Rheumatologic Serologies Can Be a Confounding Quagmire

ESTES PARK, COLO. – The high false-positive rates for autoimmune serologies make them unsuitable as screening tests for connective tissue diseases, according to Dr. Robert W. Janson.

Moreover, the prearranged test panels often pitched to primary care physicians are a particularly bad idea, he said. These panels might combine, for example, rheumatoid factor (RF), antinuclear antibodies, erythrocyte sedimentation rate (ESR), and C-reactive protein.

"I call them ‘rheum rally packs.’ They should be avoided. They can multiply testing errors, leading to additional unnecessary testing, needless angst, and inappropriate treatment," said Dr. Janson, chief of the rheumatology section at the Denver Veterans Affairs Medical Center.

Selectivity is the watchword when ordering autoimmune serologic tests. Their value comes when suspicion of a connective tissue disease (CTD) is already high based on history and physical examination, that is, when the pretest probability is relatively high, he explained at an update on internal medicine sponsored by the University of Colorado.

Take, for example, rheumatoid factor. The very name is a misnomer, suggesting a high test specificity that’s completely undeserved. While 80% of patients with rheumatoid arthritis are indeed RF+, the test is also positive in the majority of individuals with Sjögren’s syndrome or mixed CDT; in many patients with chronic infection, malignancy, or fibrotic pulmonary disorders; and even in 5% of healthy individuals. As a result, the test’s positive predictive value for rheumatoid arthritis is a mere 24%, although its negative predictive value is much better at 89%.

"Rheumatoid factor has little value as a screening test to diagnose or exclude CTD in patients with just plain arthralgias. It has a much higher positive predictive value if ordered selectively in patients with a higher probability of a CTD: morning stiffness, sicca symptoms, and arthralgias or synovitis in a rheumatoid arthritis distribution," the rheumatologist continued.

The combination of a positive RF and a positive test for anticyclic citrullinated peptide antibodies (ACPAs) is associated with a nearly 100% likelihood that an appropriately symptomatic patient has rheumatoid arthritis. Also, when both tests are positive, it’s an indicator of a more serious case of rheumatoid arthritis that will involve joint damage and disability.

"These patients need more aggressive therapy," Dr. Janson noted.

On the other hand, he said he’d urge that a patient with morning stiffness lasting longer than 1 hour, tenderness of the metacarpophalangeal or metatarsophalangeal joints, and suspected synovitis on physical examination be referred to a rheumatologist to see if an early inflammatory arthritis is involved, even if the RF and/or ACPA tests are negative. In this era of highly effective biologic therapy, negative serologic tests don’t preclude early and aggressive therapy, he noted.

Nearly all patients with SLE will have a positive antinuclear antibody (ANA) test. A negative test rules out SLE with 95% certainty. But the test’s positive predictive value for SLE is only 11%-30% because so many other conditions are associated with a positive ANA. These include numerous other CTDs, organ-specific autoimmune diseases such as Hashimoto’s thyroiditis, a variety of chronic infections, and lymphoproliferative disorders. In addition, low-titer positive ANA tests are not uncommon in normal women and the elderly.

In sum, ANA testing is useful to help establish a diagnosis when a patient’s clinical features suggest a CTD, as well as for excluding CTDs in patients with uncertain clinical findings, and in monitoring CTD disease activity. Rheumatologists consider ANA titers of 1:320 or higher to be more clinically meaningful, according to Dr. Janson.

He singled out a particular ANA subantibody test – that for antihistone antibodies – as one that "approaches being the perfect test." That’s because patients with drug-induced lupus don’t make antibodies to nonhistone nuclear antigens. As a result, antihistone antibody testing enjoys greater than 95% sensitivity and specificity for drug-induced lupus.

Two ANA subantibody tests are highly diagnostic for SLE. These are anti–double-stranded DNA and anti–Smith antibody tests, each with a specificity in excess of 95% for SLE.

The antineutrophil cytoplasmic antibody (ANCA) tests are the first serologies to order when a patient is suspected of having some kind of vasculitis as manifest, for example, by diffuse alveolar hemorrhage, nephritis without another explanation, or a pulmonary-renal syndrome.

ANCAs come in two types: cytoplasmic (cANCA), which are antibodies directed against proteinase 3, and perinuclear (pANCA), directed most often against myeloperoxidase.

The cANCA test has 98% specificity for active generalized granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis. However, limited granulomatosis with polyangiitis affecting, say, the sinuses but without kidney involvement may be ANCA negative in 40% of cases.

The pANCA test has 60%-90% sensitivity for microscopic polyangiitis, but poor sensitivity, as the test can be positive in rheumatoid arthritis and several other CTDs. However, the specificity for microscopic polyangiitis improves to greater than 95% in the setting of both positive pANCA and antimyeloperoxidase ELISA tests.

The acute phase reactants – C-reactive protein and ESR are useful in assessing patients with a suspected malignancy or infection, as well as in those in whom inflammatory arthritides or vasculitis is a concern. A CRP greater than 1.0 mg/dL indicates significant inflammation, and a value in excess of 10 mg/dL is due either to metastatic cancer, bacterial infection, or systemic vasculitis. And if both the ESR and CRP are normal, the probability that a patient has a vasculitis is "incredibly low," Dr. Janson said.

At least 80% of patients with polymyalgia rheumatica will have an elevated ESR, and the CRP should be elevated in those that don’t.

Dr. Janson reported having no relevant financial conflicts.

ESTES PARK, COLO. – The high false-positive rates for autoimmune serologies make them unsuitable as screening tests for connective tissue diseases, according to Dr. Robert W. Janson.

Moreover, the prearranged test panels often pitched to primary care physicians are a particularly bad idea, he said. These panels might combine, for example, rheumatoid factor (RF), antinuclear antibodies, erythrocyte sedimentation rate (ESR), and C-reactive protein.

"I call them ‘rheum rally packs.’ They should be avoided. They can multiply testing errors, leading to additional unnecessary testing, needless angst, and inappropriate treatment," said Dr. Janson, chief of the rheumatology section at the Denver Veterans Affairs Medical Center.

Selectivity is the watchword when ordering autoimmune serologic tests. Their value comes when suspicion of a connective tissue disease (CTD) is already high based on history and physical examination, that is, when the pretest probability is relatively high, he explained at an update on internal medicine sponsored by the University of Colorado.

Take, for example, rheumatoid factor. The very name is a misnomer, suggesting a high test specificity that’s completely undeserved. While 80% of patients with rheumatoid arthritis are indeed RF+, the test is also positive in the majority of individuals with Sjögren’s syndrome or mixed CDT; in many patients with chronic infection, malignancy, or fibrotic pulmonary disorders; and even in 5% of healthy individuals. As a result, the test’s positive predictive value for rheumatoid arthritis is a mere 24%, although its negative predictive value is much better at 89%.

"Rheumatoid factor has little value as a screening test to diagnose or exclude CTD in patients with just plain arthralgias. It has a much higher positive predictive value if ordered selectively in patients with a higher probability of a CTD: morning stiffness, sicca symptoms, and arthralgias or synovitis in a rheumatoid arthritis distribution," the rheumatologist continued.

The combination of a positive RF and a positive test for anticyclic citrullinated peptide antibodies (ACPAs) is associated with a nearly 100% likelihood that an appropriately symptomatic patient has rheumatoid arthritis. Also, when both tests are positive, it’s an indicator of a more serious case of rheumatoid arthritis that will involve joint damage and disability.

"These patients need more aggressive therapy," Dr. Janson noted.

On the other hand, he said he’d urge that a patient with morning stiffness lasting longer than 1 hour, tenderness of the metacarpophalangeal or metatarsophalangeal joints, and suspected synovitis on physical examination be referred to a rheumatologist to see if an early inflammatory arthritis is involved, even if the RF and/or ACPA tests are negative. In this era of highly effective biologic therapy, negative serologic tests don’t preclude early and aggressive therapy, he noted.

Nearly all patients with SLE will have a positive antinuclear antibody (ANA) test. A negative test rules out SLE with 95% certainty. But the test’s positive predictive value for SLE is only 11%-30% because so many other conditions are associated with a positive ANA. These include numerous other CTDs, organ-specific autoimmune diseases such as Hashimoto’s thyroiditis, a variety of chronic infections, and lymphoproliferative disorders. In addition, low-titer positive ANA tests are not uncommon in normal women and the elderly.

In sum, ANA testing is useful to help establish a diagnosis when a patient’s clinical features suggest a CTD, as well as for excluding CTDs in patients with uncertain clinical findings, and in monitoring CTD disease activity. Rheumatologists consider ANA titers of 1:320 or higher to be more clinically meaningful, according to Dr. Janson.

He singled out a particular ANA subantibody test – that for antihistone antibodies – as one that "approaches being the perfect test." That’s because patients with drug-induced lupus don’t make antibodies to nonhistone nuclear antigens. As a result, antihistone antibody testing enjoys greater than 95% sensitivity and specificity for drug-induced lupus.

Two ANA subantibody tests are highly diagnostic for SLE. These are anti–double-stranded DNA and anti–Smith antibody tests, each with a specificity in excess of 95% for SLE.

The antineutrophil cytoplasmic antibody (ANCA) tests are the first serologies to order when a patient is suspected of having some kind of vasculitis as manifest, for example, by diffuse alveolar hemorrhage, nephritis without another explanation, or a pulmonary-renal syndrome.

ANCAs come in two types: cytoplasmic (cANCA), which are antibodies directed against proteinase 3, and perinuclear (pANCA), directed most often against myeloperoxidase.

The cANCA test has 98% specificity for active generalized granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis. However, limited granulomatosis with polyangiitis affecting, say, the sinuses but without kidney involvement may be ANCA negative in 40% of cases.

The pANCA test has 60%-90% sensitivity for microscopic polyangiitis, but poor sensitivity, as the test can be positive in rheumatoid arthritis and several other CTDs. However, the specificity for microscopic polyangiitis improves to greater than 95% in the setting of both positive pANCA and antimyeloperoxidase ELISA tests.

The acute phase reactants – C-reactive protein and ESR are useful in assessing patients with a suspected malignancy or infection, as well as in those in whom inflammatory arthritides or vasculitis is a concern. A CRP greater than 1.0 mg/dL indicates significant inflammation, and a value in excess of 10 mg/dL is due either to metastatic cancer, bacterial infection, or systemic vasculitis. And if both the ESR and CRP are normal, the probability that a patient has a vasculitis is "incredibly low," Dr. Janson said.

At least 80% of patients with polymyalgia rheumatica will have an elevated ESR, and the CRP should be elevated in those that don’t.

Dr. Janson reported having no relevant financial conflicts.

ESTES PARK, COLO. – The high false-positive rates for autoimmune serologies make them unsuitable as screening tests for connective tissue diseases, according to Dr. Robert W. Janson.

Moreover, the prearranged test panels often pitched to primary care physicians are a particularly bad idea, he said. These panels might combine, for example, rheumatoid factor (RF), antinuclear antibodies, erythrocyte sedimentation rate (ESR), and C-reactive protein.

"I call them ‘rheum rally packs.’ They should be avoided. They can multiply testing errors, leading to additional unnecessary testing, needless angst, and inappropriate treatment," said Dr. Janson, chief of the rheumatology section at the Denver Veterans Affairs Medical Center.

Selectivity is the watchword when ordering autoimmune serologic tests. Their value comes when suspicion of a connective tissue disease (CTD) is already high based on history and physical examination, that is, when the pretest probability is relatively high, he explained at an update on internal medicine sponsored by the University of Colorado.

Take, for example, rheumatoid factor. The very name is a misnomer, suggesting a high test specificity that’s completely undeserved. While 80% of patients with rheumatoid arthritis are indeed RF+, the test is also positive in the majority of individuals with Sjögren’s syndrome or mixed CDT; in many patients with chronic infection, malignancy, or fibrotic pulmonary disorders; and even in 5% of healthy individuals. As a result, the test’s positive predictive value for rheumatoid arthritis is a mere 24%, although its negative predictive value is much better at 89%.

"Rheumatoid factor has little value as a screening test to diagnose or exclude CTD in patients with just plain arthralgias. It has a much higher positive predictive value if ordered selectively in patients with a higher probability of a CTD: morning stiffness, sicca symptoms, and arthralgias or synovitis in a rheumatoid arthritis distribution," the rheumatologist continued.

The combination of a positive RF and a positive test for anticyclic citrullinated peptide antibodies (ACPAs) is associated with a nearly 100% likelihood that an appropriately symptomatic patient has rheumatoid arthritis. Also, when both tests are positive, it’s an indicator of a more serious case of rheumatoid arthritis that will involve joint damage and disability.

"These patients need more aggressive therapy," Dr. Janson noted.

On the other hand, he said he’d urge that a patient with morning stiffness lasting longer than 1 hour, tenderness of the metacarpophalangeal or metatarsophalangeal joints, and suspected synovitis on physical examination be referred to a rheumatologist to see if an early inflammatory arthritis is involved, even if the RF and/or ACPA tests are negative. In this era of highly effective biologic therapy, negative serologic tests don’t preclude early and aggressive therapy, he noted.

Nearly all patients with SLE will have a positive antinuclear antibody (ANA) test. A negative test rules out SLE with 95% certainty. But the test’s positive predictive value for SLE is only 11%-30% because so many other conditions are associated with a positive ANA. These include numerous other CTDs, organ-specific autoimmune diseases such as Hashimoto’s thyroiditis, a variety of chronic infections, and lymphoproliferative disorders. In addition, low-titer positive ANA tests are not uncommon in normal women and the elderly.

In sum, ANA testing is useful to help establish a diagnosis when a patient’s clinical features suggest a CTD, as well as for excluding CTDs in patients with uncertain clinical findings, and in monitoring CTD disease activity. Rheumatologists consider ANA titers of 1:320 or higher to be more clinically meaningful, according to Dr. Janson.

He singled out a particular ANA subantibody test – that for antihistone antibodies – as one that "approaches being the perfect test." That’s because patients with drug-induced lupus don’t make antibodies to nonhistone nuclear antigens. As a result, antihistone antibody testing enjoys greater than 95% sensitivity and specificity for drug-induced lupus.

Two ANA subantibody tests are highly diagnostic for SLE. These are anti–double-stranded DNA and anti–Smith antibody tests, each with a specificity in excess of 95% for SLE.

The antineutrophil cytoplasmic antibody (ANCA) tests are the first serologies to order when a patient is suspected of having some kind of vasculitis as manifest, for example, by diffuse alveolar hemorrhage, nephritis without another explanation, or a pulmonary-renal syndrome.

ANCAs come in two types: cytoplasmic (cANCA), which are antibodies directed against proteinase 3, and perinuclear (pANCA), directed most often against myeloperoxidase.

The cANCA test has 98% specificity for active generalized granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis. However, limited granulomatosis with polyangiitis affecting, say, the sinuses but without kidney involvement may be ANCA negative in 40% of cases.

The pANCA test has 60%-90% sensitivity for microscopic polyangiitis, but poor sensitivity, as the test can be positive in rheumatoid arthritis and several other CTDs. However, the specificity for microscopic polyangiitis improves to greater than 95% in the setting of both positive pANCA and antimyeloperoxidase ELISA tests.

The acute phase reactants – C-reactive protein and ESR are useful in assessing patients with a suspected malignancy or infection, as well as in those in whom inflammatory arthritides or vasculitis is a concern. A CRP greater than 1.0 mg/dL indicates significant inflammation, and a value in excess of 10 mg/dL is due either to metastatic cancer, bacterial infection, or systemic vasculitis. And if both the ESR and CRP are normal, the probability that a patient has a vasculitis is "incredibly low," Dr. Janson said.

At least 80% of patients with polymyalgia rheumatica will have an elevated ESR, and the CRP should be elevated in those that don’t.

Dr. Janson reported having no relevant financial conflicts.