Red Blood Cell Count

Anemia is seen in many of the rheumatic diseases and can be multifactorial. An anemia of chronic disease is usually normocytic, but may be microcytic, and can be associated with any inflammatory disease. The cause likely relates to cytokine-mediated shortened red blood cell (RBC) survival and impaired bone marrow response to erythropoietin. Another major contribution to the anemia of chronic disease is the inflammation-induced activation of the interleukin 6 (IL-6)-hepcidin axis, which leads to decreased intestinal iron absorption and decreased iron release from stores. This condition must be distinguished from iron-deficiency anemia, which can also be seen in any of the rheumatic diseases. Table 1 contrasts these 2 conditions based on commonly used serum parameters. Complicating factors include the frequent coexistence of these 2 conditions and the fact that ferritin is an acute phase reactant so it may be normal, or even increased, in iron deficiency. Measurement of the soluble transferrin receptor, which is gaining acceptance, may help to more reliably distinguish anemia of chronic disease from iron-deficiency anemia.

Autoimmune hemolytic anemia may be seen in systemic lupus erythematosus (SLE) and related conditions (ie, Sjögren syndrome and mixed connective tissue disease [MCTD]). This diagnosis is made through a positive direct Coombs test and evidence of hemolysis (decreased hemoglobin or hematocrit, increased reticulocyte count, increased serum lactate dehydrogenase (LDH), increased unconjugated bilirubin, decreased haptoglobin, and hemoglobinuria). Nonimmune-mediated hemolysis is seen in the macrophage activation syndrome (MAS) (see later discussion) and thrombotic thrombocytopenic purpura.

White Blood Cell Count

SLE and related conditions frequently cause leukopenia, specifically lymphopenia and neutropenia. These abnormalities may confer an increased risk of infection in patients with SLE. Increased white blood cell (WBC) counts can be seen in other inflammatory diseases, and particularly increased counts may be seen in systemic juvenile idiopathic arthritis (sJIA; often >30,000 cells/mm ³ ). Malignancies can cause either increased or depressed WBC counts, and they must be considered in any patient who presents with WBC abnormalities.

Platelet Count

Because of their role as an acute phase reactant, platelets are frequently modestly increased in the rheumatic diseases. Significant increases (occasionally more than 1,000,000 cells/mm ³ ) may be seen in sJIA, Kawasaki disease, or Takayasu arteritis. SLE and related conditions often cause thrombocytopenia, and a depressed platelet count in the face of signs of systemic inflammation or arthritis should raise suspicion for these diseases or for malignancy. Thrombocytopenia may also be seen in the antiphospholipid antibody syndrome (APS) and in thrombotic thrombocytopenic purpura.

Special Considerations

MAS is a potentially life-threatening complication of any of the rheumatic diseases, and is particularly associated with sJIA. An overwhelming inflammatory reaction is seen and phagocytosis of all hematopoietic components ensues. Thus, any of WBC, RBC, and platelets may decrease. Therefore, normalization of previously increased WBC or platelets (and significantly increased ferritin level) in the face of a clinically worsening patient should alert the provider to the possibility of MAS.

ESR

The ESR evaluates the distance RBCs sediment in 1 hour. Its increase in inflammatory conditions primarily reflects increased fibrinogen production because fibrinogen is an acute phase reactant and causes RBCs to form rouleaux, which decrease at a faster rate than free RBCs. As an indirect measure of inflammation, the ESR can be influenced by several nonpathologic conditions. One of the most commonly encountered of these conditions in the pediatric outpatient setting is obesity, which can cause the ESR to be increased outside the normal age-specific range. Other increasing factors include anemia, increasing age, and pregnancy. For these reasons, mild increases in the ESR (ie, ESR <50 mm/h) in the absence of signs and symptoms of localized or systemic inflammation should not prompt further investigation or subspecialty referral. Conversely, an ESR of more than 100 mm/h is frequently associated with infection, malignancy, or inflammatory disease and warrants further workup.

Although it is not specific for inflammatory diseases, the ESR is valuable as a tool to monitor disease activity and determine prognosis in patients with these conditions. Persistently increased ESR is predictive of a more aggressive course or worse outcome in sJIA, enthesitis-related arthritis (ERA), and oligoarticular JIA. Increased ESR is associated with active synovitis in JIA and a normal ESR is one of the provisional criteria for inactive disease in JIA. The ESR is frequently normal in oligoarticular, and occasionally polyarticular, JIA, in contrast to malignancy (eg, leukemia or neuroblastoma), which may present with pain in 1 or a few joints but often has an extremely increased ESR. In SLE, an increased ESR has been shown to be associated with disease activity and damage accrual. However, ESR increases are not always associated with disease activity. Likewise, a normal ESR does not invariably suggest inactive disease.

As previously mentioned, MAS is a severe complication of pediatric rheumatic diseases, most frequently seen with sJIA. Consequent to the intense systemic inflammation seen in MAS, hypofibrinogemia occurs, likely because of both liver dysfunction and fibrinogen consumption from coagulopathy. This situation leads to a paradoxic decrease in the ESR. Therefore, a decreasing ESR in a patient who otherwise has active rheumatologic disease by clinical and other laboratory parameters should raise suspicion of MAS and indicate the need for emergent rheumatology consultation.

CRP

In contrast to the indirect association of ESR increase with inflammation, the CRP is produced by the liver as an acute phase reactant and plays a role in the innate host defense system. It is a sensitive, but not specific, marker of inflammation. Plasma CRP more rapidly increases, in response to inflammation, and decreases, with its resolution, than does the ESR.

Similarly to the ESR, the CRP is predictive of disease course in JIA, although it may more closely reflect severe disease in polyarthritis. Its normalization is a criterion for disease inactivity in JIA. One particular usefulness of the CRP in rheumatology is in the differentiation of flare from active infection in a patient with SLE. Given that either flare or infection can present with constitutional symptoms and that the immunosuppressive therapy used in SLE increases patients’ risk for serious infection, this is often a difficult distinction to make clinically. Whereas the ESR can be increased in both disease flare and infection, the CRP tends not to increase with disease flare (with the exception of serositis) but does increase with active infection. In a recent study of adult patients with SLE, a CRP greater than 5 mg/dL was 80% specific for infection.

Ferritin

Ferritin is central to iron homeostasis and its synthesis and expression are regulated at multiple steps by iron, cytokines (IL-1, IL-6, and tumor necrosis factor α), hormones (thyroid hormones, insulin, and insulinlike growth factor 1), and oxidative stress. During inflammation, serum ferritin level frequently increases in response to a decrease in serum iron. In sJIA, ferritin levels correlate with disease activity, with mild to moderate increases with active disease and normalization with quiescence. Ferritin levels also correlate with disease activity in SLE, but this is not a widely used method of monitoring patients, unlike in sJIA, in which it is part of routine surveillance and helps to guide treatment. In MAS, the ferritin level is often increased, and in hemophagocytic lymphohistiocytosis, which shares many similarities to MAS, the ferritin level is frequently more than 10,000 ng/mL. Very low glycosylated ferritin percentage (<20%) has been seen in both adult-onset Still disease and other hemophagocytic syndromes. It remains to be established whether glycosylated ferritin measurement has a role in diagnosis of MAS associated with pediatric rheumatic diseases.

ESR

The ESR evaluates the distance RBCs sediment in 1 hour. Its increase in inflammatory conditions primarily reflects increased fibrinogen production because fibrinogen is an acute phase reactant and causes RBCs to form rouleaux, which decrease at a faster rate than free RBCs. As an indirect measure of inflammation, the ESR can be influenced by several nonpathologic conditions. One of the most commonly encountered of these conditions in the pediatric outpatient setting is obesity, which can cause the ESR to be increased outside the normal age-specific range. Other increasing factors include anemia, increasing age, and pregnancy. For these reasons, mild increases in the ESR (ie, ESR <50 mm/h) in the absence of signs and symptoms of localized or systemic inflammation should not prompt further investigation or subspecialty referral. Conversely, an ESR of more than 100 mm/h is frequently associated with infection, malignancy, or inflammatory disease and warrants further workup.

Although it is not specific for inflammatory diseases, the ESR is valuable as a tool to monitor disease activity and determine prognosis in patients with these conditions. Persistently increased ESR is predictive of a more aggressive course or worse outcome in sJIA, enthesitis-related arthritis (ERA), and oligoarticular JIA. Increased ESR is associated with active synovitis in JIA and a normal ESR is one of the provisional criteria for inactive disease in JIA. The ESR is frequently normal in oligoarticular, and occasionally polyarticular, JIA, in contrast to malignancy (eg, leukemia or neuroblastoma), which may present with pain in 1 or a few joints but often has an extremely increased ESR. In SLE, an increased ESR has been shown to be associated with disease activity and damage accrual. However, ESR increases are not always associated with disease activity. Likewise, a normal ESR does not invariably suggest inactive disease.

As previously mentioned, MAS is a severe complication of pediatric rheumatic diseases, most frequently seen with sJIA. Consequent to the intense systemic inflammation seen in MAS, hypofibrinogemia occurs, likely because of both liver dysfunction and fibrinogen consumption from coagulopathy. This situation leads to a paradoxic decrease in the ESR. Therefore, a decreasing ESR in a patient who otherwise has active rheumatologic disease by clinical and other laboratory parameters should raise suspicion of MAS and indicate the need for emergent rheumatology consultation.

CRP

In contrast to the indirect association of ESR increase with inflammation, the CRP is produced by the liver as an acute phase reactant and plays a role in the innate host defense system. It is a sensitive, but not specific, marker of inflammation. Plasma CRP more rapidly increases, in response to inflammation, and decreases, with its resolution, than does the ESR.

Similarly to the ESR, the CRP is predictive of disease course in JIA, although it may more closely reflect severe disease in polyarthritis. Its normalization is a criterion for disease inactivity in JIA. One particular usefulness of the CRP in rheumatology is in the differentiation of flare from active infection in a patient with SLE. Given that either flare or infection can present with constitutional symptoms and that the immunosuppressive therapy used in SLE increases patients’ risk for serious infection, this is often a difficult distinction to make clinically. Whereas the ESR can be increased in both disease flare and infection, the CRP tends not to increase with disease flare (with the exception of serositis) but does increase with active infection. In a recent study of adult patients with SLE, a CRP greater than 5 mg/dL was 80% specific for infection.

Ferritin

Ferritin is central to iron homeostasis and its synthesis and expression are regulated at multiple steps by iron, cytokines (IL-1, IL-6, and tumor necrosis factor α), hormones (thyroid hormones, insulin, and insulinlike growth factor 1), and oxidative stress. During inflammation, serum ferritin level frequently increases in response to a decrease in serum iron. In sJIA, ferritin levels correlate with disease activity, with mild to moderate increases with active disease and normalization with quiescence. Ferritin levels also correlate with disease activity in SLE, but this is not a widely used method of monitoring patients, unlike in sJIA, in which it is part of routine surveillance and helps to guide treatment. In MAS, the ferritin level is often increased, and in hemophagocytic lymphohistiocytosis, which shares many similarities to MAS, the ferritin level is frequently more than 10,000 ng/mL. Very low glycosylated ferritin percentage (<20%) has been seen in both adult-onset Still disease and other hemophagocytic syndromes. It remains to be established whether glycosylated ferritin measurement has a role in diagnosis of MAS associated with pediatric rheumatic diseases.

ANA

Since the first description more than 50 years ago by Friou of the binding to nuclear antigens by serum of patients with SLE, the ANA has been used as a serologic marker to aid in the diagnosis of SLE as well as other rheumatic diseases. The ANA also has special significance in pediatric rheumatology because of the well-recognized association of a positive ANA with an increased risk of chronic uveitis in patients with JIA. However, up to 20% of children who are either healthy or have benign musculoskeletal complaints have a positive ANA, and, therefore, results of ANA testing must be interpreted in combination with clinical findings. Although this positivity may persist, most patients who present to a rheumatology clinic with a positive ANA but no autoimmune condition do not go on to develop any autoimmune disease. For these reasons, the ANA should not be used as a screening tool without concerning joint symptoms (morning stiffness, persistent swelling) or signs of SLE ( Box 1 ). Conversely, a negative ANA has a strong (0.96–1) negative predictive value for SLE, MCTD, and overlap syndromes.

The method used to perform the ANA testing influences interpretation of the results. The gold standard method is immunofluorescence (IF) against human epithelial (HEp-2) cells, which have large nuclei and express a large number (>100) of nuclear antigens. From the IF, information about the pattern and intensity of staining is provided. The pattern of ANA staining on IF reflects the specific nuclear antigens to which the ANA is binding ( Fig. 1 ). However, using the ANA pattern to diagnose specific autoimmune disorders has low sensitivity and specificity, and is being replaced by specific antinuclear antibody tests (see later discussion).

ANA patterns on Immunofluorescence. ( A ) Homogenous; ( B ) Speckled; ( C ) Nucleolar; ( D ) Centromere.

( From Damoiseaux JG, Tervaert JW. From ANA to ENA: how to proceed? Autoimmun Rev 2006;5:10–7; with permission.)

Some laboratories have moved to more automated commercial enzyme-linked immunosorbent assays (ELISAs), which allow for higher throughput of samples. The ELISA tests for serum absorbance to specified nuclear antigens. A disadvantage of this method arises when a patient has an ANA that binds to a nuclear antigen not present among the ones tested, which may lead to a false-negative test. This finding is of particular concern in patients with JIA, because the antigen specificity in ANA-positive patients is not known and is likely heterogenous. Exclusive use of the ELISA in these patients could lead to misclassification of chronic uveitis risk. The practice at our institution is to order both IF and ELISA on all patients with JIA.

In addition to SLE and JIA, other rheumatologic conditions are associated with a positive ANA ( Box 2 ). In children with RP, the ANA predicts the risk of an underlying connective tissue disease, such as lupus or systemic sclerosis. In a retrospective study, 85% of children with secondary RP (RP associated with an underlying connective tissue disease) had a positive ANA, whereas only 25% of those with RP alone (primary RP) were ANA positive.

As mentioned earlier, a positive ANA correlates with an increased risk of chronic, insidious uveitis in patients with JIA. ANA positivity more than triples the risk of uveitis in JIA, and more than 80% of patients with JIA who develop uveitis are ANA positive. Therefore, patients with JIA and a positive ANA are screened more frequently for chronic uveitis, which is generally asymptomatic and detected only through slit-lamp examination by an ophthalmologist.

Indications for ordering an ANA are listed in Box 3 .

Specific Antinuclear Antibodies

Antibodies to specific nuclear antigens can be associated with specific diseases ( Table 2 ). In addition, testing for anti-dsDNA antibodies has special value in the management of SLE, because increasing levels are predictive of flares of glomerulonephritis in patients with a history of renal disease. For nonrenal manifestations of SLE, the relationship between persistently high or increasing anti-dsDNA levels and flare is less certain.

Other than antihistone antibodies, tests for specific antinuclear antibodies are not usually positive in JIA. Therefore, the presence of specific antinuclear antibodies in a patient with chronic arthritis should suggest an alternative diagnosis than JIA.

Rheumatoid Factor

Rheumatoid factor (RF) is an antibody (typically IgM) directed against the F _c portion of IgG. The primary usefulness of RF measurement in the pediatric rheumatology clinic is differentiating between the 2 subtypes of polyarticular JIA: RF positive and RF negative. Unlike adult rheumatoid arthritis, most children with JIA do not have RF. Of patients with polyarthritis, approximately 85% are RF negative. Testing for RF is generally not helpful in establishing or ruling out a diagnosis of JIA, and it is indicated only in patients who have objective signs of polyarthritis (≥4 affected joints). In those patients with polyarthritis who are RF positive, the course tends to be more aggressive, with more long-term disability and the lowest remission rates among juvenile arthritis subtypes. Other rheumatologic conditions are associated with a positive RF ( Box 4 ). The clinical significance of RF in these conditions is unknown.

Anticyclic Citrullinated Peptide Antibodies

In rheumatoid arthritis, inflamed synovium contains citrullinated peptides, and patients with RA produce antibodies that bind specifically to substrates that contain citrulline. In adults, anticyclic citrullinated peptide (anti-CCP) antibodies are highly specific for RA and may be present before the onset of symptoms. These antibodies are found primarily in children with polyarticular, and rarely other subsets of, JIA. Anti-CCP antibodies have been associated with more aggressive disease, even in RF-negative polyarticular patients, and may indicate the need for more aggressive therapy. The precise role of anti-CCP testing in JIA has not been established.

Antineutrophil Cytoplasmic Antibodies

Antineutrophil cytoplasmic antibodies (ANCA) were discovered to have an association with granulomatosis with polyangiitis (GPA; formerly known as Wegener granulomatosis) in 1985. Since then, it has been found to be closely associated with 2 other systemic vasculitides: microscopic polyangiitis (MPA) and Churg-Strauss syndrome. In these conditions, the target of ANCA-binding is usually either myeloperoxidase (MPO) or serine protease 3 (PR3), which are found in granules of neutrophils and macrophages. The binding of ANCA to its target likely plays a pathogenic role in the pathophysiology of ANCA-associated vasculitis (AAV). This topic is discussed in more detail in the article on vasculitis by Weiss elsewhere in this issue.

Two methods are used to measure the ANCA: indirect IF and ELISA. Each method has clinical usefulness and both are usually ordered in patients in whom systemic vasculitis is suspected. IF is more sensitive, whereas ELISA is more specific. On IF, one of 2 staining patterns ( Fig. 2 ) may be seen: cytoplasmic (c-ANCA) or perinuclear (p-ANCA). ELISA measures antibodies against MPO and PR3. c-ANCA staining on IF usually correlates with a positive ELISA for PR3, and this pattern is primarily seen in GPA. p-ANCA staining usually correlates with a positive MPO ELISA, and this pattern is primarily seen in MPA. However, the associations among IF staining, ELISA, and disease are not rigid and some crossover may be seen ( Table 3 ). There are other conditions in which a positive ANCA by IF is found ( Box 5 ). Other than drug exposure, these conditions are generally not associated with positive ELISA for anti-PR3 or anti-MPO antibodies.

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