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Response to: Detection of antinuclearantibodies: added-value of solid phase assay?by Bossuyt and Fieuws

We have read the letter by Bossuyt and Fieuws entitled

Detection of anti-nuclear antibodies, added-value of solid phase

assay?with great interest.1

In this letter, the authors described acomparison between anti-nuclear antibodies (ANA) performedby indirect immunouorescent assay (IIFA) and by an automatedmethod (uoroenzymeimmunoassay; EliA CTD screen, ThermoFisher) using samples obtained from patients with systemiclupus erythematosus (SLE), systemic sclerosis, Sjgrens syn-drome (SS) and healthy controls. The authors concluded thatthe favourable method for ANA detection is disease dependentand that combining IIFA with solid phase assay can increase thediagnostic accuracy.

These points, raised by Bossuyt and Fieuws, may be regardedin the perspective of the international recommendations for

ANA detection that we have recently published.2 Indeed, ourrecommendations support the use of IIFA as well as alternativemethods (such as EliA) to determine antibodies of the ANAfamily, even stating that these new methods may represent thefuture of autoimmune diagnostics. However, it should be notedthat, unlike most new methods, IIFA enables detection ofnumerous cellular antigens. Furthermore, diagnostic/classica-tion criteria of several autoimmune diseases, like SLE, auto-immune 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 thesuspected diagnosis, IIFA should remain the reference method.On the other hand, we2 have highlighted the limitations of IIFAand acknowledged, similarly to Bossuyt X and Fieuws S, thatcertain methods may be easier to perform and even more sensi-

tive than IIFA regarding a specic autoimmune disease, forinstance, SS or inammatory myopathies. However, this shouldbe evaluated for each method regarding each autoimmunedisease and addressing different populations. More importantly,information regarding each alternative method should be clearlycommunicated with the requesting physician (ie, method ofchoice and test characteristics for the respective autoimmunediseases) to avoid erroneous application of IIFA test characteris-tics to these alternative methods.

The issue of using multiple screening tests has been raised byus and by others. We believe that this may signicantly improvethe accuracy of autoimmune diagnostics, but it requires a sophis-ticated algorithm for interpretation of discrepant results.Moreover, it is highly unlikely to be cost-effective and mostlikely is in conict with most national reimbursement policies.

Notably, most requests for ANA testing are issued by generalpractitioners and non-rheumatologists/immunologists and inmany cases this is done in the context of diagnosing a widearray of conditions.3 Given the poor specicity of ANA testingby IIFA, it can be argued that in particular ANA requests forpatients with a low pretest probability solid phase assays may bepreferred.4 We agree with Bossuyt X and Fieuws S that differentdiseases do require different approaches and we have recentlydealt with the issue of multiple testing algorithms for distinctautoimmune conditions as specied in gure 1.5 Furthermore,in our international recommendations2 we highly supported theaddition of laboratory comments that will specify further

options. For instance, adding a comment such as If clinical sus-picion of SS is high, further studies using an alternative methodsuch 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 commu-nication: that is, clinical information enables appropriatechoices in the laboratory and laboratory comments direct appro-priate add-on testing to be requested by the physician.

Nancy Agmon-Levin,1 Jan Damoiseaux,2 Yehuda Shoenfeld1,3

1The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center,Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Israel2Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht,The Netherlands3Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases,Tel-Aviv University, Tel-Aviv, Israel

Competing interests None.

Provenance and peer review Commissioned; internally peer reviewed.

To cite Agmon-Levin N, Damoiseaux J, Shoenfeld Y.Ann Rheum Dis 2014;73:e11.

Received 11 November 2013Accepted 17 November 2013Published Online First 6 December 2013

http://dx.doi.org/10.1136/annrheumdis-2013-204793

Ann Rheum Dis2014;73:e11. doi:10.1136/annrheumdis-2013-204797

REFERENCES1 Bossuyt X, Fieuws S. Detection of anti-nuclear antibodies, added-value of solid phase

assay?Ann Rheum Dis2014;73:e10.2 Agmon-Levin N, Damoiseaux J, Kallenberg C, et al. International recommendations

for the assessment of autoantibodies to cellular antigens referred to as anti-nuclearantibodies. Ann Rheum Dis2014;73:1723.

3 Mahler M, Hanly JG, Fritzler MJ. Importance of the dense ne speckled pattern onHEp-2 cells and anti-DFS70 antibodies for the diagnosis of systemic autoimmunediseases. Autoimmun Rev2012;11:6425.

4 Abeles AM, Abeles M. The clinical utility of a positive antinuclear antibody testresult. Am J Med2013;126:3428.

5 Damoiseaux J, Agmon-Levin N. Anti-Nuclear Antibodies: a long way toharmonization. In: Conrad K, Chen EKL, Fritzler RL, et al. (Eds). Infections, Tumorsand AutoimmunityPabst Science Publishers; Autoantigens, Autoantibodies,Autoimmunity 2013;9:284289 (E-book).

Figure 1 Testing in systemic autoimmune rheumatic diseases andautoimmune hepatitis should be guided by the specic disease underconsideration. In this gure, solid arrows indicate rst-line testing,while dashed arrows indicate follow-up testing. AIH, autoimmunehepatitis; ANA, anti-nuclear antibodies; CENP-B, centromere protein B;IIFA, indirect immunouorescent assay; JIA, juvenile idiopathic arthritis;MCTD, mixed connective tissue disease; RNP, ribonucleoprotein; SLE,systemic lupus erythematosus; SSA, anti SSA/Ro antibodies; SSB, antiSSB/La antibodies.

Ann Rheum DisMarch 2014 Vol 73 No 3 e11

Letter response

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doi: 10.1136/annrheumdis-2013-2047972013

2014 73: e11 originally published online December 6,Ann Rheum Dis

Nancy Agmon-Levin, Jan Damoiseaux and Yehuda Shoenfeldassay?' by Bossuyt and Fieuwsantibodies: added-value of solid phaseResponse to: 'Detection of antinuclear

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