# TIF1-gamma IgG2 isotype is not associated with malignancy in juvenile dermatomyositis patients

Huong Nguyen, Fabienne Jouen, Benoit Déchelotte, Nadège Cordel, Cyril Gitiaux, Christine Bodemer, Pierre Quartier, Alexandre Belot, Kathryn O'Brien, Dario Cancemi, et al.

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## To cite this version:

Huong Nguyen, Fabienne Jouen, Benoit Déchelotte, Nadège Cordel, Cyril Gitiaux, et al. TIF1-gamma IgG2 isotype is not associated with malignancy in juvenile dermatomyositis patients. Rheumatology, 2024, 63 (10), pp.e281-e284. 10.1093/rheumatology/keae182. hal-04888251

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Letter to the Editor (Other)

# TIF1-gamma IgG2 isotype is not associated with malignancy in juvenile dermatomyositis patients

Huong D. Nguyen ID <fnref n="1" />, Fabienne Jouen <fnref n="2" />,<fnref n="3" />, Benoit Déchelotte <fnref n="2" />,<fnref n="3" />, Nadège Cordel ID <fnref n="2" />,<fnref n="4" />, Cyril Gitiaux <fnref n="5" />,<fnref n="6" />, Christine Bodemer <fnref n="7" />, Pierre Quartier ID <fnref n="5" />,<fnref n="8" />, Alexandre Belot ID <fnref n="9" />, Kathryn O’Brien <fnref n="1" />, Dario Cancemi <fnref n="1" />, Isabelle Melki ID <fnref n="10" />, Nicole Fabien <fnref n="11" />, Sarah Tansley <fnref n="12" />,<fnref n="13" />, Olivier Boyer <fnref n="2" />,<fnref n="3" />, Lucy R. Wedderburn ID <fnref n="1" />,<fnref n="14" />,<fnref n="15" />,‡,*, Brigitte Bader-Meunier <fnref n="5" />,<fnref n="8" />,‡, UK JDM Cohort and Biomarker Study <fnref n="5" />

Rheumatology key message

* TIF1γ IgG2 is a biomarker for malignancy in adult DM but not in JDM.

DEAR EDITOR, The disease presentation and associated complications of juvenile- and adult-onset dermatomyositis (JDM and adult DM) differ significantly. The pathological hallmarks of DM are similar between JDM and adult DM, including skin rashes and proximal muscle weakness; however, the prevalence and implication of associated autoantibodies varies depending on age of onset.

Myositis-specific antibodies (MSA) have been used as a prognostic tool to aid management of disease in both adult DM and JDM [1]. In JDM, a prevalent MSA is anti-transcription intermediary factor 1(anti-TIF1γ), which is the most common MSA in Caucasian patients. Although the clinical and pathological features of the anti-TIF1γ subtype are significantly heterogeneous [2, 3], this MSA has been well known to be associated with malignancy in adult DM [4]. More specifically, we have previously shown that adult DM patients with cancer have a significantly higher frequency and serological level of anti-TIF1γ-IgG2

isotype [4], which raises the question of whether there is also an association between anti-TIF1γ-IgG2 isotype and cancer in JDM. To explore this, we investigated all anti-TIF1γ isotypes and their associations with clinical manifestations in JDM.

We conducted a retrospective study of 31 patients to evaluate clinical features of anti-TIF1γ-positive patients from diagnosis to the most recent clinical visits (Supplementary Table S1, available at Rheumatology online). The median duration of follow-up was 6.6 years (min 1.0–max 20.6 years).

This cohort included 20 patients from French healthcare centres and 11 patients from the UK healthcare centres. Serum was collected near time of diagnosis or flare. Serum samples were first tested for anti-TIF1γ using either the commercial Myositis Profile 4 EUROLINE immunoblot (EUROIMMUN AG, Lübeck, Germany) or immunoprecipitation. Within those with anti-TIF1γ auto-antibodies, anti-TIF1γ isotypes including IgG1, IgG2, IgG3 and IgG4 were measured using a multiplex ALBIA assay developed by Aussy et al. [5]. The median duration from diagnosis date to sample date was 10.3 months (interquartile range 1.2–9.6).

Out of 31 children, 54.8% (17) were Caucasian, followed by North-African (Maghreb) (25.8%, n=7) and other

<footnote n="1">¹Department of Infection, Immunity & Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK</footnote>

<footnote n="2">²Department of Immunology and Biotherapy, Univ. Rouen Normandie, INSERM, U1234, Rouen, France</footnote>

<footnote n="3">³Department of Immunology and Biotherapy, CHU de Rouen, Rouen, France</footnote>

<footnote n="4">⁴Department of Dermatology and Clinical Immunology, Guadeloupe University Hospital, Pointe-à-Pitre, Guadeloupe</footnote>

<footnote n="5">⁵Department of Paediatric Immunology, Hematology and Rheumatology, Université Paris Cité, Paris, France</footnote>

<footnote n="6">⁶Department of Paediatric Neurophysiology, Necker-Enfants Malades Hospitals, Paris, France</footnote>

<footnote n="7">⁷Department of Paediatric Dermatology and Dermatology, Necker-Enfants Malades Hospitals, Paris, France</footnote>

<footnote n="8">⁸Department of Paediatric Hematology-Immunology and Rheumatology, Necker-Enfants Malades Hospitals, Paris, France</footnote>

<footnote n="9">⁹Department of Paediatric Rheumatology, Femme-Mère-Enfants Hospital, Lyon, France</footnote>

<footnote n="10">¹⁰Department of Paediatrics, Hôpital Robert Debré, Paris, France</footnote>

<footnote n="11">¹¹Department of Immunology, Laboratory of Immunology, Hôpital Lyon Sud, Lyon, France</footnote>

<footnote n="12">¹²Royal National Hospital for Rheumatic Diseases, Royal United Hospital Bath NHS Trust, Bath, UK</footnote>

<footnote n="13">¹³Department of Life Sciences, University of Bath, Bath, UK</footnote>

<footnote n="14">¹⁴NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children, London, UK</footnote>

<footnote n="15">¹⁵Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH and GOSH, London, UK</footnote>

<footnote>*Correspondence to: Lucy R. Wedderburn, Infection Immunity and Inflammation Research and Teaching Department, UCL GOS Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: l.wedderburn@ucl.ac.uk</footnote>

<footnote>†L.R.W. and B.B.-M. contributed equally.</footnote>

<footnote n="6">⁶See Acknowledgements section for a list of the UK JDM Cohort and Biomarker Study contributors.</footnote>
minority groups. Male to female ratio was 14/17. Average age at diagnosis was 6.8 ± 3.3 years. All 31 patients had IgG1 isotype, and 14/31 had more than one isotype of anti-TIF1γ. There was no mutual exclusion between the four isotypes, as various combinations of isotypes were found (Fig. 1A).

Although the IgG2 isotype of anti-TIF1γ has been shown to be a biomarker for malignancy and mortality in adult DM, there was no report of malignancy in this paediatric cohort (Supplementary Table S1, available at *Rheumatology* online). In our JDM cohort, the rate of IgG2-positive was 25.8% (8/31). We did not observe any difference in clinical presentation or outcome between IgG2-positive vs IgG2-negative patients.

Interestingly, there was a significant difference regarding anti-TIF1γ-IgG2 prevalence between ethnic groups (Kruskal–Wallis’s test, *P* = 0.01, Supplementary Fig. S1, available at *Rheumatology* online). Specifically, although Caucasian patients were the majority (17/31, 54.8%) of this cohort,

only 1/8 (12.5%) IgG2-positive cases was Caucasian, which made the IgG2 prevalence significantly different from non-Caucasian population (Fisher’s exact test, *P* = 0.01) (Fig. 1B). Notably, 4/8 IgG2-positive patients (50%) were found in North-African (Maghreb) population, making up 44.4% (4/9) of this ethnic group (Supplementary Fig. S1, available at *Rheumatology* online).

We also observed that anti-TIF1γ isotypes can change over time. Specifically, of six patients tested for anti-TIF1γ isotypes at a second time point, four cases had changes in serological levels of anti-TIF1γ isotypes: two had lower titre levels, one lost positive status for IgG2 and IgG3, and one gained positive status for IgG4. Average time duration between the first and second sample time-points was 18.7 ± 13.4 months. Further investigation in larger cohorts is needed to clarify whether the changes in isotype titre are age-dependent or correlated to treatment response.

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Detection of anti-TIF1γ auto-antibodies and demographic association in patients with JDM. Anti-TIF1γ auto-antibodies were measured by lineblot or immunoprecipitation. Anti-TIF1γ isotypes including IgG1, IgG2, IgG3 and IgG4 were measured using the multiplex ALBIA assay in both cohorts. (A) Diverse combination of anti-TIF1γ isotypes detected in JDM patients from French and UK cohorts. (B) Anti-TIF1γ IgG2 positive patients were analysed according to ethnicity: anti-TIF1γ IgG2 is more prevalent in non-Caucasian patients</figcaption></figure>
Two French patients in this JDM cohort died from persistently severe JDM which led to multi-organ failure despite being treated with CS, MTX, MMF, rituximab and plasma exchange. Both patients were positive for IgG4 but negative for IgG2. Based on the analysis in the French cohort (as IgG4 was not detected in UK cohort), IgG4-positive patients might be more likely to have severe onset (Fisher's exact test, *P* = 0.03) (Supplementary Fig. S2, available at *Rheumatology* online). Severity was defined according to previous consensus [6] by: (i) admission to intensive care unit, and/or the presence of (ii) skin ulcerations and/or (iii) severe muscle involvement, defined by Childhood Myositis Assessment Scale ≤15 or Manual Muscle Testing ≤30, and/or (iv) a severe organ involvement (e.g. cardiovascular, pulmonary or gastrointestinal involvement, dysphonia or dysphagia) within the first month of diagnosis. Larger sample sizes are required to confirm a potential association of severe JDM onset with anti-TIF1γ-IgG4 isotype and the potential impact on disease management, if this association is confirmed.

In conclusion, our study shows the distribution and fluctuation of anti-TIF1γ isotypes in JDM patients. Our data indicated that there may be a relationship between anti-TIF1γ IgG2 isotype and ethnicity. Importantly, although IgG2 is a biomarker for cancer in adult DM, it is not associated with severe onset or manifestations such as mortality or malignancy in JDM patients, which is consistent with previous reports [7, 8].

## Supplementary material

Supplementary material is available at *Rheumatology* online.

## Data availability

Data on the cohorts' studies can be applied to through the corresponding author (L.R.W.).

## Contribution statement

B.B.-M., F.J., B.D., N.C., C.G., C.B., P.Q., A.B., I.M., N.F., K.O.B., D.C., L.R.W. and S.T. contributed to the acquisition of data. S.T. ran the MSA analysis for UK cases. H.D.N. conducted analysis and prepared the manuscript. L.R.W., O.B. and B.B.-M. conceptualized and designed the study, and critically reviewed the manuscript. All authors reviewed, edited and commented on the manuscript. All authors approved the final revised manuscript.

## Funding

Funding for the UK JDM Cohort and Biomarker study has been by grants from the Wellcome Trust UK [085860]; Action Medical Research UK [SP4252]; the Myositis Support Group UK, Arthritis Research UK, now Versus Arthritis [14518, 20164, 21593]; the Henry Smith Charity and Great Ormond Street Children's Charity [V1268]; Tiny Hearts Society, Remission Charity, the Myositis Association, Cure JM (GOSH042019), the Medical Research Council [MR/N003322/1], and the National Institute for Health Research (NIHR) via the NIHR-Biomedical Research Centre at Great Ormond Street Hospital (GOSH). H.D.N., L.R.W., K.O.B. and D.C. are supported by the NIHR-Biomedical Research Centre at GOSH. The views expressed are those of the

authors and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. This work was supported by a research grant from Agence Nationale de la Recherche (ANR) via project JDMINF2 (ANR-21-CE17-0025).

**Disclosure statement:** L.R.W. declares consultancy fees paid by Pfizer to UCL for an unrelated project. O.B. declares consultancy fees paid by Argenx, BMS, CSL Behring, Egle Tx, OGD2 and UCB. O.B. also declares research grant support from Argenx and UCB. The other authors declare no competing interests.

**Ethics:** The UK cohort study was fully approved by Yorkshire REC, MREC number 1/3/22, and IRAS number 229746. The French cohort study was approved by the institutional review board of Rouen University Hospital (Ref. No. E2021-33). All patients provided full informed consent to participate.

## Acknowledgements

We would like to thank all of the patients and their families who contributed to the Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS) and Repository (UK) and the French network cohort study. We thank all local research coordinators and principal investigators who have made this research possible. The JDCBS contributors were as follows:

Dr Kate Armon, Ms Louise Coke, Ms Julie Cook and Ms Amy Nichols (Norfolk and Norwich University Hospitals); Dr Liza McCann, Mr Ian Roberts, Dr Eileen Baildam, Ms Louise Hanna, Ms Olivia Lloyd, Susan Wadeson and Ms Michelle Andrews (The Royal Liverpool Children's Hospital, Alder Hey, Liverpool); Dr Phil Riley, Ms Ann McGovern and Ms Verna Cuthbert (Royal Manchester Children's Hospital, Manchester); Dr Clive Ryder, Ms Janis Scott, Ms Beverley Thomas, Professor Taunton Southwood, Dr Eslam Al-Abadi and Ms Ruth Howman (Birmingham Children's Hospital, Birmingham); Dr Sue Wyatt, Mrs Gillian Jackson, Dr Mark Wood, Dr Tania Amin, Dr Vanessa VanRooyen, Ms Deborah Burton, Ms Louise Turner, Ms Heather Rostron and Ms Sarah Hanson (Leeds General Infirmary, Leeds); Dr Joyce Davidson, Dr Janet Gardner-Medwin, Dr Neil Martin, Ms Sue Ferguson, Ms Liz Waxman, Mr Michael Browne, Ms Roisin Boyle and Ms Emily Blyth (The Royal Hospital for Sick Children, Yorkhill, Glasgow); Dr Mark Friswell, Professor Helen Foster, Ms Alison Swift, Dr Sharmila Jandial, Ms Vicky Stevenson, Ms Debbie Wade, Dr Ethan Sen, Dr Eve Smith, Ms Lisa Qiao, Mr Stuart Watson, Ms Claire Duong, Dr Stephen Crulley, Mr Andrew Davies, Miss Caroline Miller, Ms Lynne Bell, Dr Flora McErlane, Dr Sunil Sampath, Dr Josh Bennet and Mrs Sharon King (Great North Children's Hospital, Newcastle); Dr Helen Venning, Dr Rangaraj Satyapal, Mrs Elizabeth Stretton, Ms Mary Jordan, Dr Ellen Mosley, Ms Anna Frost, Ms Lindsay Crate, Dr Kishore Warrier, Ms Stefanie Stafford and Mrs Brogan West (Queens Medical Centre, Nottingham); Professor Lucy Wedderburn, Dr Clarissa Pilkington, Dr Nathan Hasson, Dr Muthana Al-Obadi, Dr Giulia Varnier, Dr Sandrine Lacassagne, Ms Sue Maillard, Mrs Lauren Stone, Ms Elizabeth Halkon, Ms Virginia Brown, Ms Audrey Juggins, Dr Sally Smith, Ms Sian Lunt, Ms Elli Enayat, Ms Hemlata Varsani, Ms Laura Kassoumeri, Miss Laura Beard, Ms Katie Arnold, Mrs Yvonne Glackin, Ms Stephanie Simou, Dr Beverley Almeida, Dr Kiran Nistala, Dr Raquel Marques, Dr Claire Deakin, Dr Parichat Khaosut, Ms Stefanie Dowle, Dr
Charalampia Papadopoulou, Dr Shireena Yasin, Dr Christina Boros, Dr Meredyth Wilkinson, Dr Chris Piper, Ms Cerise Johnson-Moore, Ms Lucy Marshall, Ms Kathryn O'Brien, Ms Emily Robinson, Mr Dominic Igbelina, Dr Polly Livermore, Dr Socrates Varakliotis, Ms Rosie Hamilton, Ms Huong D. Nguyen and Mr Dario Cancemi (Great Ormond Street Hospital, London); Dr Kevin Murray (Princess Margaret Hospital, Perth, Western Australia); Dr Coziana Ciurtin, Dr John Ioannou, Mrs Caitlin Clifford, Ms Linda Suffield and Ms Laura Hennelly (University College London Hospital, London); Ms Helen Lee, Ms Sam Leach, Ms Helen Smith, Dr Anne-Marie McMahon, Ms Heather Chisem, Ms Jeanette Hall and Ms Amy Huffenberger (Sheffield's Children's Hospital, Sheffield); Dr Nick Wilkinson, Ms Emma Inness, Ms Eunice Kendall, Mr David Mayers, Ms Ruth Etherton, Ms Danielle Miller and Dr Kathryn Bailey (Oxford University Hospitals, Oxford); Dr Jacqui Clinch, Ms Natalie Fineman, Ms Helen Pluess-Hall, Ms Suzanne Sketchley, Ms Melanie Marsh, Ms Anna Fry, Ms Maisy Dawkins-Lloyd and Ms Mashal Asif (Bristol Royal Hospital for Children, Bristol); Dr Joyce Davidson, Margaret Connon and Ms Lindsay Vallance (Royal Aberdeen Children's Hospital); Dr Kirsty Haslam, Ms Charlene Bass-Woodcock, Ms Trudy Booth and Ms Louise Akeroyd (Bradford Teaching Hospitals); Dr Alice Leahy, Amy Collier, Rebecca Cutts, Emma Macleod, Dr Hans De Graaf, Dr Brian Davidson, Sarah Hartfree, Ms Elizabeth Fofana and Ms Lorena Caruana (University Hospital Southampton); and all the children, young people and their families who have contributed to this research.

We are grateful for Dr Restuadi Restuadi (UCL) for advice
on statistical methods.

**References**

1. Papadopoulou C, Chew C, Wilkinson MGL, McCann L, Wedderburn LR. Juvenile idiopathic inflammatory myositis: an update on pathophysiology and clinical care. Nat Rev Rheumatol 2023;19:343-62.

2. Tansley SL, Simou S, Shaddick G *et al*. Autoantibodies in juvenile-onset myositis: heir diagnostic value and associated clinical phenotype in a large UK cohort. J Autoimmun 2017;84:55-64.

3. Yasin SA, Schutz PW, Deakin CT *et al*.; UK Juvenile Dermatomyositis Research Group (UK and Ireland). Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features. Neuropathol Appl Neurobiol 2019;45:495-512.

4. Cordel N, Dechelotte B, Jouen F *et al*. Anti-transcription intermediary factor 1-gamma IgG2 isotype is associated with cancer in adult dermatomyositis: an ENMC multinational study. Rheumatology (Oxford) 2022;62:1711-5.

5. Aussy A, Fréret M, Gallay L *et al*.; OncoMyositis Study Group. The IgG2 isotype of anti-transcription intermediary factor 1γ autoantibodies is a biomarker of cancer and mortality in adult dermatomyositis. Arthritis Rheumatol 2019;71:1360-70.

6. Hinze CH, Oommen PT, Dressler F *et al*. Development of practice and consensus-based strategies including a treat-to-target approach for the management of moderate and severe juvenile dermatomyositis in Germany and Austria. Pediatr Rheumatol Online J 2018; 16:40.

7. Morris P, Dare J. Juvenile dermatomyositis as a paraneoplastic phenomenon: an update. J Pediatr Hematol Oncol 2010;32:189-91.

8. Tansley S, Wedderburn LR. Comparing and contrasting clinical and serological features of juvenile and adult-onset myositis: implications for pathogenesis and outcomes. Curr Opin Rheumatol 2015; 27:601-7.