seen in gout or sarcoidosis); nodules—specific but not pathognomonic for RA; subcutaneous nodules in
setting of arthritis with gout, amyloidosis, subcutaneous bacterial endocarditis, inflammatory bowel disease, and rheumatic
fever suggestive of RA; commonly occur on extensor surfaces but can occur anywhere (including pulmonary parenchyma)
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| Laboratory findings: rheumatoid factor (RF)—not pathognomonic for RA; 80% of patients with RA develop RF; patients
with RF have more aggressive disease, more difficult to treat, and more likely to have extraarticular manifestations;
testing 60% sensitive, 75% specific; anti-cyclic citrullinated peptide (CCP) antibody testing—commercially available;
99% specific for RA when used with RF testing; diagnosis made clinically (ie, no test available for RA); antinuclear antibody
(ANA) present in 40% to 50% of patients with RA (usually in homogenous pattern and low titers); erythrocyte sedimentation
rate; C-reactive protein
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| Predictors of poor prognosis: high titers of RF or anti-CCP antibodies; low socioeconomic status; more aggressive
disease at onset; late referral or initiation of treatment
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| Differential diagnosis: OA—bony enlargements at distal interphalangeal (DIP) and PIP joints; RA does not involve
DIP joints; psoriatic arthritis—involves DIP joints; look for characteristic nail changes and psoriatic lesions; gout—
involves DIP joints; usually in older women taking thiazide diuretics; asymmetric (RA symmetric)
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| Treatment: early aggressive therapy (must stop marginal erosions and joint destruction [high predictors of long-term disability]);
brief delay in therapy shown to have long-term negative consequences; erosions can develop before arthritis clinically
apparent; rest and nonsteroidal anti-inflammatory drugs (NSAIDs) effective for inflammation and pain, but do not
modify long-term course of disease; corticosteroids—shown to stop radiographic progression; long-term use associated
with higher incidence of hip and vertebral fractures; use brief course while instituting other therapy, then taper rapidly;
surgery—to restore function of joint; last resort; disease-modifying antirheumatic drugs (DMARDs)—slower acting; onset
of methotrexate, 6 wk (≤6 mo for other agents); reduce signs and symptoms of inflammation; shown to prevent radiographic
progression; oral or injectable; do not target specific inflammatory mediators; minocycline not approved by Food
and Drug Administration (FDA); D-penicillamine used less frequently due to toxic side effects; use of gold problematic;
leflunomide (Arava; teratogenic and abortifacient); symptom control does not mean disease control; DMARDs associated
with toxicity
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| Management: make diagnosis; start methotrexate, 15 mg/wk; if RA not completely controlled after 6 wk, increase methotrexate
to 20 mg/wk; add biologic agent if patient not completely controlled after another 6 wk; biologic agents—
adalimumab and infliximab monoclonal antibodies; etanercept mimics TNF receptor; anakinra (Kineret) —good control
of radiographic progression, but patients “don’t feel very well”; not as good for inflammation; shows promise in juvenile
RA; (Orencia) suppresses T-cell activation; rituximab (Rituxan) approved for treatment of RA; often superior to
DMARDs; onset rapid; good risk-to-benefit ratio; effects sustained for several years
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| Quantifying disease activity: American College of Rheumatology (ACR) scoring—tender and swollen joint count,
physician and patient global assessments, and erythrocyte sedimentation rate; improvement of 20% without worsening
indicates ACR score of 20; ACR score of 70 “almost remission”; Sharp scoring—higher the score, worse the x-ray finding
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| Data on drugs: etanercept—ACR score of 20 seen in ≈60% of patients; ≈15% of patients went into remission; more effective
when combined with methotrexate; adalimumab—combination with methotrexate clearly better than methotrexate
or other drug alone; after 2 yr, 60% of patients had ACR score of 50; infliximab—intravenous (IV) infusion;
combination with methotrexate clearly better than methotrexate alone; 50% of patients in remission after 1 yr;
rituximab—patients given one dose, then after 2 wk, given another dose; response tremendous (ACR scores of 20, 50,
and 70); patients feel better; stops radiographic progression; abatacept—recently approved for RA; stops radiographic
progression
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| Safety concerns with biologic agents: increased risk for serious infection; increased susceptibility to reactivation tuberculosis
(TB; every patient must be screened for latent TB); contraindications for TNF antagonists—class III or IV
heart failure; positive history of untreated TB or positive purified protein derivative (PPD) test; active serious infection
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| Questions and answers: patient with RA who does not respond to therapy—critical to see patient every 8 wk and
change therapy if needed; polyarthralgias—may be viral; consider hepatitis C if duration >6 wk; rule out inflammatory
arthritis and begin symptomatic treatment; watch longitudinally; methotrexate—“get comfortable” with starting methotrexate;
before starting biologic agent, consultation with rheumatologist recommended; pregnancy—methotrexate contraindicated;
women must be off of methotrexate for 3 cycles before attempting to conceive (men must be off for 3 mo before
attempting to conceive); Arava contraindicated in pregnancy; biologic agents appear to be safe in pregnancy (“we don’t
have as much data”; discuss with patient); RA improves in ≈80% of women during pregnancy; juvenile RA—follows different
disease course than adult RA; fibromyalgia—problem of pain perception in central nervous system (CNS); rule out
aggressive inflammatory disease; educate patient; use coping mechanisms and adjuncts to pain control; after recovery
from lymphoma—treat as though patient did not have lymphoma; suggested that risk for lymphoma may be decreased
with early aggressive therapy with biologic agents; aggressive disease—aggressive treatment with new medications may
prevent further damage; complementary medicine or dietary changes—probably no role; suggested that omega-3 and
other fatty acids beneficial; discuss with patient to avoid drug interactions; tapering drugs in remission—disease almost
always returns when drug discontinued, and may be more difficult to control; counsel patients that medication life-long
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| SPECTRUM OF RHEUMATIC DISORDERS —Kenneth E. Sack, MD, Professor of Clinical Medicine, and Co-Director,
Clinical Programs in Rheumatology, University of California, San Francisco, School of Medicine
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| Osteoarthritis: affects DIP joints; active inflammatory OA may have mild MCP joint involvement; rarely involves
wrists; first carpometacarpal joint commonly involved
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| DIP joint involvement: typical OA exacerbation in perimenopausal women involves same joints as regular OA; DIP
joints rarely involved in primary joint infection; nail changes (eg, onychodystrophy, pitting) occur with psoriatic arthritis;
women with hypertension who take thiazide diuretic can develop chronic hyperuricemia and secondary gout superimposed
on Heberden’s node
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| Other joint involvement: OA can involve joints of spine, elbow (rare, unless overused [eg, baseball pitcher]), glenohumeral
joint (rare), and acromioclavicular joint
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| Degenerative disc disease of spine: not OA; pulling on Sharpey’s fibers results in beaking osteophyte; also called
cervical spondylosis; apophyseal joints pristine (in OA, apophyseal joints narrowed with subchondral bony sclerosis, often
with damaged disc and stress on posterior joints); bony overgrowth at neural foramina can cause radiculopathy; x-ray
findings and magnetic resonance imaging (MRI) often do not correlate with symptoms; thoracic spine rarely involved in
severe disc disease
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| OA in hips: usually genetic; common in whites; uncommon in blacks; common in Japanese, due to higher likelihood of
congenital hip dysplasia; uncommon in Chinese; may be more common in farmers (due to, eg, heavy lifting at early age);
slight correlation with obesity
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| Psoriatic arthritis: spondyloarthropathy; seronegative for RF; can affect spine or joints; fluffy periosteal proliferation
(classic “pencil and cup” deformity)
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| Parvovirus: systemic illness; patients sick, tired, and stiff in morning; DIP joints spared; symmetric polyarthritis; involves
PIP and MCP joints; can mimic RA with transient positive RF; usually resolves in 1 to 2 wk, but can last for years;
mild synovitis; nondestructive; joint space changes (eg, swelling, involvement of hands) must be present for ≥6 wk before
diagnosing RA; post-rubella arthritis (particularly post-rubella vaccination arthritis) can mimic RA; patient with polyarthritis
and positive RF may have hepatitis C (negative for anti-CCP antibody)
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| Foot and leg involvement: MTP joints subluxed; migration of protective fat feels like “walking on marbles”; counsel
patients about cushioning shoes, arch support, wide toe boxes, and surgery; acutely swollen calf—ruptured popliteal cyst
(Baker’s cyst) in calf may result in crescent sign (hemorrhagic infiltrate near malleolus); can mimic thrombophlebitis
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| Eye involvement: dry eye common (associated with Sjögren’s syndrome); episcleritis—mild discomfort with dilated
conjunctival vessels; benign; resolves with mild steroid drops; scleritis—more painful with involvement of deeper scleral
vessels; can cause thinning of sclera; often treated with systemic drugs (rarely, can lead to perforation of sclera)
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| Lung involvement: cavitary nodules in patients with RA can be rheumatoid nodules (infection or other cause until
proven otherwise); mild pleuritis; rheumatoid pleural effusion associated with low glucose level and can precede arthritis;
small-vessel vasculitis rare and fairly benign; medium-vessel vasculitis, resembling polyarteritis with nerve and organ infarcts,
severe (rare); unlike OA, RA characterized by thinning of bone, symmetric loss of cartilage, and no osteophytes
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| Neck involvement: if patient complains about pain going up back of head, unsteady gait, or neck discomfort, or if neck
involvement suspected, order radiographic lateral flexion extension views; atlantoaxial subluxation—loss of transverse
ligament that holds odontoid in place; with flexion of neck, distance between odontoid and anterior portion of first cervical
vertebrae should be ≤1 mm (2-4 mm indicates atlantoaxial subluxation); look for hard neurologic findings (eg, new
numbness, weakness); cervical collars not helpful; refer to neurosurgeon or perform MRI
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| Spondyloarthropathy: onset usually insidious (before age 40 yr); duration long; morning stiffness improves as day
progresses; inflammation at tendon insertions; uveitis (iritis)—HLA-B27 positive; usually anterior; diagnose and treat early
to avoid posterior synechia (gluing of iris to lens); keratoderma blenorrhagicum—appears identical to psoriasis (even microscopically);
tends to start on soles of feet; plaquelike lesions occur on fingernails; smooth osteophytic overgrowths (calcaneus
spurs) seen in normal people and people with plantar fasciitis (irregular spur formation seen in spondyloarthropathy);
in patients with back pain, perform HLA-B27 test and use anteroposterior x-ray of pelvis to look for sacroiliitis; ankylosing
spondylitis—squaring of lumbar vertebrae early radiographic sign; “bambooing” of spine; appears identical to spondylitis
of inflammatory bowel disease; spondylitis of psoriatic or reactive arthritis more asymmetric with greater proliferative bony
overgrowth and asymmetric sacroiliac involvement
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| Lupus: most common in young women; cheeks become red from heat from sun, anger, alcohol, and hot beverages; weak
positive ANA results (perform antithyroid peroxidase antibody testing; thyroiditis can be associated with positive ANA);
aches and pains can occur with normal thyroid function tests; discoid lesion—characteristic skin lesion of lupus; can occur
with or without systemic lupus; central atrophy; heaped-up margins; follicular plugging; when on scalp, causes scarring
alopecia; difficult to treat; criteria not weighted (eg, patient with proteinuria on renal biopsy with classic lupus
lesions has one criterion, but patient with aches, pains, canker sores, rosacea, and anemia also meets lupus criteria; “can
be treacherous”)
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| Crystal diseases: bunion or inflamed bursa most common cause of pain in first MTP joint; gout—acute pain, erythema,
and sensitivity; 50% in first MTP joint (90% eventually in first MTP joint); common in instep of foot; looking for urate
crystals in acutely inflamed joint sometimes critical; rule out infection; tophi seen on ears, hands, and traumatized surfaces;
gout lesions can lead to bony overhang; pseudogout—calcium pyrophosphate dihydrate deposits on cartilage along
collagen fibers; more common with increasing age; diagnosed when crystals demonstrated in synovial fluid; attacks immediately
after surgery not uncommon
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Suggested Reading
Breedveld FC et al: The PREMIER study: A multicenter.randomized, double-blind clinical trial of combination therapy
with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid
arthritis who had not had previous methotrexate treatment. Arthritis Rheum 54:26, 2006; Cohen SB et al: Rituximab for
rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled,
phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793, 2006;
Damián-Abrego G et al: Anti-citrullinated peptide antibodies in lupus patients with or without deforming arthropathy.
Lupus17:300, 2008; Emery P et al: Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence
based development of a clinical guide. Ann Rheum Dis 61:290, 2002; Gorman JD et al: Treatment of ankylosing spondylitis
by inhibition of tumor necrosis factor alpha. N Engl J Med 346:1349, 2002; Hassan W: Eye and lung involvement in rheumatoid
arthritis. Br J Hosp Med 48:605, 1992; Lipsky PE et al: Infliximab and methotrexate in the treatment of rheumatoid
arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med
343:1594, 2000; Mathsson L et al: Antibodies against citrullinated vimentin in rheumatoid arthritis: higher sensitivity and
extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated
peptides. Arthritis Rheum 58:36, 2008; O'Dell JR: Treating rheumatoid arthritis early: a window of opportunity? Arthritis
Rheum 46:283, 2002; Reginato AJ et al: Crystal-associated arthropathies. Clin Geriatr Med 4:295, 1988; Roubenoff R
et al: Biological significance of anti-cyclic citrullinated peptide antibody in rheumatoid arthritis. Ann Intern Med 148:403; author
reply 403, 2008; Sack KE: Osteoarthritis. A continuing challenge. West J Med 163:579, 1995; Van der Horst-Bruinsma
IE et al: Diagnosis and course of early-onset arthritis: results of a special early arthritis clinic compared to routine
patient care. Br J Rheumatol 37:1084, 1998; Wolfe F et al: The assessment and prediction of functional disability in rheumatoid
arthritis. J Rheumatol 18:1298, 1991.
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