Journal of the American Academy of Orthopaedic Surgeons 60 Ordering and interpreting rheuma- tologic laboratory tests for patients with inflammatory symptoms can be challenging. Having conceptual guidelines and indications to effec- tively order serologic tests can help to avoid unnecessary testing and potentially confusing results. The tests should help confirm a clinical impression or sort out a differential diagnosis. Indiscriminate ordering or asking for the “arthritis panel” should be avoided. Many rheuma- tologic illnesses are relatively rare, and because all tests have false- positive rates, a positive result in a patient with a low pretest probabil- ity of having the illness is likely a false-positive. Acute Phase Reactants Erythrocyte Sedimentation Rate The erythrocyte sedimentation rate (ESR) is a widely used, nonspe- cific, indirect measure of systemic inflammation. The Westergren method, the current accepted method for performing the ESR, uses a 200- mm vertically aligned column with a 2.5-mm diameter. The column is filled with blood anticoagulated with K 3 EDTA. 1 The distance that the col- umn of red blood cells settles within the plasma in 1 hour is reported in mm/h. The factors affecting the sedi- mentation of red blood cells include the size of the cells, the viscosity of the plasma, and the repellent forces between the negatively charged sialic acid molecules on the surface of each red blood cell (Fig. 1). The presence of large or positively charged asymmetric proteins, espe- cially fibrinogen but also immuno- globulins, counteracts the repellent force and allows the formation of rouleaux, or coin-like rolls of cells, causing the cells to settle more rapidly than usual. 2 Many factors influence the ESR (Table 1). The range of normal in many laborato- ries is 0 to 15 mm/h for men and 0 to 20 mm/h for women. The ESR increases with age, and to avoid unnecessary concern, it has been suggested that age divided by 2 for men and age plus 10 divided by 2 for women be used as the upper limits of normal. 3 Besides age, the other important factor that elevates the ESR is obesity. 4 Adipose tissue is a source of interleukin-6 (IL-6), which increases liver production of acute phase reactants, including fi- brinogen and C-reactive protein (CRP). 5 Although widely used, the ESR has limited application as a diag- nostic test, and it must always be interpreted in a clinical context. Sox and Liang 2 have pointed out that, for patients with vague symp- toms who appear to be normal on examination, fewer than 6 in 10,000 benefit from an ESR test. In addi- tion, a sample of patients from Scandinavia with unexplained ele- vation in the ESR followed over Dr. Gardner is Associate Professor, Division of Rheumatology, and Adjunct Associate Professor, Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Washington School of Medicine, Seattle, WA. Dr. Kadel is Assistant Professor, Department of Orthopaedic Surgery, University of Washington School of Medicine. Reprint requests: Dr. Gardner, Division of Rheumatology, Box 356428, University of Washington, Seattle, WA 98195. Copyright 2003 by the American Academy of Orthopaedic Surgeons. Abstract Many mechanical and systemic conditions can cause joint pain and synovitis. When rheumatologic illness is suspected, the initial evaluation begins with an accurate history, physical examination, and selective use of confirmatory test- ing, which can help avoid common pitfalls inherent in serologic evaluation. Tests for erythrocyte sedimentation rate, C-reactive protein level, rheumatoid factor, antinuclear antibodies, anticardiolipin antibodies and lupus anticoagu- lant, HLA-B27, uric acid level, and Lyme disease, either alone or in combina- tion, may support certain diagnoses. Using these tests nonselectively may yield false-positive results, causing unnecessary concern and expense. However, using these tests effectively may reduce the number of unneeded invasive procedures. J Am Acad Orthop Surg 2003;11:60-67 Ordering and Interpreting Rheumatologic Laboratory Tests Gregory C. Gardner, MD, and Nancy J. Kadel, MD Gregory C. Gardner, MD, and Nancy J. Kadel, MD Vol 11, No 1, January/February 2003 61 time rarely developed any serious illness. 6 The following are general guidelines: (1) The ESR may take a few days to a week to elevate and a similar amount of time to regress once the inflammatory stimulus is gone. (2) An ESR is helpful to confirm a clinical impression regarding the presence or absence of inflammatory disease, although occasionally pa- tients with inflammatory diseases present with a normal ESR. Age and obesity elevate the ESR. (3) Resolution of the ESR is a useful marker of treatment success in illnesses such as rheumatoid arthritis, septic arthritis, and osteo- myelitis. (4) A very high ESR (>100 mm/h) almost always is associated with underlying pathology. C-Reactive Protein First discovered in 1930 by Tillet and Frances, CRP owes its name to the ability of this liver-derived pro- tein to precipitate pneumococcal C- polysaccharide in the presence of calcium. 7 The liver produces CRP under the influence of the inflam- matory cytokines IL-1 and IL-6. CRP levels begin to rise within 6 hours of an inflammatory stimulus, peak in approximately 50 hours, 8 and fall rapidly once the stimulus is removed. CRP thus provides a more immediate picture of the level of inflammation than does the ESR, in which the fibrinogen level rises and falls more slowly 9 (Fig. 2). Its function in vivo is thought to be to assist in the activation of the com- plement system, influence phago- cytic cell function, and augment cell-mediated cytotoxicity to amplify the immune response. 8 The normal range of the CRP level is 0 to 1 mg/dL. A level be- tween 1 and 10 mg/dL is consid- ered a moderate elevation and a level above 10 mg/dL, a marked elevation. Elevations are seen not only in expected situations, such as with infectious, inflammatory, and malignant diseases, but also with pregnancy and trauma. Factors such as age, sex, anemia, and red blood cell shape have little effect on the CRP level, so there may be a lower false-positive rate than occurs with the ESR. The CRP level is a direct measure of inflammation and is as useful as the ESR in most situa- tions. Since CRP is becoming easier and cheaper to assess, it may some- day supersede the ESR because it more accurately reflects the current level of inflammation. Rheumatoid Factor Rheumatoid factor (RF) as mea- sured clinically is an IgM antibody directed against the Fc portion of the patient’s own IgG (Fig. 3). Why the body makes RF is uncertain, although it may be to help clear immune complexes by stabilizing low-affinity IgG-antigen interac- tions and improving opsonization by fixing complement more effi- ciently than would occur without RF. 10 RF is commonly secreted during acute infections and proba- bly is part of the normal immune response. Other isotypes of RF can be produced (IgG, IgA) but cur- rently are not measured clinically. However, IgA RF may prove to be useful clinically because it has been Figure 1 Fibrinogen reduces red blood cell repellent forces and increases the ESR. - = sialic acid; + = fibrinogen. Table 1 Factors That Influence the ESR Elevate the ESR Lower the ESR Inflammatory diseases Increased plasma viscosity (eg, rheumatoid arthritis, systemic (eg, cold agglutinin disease) lupus erythematosus, osteomyelitis) Increased globulin proteins Abnormal red cell shape (eg, multiple myeloma) (eg, sickle cell disease) Extensive tissue necrosis Decreased plasma proteins (eg, myocardial infarction, (eg, hepatic necrosis, cachexia) trauma, tumors) Others: pregnancy, age, obesity, Other: trichinosis heparinized blood Figure 2 Comparison of time course of the ESR and CRP level after a single inflamma- tory stimulus. (Adapted with permission from Barland P, Lipstein E: Selection and use of laboratory tests in the rheumatic dis- eases. Am J Med 1996;100[suppl 2A]:16S-23S.) Rouleau formation with elevated level of fibrinogen Normal level of fibrinogen Relative change in plasma concentration C-reactive protein Fibrinogen (ESR) Inflammatory event Days 7 14 21 Ordering and Interpreting Rheumatologic Laboratory Tests Journal of the American Academy of Orthopaedic Surgeons 62 shown to help predict a more severe disease course. 11 Latex agglutination testing, usu- ally done by hand, is widely used to measure RF, although it is being supplanted by other methods. Enzyme-linked immunosorbent assay (ELISA) and nephelometry are capable of being automated and are more sensitive than the latex method. 11 The latex test is reported in a titer, that is, serial dilution of serum, which is a discontinuous measurement and has an accuracy of ±1 dilution. Most clinical labora- tories consider a dilution >1:40 to be positive. Nephelometry is able to quantitate antigen-antibody interac- tion by measuring laser light scatter caused by the formation of immune complexes. The nephelometry test is usually reported in international units (IU); the normal range de- pends on the specific laboratory but usually is <20 IU. When RF testing is ordered indis- criminately, the false-positive rate can be quite high. In one study, only 86 of 563 RF tests ordered dur- ing a 6-month period were positive, and only 21 of the 86 patients actu- ally had rheumatoid arthritis. 12 Thus, three quarters of positive re- sults were false-positive for the diagnosis of rheumatoid arthritis. A number of critical points should be kept in mind when ordering RF tests: (1) RF is present in 70% to 90% of patients with rheumatoid arthritis; therefore, a negative RF result does not rule out rheumatoid arthritis. 11 (2) RF may take several months to appear in the serum after arthritis develops. (3) The level of RF is prognostic, that is, the higher the level, the worse the prognosis. (4) An elevated RF level is not specific for rheumatoid arthritis and can be found in a variety of other illnesses, including other rheuma- tologic diseases (eg, lupus eryth- ematosus, Sjögren’s syndrome, myositis, and cryoglobulinemia) as well as infectious diseases (eg, endocarditis, tuberculosis, syphilis, and hepatitis C). An elevated RF level also is associated with aging, idiopathic pulmonary fibrosis, cir- rhosis, and sarcoidosis. This fact is particularly important because dis- eases like hepatitis C can present with rheumatoid-like synovitis and a positive RF test result. Antinuclear Antibodies Diagnostic testing for systemic lupus erythematosus (SLE) began in 1948 with the description of the lupus erythematosus cell, a poly- morphonuclear neutrophil that had engulfed a cell nucleus. The lupus erythematosus cell test is now of historical significance and is no longer available at most immunolo- gy laboratories. In 1957, Friou described the fluorescent antinu- clear antibody (FANA) test, which marked a new era in the diagnostic testing of SLE. 13 Over time, subsets of antinuclear antibodies (ANAs) have been used to classify various autoimmune syndromes. ANA testing is done in two se- quential steps. The first is testing for the presence of a FANA; the sec- ond, if the FANA test is positive, is testing for specific autoantibodies that help to classify the potential underlying connective tissue dis- ease. 13,14 The FANA test is done by placing patient sera over a thin layer of cells from a HEp-2 cell line (a line of human epithelioma cells) (Fig. 4). ANAs attach to the specific nuclear antigen in the cell nucleus and will not wash away. An antihuman IgG conjugated to a fluorochrome tag is then added to the cells, and the cells are viewed under a microscope with ultraviolet light excitation. Common patterns include speckled, rim, homogeneous, centromere, and nucleolar, reflecting the types of antigens present, which have a loose association with specific syn- dromes (Table 2). 13 If the FANA test is positive, a more specific test, such as an ELISA, can be done to detect specific antinuclear antigens. The ELISA results help to classify the autoimmune disorder. Most laboratories report a FANA titer of 1:40 to 1:80 as positive, although patients with an active autoimmune disorder rarely have such low titers. Most rheumatologists view titers ≥1:160 as significant. The most helpful result on the FANA test is a negative one. A positive test does not mean the patient has an autoim- mune condition but indicates that clinical correlation is needed. The following points may be useful Figure 3 Rheumatoid factor is an IgM anti- body directed against the Fc region of IgG. Figure 4 FANA test technique. Step 1 (top): Patient serum containing ANAs is placed on a slide containing HEp-2 cells. The ANAs attach to the cell nucleus. Step 2 (bottom): The preparation is washed, and fluorescein-labeled antihuman IgG is added. If RF is present, the preparation glows under the fluorescence microscope. IgM rheumatoid factor IgG Nucleus Slide Antinuclear antibody HEp-2 cells Antihuman IgG Fluorescein-labeled antihuman antibody Gregory C. Gardner, MD, and Nancy J. Kadel, MD Vol 11, No 1, January/February 2003 63 when interpreting ANA test re- sults: (1) Ninety-five percent of pa- tients with SLE have a positive FANA test result; the remaining 5% have a negative FANA test result but a positive result for antibodies to SS-A (Sjögren’s syndrome A, also known as antibodies to Ro). Thus, negative FANA and negative SS-A test results rule out SLE. (2) A positive FANA test result does not mean a disease is present. Low titers (eg, 1:40, 1:80) in patients without objective abnormalities (aches and pains, fatigue) are likely false positive. 15 (3) A diagnosis of SLE is made on the basis of a positive FANA test result at a reasonable titer and the presence of three other objective cri- teria for SLE, such as swollen joints, nephritis, or pericarditis (not aches and pains or reports of a rash in the distant past). (4) Other diseases can cause a positive FANA test result, notably diseases of the thyroid, such as Graves’ disease or Hashimoto’s thy- roiditis. The false-positive rate in- creases with age, as do false-positive rates for many other autoantibodies. Several specific patterns of auto- antibodies are useful to remember: (1) A centromere pattern on the FANA test indicates CREST syn- drome (calcinosis, Raynaud’s phe- nomenon, esophageal problems, sclerodactyly, telangiectasias). (2) Antibodies to dsDNA (double- stranded DNA) or Sm (Smith) are seen in SLE. (3) Antibodies to Scl-70 are seen in a minority of persons with scleroderma but predict severe dis- ease. (4) Antibodies to histone are seen primarily in persons with drug- induced SLE. (5) High levels of antibodies to ribonucleoprotein are seen in mixed connective tissue disease, a condi- tion that has features of scleroderma and SLE. Anticardiolipin Antibodies and Lupus Anticoagulant These tests are used to evaluate patients with hypercoagulable states. Anticardiolipin (or antiphos- pholipid) antibodies are a heteroge- neous family of antibodies that are directed against components of the coagulation pathway. Their pres- ence may put patients at risk of thrombosis. The same is true of the lupus anticoagulant antibodies, which prolong the partial thrombo- plastin time and also may lead to thrombosis. These two kinds of antibodies can be present in up to 40% of patients with SLE or can occur in isolation, leading to primary anti- phospholipid syndrome. Clinical manifestations of these antibodies include recurrent fetal loss in the second trimester, venous and arte- rial thrombosis, and thrombocyto- penia. 16 Other possible manifesta- tions include transverse myelopathy, cardiac valvular disease, and osteo- necrosis. Three points should be kept in mind when considering whether testing will be useful: (1) Anticardiolipin antibodies and lupus anticoagulant are not diagnostic tests for SLE or other con- nective tissue diseases. (2) If hypercoagulability is a con- cern, testing should be done for both lupus anticoagulant and anticardio- lipin antibodies because a patient may have one or both. These tests are only part of an evaluation for a hypercoagulable state. Table 2 Autoantibody Profiles in Rheumatic Diseases Drug-Induced Condition Systemic Lupus Systemic Lupus Sjögren’s Mixed Connective Autoantibody Erythematosus Erythematosus Syndrome Tissue Disease Scleroderma ANA pattern Homogeneous, Speckled Speckled Speckled Nucleolar (diffuse), rim, speckled centromere (crest) Anti-dsDNA 60% Rare Absent Absent Absent Anti-Sm 20% Absent Absent Absent Absent Anti-SSA 30% Absent 70% Rare Rare Anti-SSB 15% Absent 35% Rare Rare Anti-RNP 30% Absent Absent 95% Rare Antihistone 30% - 50% 95% Absent Absent 10% - 25% (diffuse) Anti–Scl-70 Absent Absent Absent Absent 25% - 30% (diffuse) Rheumatoid factor 15% - 35% Rare 50% - 75% 25% - 50% Rare ANA = antinuclear antibody; dsDNA = double-stranded DNA; Sm = Smith; SSA/SSB = Sjögren’s syndrome A/B; RNP = ribonucleo- protein; Scl = scleroderma Ordering and Interpreting Rheumatologic Laboratory Tests Journal of the American Academy of Orthopaedic Surgeons 64 (3) These tests should be ordered only when hypercoagulability is strongly suspected. Like all other such tests, they have a relatively constant false-positive rate and could lead to unwarranted concern and expensive follow-up tests. Human Leukocyte Antigen–B27 The human leukocyte antigen (HLA) molecules are part of the major histocompatibility complex encoded by genes on the short arm of chromosome 6. These molecules are important in self-recognition and immune response. HLA-B27 is one of the class I antigens that are found on all cells except red blood cells and are important for cell-mediated immunity. Certain HLA molecules have been found to indicate risk of various diseases. The HLA-B27 antigen indicates a risk of spondy- loarthropathies. 17 This antigen is found in approximately 8% of European-Americans and 4% of African-Americans. The test has a 92% sensitivity and specificity for ankylosing spondylitis in European- Americans and is present in >90% of affected individuals. The test also is useful for diagnosing Reiter’s syn- drome because 80% of these patients carry the antigen. The diagnosis of ankylosing spondylitis depends on the history, examination, and typical radio- graphic findings of sacroiliitis. When the history and examination are highly suggestive but there is no radiographic evidence of the disease (either on plain radiographs or com- puted tomography [CT]), HLA-B27 may be helpful in decision-making. In these borderline situations, a posi- tive test makes the likelihood of the disease approximately equal to the specificity (ie, about a 92% chance of having ankylosing spondylitis), whereas a negative test makes the likelihood of not having the disease approximately equal to the sensi- tivity (ie, about a 92% chance of not having ankylosing spondylitis). 16 Generally, an HLA-B27 test should be ordered only when the patient’s history is compatible with ankylosing spondylitis or Reiter’s syndrome and definitive radio- graphic changes are lacking, or, in the case of Reiter’s syndrome, when clinical features are insufficient to make a definitive diagnosis. The test should not be ordered when the history clearly is that of mechanical low back pain because <20% of HLA-B27–positive patients have associated clinical manifestations. Uric Acid Prolonged hyperuricemia fre- quently leads to the clinical symp- toms of gout. In patients with ar- thritis consistent with gout, demon- strating the presence of intracellular crystals is key to the diagnosis. Serum uric acid levels may be ele- vated during an acute attack of gout, but in some patients, the levels may decrease 1 to 2 mg/dL or more while inflammation is present. Thus, in a patient with gout with a preattack serum uric acid level of 7 to 9 mg/dL, that elevated level may fall into the normal range during an acute attack. 18 This is particularly true in alcoholics. 19 Uric acid levels are best checked once the attack has subsided. Demonstrating uric acid crystals from a joint aspiration is not necessary with each attack but should be done at least once to aid decision-making. The diagnosis of gout sometimes is assigned incorrectly, especially to patients with joint pain and asymp- tomatic hyperuricemia but without a convincing history of gout. 20 There- fore, the diagnosis rests on visualiz- ing urate crystals in white blood cells taken from the inflamed joint, not simply on the presence of hyper- uricemia. Only a small amount of fluid (a drop or less) is necessary to make the diagnosis. Because gout can mimic septic arthritis, aggressive therapy for infection should be avoid- ed before gout has been ruled out. Lyme Disease Lyme arthritis is a late manifes- tation of infection with the tick- borne organism Borrelia burgdorferi. The disease most commonly occurs in the spring and summer in the northeast and upper midwest of the United States. 21 Arthritis occurs either as an intermittent, migratory polyarthritis in half of the patients who develop late-stage disease or as a chronic monoarthri- tis, usually affecting the knee with large, inflammatory effusions. The diagnosis should be made on clinical grounds (the season, regional location, and pattern of the rash— erythema chronicum migrans). Positive serologic testing increases the posttest probability of Lyme dis- ease and helps in deciding on anti- biotic therapy. Testing detects the presence of antibodies to the causa- tive organism, not the organism itself, so those who may have been infected but have cleared the organ- ism still would test positive but may not have active disease. In addition, the test has a 5% false-positive rate, and false-positive results are com- mon among persons with other forms of arthritis, such as rheuma- toid arthritis and SLE. The initial test is an ELISA; if it is positive, it is followed by a confirmatory Western blot analysis. In addition, poly- merase chain reaction (PCR) testing can detect B burgdorferi DNA within the joint fluid of patients suspected to have Lyme arthritis. 21 This test has a high specificity and sensitivity for the organism and may be useful in distinguishing patients with active B burgdorferi infections from those who are simply seropositive and have other causes of arthritis. Pa- tients with late Lyme disease (ie, those with arthritis) almost always are seropositive, so a negative test virtually rules out Lyme arthritis. Lyme serology should be ordered only when the clinical diagnosis is highly suggestive. Using this test for evaluating patients with a low Gregory C. Gardner, MD, and Nancy J. Kadel, MD Vol 11, No 1, January/February 2003 65 probability of infection can lead to incorrect diagnosis and overtreat- ment. In high-risk areas, a certain percentage of the population will be antibody-positive but disease-nega- tive, so clinical correlation is partic- ularly important. In this situation, PCR for B burgdorferi in the joint fluid may be useful. Clinical Scenarios Carpal Tunnel Syndrome and Stiff Joints A 26-year-old woman was re- ferred for evaluation and treatment of carpal tunnel syndrome. She reported paresthesias in both hands, especially the right, that awakened her from sleep and also were pres- ent while driving. She also reported stiffness of 2 months’ duration in the hands and wrists that was worse in the morning than during the day. The physical examination dis- closed swelling and tenderness of the metacarpophalangeal, proximal interphalangeal, metatarsopha- langeal, and wrist joints. She had positive Tinel’s and Phalen’s signs, greater on the right than left. Other- wise, the examination was normal. Laboratory testing included a nor- mal complete blood count, an ESR of 42 mm/h, a FANA titer of 1:40, and negative results for SS-A and hepatitis C antibodies. RF was ele- vated at 215 IU. She was given neutral wrist splints and referred with the diagno- sis of RA to a rheumatologist. She was given methotrexate and low- dose prednisone. In spite of this therapy, she required endoscopic carpal tunnel release on the right to relieve symptoms. Her rheumatoid arthritis currently is well controlled by methotrexate 15 mg/week and prednisone 2.5 mg/day. This patient presented with an inflammatory polyarthritis affecting small joints of the hands and feet, with carpal tunnel syndrome as a result of underlying synovitis. The initial differential diagnosis included RA, lupus, and hepatitis C infection. A diagnosis of RA was made on the basis of clinical and laboratory data. Typically, a FANA titer of 1:40 is not clinically meaningful. Low Back Pain With a Sore Heel A 25-year-old man was referred for persistent right Achilles tendini- tis. The tendinitis had appeared 2 months earlier and possibly began after a game of soccer. He had tried nonsteroidal anti-inflammatory drugs (NSAIDs), rest, and a heel lift, all without benefit. On physical examination, he had trouble removing his socks because of back stiffness. There was tender- ness to palpation of the sacroiliac joints bilaterally and also low back pain on both sides with Patrick’s test. Lumbar range of motion was normal. There was also tenderness and swelling of the right Achilles tendon at the insertion into the cal- caneus. A plain radiograph, pelvic outlet view, demonstrated sacroili- itis consistent with ankylosing spondylitis. His ESR was elevated at 45 mm/h. He was referred to a rheumatologist and given high-dose NSAIDs and sulfasalazine; the symp- toms resolved. Insertional Achilles tendinitis is often caused by a spondylo- arthropathy. This, together with back stiffness, suggests ankylosing spondylitis. If the radiograph of the sacroiliac joints had been negative or equivocal, CT of the sacroiliac joints could have been done. If this were negative, an HLA-B27 test could have been considered. Testing for RA and SLE was not needed because Achilles tendinitis is unusu- al in these diseases. Arthralgias and Fatigue A 36-year-old woman reported bilateral hand pain and numbness. She was referred for possible carpal tunnel syndrome. She had devel- oped the pain in the hands several years earlier and had recently quit her job as a secretary because of her symptoms. She also reported fa- tigue and diffuse muscle aches. The physical examination was remarkable for tenderness without swelling of multiple metacar- pophalangeal, proximal interpha- langeal, and distal interphalangeal joints of both hands, with grimac- ing. She had tenderness around various joints and muscles to the pressure of the examination, with- out evidence of swelling. Neuro- logic examination was unremark- able except for Tinel’s sign at the right wrist, which produced pain into all of the fingers. Review of previous laboratory tests for her complaints demonstrated a normal complete blood count, chemistry panel, ESR, and thyroid-stimulat- ing hormone, calcium, and creatine kinase levels. Electrodiagnostic study results were normal. She was referred to a rheumatologist. A diagnosis of fibromyalgia was made, and she was prescribed low- dose nortriptyline and an exercise program. Her presentation is not unusual for fibromyalgia. RF, FANA, and SS- A tests should be avoided in such sit- uations because they confuse the issue. Many patients with fibromy- algia have been told that they have SLE, based on a false-positive FANA test result. Bilateral Shoulder Pain A 66-year-old woman was referred to an orthopaedic clinic for persistent rotator cuff tendinitis. The symptoms had begun 4 months earlier. She had stiffness and aching in both shoulders with overhead activities. Morning stiffness in the shoulders and hips required her to roll out of bed. She had completed two courses of physical therapy for the shoulder, without much benefit. After her latest physical therapy Ordering and Interpreting Rheumatologic Laboratory Tests Journal of the American Academy of Orthopaedic Surgeons 66 course, her primary care physician had given her a corticosteroid injec- tion in the right shoulder, which improved her general stiffness and pain for 4 days, although both then returned. The physical examination revealed signs of rotator cuff ten- dinitis bilaterally. The rest of the examination was normal; in partic- ular, there was no evidence of sy- novitis of the small joints of the hands or feet. Laboratory tests demonstrated a hematocrit level of 33%, normal chemistry panel, and ESR of 80 mm/h. A suspected diagnosis of polymyalgia rheumatica was confirmed by a rheumatology consultant. Low-dose prednisone was started, and her symptoms resolved dramatically within 24 hours. The distribution of symptoms and signs suggests the diagnosis of polymyalgia rheumatica. RF and FANA tests are not needed unless there is joint swelling or other objec- tive abnormalities. The arthritis/ periarthritis typical of polymyalgia often can cause rotator cuff signs and symptoms. In any older person with bilateral shoulder symptoms, polymyalgia rheumatica should be considered in the differential diag- nosis. Swollen Knee and Inflammatory Fluid A 55-year-old man reported swelling of 1 month’s duration in the left knee. His history was negative for trauma or previous problems with the knee. He had stiffness in the morning, with some improve- ment during activity. The physical examination revealed a moderate-sized effusion of the knee. There was diffuse swelling of the left second toe and a patch of psoriasis on his scalp. Aspiration of the joint yielded 40 mL of cloudy fluid with a white blood cell count of 30,000/µL, mostly neutrophils. Laboratory tests demonstrated a normal complete blood count and an ESR of 35 mm/h. The diagnosis of psoriatic arthri- tis was considered; he was pre- scribed NSAIDs and referred to a rheumatologist, who prescribed methotrexate. There was moderate improvement of the joints and skin. Etanercept was added, with notable improvement. This patient had an inflammatory form of arthritis confirmed by the fluid in the knee. Checking the syno- vial fluid cell count at the knee may help avoid arthroscopy. The presen- tation in this case is typical of psori- atic arthritis, and there is no need for FANA or RF tests. A follow-up ESR or CRP test is reasonable as a marker of treatment success. Psoriatic ar- thritis is not associated with HLA- B27, and testing would not be use- ful in this situation. In an endemic area, Lyme serology is not unrea- sonable when only the knee is affected. Bilateral Heel Pain A 24-year-old soccer player reported bilateral heel pain of 6 months’ duration that was worse in the morning and partially improved with activity. He had tried NSAIDs (with some benefit), over-the- counter orthotics, and even a poste- rior night splint, without a notable change in symptoms. He also re- ported occasional low back stiffness that he ascribed to his soccer play. He was diagnosed with bilateral plantar fasciitis and referred for other therapeutic options. Examination demonstrated evi- dence of bilateral plantar fasciitis and was otherwise negative. Plain radiographs, including a pelvic outlet view of the sacroiliac joints and views of the feet, were unre- markable. The CRP level was ele- vated at 2.8 mg/dL, and results of subsequent CT of the sacroiliac joints were negative. HLA-B27 antigen was then checked and was positive. He was referred to a rheumatolo- gist and begun on indomethacin and sulfasalazine, with excellent re- sponse. His subsequent course was marked by intermittent bouts of iri- tis, and 2 years later, radiography revealed that he had developed sacroiliitis. An HLA-B27 determination is useful in this situation, that is, neg- ative radiographic results but posi- tive symptoms and an elevated CRP level. HLA-B27 antigen test- ing was helpful because of the impression that the patient had an inflammatory form of enthesopa- thy. The HLA-B27 test also aided in treatment decisions. The CRP level was useful to confirm the inflammatory nature of the symp- toms, but it would not have ruled out an inflammatory cause if the level had been normal. Knee Swelling A 45-year-old forest ranger who worked in Minnesota was referred for persistent right knee swelling. He was known to be antibody posi- tive for B burgdorferi. One year ear- lier, his right knee had swelled, with the synovial fluid showing 25,000 white blood cells/µL, most- ly neutrophils. He had been treat- ed with 60 days of doxycycline without change in the swelling. Before treatment with doxycycline, PCR results of the synovial fluid were positive for B burgdorferi. He was sent for arthroscopic biopsy to rule out granulomatous disease and to obtain synovium for B burgdorferi culture. The physical examination re- vealed only the swollen right knee. A repeat synovial PCR for B burg- dorferi was negative, and the patient was thought to have post-Lyme inflammatory arthritis. A right knee synovectomy was done, and he was given hydroxychloroquine, which controlled his synovitis. This is a case in which persistent synovitis developed after Lyme Gregory C. Gardner, MD, and Nancy J. Kadel, MD Vol 11, No 1, January/February 2003 67 arthritis. Many such patients carry the HLA-DR4 gene and require treatment with disease-modifying antirheumatic drugs, such as hy- droxychloroquine, as well as re- duction of the synovial mass by arthroscopic synovectomy. With- out such treatment, some patients develop erosive arthritis. Summary Understanding the basic principles of tests for inflammatory joint disor- ders can help the clinician distin- guish various forms of synovitis. Testing should be ordered only after a thorough history and physical examination. The selection of tests should be specific to help clarify a borderline clinical scenario. Nonselective use of testing may lead to false-positive results, which can cause unnecessary concern and increased expense. Acknowledgment: We wish to thank Mart Mannik, MD, for his thoughtful review and useful suggestions. References 1. International Committee for Standard- ization in Haematology. Recommen- dation of measurement of erythrocyte sedimentation rate of human blood. Am J Clin Pathol 1977;68:505-507. 2. Sox HC Jr, Liang MH: The erythrocyte sedimentation rate: Guidelines for rational use. Ann Intern Med 1986;104:515-523. 3. Miller A, Green M, Robinson D: Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J (Clin Res Ed) 1983;286:266. 4. Leff RD, Akre SP: Letter: Obesity and the erythrocyte sedimentation rate. Ann Intern Med 1986;105:143. 5. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW: C-reactive protein in healthy subjects: Associations with obe- sity, insulin resistance, and endothelial dysfunction: A potential role for cytokines originating from adipose tis- sue? Arterioscler Thromb Vasc Biol 1999;19:972-978. 6. Rafnsson V, Bengtsson C, Lennartsson J, Lindquist O, Noppa H, Tibblin E: Erythrocyte sedimentation rate in a population sample of women with spe- cial reference to its clinical and prog- nostic significance. Acta Med Scand 1979;206:207-214. 7. Foglar C, Lindsey RW: C-reactive protein in orthopedics. Orthopedics 1998;21:687-691. 8. Young B, Gleeson M, Cripps AW: C- reactive protein: A critical review. Pathology 1991;23:118-124. 9. Barland P, Lipstein E: Selection and use of laboratory tests in the rheumatic diseases. Am J Med 1996;100(suppl 2A):16S-23S. 10. Tighe H, Carson DA: Rheumatoid fac- tor, in Ruddy S, Harris ED Jr, Sledge CB, Budd RC, Sergent JS (eds): Kelley’s Textbook of Rheumatology, ed 6. Phila- delphia, PA: WB Saunders, 2001, pp 151-160. 11. Jonsson T, Steinsson K, Jonsson H, Geirsson AJ, Thorsteinsson J, Valdi- marsson H: Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheuma- toid arthritis. Rheumatol Int 1998;18: 119-122. 12. Shmerling RH, Delbanco TL: How useful is the rheumatoid factor? An analysis of sensitivity, specificity, and predictive value. Arch Intern Med 1992;152:2417-2420. 13. Peng SL, Craft J: Antinuclear antibod- ies, in Ruddy S, Harris ED Jr, Sledge CB, Budd RC, Sergent JS (eds): Kelley’s Textbook of Rheumatology, ed 6. Phila- delphia, PA: WB Saunders, 2001, pp 161-174. 14. Shmerling RH, Liang MH: Laboratory assessment, in Klippel JH, Weyand CM, Wortmann RL (eds): Primer on the Rheumatic Diseases, ed 11. Atlanta, GA: Arthritis Foundation, 1997, pp 94-97. 15. Slater CA, Davis RB, Shmerling RH: Antinuclear antibody testing: A study of clinical utility. Arch Intern Med 1996;156:1421-1425. 16. Harris EN: Antiphospholipid syn- drome, in Klippel JH, Weyand CM, Wortmann RL (eds): Primer on the Rheumatic Diseases, ed 11. Atlanta, GA: Arthritis Foundation, 1997, pp 313-315. 17. Khan MA: Clinical features of anky- losing spondylitis, in Klippel JH, Dieppe PA (eds): Practical Rheuma- tology. London, UK: Times Mirror International Publishers Limited, 1995, pp 211-220. 18. Hadler NM, Franck WA, Bress NM, Robinson DR: Acute polyarticular gout. Am J Med 1974;56:715-719. 19. Vandenberg MK, Moxley G, Breitbach SA, Roberts WN: Gout attacks in chronic alcoholics occur at lower serum urate levels than in non-alcoholics. J Rheumatol 1994;21:700-704. 20. Wolfe F, Cathey MA: The misdiagnosis of gout and hyperuricemia. J Rheumatol 1991;18:1232-1234. 21. Steere AC: Diagnosis and treatment of Lyme arthritis. Med Clin North Am 1997;81:179-194. . and indications to effec- tively order serologic tests can help to avoid unnecessary testing and potentially confusing results. The tests should help confirm a clinical impression or sort out a. if the FANA test is positive, is testing for specific autoantibodies that help to classify the potential underlying connective tissue dis- ease. 13,14 The FANA test is done by placing patient. in healthy subjects: Associations with obe- sity, insulin resistance, and endothelial dysfunction: A potential role for cytokines originating from adipose tis- sue? Arterioscler Thromb Vasc Biol 1999;19:972-978. 6.