EDITORIAL - New ANA testing: does it cut costs and corners without jeopardizing clinical reliability?

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New Antinuclear Antibody Testing: Does it Cut Costs and

Corners Without Jeopardizing Clinical Reliability?

Medscape Rheumatology

Posted 09/28/2006

J Wallace

Synopsis

Background

Antinuclear antibodies (ANAs) are detected in the serum of

patients with most systemic autoimmune diseases. The traditional tool used

to detect ANAs is indirect immunofluorescence. A new, automated test, the

ELiA Symphony, detects antibodies against a mixture of nuclear and

cytoplasmic antigens (ENAs), in order to select sera samples that should be

further tested using a more expensive, automated line immunoassay, the

Lineblot test, to test for ANAs to non-antidouble-stranded-DNA.

Objective

The object of this study was to compare the cost and efficacy of

indirect immunofluorescence for the detection of ANAs with a fully automated

test, the ELiA Symphony, in order to diagnose autoimmune disease.

Design and Intervention

This study included sera samples from patients that were sent to

the laboratory of Immunology at the University Hospital Utrecht to be tested

for the presence of ANAs or anti-ENAs. Over a 4-month period, sera samples

were evaluated using indirect immunofluorescence, the ELiA Symphony test and

the Lineblot test. Sera testing positive for ANAs using indirect

immunofluorescence were then tested for antidouble-stranded DNA antibodies,

using the Farr assay. Results were compared to the incidence of signs and

symptoms of systemic autoimmune disease, which was determined both before

and after samples were taken.

Outcome Measures

The primary outcome measure of this trial was the comparative

accuracy and cost-effectiveness of indirect immunofluorescence, the ELiA

Symphony test and the Lineblot test in detecting ANAs related to systemic

autoimmune disease.

Results

In total, 328 sera samples were analyzed, of which 72 (22%) of

samples were Lineblot positive. Of the 198 patients who did not have

clinical indications of systemic autoimmune disease, 7% were Lineblot

positive. When the Lineblot test was used to analyze only

indirect-immunofluorescence-positive and ELiA-Symphony-positive samples,

Lineblot-positive sera were not detected in either case (26 samples from the

indirect-immunofluorescence group and 22 samples from the ELiA-Symphony

group); a total of 15 samples were detected as negative for ANAs. This

failure to detect reactivity was classified as clinically unimportant by the

authors.

Conclusion

The authors conclude that patients who meet at least one

criterion for systemic autoimmune disease can be restricted to the Lineblot

test; this is both an efficacious and cost-effective strategy. Screening

sera samples using indirect immunofluorescence or the ELiA Symphony test,

when clinical symptoms of disease have not been observed, will strongly

reduce the costs of anti-ENA detection. In this case, it is preferable to

screen patients with indirect immunofluoresence, rather than the ELiA

Symphony test.

Commentary

The lupus erythematosus (LE) cell-preparation assay was a perfectly

good test. Less than 1% of healthy individuals had a positive result, and

over 95% who demonstrated the LE cell phenomena had either systemic lupus

erythematosus (SLE), scleroderma or rheumatoid arthritis. Patients were

diagnosed with SLE if they had had positive LE cell preparations and

negative ANA test results.[1] There are only three reasons why the test is

rarely performed today: it is labor intensive; requires a special tube; and

cannot be automated.

Last year, the Cedars-Sinai Medical Center in Los Angeles instituted a

new process for ANA testing, using beads coupled with different antigens or

antigen mixtures to test for multiple autoantibodies in the same tube. The

main problem (among many others) was that multiple autoantibodies can be

present in the sera of SLE patients that are not necessarily detected by the

antigens that coat the beads. So many patients with documented SLE tested as

ANA negative, and the diagnosis of SLE was missed among so many hospital

admissions, that all 32 rheumatologists in our division signed a petition

asking the Department of Clinical Pathology to reconsider the use of this

new test. This scenario is being played out in different ways throughout the

US. It is compounded by the relatively high reimbursement rates for these

sophisticated tests, the cost savings of newer techniques, and the lucrative

contracts being offered to laboratory directors (who often have no clinical

rheumatology training) to change methodologies. One saving grace is that the

newer technologies have yet to refine methodologies for anti-DNA testing.

An additional problem is that most of the papers touting newer

anti-DNA refinements are industry funded and ghost-written, and thus are

biased to varying degrees. Charts are almost never reviewed by a

rheumatologist, or, if they are, without the rigor that such a cataclysmic

change in our practice should require. The comparative study by Vos et al.

likewise needs to be seriously examined.[1] At least all patients were

initially screened as being ANA positive by indirect immunofluorescence.

Additional autoantibodies were tested for by an automated line immunoassay,

as well as by traditional ELISA (enzyme-linked immunosorbent assay) and

immunoblotting techniques. The study raises as many questions as it answers.

Although 328 sera samples were studied, we cannot be sure how many patients

the samples were from. One of the authors reviewed some of the charts (it is

not known how many), not to check for fulfillment of ACR criteria, but to

look for undefined " autoimmune symptoms " . The article is replete with

references to " SLE like " and " scleroderma like " clinical profiles, which are

also undefined. Patient permission or consent for chart reviews was felt to

be unnecessary. It is also not stated who provided the reagents, or if any

of the authors served as consultants for the manufacturers. The discussion

disturbingly ruminates about going to the next step: restricting access and

permissions to order additional autoantibody testing in patients who are ANA

negative, in order to lower costs.

Refinements of testing for ANAs to non-antidouble-stranded-DNA that

are cost-effective, sensitive and specific are admirable and achievable

goals and should follow evidence-based guidelines.[2] This author believes

that such an undertaking should be validated by a study underwritten by a

nonprofit organization with detailed chart reviews. There is nothing worse

than telling a patient they do or do not have a disease on the basis of

anything less than the best methodologies of ascertainment.

Practice Point

Pending a detailed review of alternative, cost-effective tests,

screening for antinuclear antibodies should be performed by indirect immune

fluorescence.

http://www.medscape.com/viewarticle/543901_1

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