During her initial visit, a well-nourished, 41-year-old woman presented to her primary care physician (PCP) complaining
of general malaise, fatigue, joint pain, and morning joint stiffness. These symptoms began approximately 10 weeks prior to
her visit. Her joint pain became progressively worse during the week before she sought medical attention.
She reported no major health problems before this visit. During the week before her visit to the PCP, the patient self-medicated
with an over-the-counter (OTC) preparation arthritis formula that contained acetaminophen. This OTC product produced partial
relief of her joint pain, but it did not alter her sense of fatigue or her feeling of general malaise.
The patient denied any recent travel outside her suburban northeastern community, exposure to insect bites, or previous
treatment for infectious diseases. She did mention, however, that one of her three young children had a cold, which was manifested
by a low-grade fever and rhinorrhea about 2 weeks previous to the onset of her own symptoms. The only medication the patient
was taking in addition to the acetaminophen was a daily birth control pill.
The patient's lungs were clear by both auscultation and palpation. Her heart sounds were normal. She had no cervical
or axial lymphadenopathy. Funduscopy and otoscopy were both unremarkable.
Swelling and tenderness were noted in both wrists, with exaggerated tenderness in metacarpophalangeal (MCP) joints 2
and 5 bilaterally. The proximal interphalangeal (PIP) joints 3 and 4 of the left hand and 2 of the right hand were also swollen.
On a scale of 0 to 10, the patient reported her pain as being a 5.
Pain was also elicited by range-of-motion testing of the right knee and both ankles, although there was no swelling in
any of these joints.
Hematology: Blood was drawn for a complete blood count (CBC). The results of her CBC were as follows: Hemoglobin: 10.1
g/dL (Normal range: 12 to 16 g/dL for women) ;Hematocrit: 31% (Normal range: 35% to 47% for women) ;WBC: 7,300/mm3 (Normal
range: 3,600 to 11,000/mm3) ;Platelets: 459,000/mm3 (Normal range: 150,000 to 400,000/mm3) ;Leukocyte differential count:
Within normal limits
Blood Chemistries: Electrolytes, renal function and liver function tests were near the lower limits of normal: AST: 15.3
(Normal range: 15 to 37 U/L)
ALT: 30.2 (Normal range: 30 to 65 U/L) ;Total bilirubin: 0.3 (Normal range: 0 to 1 mg/dL)
Imaging Studies: A routine chest x-ray (CXR) was performed. It was unremarkable and all lung fields were clear.
Initial Diagnosis: A presumptive diagnosis of probable early rheumatoid arthritis (RA) was based on her physical examination.
Laboratory studies were within normal limits.
Initial Treatment: The patient was instructed to rest for a few days and was prescribed ibuprofen 600 mg. She was requested
to return for a follow-up visit in 4 weeks with a plan to refer her to a rheumatologist if her symptoms persisted.
At this point which of the following tests would a physician have ordered? Tests ordered by the attending PCP are indicated
later. (physicians comment follows each test;in this case history)
Urinalysis: The importance of urinalysis as a routine diagnostic tool has declined. However, it remains an important
test in the diagnosis of liver abnormalities, urinary tract disease, or metabolic diseases such as diabetes.
Somewhat
useful
Erythrocyte sedimentation rate (ESR): The ESR is a nonspecific acute-phase biomarker. An elevated ESR (normal range:
0-20 mm/hr) is a broad indicator of inflammation, and elevated values are often found in patients with systemic inflammatory
diseases, such as inflammatory arthritis. However, the ESR is often elevated in infectious processes and in certain malignancies.
The ESR may take many days to return to within a normal range, even after the infectious agent or inflammatory process has
been cleared from the body. A normal value does not exclude inflammatory arthropathy. Very useful
C-reactive protein (CRP): The CRP is also a non-specific indicator of the acute phase response. Elevated levels of CRP
indicate an inflammatory state and can be associated with an infectious disease, rheumatic condition, or other process that
produces inflammation. Although the ESR and CRP are both nonspecific in their response to an acute inflammatory reaction within
the body, the levels of CRP rise and fall more quickly and reveal a wider dynamic range than the ESR. Very useful
Rheumatoid factor (RF): RF titers may be elevated in rheumatoid arthritis. Eventually 80% to 85% of patients with RA
will have a positive test for RF. However, early in the disease course, 50% or less may have it. By definition, 5% of normal
persons will have a positive test for RF, and for some populations, such as elderly women, the prevalence among normals may
be as high as 15% to 20%. Higher titers or concentrations of RF are more specific for the diagnosis of RA than are lower values,
although high levels may also be seen in patients with Sjögren's syndrome, cryroglobulinemia, hepatitis, and some other arthridites.
High titers of RF are associated with a poor prognosis in patients with RA. Useful
Antinuclear antibody (ANA)
titer: ANA titers may be elevated in patients with systemic lupus erythematosus (SLE) and other inflammatory conditions often
associated with polyarthropathy. These conditions include RA and systemic sclerosis (scleroderma). ANA titers may be normal
in healthy relatives of patients with SLE. Somewhat useful
Radiographs of affected joints: Radiographic changes may occur early in the course of RA, but in early RA, the only changes
observed may be soft tissue swelling, as may be noticed during a physical examination. Subsequent x-rays may show periarticular
osteoporosis, joint space narrowing (indicating damage to articular cartilage), and marginal bony erosions. In some cases,
erosions indicating bony damage may be evident within the first year. The presence of erosions is important as it is associated
with a poorer outcome. Useful
Magnetic resonance imaging (MRI): An MRI may demonstrate joint changes specific to RA. The superior soft tissue discrimination
of the MRI is useful in evaluating patients in both the early and advanced stages of RA. Conventional radiography has been
a cornerstone of evaluation and follow-up of arthridites that involve the hand and wrist. The MRI achieves noninvasive and
accurate delineation of hyaline articular cartilage, ligaments, tendons, and synovium as distinct from cortical bone. MRI
can be used to measure RA abnormalities, including erosions, articular cartilage thickness, synovial membrane volume, and
pannus. The widespread utilization of MRI has been limited by cost constraints, availability of the devices, and the time
required to image. Useful
Ultrasound evaluation: In patients with RA, ultrasonography can detect signs of bone resorption before it is detectable
using conventional radiography. Sonography is superior to other imaging modalities in diagnosing fluid accumulations and should
be first-line for the diagnosis of joint effusions and synovial cysts. In proliferative diseases of the synovium such as RA,
high-frequency ultrasound can depict the hypoechoic, thickened synovium, especially when it is outlined by an effusion. Useful
At the time of her follow-up visit, the patient reported that she felt worse and that more joints were hurting. She had
been taking 650 mg of acetaminophen tid along with her prescribed 600 mg of ibuprofen tid. She reported that she could not
take the prescribed ibuprofen more than three times daily due to dyspepsia.
During this visit, the patient reported her pain as being 7 on a scale of 0 to 10. On her previous visit, she reported
her pain as being a 5. When asked about her morning stiffness, she reported that she experienced stiffness for about 2 hours
after awakening and that some of her joints, including her hands, felt stiff all day to the extent that she had difficulty
opening jars or even putting on her clothing.
Physical examination during the follow-up visit established tenderness and swelling of both wrists and the right elbow.
Her MCP joints 2, 3, and 5 were swollen bilaterally. During her initial visit only the MCP joints 2 and 5 were affected. The
patient's PIP joints 2, 3, and 4 of the left hand and 2, 3, and 5 of the right hand were swollen. During the patient's initial
visit, only PIP joints 3 and 4 of the left hand were affected as well as 2 of the right hand.
In addition, it was also evident that there was swelling in the right acromioclavicular joint, both knees, and left ankle.
Her metatarsophalangeal (MTP) joints were diffusely tender and painful on movement, as were both shoulders, although it was
not clear whether there was swelling of these joints.
It was apparent that her condition had worsened during the 4 weeks following her initial visit. The PCP ordered the patient
to stop taking both ibuprofen and acetaminophen and switched her medication to diclofenac (Voltaren®) 75 mg bid. A referral
to a rheumatologist in 3 weeks time was made for the patient.
Radiographs of her feet demonstrated 3 periarticular erosions about the distal metatarsal heads at 3 months.
Her PCP continued to consider that the initial presumptive diagnosis of RA was the strongest probability in this case.
Although the patient had relatively short history of illness, the presence of symmetric polyarthropathy accompanied by swelling
and tenderness in more than three joints, including MCP and MTP joints, reinforced the diagnosis of RA. Additional evidence
to suggest a diagnosis of RA included persistent fatigue, generalized malaise, and prolonged morning joint stiffness.
The primary attending physician did not order the following tests to be performed: CBC, uric acid, hepatitis panel, borreliosis
titer, parvovirus B19 IgM titer, ASO titer, ANA titer, ACE level, HLA typing, another CXR, MRI, or joint sonograms.
A CBC was performed during the patient's initial visit to her attending physician. At that time, and on the basis of
a thorough medical history and physical examination, her PCP thought the following conditions unlikely: gout, acute hepatitis,
Lyme disease, parvovirus infection, rheumatic fever, SLE, sarcoidosis, ankylosing spondylitis, and reactive arthritis (Reiter's
syndrome). Specific tests to reinforce this differential diagnosis were not performed. An ESR was performed at the time of
the follow-up visit.
What is the most likely diagnosis? What other conditions should be considered in the differential diagnosis?
Pseudogout:
The principal differential diagnosis for pseudogout is the presence of sepsis or gout (both of which may coexist with calcium
pyrophosphate dihydrate deposition). Gram stain and culture of the synovial fluid should be undertaken even when calcium pyrophosphate
dihydrate (or monosodium urate monohydrate) crystals are identified. Pseudogout affects only or a few joints in mostly elderly
patients. Somewhat likely
Psoriatic arthritis (PsA): This diagnosis should be considered in patients with both psoriasis and symptoms of arthritis.
Psoriatic lesions can often be small and hidden in the scalp, umbilicus, and gluteal folds. PsA is difficult to distinguish
from reactive arthritis (Reiter's syndrome), since both manifest dactylitis. Psoriasis is associated with swelling of DIP
and PIP joints. PsA differs from RA by its general lack of rheumatoid factor, tendency to asymmetry, presence of dactylitis,
iritis, the axial skeletal involvement, and characteristic radiologic features. Somewhat likely
Reactive arthritis: Also known as Reiter's syndrome, this reactive polyarthritis develops several weeks after 1% of cases
of nongonococcal urethritis and 2% of enteric infections, particularly those caused by Yersinia enterocolitica, Shigella flexneri,
Campylobacter jejuni, and Salmonella species. Diagnosis is made by needle aspiration of the joint. Likely
Viral arthritis: Viruses may produce arthritis by infecting synovial fluid during a systemic invasion or by provoking
an immunologic reaction involving the joints. 50% of women report persistent arthralgias and 10% frank arthritis within 3
days of the rash accompanying natural infection with rubella virus and within 2 to 6 weeks after receiving live virus vaccine.
In a few cases, symmetric inflammation of the fingers, wrists, and knees recurs for longer than a year. A syndrome of chronic
fatigue, low-grade fever, headaches, and myalgias can persist for months and even years. Approximately 60% of women develop
arthritis after infection with parvovirus B19. Serologic testing can rule this out. Likely
Lyme disease: Tick-borne infection by the spirochete Borrelia burgdorferi causes arthritis in up to 70% of persons who
are not treated. Serologic testing for IgG antibodies to B. burgdorferi are positive in >90% of persons with Lyme arthritis.
A PCR-based assay also detects Borrelia DNA in 85% of all cases. Unlikely
Rheumatoid arthritis (RA): A typical picture of RA is bilateral symmetric inflammatory polyarthritis involving large
and small joints in both upper and lower extremities, with the sparing of the axial skeleton except the cervical spine. Constitutional
features that indicate the inflammatory nature of RA such as morning stiffness support the diagnosis. Additional help in establishing
a diagnosis is the presence of the rheumatoid factor, inflammatory synovial fluid with increased numbers of neutrophils, plus
radiologic findings of juxta-articular bone demineralization and erosions of the affected joints. Very likely
In the rheumatologist's office, the patient reported that she was perhaps 20% better overall since her switch to diclofenac,
but that she was still distressed by her continuing symptoms.
Additional laboratory studies were ordered at this time, with the following results: ESR: 68 mm/hr (Normal range 0 to
20 mm/hr) ;ALT: 65 U/L (Normal range: 30 to 65 U/L) ;AST: 49 U/L (Normal range: 15 to 37 U/L) ;Alkaline phosphatase: 65 U/L
(Normal range: 20 to 140 U/L) ;Total bilirubin: 0.9 mg/dL (Normal range: 0 to 1.0 mg/dL) ;Albumin: 3.5 g/dL (Normal range:
3.4 to 5.0 g/dL)
Her prolonged ESR demonstrated the presence of an inflammatory process. Elevations slightly above the higher limit of
normal in both AST and ALT and total bilirubin suggested minor liver abnormalities. Other assays in her Chem-20 panel were
unremarkable.
What are the most likely causes of abnormal liver function tests? What are other potential causes of abnormal liver function
tests? What are the reasons for considering a diagnosis being likely
Drug-induced (acetaminophen): Hepatic toxicity may occur following ingestion of over 7.5 g to 10 g acetaminophen over
a period of 8 hours. Symptoms of overdose include nausea, vomiting, diaphoresis, and general malaise. Dr's opinion:
Somewhat likely
Elevations of ALT or bilirubin may occur during therapy. Borderline elevations (<3x ULN) or elevated ALTs occur in
15% of patients. Dr's opinion: Very likely
About 1% to 2% of women taking oral contraceptives develop steroid-type cholestasis, which may also be caused by methyltestosterone
and related drugs. Onset is usually gradual, and systemic symptoms are generally absent. There is little or no hepatocellular
inflammation. Alkaline phosphatase is elevated, but aminotransferase levels are usually unremarkable, and liver biopsy shows
only centrizonal bile stasis with little portal reaction or hepatocellular disarray. Complete resolution follows drug withdrawal.
Unlikely
Alcoholic hepatitis: Alcoholic hepatitis develops in about 15% to 20% of chronic alcoholics and is the most common precursor
to cirrhosis. Liver biopsy is the most certain approach to definitive diagnosis. In this case, the patient drank little alcohol.
Unlikely
The rheumatologist's diagnosis was early aggressive RA. His initial diagnosis concurred with that of the PCP's because
of the patient's overall clinical picture of symmetrical joint swelling and pain, erosive processes in the feet as demonstrated
via radiography, and her elevated ESR.
The rheumatologist attributed the liver enzyme abnormalities to the diclofenac, which he discontinued. Because of her
slightly elevated ALT, AST, and total bilirubin levels, the rheumatologist suggested that he could not begin a number of potential
therapies for her arthritis until her liver function tests returned to within the normal range. In order to provide immediate
relief of the pain and swelling, the rheumatologist placed the patient on a regimen of oral prednisone (10 mg/d for 1 week,
then 7.5 mg/d). The patient was scheduled for a follow-up visit to the rheumatologist in 4 weeks.
Which of the following treatment options are indicated at this time? Begin prophylaxis for glucocorticoid-induced osteoporosis
(GIOP)
Even though the patient was not taking glucocorticoid medication for an overly
prolonged period of time, consideration should be given to prophylaxis for GIOP. She is still actively menstruating, so appropriate
Rx would be calcium plus vitamin D.--Most indicated
Add a COX-2 inhibitor: The choice of a different NSAID or a COX-2 inhibitor would not be unreasonable, but still might
be associated with increased LFTs. The safety benefit of the COX-2 agents, deceased bleeding and in particular decreased GI
bleeding, is of lesser relevance in this case. --Not indicated
Add methotrexate (MTX): MTX, an immunosuppressive drug, can suppress inflammation and may allow reduction of corticosteroid
doses. In the course of severe active disease, MTX may be used reasonably early, and benefit is often evident within 3 to
4 weeks. However, major side effects can occur, including liver disease, pneumonitis, and bone marrow suppression. In this
case, addition of MTX may be a good idea but should not be undertaken until LFT abnormalities resolve. Liver function must
be monitored in all patients taking MTX. --Somewhat indicated
Add a tumor necrosis factor (TNF) antagonist: This is a possibility; most practitioners would try a DMARD first, but
data from ERA show (Bathon JM et al. N Engl J Med. 2000;343:1586-1593) some benefit to early use of TNF antagonists. The only
trial to date comparing biologic DMARDs against an active comparator, the ERA trial was an early disease trial but not an
initial therapy trial; 45% of patients had already received DMARDs, although not MTX. -- Minimally indicated
Add hydroxychloroquine (HCQ): A reasonable but weak choice, hydroxychloroquine (HCQ) is an immunosuppressive agent used
in the treatment of RA. However, it does not possess either anti-inflammatory or analgesic properties. Studies have shown
that 60% to 80% of RA patients note some benefit with HCQ, whereas 20% to 30% remain unchanged or worse, and about 8% stop
treatment because of side effects. About 50% of those who do respond do so within 2 months, whereas 88% respond within 6 months.
--Somewhat indicated
Eventually taper off prednisone (5 mg/d): Because of her young age and the deleterious effects of long-term steroid use,
she should eventually be tapered off the prednisone therapy. This reduction in dosage should take place slowly, over the course
of 2 to 6 months.-- Indicated
Third Visit to the Rheumatologist: The patient asked if her steroid medication could be reduced, since she had gained
5 pounds over the course of 4 weeks and was feeling irritable. A schedule was worked out whereby it was decided that she would
reduce her dose of prednisone by increments of 1 mg/day at monthly intervals.
Additional Follow-up Visits to the Rheumatologist: The patient was seen during additional follow-up visits at approximately
6-week intervals. She continued to do well on steroid therapy, except she noticed that fatigue and arthralgia developed when
she decreased her prednisone dose below 3 mg/day. It was decided to maintain this dosing level.
Laboratory studies demonstrated that her ALT levels had returned to normal.
About 5 months after her initial visit to the rheumatologist, the patient demonstrated marked disease progression manifested
by the increased number and severity of swollen, tender, and painful joints, progressive physical disability, and fatigue.
Her ESR had risen once again to 72 mm/hour. Radiographic evaluation of her feet and hands revealed additional small areas
of erosion in the bones of her feet and greater swelling in her hand and wrist joints.
Which of the following treatment options are indicated at this time?
Increase the dose of prednisone back
to 10 mg/d: An increase in her prednisone dose might be useful in alleviating her pain and swelling. However, toxicities associated
with prolonged steroid use, including osteoporosis, should be kept in mind. --Most indicated
Add a NSAID or COX-2 inhibitor: NSAIDs provide important symptomatic relief and may be adequate as simple therapy for
mild RA, but they do not appear to alter the long-term course of the disease. Using drugs that may inhibit only or predominantly
COX-2 (eg, celecoxib, rofecoxib) may avoid many of the side effects that result from drugs that also inhibit COX-1. --
Minimally indicated
Add MTX: This anti-inflammatory drug has been shown to help patients with RA. She might be started on a low dose of MTX
and closely monitored for side effects. --Most indicated
Add HCQ: This agent can be effective for controlling the symptoms of mild or moderately active RA. Although toxic effects
are usually mild, irreversible retinal degeneration has been reported. For this reason, ophthalmologic testing of visual fields
using a red test object is recommended before and every 6 months during treatment. The drug can be continued as a long as
it is effective, but should be discontinued if no improvement is shown after 6 to 9 months. Somewhat indicated
The physician was not sold on biologic therapy. His thoughts: Further studies are needed to assess the value of the TNF
antagonists in the treatment of RA. The referrel rheumatologist did not completely agree (case by case-suitability).
Actual-reality: The patient refused increased doses of prednisone, so MTX was added, and then a TNF antagonist when the
patient had a suboptimal response to aggressive MTX dosing.
This case emphasizes the need to individualize diagnosis and treatment of patients with rheumatoid arthritis, particularly
in early stages when appropriate treatment may halt progression of disease.
