Letter to the Editor
Reply to: “Understanding the Immunogenicity Concept”
Respuesta a: «Comprender el concepto de inmunogenicidad»
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Valor and de la Torre entitled “Understanding the concept of immunogenicity”<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and we would like to provide some comments and considerations.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Immunogenicity is defined as the formation of antibodies directed against a protein and all therapeutic proteins may trigger an unwanted immune response, which is highly dependent on the structure.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> There are 2 types of antibodies<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> non-neutralizing antibodies, formed against recombinant structures and immunoglobulin receptors and which bind to the drug through an area different from that used to bind to the ligand, so they theoretically do not affect its mechanism of action. These antibodies form immune complexes bound to the drug that are slowly removed from the circulation decreasing its bioavailability. Another type of antibodies are neutralizing, recognizing idiotypes of therapeutic antibodies, such as infliximab and adalimumab, inhibiting the binding of the drug to its ligand, leading not only to a decrease in the concentration of free drug but also reduced efficacy.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The difference between them lies not only in their clinical consequences, but also in the difficulty for their detection.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Treatment with anti-TNF follows the rules of the classical pharmacokinetic,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> in which circulating drug levels are related to efficiency, with very high levels (above threshold) associated with toxicity and<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> inefficiency. Serum concentrations of anti-TNF drugs are variable due to a variety of factors, the presence of antibodies against the drug, the main cause of evident suboptimal concentrations, which is related to the loss of efficiency, a need to increase the dose and the occurrence of infusion reactions.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> A meta-analysis and systematic review of the recent literature, which analyzes all articles published to date on the immunogenicity of anti-TNF treatment, reaches these conclusions.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">There are still many clinicians, probably supported by clinical trial data,<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–9</span></a> considering immunogenicity as an unimportant issue and have the idea that antibody formation to TNF blockers has limited clinical consequences, and there are several reasons that may explain this view. First, the use of very sensitive techniques<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> limits the detection of antibodies in many patients and does not give a real idea of their frequency. Second, the different incidence of immunogenicity, even with the same drug and the same disease, reduces clinical credibility from immunogenicity, but this may be due to serum collection time, the various methods used for the determination of antibodies, drug exposure and other undefined variables. Third, the impact of immunogenicity in clinical practice can not be measured in all its consequences while its determination is not used routinely and does not obtain enough data to relate the different clinical events with drug levels and the presence of anti-drug antibodies.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Immunogenicity is a dynamic process,<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11–13</span></a> and anti-drug antibodies can appear even at 2 years or more after biological treatment, so the determination of the frequency of immunogenicity in clinical trials, usually of short duration, and in extension studies, which only include completers, is obviously underestimated. The fact that a patient has not been shown to have antibodies after treatment does not mean that they can not be detected months later, because this involves various factors such as the duration of treatment, concomitant treatment and dosing schedules, among others. For example, a patient who has produced a small amount of antibodies that then bind to drug and are undetected, may result positive for these if drug administration is spaced so as to disappear from circulation following the usual patterns of pharmacokinetics.</p><p id="par0030" class="elsevierStylePara elsevierViewall">One of the biggest obstacles to assess immunogenicity is the difficulty of measuring antidrug antibodies. As the immunogenic epitopes of each drug are not yet identified, assays have been developed to evaluate the binding of labeled drug (enzymatically or radioactively) with the antibody present in the serum. The most commonly used tests to date, and which are reflected in some.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,6</span></a> 2 good reviews are grouped mainly into two methods: ELISA and RIA, as is well mentioned in the editorial that we are commenting upon. The fact that there are no standard or known concentration patterns, that would permit us to establish threshold values of positivity, does not mean that the tests are not validated, not reproducible or not useful to obtain clinically relevant conclusions. The ELISA and RIA methods have ample evidence, throughout the history of immunology, including the field of rheumatology, that show them to be extremely useful to obtain data for diagnosis and prognosis. Even so, poorly standardized ELISA is used to detect antiphospholipid antibodies, which 25 years since its description still shows no consensus on the nature of the antigenic epitopes, or on the specific assay conditions of,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> but are used in daily clinical and gives a clear diagnostic and prognostic value. There is, in addition, little uniformity between the methods for detecting antibodies against granulocyte cytoplasm,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> a field in which there is still no standardization to establish whether it is more appropriate or more relevant to perform granulocyte immunofluorescence or enzyme assays with specific purified antigens. However, these tests produce very useful clinical information, with both the laboratory and the clinician aware of their limitations. In our opinion, the tests that are being used today to evaluate immunogenicity do not lack sensitivity, specificity or reproducibility, but rather we need to learn to interpret the results in the context of the circumstances of the patients being treated.</p><p id="par0035" class="elsevierStylePara elsevierViewall">All these tests have the problem of interference from the presence of the drug when detecting the antibodies. If any drug is present in the serum antibodies, it forms immune complexes, and the complexes are not detected by standard ELISA and RIA. Some authors have described<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16,17</span></a> acid dissociation methods to detect low levels of antibodies to immune complexes present in early stages of treatment, but with little or no clinical significance, since they fail to neutralize circulating drug levels. A bridge ELISA assay, which detects only antibody levels in excess of the concentration of drug, is currently used<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> as it best reflects the clinical impact of immunogenicity, since a positive result in this test means a total absence of free drug and, therefore, a lack of clinical efficacy.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion, we could say that, in our opinion, the immunogenicity of biologics is an alarm signal, which can be very useful when making treatment decisions. However, according to the authors of the editorial, the clinical efficacy of the drugs is in circulating therapeutic levels, with immunogenicity being a minor player that has to be taken into account mainly because it causes an abnormal decrease or disappearance of the drug and, therefore, the loss of its effectiveness.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Balsa A, et al. Respuesta a: «Comprender el concepto de inmunogenicidad». Reumatol Clin. 2013. <span class="elsevierStyleInterRef" id="intr0005" href="doi:10.1016/j.reuma.2013.03.004">http://dx.doi.org/10.1016/j.reuma.2013.03.004</span>.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Understanding the immunogenicity concept" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 10 | 18 |
| 2024 October | 23 | 25 | 48 |
| 2024 September | 26 | 12 | 38 |
| 2024 August | 42 | 26 | 68 |
| 2024 July | 31 | 31 | 62 |
| 2024 June | 30 | 30 | 60 |
| 2024 May | 37 | 24 | 61 |
| 2024 April | 33 | 10 | 43 |
| 2024 March | 40 | 27 | 67 |
| 2024 February | 44 | 21 | 65 |
| 2024 January | 24 | 20 | 44 |
| 2023 December | 39 | 17 | 56 |
| 2023 November | 33 | 25 | 58 |
| 2023 October | 29 | 31 | 60 |
| 2023 September | 82 | 38 | 120 |
| 2023 August | 21 | 12 | 33 |
| 2023 July | 28 | 28 | 56 |
| 2023 June | 29 | 18 | 47 |
| 2023 May | 26 | 24 | 50 |
| 2023 April | 28 | 8 | 36 |
| 2023 March | 45 | 29 | 74 |
| 2023 February | 31 | 29 | 60 |
| 2023 January | 35 | 13 | 48 |
| 2022 December | 50 | 42 | 92 |
| 2022 November | 55 | 27 | 82 |
| 2022 October | 38 | 27 | 65 |
| 2022 September | 67 | 64 | 131 |
| 2022 August | 75 | 38 | 113 |
| 2022 July | 69 | 64 | 133 |
| 2022 June | 50 | 36 | 86 |
| 2022 May | 52 | 42 | 94 |
| 2022 April | 48 | 48 | 96 |
| 2022 March | 68 | 40 | 108 |
| 2022 February | 21 | 33 | 54 |
| 2022 January | 17 | 30 | 47 |
| 2021 December | 21 | 44 | 65 |
| 2021 November | 25 | 46 | 71 |
| 2021 October | 42 | 53 | 95 |
| 2021 September | 24 | 29 | 53 |
| 2021 August | 21 | 42 | 63 |
| 2021 July | 18 | 27 | 45 |
| 2021 June | 22 | 41 | 63 |
| 2021 May | 23 | 22 | 45 |
| 2021 April | 49 | 67 | 116 |
| 2021 March | 44 | 15 | 59 |
| 2021 February | 18 | 23 | 41 |
| 2021 January | 19 | 13 | 32 |
| 2020 December | 32 | 18 | 50 |
| 2020 November | 28 | 17 | 45 |
| 2020 October | 12 | 13 | 25 |
| 2020 September | 21 | 18 | 39 |
| 2020 August | 19 | 13 | 32 |
| 2020 July | 17 | 14 | 31 |
| 2020 June | 31 | 7 | 38 |
| 2020 May | 14 | 19 | 33 |
| 2020 April | 27 | 12 | 39 |
| 2020 March | 20 | 8 | 28 |
| 2020 February | 2 | 0 | 2 |
| 2019 April | 2 | 0 | 2 |
| 2019 January | 1 | 0 | 1 |
| 2018 May | 5 | 6 | 11 |
| 2018 April | 30 | 8 | 38 |
| 2018 March | 37 | 5 | 42 |
| 2018 February | 24 | 2 | 26 |
| 2018 January | 19 | 6 | 25 |
| 2017 December | 22 | 5 | 27 |
| 2017 November | 22 | 9 | 31 |
| 2017 October | 20 | 1 | 21 |
| 2017 September | 26 | 5 | 31 |
| 2017 August | 30 | 6 | 36 |
| 2017 July | 19 | 6 | 25 |
| 2017 June | 36 | 8 | 44 |
| 2017 May | 31 | 13 | 44 |
| 2017 April | 26 | 4 | 30 |
| 2017 March | 32 | 5 | 37 |
| 2017 February | 25 | 10 | 35 |
| 2017 January | 30 | 10 | 40 |
| 2016 December | 70 | 25 | 95 |
| 2016 November | 37 | 8 | 45 |
| 2016 October | 67 | 8 | 75 |
| 2016 September | 58 | 10 | 68 |
| 2016 August | 63 | 11 | 74 |
| 2016 July | 28 | 4 | 32 |
| 2016 June | 0 | 14 | 14 |
| 2016 May | 1 | 14 | 15 |
| 2016 February | 1 | 0 | 1 |
| 2016 January | 1 | 0 | 1 |
| 2015 December | 2 | 0 | 2 |
| 2015 October | 0 | 14 | 14 |
| 2015 September | 1 | 0 | 1 |
| 2015 August | 1 | 0 | 1 |
| 2015 July | 11 | 6 | 17 |
| 2015 June | 31 | 4 | 35 |
| 2015 May | 18 | 8 | 26 |
| 2015 April | 33 | 11 | 44 |
| 2015 March | 23 | 3 | 26 |
| 2015 February | 30 | 5 | 35 |
| 2015 January | 30 | 6 | 36 |
| 2014 December | 23 | 8 | 31 |
| 2014 November | 28 | 6 | 34 |
| 2014 October | 28 | 10 | 38 |
| 2014 September | 29 | 7 | 36 |
| 2014 August | 32 | 9 | 41 |
| 2014 July | 36 | 12 | 48 |
| 2014 June | 42 | 10 | 52 |
| 2014 May | 43 | 20 | 63 |
| 2014 April | 35 | 7 | 42 |
| 2014 March | 31 | 14 | 45 |
| 2014 February | 35 | 10 | 45 |
| 2014 January | 26 | 14 | 40 |
| 2013 December | 22 | 15 | 37 |
| 2013 November | 17 | 9 | 26 |
| 2013 October | 33 | 3 | 36 |
| 2013 September | 31 | 13 | 44 |
| 2013 August | 43 | 21 | 64 |
| 2013 July | 21 | 11 | 32 |
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