Letter to the Editor
The Value of a Negative Antinuclear Antibody (ANA) Test: An Often Forgotten Result
El valor de una prueba de anticuerpos antinucleares (ANA) negativa: un resultado a menudo olvidado
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Lee" "autores" => array:1 [ 0 => array:4 [ "nombre" => "Adrian Y.S." "apellidos" => "Lee" "email" => array:1 [ 0 => "adrian.lee1@health.nsw.gov.au" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "ICPMR & Department of Immunology, Westmead Hospital, Westmead, NSW, Australia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Westmead Clinical School, The University of Sydney, Westmead, NSW, Australia" "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "El valor de una prueba de anticuerpos antinucleares (ANA) negativa: un resultado a menudo olvidado" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1001 "Ancho" => 1255 "Tamanyo" => 287998 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Example cytoplasmic staining on the HEp-2 substrate. (A) F-actin staining suggesting the presence of smooth muscle antibodies found in autoimmune hepatitis and related disorders. (B) Coarse, granular cytoplasmic staining suggestive of anti-mitochondrial antibodies found in primary biliary cirrhosis. (C) Smooth, homogenous cytoplasmic staining suggestive of anti-ribosomal P antibodies found in systemic lupus erythematosus. (D) Large cytoplasmic dots staining suggestive of anti-GW bodies. All micrographs are taken at a magnification of 400×.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">It is quite clear that medicine is biased towards positive results and the same applies to the practice of pathology.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a> One of the ubiquitous tests in autoimmunity, the antinuclear antibody (ANA) suffers from this very same fate. A number of guidelines report on the clinical utility of a positive ANA and dissuade clinicians from requesting this test in the setting of low pre-test probability for an ANA-associated autoimmune disorder (AAD).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">2</span></a> This is certainly sound advice and prevents unnecessary investigations and healthcare expenditure. Yet, it is important to realise the clinical importance and pitfalls of a negative ANA results which sometimes becomes forgotten.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The internationally-accepted “gold standard” to measure ANA is via indirect immunofluorescence on HEp-2 cells.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a> A negative ANA test on HEp-2 substrate usually means that there is no significant detection of IgG ANA (in the nucleus) at a specified dilution of serum – usually 1:80 to 1:160. There is a move to also classify positive cytoplasmic and mitotic staining of the HEp-2 substrate as ANA positive.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">3,4</span></a> This may improve the sensitivity of detecting AADs and prompt appropriate further testing and follow-up (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The high sensitivity and negative predictive value (NPV) for systemic lupus erythematosus (SLE) makes the ANA test a good “rule out” test to essentially exclude this disorder if it is negative.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> Indeed, the most recent European League Against Rheumatism/American College of Rheumatology guidelines for the diagnosis of SLE mandates a positive ANA (<span class="elsevierStyleUnderline">></span>1:80) on the HEp-2 substrate to be considered for this diagnosis.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> Sensitivities for detecting other AADs is low-moderate at best; yet also demonstrates very high NPVs.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> Unless there has been a significant change in clinical picture or there is a suspicion of a laboratory issue, there is little value in repeating an ANA that is initially negative.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">A pitfall is that ANA is a screening test and may, in rare instances, miss low-level specific autoantibodies/anti-extractable nuclear antigens (ENAs) if more sensitive assays are not performed,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a> or miss anti-ENA that do not produce a characteristic ANA pattern e.g., anti-Ro52. Therefore, the substrate should be specified in the report since substrates such as the HEp-2000® (Immunoconcepts) which has transfected Ro60 increase the detection of anti-Ro60 and hence, a negative result makes the presence of anti-Ro60 less likely.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">If there is a high clinical suspicion for an AAD, the clinician should request further anti-ENA tests and the overall clinical picture and physician's interpretation of the patient should prevail. This is especially of importance since commercial HEp-2 substrates, whilst generally demonstrating excellent inter-assay and inter-laboratory agreement, display subtle staining differences that affect the microscopist's final interpretation.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> The significance of low levels of anti-ENA with negative ANA is not well established.</p><p id="par0030" class="elsevierStylePara elsevierViewall">To conclude, clinicians should be aware of the value, implications and pitfalls of a negative ANA result when considering AADs. They should also be aware of their laboratory's definitions of a “negative” ANA result, the substrate used and whether they report non-nuclear patterns which may have important implications for their patients. Importantly, the overall clinical picture of the patient should be taken into considerations when deciding on the relevancy of a negative ANA test.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0035" class="elsevierStylePara elsevierViewall">Nil.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interests</span><p id="par0040" class="elsevierStylePara elsevierViewall">None declared.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interests" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1001 "Ancho" => 1255 "Tamanyo" => 287998 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Example cytoplasmic staining on the HEp-2 substrate. (A) F-actin staining suggesting the presence of smooth muscle antibodies found in autoimmune hepatitis and related disorders. (B) Coarse, granular cytoplasmic staining suggestive of anti-mitochondrial antibodies found in primary biliary cirrhosis. (C) Smooth, homogenous cytoplasmic staining suggestive of anti-ribosomal P antibodies found in systemic lupus erythematosus. (D) Large cytoplasmic dots staining suggestive of anti-GW bodies. All micrographs are taken at a magnification of 400×.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib0060" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Publication bias in clinical trials of electronic health records" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D.K. Vawdrey" 1 => "G. 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| 2023 Febrero | 2 | 2 | 4 |
| 2023 Enero | 1 | 0 | 1 |
| 2022 Diciembre | 56 | 0 | 56 |
| 2022 Noviembre | 7 | 5 | 12 |
| 2022 Octubre | 6 | 2 | 8 |
| 2022 Junio | 1 | 0 | 1 |
| 2022 Mayo | 1 | 0 | 1 |
| 2021 Octubre | 1 | 0 | 1 |
| 2021 Septiembre | 1 | 0 | 1 |
| 2021 Julio | 1 | 0 | 1 |
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