Response to: Detection of anti-nuclear antibodies. Added-value of solid phase assay?
We have read the letter by Bossuyt X. and Fieuws S. entitled "Detection of anti-nuclear antibodies, added-value of solid phase assay?" with great interest (1). In this letter the authors described a comparison between anti-nuclear antibodies (ANA) performed by indirect immunofluorescent assay(IIFA) and by an automated method (fluoroenzymeimmunoassay; EliA CTD screen, Thermo Fisher) using samples obtained from patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc),Sj?gren's syndrome (SS) and healthy controls. The authors concluded that the favorable method for ANA detection is disease-dependent and that combining IIFA with solid phase assay can increase the diagnostic accuracy. These points, raised by Bossuyt X. and Fieuws S., may be regarded in the perspective of the international recommendations for ANA detection that we have recently published (2). Indeed, our recommendations support the use of IIFA as well as alternative methods (such as EliA) to determine antibodies of the ANA family, even stating that these new methods may represent the future of autoimmune diagnostics. However, it should be noted that, unlike most new methods, IIFA enables detection of numerous cellular antigens. Furthermore, diagnostic/classification criteria of several autoimmune diseases, like SLE, autoimmune hepatitis and juvenile idiopathic arthritis, are based on ANA results obtained by IIFA. Thus, for screening purposes, especially as laboratory personnel are usually unaware of the suspected diagnosis, IIFA should remain the reference method. On the other hand we (2) have highlighted the limitations of IIFA and acknowledged, similarly to Bossuyt X. and Fieuws S., that certain methods may be easier to perform and even more sensitive than IIFA regarding a specific autoimmune disease, for instance SS or inflammatory myopathies. However, this should be evaluated for each method regarding each autoimmune disease and addressing different populations. More importantly, information regarding each alternative method should be clearly communicated with the requesting physician (i.e. method of choice and test characteristics for the respective autoimmune diseases) to avoid erroneous application of IIFA test characteristics to these alternative methods.
The issue of using multiple screening tests has been raised by us and by others. We believe that this may significantly improve the accuracy of autoimmune diagnostics, but it requires a sophisticated algorithm for interpretation of discrepant results. Moreover, it is highly unlikely to be cost-effective and most likely is in conflict with most national reimbursement policies.
Notably, most requests for ANA testing are issued by general practitioners and non-rheumatologists/immunologists and in many cases this is done in the context of diagnosing a wide array of conditions (3). Given the poor specificity of ANA testing by IIFA, it can be argued that in particular ANA requests for patients with a low pre-test probability solid-phase assays may be preferred (4). We agree with Bossuyt X. and Fieuws S. that different diseases do require different approaches and we have recently dealt with the issue of multiple testing algorithms for distinct autoimmune conditions as specified in Fig. 1 (5). Furthermore, in our international recommendations (2) we highly supported the addition of laboratory comments that will specify further options. For instance, adding a comment such as "If clinical suspicion of SS is high, further studies using an alternative method such as EliA should be considered" may guide the physician to request the additional tests in a much more restricted way. Again, this underscores the importance of bidirectional communication: i.e. clinical information enables appropriate choices in the laboratory and laboratory comments direct appropriate add-on testing to be requested by the physician.
Figure see the monthly ePage for Annals of the Rheumatic Diseases
1. Bossuyt X and Fieuws S. "Detection of anti-nuclear antibodies, added- value of solid phase assay?" Current Issue.
2. Agmon-Levin N, Damoiseaux J, Kallenberg C, et al. International recommendationsfor the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis 2013 Oct 14.
3. Mahler M, Hanly JG, Fritzler MJ. Importance of the dense fine speckled pattern on HEp-2 cells and anti-DFS70 antibodies for the diagnosis of systemic autoimmune diseases. Autoimmun Rev 2012;11(9):642-5.
4. Abeles AM, Abeles M. The clinical utility of a positive antinuclear antibody test result. Am J Med 2013;126:342-348.
5. Damoiseaux JandAgmon-Levin N. Anti-Nuclear Antibodies: a long way to harmonization. In: Infections, Tumors and Autoimmunity (Eds: Conrad K, Chen EKL, Fritzler RL et al.), Autoantigens, Autoantibodies, Autoimmunity 2013;9:284-289 (E-book).
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