Publish in this journal
Journal Information
Vol. 9. Issue 4.
Pages 253-254 (July - August 2013)
Vol. 9. Issue 4.
Pages 253-254 (July - August 2013)
Letter to the Editor
DOI: 10.1016/j.reumae.2013.03.009
Full text access
Reply to Balsa et al. Relative With the Review “Understanding the Concept of Immunogenicity”
Respuesta a Balsa et al. en relación con la revisión «Entendiendo el concepto de inmunogenicidad»
Lara Valor, Inmaculada de la Torre??
Corresponding author
Servicio de Reumatología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
Article information
Full Text
Download PDF
Full Text
Dear Editor,

We would like to thank Balsa et al. their interest and comments on the review “Understanding the concept of immunogenicity”,1 in giving their opinion on the concept of immunogenicity, more specifically when applied to biological therapies in rheumatology. We would also like to thank the editor of Reumatología CLínica the opportunity to reply, which manifests the commitment of this journal in the settlement of very current controversies. With these lines we would like to mention some of the comments made.

It is well known that both standardizing and validating assays in immunology, especially in the area of autoimmunity, are an extremely difficult and complex task. Therefore, determinations made over time have high inter and/or intra laboratory methodological variability which always requires consensus to establish the steps to be followed in order to standardize results and to optimize techniques in order to have an adequate sensitivity, specificity and reproducibility. In the case of the determination of immunogenicity in biological therapies, such procedures have not been well documented in the field of rheumatology. Our duty is to promote the validation and standardization of techniques and when this is not possible, the next step is to establish rules among the relevant stakeholders and build consensus.

Fortunately, the international scientific community has recognized the need to work together and in 2012 created the group Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the risk. European Union Innovative Medical Initiative (ABIRISK).2 Its main objective is the establishment of international standards, internal standards and consistent detection techniques applied to each biologic drug marketed. In the near future, establishing multicenter studies and using appropriate techniques, the determination of both the immunogenicity and drug levels will gain ground in the monitoring of patients on biological therapies.

The examples mentioned by Balsa et al., to highlight the difficulties that have existed in the standardization of the detection techniques for antiphospholipid antibodies (APA) and3,4 anti granulocyte cytoplasmic antibodies and their application in clinical practice, are perfectly valid.However, both measurements and their interpretation are supported by international consensus groups, numerous publications and multicenter studies that have exchanged biological samples, with the aim of agreeing on detection ranges, establishing guidelines for testing and the use of calibration curves and appropriate cut points.3,5,6

In the specific case of the APL, which were described in 1983, the consensus of Sapporo, in 1999 helped to define the clinical and especially the laboratory data for the diagnosis of antiphospholipid syndrome (APS), which included the presence of lupus anticoagulant and the G and/or M anticardiolipin isotypes.7 In view of the persistent variability of APL determinations by various research groups within APS, these criteria were reviewed in the consensus of Sydney in 2005, adding B2 glycoprotein determinations to the criteria i for laboratory diagnoses, criteria currently considered valid internationally.3,8–10

With respect to the regulated analysis of observational studies in epidemiology and the review of the literature cited by Balsa et al., both publications conclude that although the trends with respect to clinical response are clear, different studies evaluating the whole, the heterogeneity of the cohorts studied, using techniques not yet standardized and the imprecision of the assays makes the reliable correlations with clinical response to biologic therapy risky.11,12 Especially noteworthy is the review by Vincent et al., detailing the great variability of results regarding drug-drug immunogenicity data.12

As discussed Balsa et al., for the detection of specific antibodies traits such as isotype and affinity, the technique known as acid dissociation procedure is very helpful in immunology and has already been used to determine anti-drug antibody and is likely to be integrated in the design these techniques.13–15

Finally, as authors, we would say that the highest motivation of this review was to highlight the complexity surrounding the determination of immunogenicity that other medical specialties have previously experienced and to understand and apply these important concepts in an effective way in the area of rheumatology. The editorial entitled “Understanding the concept of immunogenicity” has achieved the most important of our goals, to increase the interest and promote discussion on this topic among readers of Reumatología Clínica.

L. Valor, I. de la Torre.
Understanding the immunogenicity concept.
Reumatol Clin, 9 (2013), pp. 1-4
Anti-biopharmaceutical immunization: prediction and analysis of clinical relevance to minimize the RISK.
Newsletter, (2012),
G. Reber, A. Tincani, M. Sanmarco, P. de Moerloose, M.C. Boffa, European Forum on Antiphospholipid Antibodies Standardization Group.
Proposals for the measurement of anti-beta2-glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies.
J Thromb Haemost, 2 (2004), pp. 1860
M. Segelmark, K. Westman, J. Wieslander.
How and why should we detect ANCA?.
Clin Exp Rheumatol, 18 (2000), pp. 629-635
E.C. Hagen, M.R. Daha, J. Hermans, K. Andrassy, E. Csernok, G. Gaskin, et al.
Diagnostic value of standardized assays for antineutrophil cytoplasmic antibodies in idiopathic systemic vasculitis: EC/BCR Project for ANCA assay standardization.
Kidney Int, 53 (1998), pp. 743-753
J. Savige, S.D. Gillis, E. Benson, D. Davies, V. Esnault, R.J. Falk, et al.
International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies.
Am J Clin Path, 112 (1999), pp. 507-513
W.A. Wilson, A.E. Gharavi, T. Koike, M.D. Lockshin, D.W. Branch, J.C. Piette, et al.
International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop.
S. Miyakis, M.D. Lockshin, T. Atsumi, D.W. Branch, R.L. Brey, R. Cervera, et al.
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost, 4 (2006), pp. 295-306
B. Giannakopoulos, F. Passam, Y. Ioannou, S.A. Krilis.
How we diagnose the antiphospholipid syndrome.
S. Pierangeli, P. Groot, J. Dlott, E. Favaloro, E.N. Harris, G. Lakos, et al.
“Criteria” aPL tests: report of a task force and preconference workshop at the 13th international congress on antiphospholipid antibodies, Galveston, TX, April, 2010.
Lupus, 20 (2011), pp. 182-190
S. Garces, J. Demengeot, E. Benito-Garcia.
The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis.
Ann Rheum Dis, (2012),
F.B. Vincent, E.F. Morand, K. Murphy, F. Mackay, X. Mariette, C. Marcelli.
Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective.
Ann Rheum Dis, 72 (2013), pp. 165-178
A. Patton, M.C. Mullenix, S.J. Swanson, E. Koren.
An acid dissociation bridging ELISA for detection of antibodies directed against therapeutic proteins in the presence of antigen.
J Immunol Methods, 304 (2005), pp. 189-195
H.W. Smith, A. Butterfield, D. Sun.
Detection of antibodies against therapeutic proteins in the presence of residual therapeutic protein using a solid-phase extraction with acid dissociation (SPEAD) sample treatment prior to ELISA.
Regul Toxicol Pharmacol, 49 (2007), pp. 230-237
P.A. Van Schouwenburg, G.M. Bartelds, M.H. Hart, L. Aarden, G.J. Wolbink, D. Wouters.
A novel method for the detection of antibodies to adalimumab in the presence of drug reveals “hidden” immunogenicity in rheumatoid arthritis patients.
J Immunol Methods, 362 (2010), pp. 82-88

Please cite this article as: Valor L, De la Torre I. Respuesta a Balsa et al. en relación con la revisión «Entendiendo el concepto de inmunogenicidad». Reumatol. Clin. 2013.

Reumatología Clínica (English Edition)

Subscribe to our newsletter

Article options
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

es en
Política de cookies Cookies policy
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.