Lupus: The Essential Clinician's Guide (Oxford American Rheumatology Library), 2nd Ed

Chapter 6. Laboratory and Imaging Abnormalities

Routine Testing in General Medical Offices

A typical primary care physician’s clinical laboratory and imaging center allows him or her to successfully diagnose, stage, and monitor response to therapy in lupus patients. The complete blood count screens for anemia, autoimmune hemolytic anemia, leucopenia, lymphopenia, leukocytosis, and thrombocytopenias. A comprehensive metabolic panel, along with lipid and thyroid testing, evaluates liver, renal, and metabolic functions. A routine urinalysis shows sediment, casts, or protein excretion in individuals with renal involvement. Muscle enzymes are elevated with myositis. The partial thromboplastin time is prolonged in many patients with the lupus anticoagulant. Acute-phase reactants such as erythrocyte sedimentation rate and C-reactive protein are elevated with active disease. Chest radiographs reveal pleural effusions, pleural scarring, and interstitial or alveolar changes, while electrocardiograms may suggest pericarditis or myocarditis as well as screen for infarction, strain patterns, or arrhythmias. Joint imaging screens for erosions, calcinosis, and avascular necrosis.1

Table 6.1 provides a summary of the levels and type of testing useful in managing lupus patients.2

Useful, Readily Available, Community-Based Testing

Lupus practitioners may order readily available testing outside of their clinic or office that may be useful in specific settings. Examples include a 2-D echo-cardiogram to screen for pulmonary hypertension or pericardial effusion, electromyography with nerve conduction velocities to confirm the presence of myositis or neuropathies, electroencephalography for seizures, computed tomography (CT) scans to confirm or evaluate splenomegaly and interstitial lung disease, and magnetic resonance imaging for avascular necrosis or cerebritis, among others (Table 6.1).

Complement

The complement system comprises more than 30 plasma- and membrane-bound proteins designed to protect against invading pathogens. Most exist in the plasma as functionally inactive proproteins until appropriate events trigger their activation. Classical and alternative pathways involve C1-C4, among other proteins, which converge into a membrane attack complex consisting of C5b-C9. A hereditary deficiency of C1, C2, or C4 has been associated with the development of SLE (relevant in less than 1% of patients). In systemic lupus erythematosus patients, decreased serum levels of C3 and C4 components are usually associated with inflammation and correlate with disease activity.

Table 6.1 Summary of useful tests used in systemic lupus erythematosus

Level 1: Routine screening for all patients (total cost <$500)

• Complete blood count

• Comprehensive metabolic profile

• Urinalysis

• Muscle enzymes (e.g., creatine phosphokinase)

• Acute-phase reactants (e.g., C-reactive protein or sedimentation rate)

• Chest radiograph

• Electrocardiogram

• Antinuclear antibody

• C3 or C4 complement

• Anti-dsDNA

Level 2: Readily available, inexpensive testing for selected patients

• Partial thromboplastin time

• 2-D echocardiography

• Hand or feet radiographs

• Rheumatoid factor

• Bone densitometry

Level 3: Reflex panel testing to characterize nature of lupus involvement

• Anti-extractable nuclear antigen panel (anti-Sm, -RNP, -SSA, -SSB)

• Antiphospholipid panel (syphilis serology, lupus anticoagulant, anticardiolipin)

Level 4: Specialized testing limited to selected clinical circumstances

• Computed tomography or magnetic resonance imaging

• Electrical studies (e.g., electroencephalography, electromyography)

• Niche serologies (e.g., antihistone, chromatin, neuronal, ribosomal P)

• Bone scan

Serological Evaluations

The antinuclear antibody (ANA) is considered the gold standard for identifying SLE. Positive in 96% of those with the disease, it has very poor specificity and can be present in up to 10% of a healthy population, and may be found in patients with other autoimmune conditions (Table 6.2).3 ANA-negative lupus is usually seen in patients with chronic cutaneous disease or antiphospholipid syndrome or in individuals who have had long-term corticosteroid or immunosuppressive therapy, during which a positive ANA becomes negative. Titers are of little value, but higher numbers are associated with autoimmune disorders. A homogeneous or rimmed pattern on immune fluorescence is suggestive of lupus, whereas speckled patterns are nonspecific, and nucleolar or centromere staining suggests a scleroderma component.

Table 6.2 Hypercoagulability in SLE: A Venn diagram of overlapping features.

Prevalence of ANA in the US

Cross-sectional analysis of 4754 NHANES individuals

13.8% older than 12 years of age were positive

Prevalence higher among

• African Americans

• Females

• Older individuals

32 million people in the US have elevated ANAs, fewer than 1 million have lupus, but 98%

Satoh M. Arthritis Rheum. 2012;64:2319–2327. Kavanaugh A, et al. Arch Pathol Lab Med. 2000;124(1):71–81.

Most laboratories have a “reflex panel,” whereby additional serologies are performed if the antinuclear antibody is positive.4 Over 140 autoantibodies have been identified in rheumatic diseases. Those clinically relevant to SLE are reviewed in this section. Antibodies to nuclear components of the cell include anti-DNA, antihistone, antichromatin, and antibodies to extractable nuclear antigens (ENAs) (e.g., anti-Sm/RNP). Antibodies to double-stranded DNA are present in half of those with lupus; positively charged antibodies can directly damage tissue and are especially important in nephritis. If measured by a Farr or enzyme-linked immunosorbent assay (ELISA), anti-DNA levels are used to follow the patient’s response to therapy. Antihistone antibodies are present in drug-induced lupus and a small percentage of those with rheumatoid arthritis. These structural proteins are responsible for the LE cell phenomenon. Antichromatin antibodies appear phylogenetically before anti-DNA and are usually fairly specific for the presence of SLE but are of little clinical significance. The anti-Sm (or Smith) antibody is named after the patient in whom it was first reported, and it interferes with one’s ability to transcribe RNA from DNA. It is seen in 20% of those with SLE but less than 1% of healthy individuals. Following its levels is of no clinical value. Antibodies to ribonucleoprotein are seen in low titers in SLE patients and in higher titers in those with mixed connective tissue disease. By definition, the diagnosis of MCTD is not possible without anti-RNP. This antibody interferes with the ability of RNA to bind in the cytoplasm of cells. Clinically, individuals with moderate to high titers of anti-RNP have puffy hands, Raynaud’s phenomenon, and an increased prevalence of pulmonary hypertension.

The principal antibodies to cytoplasmic components include antibodies to Ro and La (also known as the Sjögren’s antibodies, SS-A and SS-B). Anti-Ro is found in the majority of patients with primary Sjögren’s syndrome and approximately 20% to 30% of those with SLE. It interferes with the cell’s ability to process RNA and is clinically associated with increased photosensitivity and subacute cutaneous lupus. Anti-Ro has the ability to cross the placenta, and its 52-kDa protein can induce a transient rash in newborns (known as neonatal lupus) or congenital heart block. Anti-Ro is 50% more common than anti-La, and the latter may mitigate some of the injury associated with the former. La functions as a way station on the road to where RNA transcripts are carried from the nucleus to the cytoplasm. Antibodies to ribosomal P are seen in 20% of individuals with SLE. Its levels are not important in lupus treatment, but they do clinically correlate with liver injury, depression, and psychosis. Antibodies to phospholipids in cell membranes are features of the antiphospholipid syndrome5,6 (see Fig. 6.1).

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Figure 6.1 Antiphospholipid antibodies In 1/3 with SLE, 1/3 of whom have APS.

Antibodies to cellular components noted in lupus include antierythrocyte, antilymphocyte, antiplatelet, antineutrophil (antineutrophil cytoplasmic antibodies [ANCA]), and antineuronal antibodies. These are markers of damage to these cells and are infrequently useful in a clinical setting. Additionally, antibodies form against circulating antigens. Rheumatoid factor is reported in 30% with SLE and is nonspecific, although joint inflammation is more common in these patients. Last, circulating immune complexes can vary according to charge, avidity, size, antigen excess, or antibody excess, and are rarely followed. Their levels are increased in active lupus as well as in a variety of infections (see Table 6.3).

Table 6.3 Important autoantibodies and antibodies in lupus

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References

1. Sheldon J. Laboratory testing in autoimmune rheumatic diseases. Best Pract Res Clin Rheumatol. 2004;18:249-269.

2. Wallace DJ, Schwartz E, Lin H-C, Peter JB. The “rule-out lupus” rheumatology consultation: clinical outcomes and perspectives. J Clin Rheumatol. 1995;1:158–164.

3. Kurien BT, Scofield RH. Autoantibody testing in the diagnosis of systemic lupus erythematosus. ScandJ Immunol. 2006;64:227–235.

4. Sherer Y, Gorstem A, Fritzler MJ, Shoenfeld Y. Autoantibody explosion in systemic lupus: more than 100 different autoantibodies found in SLE patients. Semin Arthritis Rheum. 2004;34:501–537.

5. Satoh M, Chan EK, Ho LA. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum. 2012;64:2319–2327.

6. Kavanaugh A, Romar R, Reveille J, et al. Guidelines for clinical use of the antinuclear tests for specific autoantibodies and nuclear antigens. Arch Pathol Lab Med. 2000;124:71–81.



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