Comment on: IgG4-related disease presenting with raised serum IgG2—real timeline of IgG4-RD?

Comment on: IgG4-related disease presenting with raised serum IgG2—real timeline of IgG4-RD? Sir, Dunkley and Mudhar [1] describe an infrequent presentation of IgG4-related disease (IgG4-RD) manifesting initially with adult-onset asthma and periorbital xanthogranulomatosis, in addition to an apparently isolated elevation of serum IgG2 (with a normal IgG4). After 3 years, the patient was noted to have elevations of both serum IgG2 and IgG4 (see Table 1). Our group suspects that this evolution of the clinical laboratory findings primarily reflects analytical errors associated with immunonephelometric IgG subclass measurement, rather than the hypothesized evolution of disease from an IgG2-predominant phase to a later phase involving elevation in serum IgG4. Table 1 Clinical laboratory IgG subclass concentrations from Dunkley and Mudhar [1], with suggested interpretation Date Therapy Serum IgG2 (1.2–6.6), g/l Serum IgG4 (0–1.3), g/l Interpretation March 2013 Initial 7.24 0.38 Reported IgG2 elevation owing to cross-reactivity of test reagents with IgG4 (i.e. reported IgG2 = actual IgG2 + actual IgG4) Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess February 2014 CS 6.27 0.4 Reported IgG2 decreased modestly owing to a decrease in the actual sum of IgG2 and IgG4 Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess June 2016 MTX 6.43 5.26 Reported IgG2 relatively unchanged with change from CS to MTX, suggesting no marked change in the sum of IgG2 and IgG4 Reported IgG4 increased compared with previous because the error of antigen excess was corrected,a allowing the reported IgG4 value to reflect the actual value December 2016 No therapy for 3 months 11.7 11.5 Off treatment, the actual IgG4 increases, resulting in both the reported IgG4 and the reported IgG2 (= IgG2 + IgG4) concentrations increasing by the same amount, 5.75 (±0.5) g/L Date Therapy Serum IgG2 (1.2–6.6), g/l Serum IgG4 (0–1.3), g/l Interpretation March 2013 Initial 7.24 0.38 Reported IgG2 elevation owing to cross-reactivity of test reagents with IgG4 (i.e. reported IgG2 = actual IgG2 + actual IgG4) Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess February 2014 CS 6.27 0.4 Reported IgG2 decreased modestly owing to a decrease in the actual sum of IgG2 and IgG4 Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess June 2016 MTX 6.43 5.26 Reported IgG2 relatively unchanged with change from CS to MTX, suggesting no marked change in the sum of IgG2 and IgG4 Reported IgG4 increased compared with previous because the error of antigen excess was corrected,a allowing the reported IgG4 value to reflect the actual value December 2016 No therapy for 3 months 11.7 11.5 Off treatment, the actual IgG4 increases, resulting in both the reported IgG4 and the reported IgG2 (= IgG2 + IgG4) concentrations increasing by the same amount, 5.75 (±0.5) g/L a The IgG4 analytical error of antigen excess was published in a major clinical journal in 2014 [2] and, consequently, solutions to the error of antigen excess were published, facilitating clinical laboratory correction of antigen excess errors [5]. Table 1 Clinical laboratory IgG subclass concentrations from Dunkley and Mudhar [1], with suggested interpretation Date Therapy Serum IgG2 (1.2–6.6), g/l Serum IgG4 (0–1.3), g/l Interpretation March 2013 Initial 7.24 0.38 Reported IgG2 elevation owing to cross-reactivity of test reagents with IgG4 (i.e. reported IgG2 = actual IgG2 + actual IgG4) Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess February 2014 CS 6.27 0.4 Reported IgG2 decreased modestly owing to a decrease in the actual sum of IgG2 and IgG4 Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess June 2016 MTX 6.43 5.26 Reported IgG2 relatively unchanged with change from CS to MTX, suggesting no marked change in the sum of IgG2 and IgG4 Reported IgG4 increased compared with previous because the error of antigen excess was corrected,a allowing the reported IgG4 value to reflect the actual value December 2016 No therapy for 3 months 11.7 11.5 Off treatment, the actual IgG4 increases, resulting in both the reported IgG4 and the reported IgG2 (= IgG2 + IgG4) concentrations increasing by the same amount, 5.75 (±0.5) g/L Date Therapy Serum IgG2 (1.2–6.6), g/l Serum IgG4 (0–1.3), g/l Interpretation March 2013 Initial 7.24 0.38 Reported IgG2 elevation owing to cross-reactivity of test reagents with IgG4 (i.e. reported IgG2 = actual IgG2 + actual IgG4) Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess February 2014 CS 6.27 0.4 Reported IgG2 decreased modestly owing to a decrease in the actual sum of IgG2 and IgG4 Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess June 2016 MTX 6.43 5.26 Reported IgG2 relatively unchanged with change from CS to MTX, suggesting no marked change in the sum of IgG2 and IgG4 Reported IgG4 increased compared with previous because the error of antigen excess was corrected,a allowing the reported IgG4 value to reflect the actual value December 2016 No therapy for 3 months 11.7 11.5 Off treatment, the actual IgG4 increases, resulting in both the reported IgG4 and the reported IgG2 (= IgG2 + IgG4) concentrations increasing by the same amount, 5.75 (±0.5) g/L a The IgG4 analytical error of antigen excess was published in a major clinical journal in 2014 [2] and, consequently, solutions to the error of antigen excess were published, facilitating clinical laboratory correction of antigen excess errors [5]. Two major analytical errors that may affect the immunonephelometric IgG subclass methods, when used in patients with IgG4-RD or any patient with an elevation of serum IgG4, have been described: antigen excess, leading to falsely low serum IgG4 measurement in a patient who in fact has a marked elevation of serum IgG4 [2]; and cross-reactivity of the reagent used to measure IgG2 with serum IgG4, leading to falsely high serum IgG2 measurement (this may be attributable to a direct and specific recognition of IgG4 epitopes or to non-specific novel RF interaction) [3, 4]. The means by which these immunonephelometric errors might have affected the clinical laboratory results presented in the report by Dunkley and Mudhar [1] is described in Table 1. As the methodology used for the serial measurements of IgG subclasses was not described, the proposed interpretations are not definitive. However, in order to understand whether serum IgG2 concentrations are significantly associated with the presence and severity of IgG4-RD in this case, or any other, requires the use of an IgG subclass method, such as mass spectrometry, which has been documented as free from error in the setting of high IgG4 concentrations [4]. In addition, this article highlights the need to reconsider the diagnosis of IgG4-RD in patients who were historically assessed as unlikely to have the disease, on the basis of a low serum IgG4 concentration (that was potentially affected by the error of antigen excess). Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Dunkley L , Mudhar HS. IgG4-related disease presenting with raised serum IgG2—real timeline of IgG4-RD? Rheumatology 2018 ; 57 : 197 – 9 . Google Scholar CrossRef Search ADS PubMed 2 Khosroshahi A , Cheryk LA , Carruthers MN et al. Brief Report: spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease . Arthritis Rheumatol 2014 ; 66 : 213 – 7 . Google Scholar CrossRef Search ADS PubMed 3 Ito T , Kitahara K , Umemura T et al. A novel heterophilic antibody interaction involves IgG4 . Scand J Immunol 2010 ; 71 : 109 – 14 . Google Scholar CrossRef Search ADS PubMed 4 van der Gugten G , DeMarco ML , Chen LYC et al. Resolution of spurious immunonephelometric IgG subclass measurement discrepancies by LC-MS/MS . Clin Chem 2018 ; 19 : 30 . 5 Parker AR , Carr-Smith HD. Calibration differences and the prozone phenomenon in IgG4-related disease: comment on the article by Khosroshahi et al . Arthritis Rheumatol 2014 ; 66 : 1964 – 5 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Comment on: IgG4-related disease presenting with raised serum IgG2—real timeline of IgG4-RD?

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
1462-0324
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1462-0332
D.O.I.
10.1093/rheumatology/key044
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Abstract

Sir, Dunkley and Mudhar [1] describe an infrequent presentation of IgG4-related disease (IgG4-RD) manifesting initially with adult-onset asthma and periorbital xanthogranulomatosis, in addition to an apparently isolated elevation of serum IgG2 (with a normal IgG4). After 3 years, the patient was noted to have elevations of both serum IgG2 and IgG4 (see Table 1). Our group suspects that this evolution of the clinical laboratory findings primarily reflects analytical errors associated with immunonephelometric IgG subclass measurement, rather than the hypothesized evolution of disease from an IgG2-predominant phase to a later phase involving elevation in serum IgG4. Table 1 Clinical laboratory IgG subclass concentrations from Dunkley and Mudhar [1], with suggested interpretation Date Therapy Serum IgG2 (1.2–6.6), g/l Serum IgG4 (0–1.3), g/l Interpretation March 2013 Initial 7.24 0.38 Reported IgG2 elevation owing to cross-reactivity of test reagents with IgG4 (i.e. reported IgG2 = actual IgG2 + actual IgG4) Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess February 2014 CS 6.27 0.4 Reported IgG2 decreased modestly owing to a decrease in the actual sum of IgG2 and IgG4 Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess June 2016 MTX 6.43 5.26 Reported IgG2 relatively unchanged with change from CS to MTX, suggesting no marked change in the sum of IgG2 and IgG4 Reported IgG4 increased compared with previous because the error of antigen excess was corrected,a allowing the reported IgG4 value to reflect the actual value December 2016 No therapy for 3 months 11.7 11.5 Off treatment, the actual IgG4 increases, resulting in both the reported IgG4 and the reported IgG2 (= IgG2 + IgG4) concentrations increasing by the same amount, 5.75 (±0.5) g/L Date Therapy Serum IgG2 (1.2–6.6), g/l Serum IgG4 (0–1.3), g/l Interpretation March 2013 Initial 7.24 0.38 Reported IgG2 elevation owing to cross-reactivity of test reagents with IgG4 (i.e. reported IgG2 = actual IgG2 + actual IgG4) Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess February 2014 CS 6.27 0.4 Reported IgG2 decreased modestly owing to a decrease in the actual sum of IgG2 and IgG4 Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess June 2016 MTX 6.43 5.26 Reported IgG2 relatively unchanged with change from CS to MTX, suggesting no marked change in the sum of IgG2 and IgG4 Reported IgG4 increased compared with previous because the error of antigen excess was corrected,a allowing the reported IgG4 value to reflect the actual value December 2016 No therapy for 3 months 11.7 11.5 Off treatment, the actual IgG4 increases, resulting in both the reported IgG4 and the reported IgG2 (= IgG2 + IgG4) concentrations increasing by the same amount, 5.75 (±0.5) g/L a The IgG4 analytical error of antigen excess was published in a major clinical journal in 2014 [2] and, consequently, solutions to the error of antigen excess were published, facilitating clinical laboratory correction of antigen excess errors [5]. Table 1 Clinical laboratory IgG subclass concentrations from Dunkley and Mudhar [1], with suggested interpretation Date Therapy Serum IgG2 (1.2–6.6), g/l Serum IgG4 (0–1.3), g/l Interpretation March 2013 Initial 7.24 0.38 Reported IgG2 elevation owing to cross-reactivity of test reagents with IgG4 (i.e. reported IgG2 = actual IgG2 + actual IgG4) Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess February 2014 CS 6.27 0.4 Reported IgG2 decreased modestly owing to a decrease in the actual sum of IgG2 and IgG4 Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess June 2016 MTX 6.43 5.26 Reported IgG2 relatively unchanged with change from CS to MTX, suggesting no marked change in the sum of IgG2 and IgG4 Reported IgG4 increased compared with previous because the error of antigen excess was corrected,a allowing the reported IgG4 value to reflect the actual value December 2016 No therapy for 3 months 11.7 11.5 Off treatment, the actual IgG4 increases, resulting in both the reported IgG4 and the reported IgG2 (= IgG2 + IgG4) concentrations increasing by the same amount, 5.75 (±0.5) g/L Date Therapy Serum IgG2 (1.2–6.6), g/l Serum IgG4 (0–1.3), g/l Interpretation March 2013 Initial 7.24 0.38 Reported IgG2 elevation owing to cross-reactivity of test reagents with IgG4 (i.e. reported IgG2 = actual IgG2 + actual IgG4) Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess February 2014 CS 6.27 0.4 Reported IgG2 decreased modestly owing to a decrease in the actual sum of IgG2 and IgG4 Reported IgG4 is normal, instead of markedly elevated, owing to error of antigen excess June 2016 MTX 6.43 5.26 Reported IgG2 relatively unchanged with change from CS to MTX, suggesting no marked change in the sum of IgG2 and IgG4 Reported IgG4 increased compared with previous because the error of antigen excess was corrected,a allowing the reported IgG4 value to reflect the actual value December 2016 No therapy for 3 months 11.7 11.5 Off treatment, the actual IgG4 increases, resulting in both the reported IgG4 and the reported IgG2 (= IgG2 + IgG4) concentrations increasing by the same amount, 5.75 (±0.5) g/L a The IgG4 analytical error of antigen excess was published in a major clinical journal in 2014 [2] and, consequently, solutions to the error of antigen excess were published, facilitating clinical laboratory correction of antigen excess errors [5]. Two major analytical errors that may affect the immunonephelometric IgG subclass methods, when used in patients with IgG4-RD or any patient with an elevation of serum IgG4, have been described: antigen excess, leading to falsely low serum IgG4 measurement in a patient who in fact has a marked elevation of serum IgG4 [2]; and cross-reactivity of the reagent used to measure IgG2 with serum IgG4, leading to falsely high serum IgG2 measurement (this may be attributable to a direct and specific recognition of IgG4 epitopes or to non-specific novel RF interaction) [3, 4]. The means by which these immunonephelometric errors might have affected the clinical laboratory results presented in the report by Dunkley and Mudhar [1] is described in Table 1. As the methodology used for the serial measurements of IgG subclasses was not described, the proposed interpretations are not definitive. However, in order to understand whether serum IgG2 concentrations are significantly associated with the presence and severity of IgG4-RD in this case, or any other, requires the use of an IgG subclass method, such as mass spectrometry, which has been documented as free from error in the setting of high IgG4 concentrations [4]. In addition, this article highlights the need to reconsider the diagnosis of IgG4-RD in patients who were historically assessed as unlikely to have the disease, on the basis of a low serum IgG4 concentration (that was potentially affected by the error of antigen excess). Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Dunkley L , Mudhar HS. IgG4-related disease presenting with raised serum IgG2—real timeline of IgG4-RD? Rheumatology 2018 ; 57 : 197 – 9 . Google Scholar CrossRef Search ADS PubMed 2 Khosroshahi A , Cheryk LA , Carruthers MN et al. Brief Report: spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease . Arthritis Rheumatol 2014 ; 66 : 213 – 7 . Google Scholar CrossRef Search ADS PubMed 3 Ito T , Kitahara K , Umemura T et al. A novel heterophilic antibody interaction involves IgG4 . Scand J Immunol 2010 ; 71 : 109 – 14 . Google Scholar CrossRef Search ADS PubMed 4 van der Gugten G , DeMarco ML , Chen LYC et al. Resolution of spurious immunonephelometric IgG subclass measurement discrepancies by LC-MS/MS . Clin Chem 2018 ; 19 : 30 . 5 Parker AR , Carr-Smith HD. Calibration differences and the prozone phenomenon in IgG4-related disease: comment on the article by Khosroshahi et al . Arthritis Rheumatol 2014 ; 66 : 1964 – 5 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

RheumatologyOxford University Press

Published: Mar 23, 2018

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