SpringerLink
Log in

Pediatric mixed connective tissue disease versus other overlap syndromes: a retrospective multicenter cohort study

  • Observational Research
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Pediatric mixed connective tissue disease (MCTD) is a subgroup of overlap syndromes. We aimed to compare the characteristics and outcomes in children with MCTD and other overlap syndromes. All MCTD patients met either Kasukawa or Alarcon-Segovia and Villareal criteria. The patients with other overlap syndromes had the features of ≥ 2 autoimmune rheumatic diseases but did not meet MCTD diagnostic criteria. Thirty MCTD (F/M = 28/2) and thirty (F/M = 29/1) overlap patients were included (disease onset < 18 years). The most prominent phenotype at disease onset and the last visit was systemic lupus erythematosus (SLE) in the MCTD group; juvenile idiopathic arthritis and dermatomyositis/polymyositis, respectively, in the overlap group. At the last visit, systemic sclerosis (SSc) phenotype was more frequent among MCTD than overlap patients (60% vs. 33.3%; p = 0.038). The frequency of the predominant SLE phenotype had decreased (60% to 36.7%), while predominant SSc phenotype had increased (13.3% to 33.3%) during follow-up in MCTD patients. Weight loss (36.7% vs. 13.3%), digital ulcers (20% vs. 0), swollen hands (60% vs. 20%), Raynaud phenomenon (86.7% vs. 46.7%), hematologic involvement (70% vs. 26.7%), and anti-Sm positivity (29% vs. 3.3%) were more common, while Gottron papules (16.7% vs. 40%) were less frequent among MCTD than overlap patients (p < 0.05). A higher percentage of overlap patients achieved complete remission than MCTD patients (51.7% vs. 24.1%; p = 0.047). The disease phenotype and outcome differ between pediatric MCTD and other overlap syndromes where MCTD may be regarded as a more severe disease. Analyzing these patients could pave the way for early and effective treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data availability

The entire dataset used for this study can be accessed from the corresponding author upon reasonable request.

References

  1. Berard RA, Laxer RM (2016) Pediatric mixed connective tissue disease. Curr Rheumatol Rep 18:28. https://doi.org/10.1007/s11926-016-0576-x

    Article  PubMed  Google Scholar 

  2. Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, Matteson EL (2016) Epidemiology of mixed connective tissue disease, 1985–2014: a population-based study. Arthritis Care Res 68:1843–1848. https://doi.org/10.1002/acr.22872

    Article  Google Scholar 

  3. Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC (1999) Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum 42:899–909. https://doi.org/10.1002/1529-0131(199905)42:5%3c899::AID-ANR8%3e3.0.CO;2-L

    Article  CAS  PubMed  Google Scholar 

  4. Kotajima L, Aotsuka S, Sumiya M, Yokohari R, Tojo T, Kasukawa R (1996) Clinical features of patients with juvenile onset mixed connective tissue disease: analysis of data collected in a nationwide collaborative study in Japan. J Rheumatol 23:1088–1094

    CAS  PubMed  Google Scholar 

  5. Cappelli S, Bellando Randone S, Martinovic D, Tamas MM, Pasalic K, Allanore Y, Mosca M, Talarico R, Opris D, Kiss CG, Tausche AK, Cardarelli S, Riccieri V, Koneva O, Cuomo G, Becker MO, Sulli A, Guiducci S, Radic M, Bombardieri S, Aringer M, Cozzi F, Valesini G, Ananyeva L, Valentini G, Riemekasten G, Cutolo M, Ionescu R, Czirjak L, Damjanov N, Rednic S, MatucciCerinic M (2012) “To be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum 41:589–598. https://doi.org/10.1016/j.semarthrit.2011.07.010

    Article  PubMed  Google Scholar 

  6. Michels H (1997) Course of mixed connective tissue disease in children. Ann Med 29:359–364. https://doi.org/10.3109/07853899708999362

    Article  CAS  PubMed  Google Scholar 

  7. Hetlevik SO, Flato B, Rygg M, Nordal EB, Brunborg C, Hetland H, Lilleby V (2017) Long-term outcome in juvenile-onset mixed connective tissue disease: a nationwide Norwegian study. Ann Rheum Dis 76:159–165. https://doi.org/10.1136/annrheumdis-2016-209522

    Article  PubMed  Google Scholar 

  8. Mier RJ, Shishov M, Higgins GC, Rennebohm RM, Wortmann DW, Jerath R, Alhumoud E (2005) Pediatric-onset mixed connective tissue disease. Rheum Dis Clin North Am 31(483–496):vii. https://doi.org/10.1016/j.rdc.2005.04.002

    Article  PubMed  Google Scholar 

  9. Rutkowska-Sak L, Gietka P (2019) Clinical features and outcome of mixed connective tissue disease in developmental age—observational study from one center. Reumatologia 57:315–319. https://doi.org/10.5114/reum.2019.91275

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kasukawa R, Tojo T, Miyawaki S (1987) Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC (eds) Mixed connective tissue disease and antinuclear antibodies. Elsevier Science Publishers BV (Biomedical Division), Amsterdam, pp 41–47

    Google Scholar 

  11. Alarcón-Segovia D, Villareal M (1987) Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharp GC (eds) Mixed connective tissue disease and antinuclear antibodies. Elsevier Science Publishers BV (Biomedical Division), Amsterdam, pp 33–40

    Google Scholar 

  12. Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly JG, Sanchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MA, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim SS, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG Jr, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G Jr, Magder LS (2012) Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677–2686. https://doi.org/10.1002/art.34473

    Article  PubMed  PubMed Central  Google Scholar 

  13. Liberal R, Vergani D, Mieli-Vergani G (2015) Update on autoimmune hepatitis. J Clin Transl Hepatol 3:42–52. https://doi.org/10.14218/JCTH.2014.00032

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zanin-Silva DC, Santana-Goncalves M, Kawashima-Vasconcelos MY, Oliveira MC (2021) Management of endothelial dysfunction in systemic sclerosis: current and develo** strategies. Front Med 8:788250. https://doi.org/10.3389/fmed.2021.788250

    Article  Google Scholar 

  15. Akca UK, Batu ED, Kisaarslan AP, Poyrazoglu H, Ayaz NA, Sozeri B, Sag E, Atalay E, Demir S, Karadag SG, Demir F, Bilginer Y, Gumruk F, Ozen S (2021) Hematological involvement in pediatric systemic lupus erythematosus: a multicenter study. Lupus 30:1983–1990. https://doi.org/10.1177/09612033211038824

    Article  CAS  PubMed  Google Scholar 

  16. Batu ED, Akca UK, Kisaarslan AP, Sag E, Demir F, Demir S, Cicek SO, Poyrazoglu H, Sozeri B, Bilginer Y, Ozen S (2021) The performances of the ACR 1997, SLICC 2012, and EULAR/ACR 2019 classification criteria in pediatric systemic Lupus Erythematosus. J Rheumatol 48:907–914. https://doi.org/10.3899/jrheum.200871

    Article  CAS  PubMed  Google Scholar 

  17. Gorkem SB, Doria AS, Tse S (2019) Imaging findings of mixed connective tissue disease in children and adolescents: a case series. Jpn J Radiol 37:371–379. https://doi.org/10.1007/s11604-019-00824-4

    Article  PubMed  Google Scholar 

  18. Singsen BH, Bernstein BH, Kornreich HK, King KK, Hanson V, Tan EM (1977) Mixed connective tissue disease in childhood. A clinical and serologic survey. J Pediatr 90:893–900. https://doi.org/10.1016/s0022-3476(77)80555-6

    Article  CAS  PubMed  Google Scholar 

  19. Singsen BH, Swanson VL, Bernstein BH, Heuser ET, Hanson V, Landing BH (1980) A histologic evaluation of mixed connective tissue disease in childhood. Am J Med 68:710–717. https://doi.org/10.1016/0002-9343(80)90258-2

    Article  CAS  PubMed  Google Scholar 

  20. Alduraibi F, Fatima H, Hamilton JA, Chatham WW, Hsu HC, Mountz JD (2022) Lupus nephritis correlates with B cell interferon-beta, anti-Smith, and anti-DNA: a retrospective study. Arthritis Res Ther 24:87. https://doi.org/10.1186/s13075-022-02766-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Estevez Del Toro M, Varela Ceballos I, Chico Capote A, Kokuina E, Sanchez Bruzon Y, Casas Figueredo N (2022) Predictive factors for the development of lupus nephritis after diagnosis of systemic lupus erythematosus. Reumatol Clin 18:513–517. https://doi.org/10.1016/j.reumae.2021.08.003

    Article  PubMed  Google Scholar 

  22. Tellier S, Bader-Meunier B, Quartier P, Belot A, Deslandre C, Kone-Paut I, Tiriau S, Jurquet AL, Rosellini D, Dheu-Bentz C, Mestrallet G, Decramer S (2016) Initial presentation and outcome of pediatric-onset mixed connective tissue disease: a French multicenter retrospective study. Joint Bone Spine 83:369–371. https://doi.org/10.1016/j.jbspin.2015.05.013

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was presented as an abstract at the 28th European Paediatric Rheumatology Congress of the Paediatric Rheumatology European Association (PReS), held in Prague, Czech Republic, on 20-23 September 2022. The abstract of this study was published in the Proceedings of the Congress (https://doi.org/10.1186/s12969-022-00729-z).

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Ezgi Deniz Batu, Muserref Kasap Cuceoglu, Yelda Bilginer & Seza Özen

  2. Cerrahpasa Medical School, Department of Pediatrics, Division of Rheumatology, Istanbul University Cerrahpasa, Istanbul, Turkey

    Aybüke Günalp, Sezgin Şahin & Özgür Kasapçopur

  3. Dr. Sami Ulus Maternity and Child Health and Diseases Research and Training Hospital, Department of Pediatrics, Division of Rheumatology, University of Health Sciences, Ankara, Turkey

    Semanur Özdel & İlknur Bağrul

  4. Department of Pediatrics, Division of Rheumatology, Dokuz Eylül University Faculty of Medicine, Izmir, Turkey

    Zehra Kızıldağ & Erbil Ünsal

  5. Faculty of Medicine, Department of Pediatrics, Division of Rheumatology, Erciyes University, Kayseri, Turkey

    Aysenur Pac Kısaarslan & M. Hakan Poyrazoğlu

  6. Faculty of Medicine, Department of Pediatrics, Division of Rheumatology, Istanbul University, Istanbul, Turkey

    Ayşe Tanatar & Nuray Aktay Ayaz

  7. Faculty of Medicine, Department of Pediatrics, Division of Rheumatology, Kocaeli University, Kocaeli, Turkey

    Hafize Emine Sonmez

  8. Ankara Research and Training Hospital, Department of Pediatrics, Division of Rheumatology, University of Health Sciences, Ankara, Turkey

    Erdal Sag

  9. Department of Pediatrics, Division of Rheumatology, Erzurum Regional Research and Training Hospital, Erzurum, Turkey

    Selcan Demir

  10. Ankara City Hospital, Department of Pediatrics, Division of Rheumatology, University of Health Sciences, Ankara, Turkey

    Elif Çelikel & Banu Çelikel Acar

  11. Umraniye Research and Training Hospital, Department of Pediatrics, Division of Rheumatology, University of Health Sciences, Istanbul, Turkey

    Sengul Cağlayan & Betül Sözeri

  12. Çocuk Romatoloji Bölümü, Hacettepe Üniversitesi İhsan Doğramacı Çocuk Hastanesi, Kat: 3 Sıhhiye, 06100, Ankara, Turkey

    Ezgi Deniz Batu

Authors
  1. Ezgi Deniz Batu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aybüke Günalp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sezgin Şahin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Semanur Özdel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zehra Kızıldağ
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aysenur Pac Kısaarslan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. İlknur Bağrul
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Muserref Kasap Cuceoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ayşe Tanatar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hafize Emine Sonmez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Erdal Sag
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Selcan Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Elif Çelikel
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Sengul Cağlayan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Banu Çelikel Acar
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Betül Sözeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Nuray Aktay Ayaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yelda Bilginer
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M. Hakan Poyrazoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Erbil Ünsal
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Özgür Kasapçopur
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Seza Özen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: EDB; methodology: EDB, APK, BÇA, BS, NAA, YB, MKP, EU, ÖK; formal analysis and investigation: EDB, AG, SS, SÖ, ZK, İB, MKC, AT, HES, ES, SD, EC, SC; writing—original draft preparation: EDB; writing—review and editing: EDB, APK, BCA, BS, NAA, YB, MKP, EU, ÖK, SÖ; supervision: SÖ. All co-authors take full responsibility for the integrity and accuracy of all aspects of the work.

Corresponding author

Correspondence to Ezgi Deniz Batu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Statement of ethics and consent

The study protocol was approved by the ethical committee of Hacettepe University (GO 21/925). And, local ethics committee approvals were obtained in the participating centers. The study was performed according to the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. At the time of hospital admission, all patients/parents provided written informed consent for the use of their data anonymously for academic purposes.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Batu, E.D., Günalp, A., Şahin, S. et al. Pediatric mixed connective tissue disease versus other overlap syndromes: a retrospective multicenter cohort study. Rheumatol Int 43, 1485–1495 (2023). https://doi.org/10.1007/s00296-023-05300-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-023-05300-x

Keywords

Search

Navigation