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Thymomatous myasthenia gravis: novel association with HLA DQB1*05:01 and strengthened evidence of high clinical and serological severity

  • Roberto MassaEmail author
  • Giulia Greco
  • Manuela Testi
  • Emanuele Rastelli
  • Chiara Terracciano
  • Erica Frezza
  • Matteo Garibaldi
  • Girolama A. Marfia
  • Franco Locatelli
  • Nicola B. Mercuri
  • Eugenio Pompeo
  • Giovanni Antonini
  • Marco Andreani
Original Communication
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Abstract

Background

The relative prevalence of myasthenia gravis (MG) subtypes is changing, and their differential features and association with HLA class II alleles are not completely understood.

Methods

Age at onset, presence/absence of autoantibodies (Ab) and thymoma were retrospectively considered in 230 adult Italian patients. Clinical severity, assessed by MGFA scale, and the highest Ab titer were recorded. Furthermore, we performed low/high resolution typing of HLA-DRB1 and HLA-DQB1 alleles to detect associations of these loci with MG subtypes.

Results

There were two peaks of incidence: under 41 years of age, with female preponderance, and over 60 years, with higher male prevalence. The former group decreased and the latter increased significantly when comparing onset period 2008–2015 to 2000–2007. Thymomatous (TMG) patients showed a higher prevalence of severe phenotype and significantly higher anti-AChR Ab titer than non-thymomatous (NTMG) patients. Among the latter, those with onset after 60 years of age (LO-NTMG) displayed significantly higher Ab titers but lower MGFA grade compared to early-onset patients (< 41 years; EO-NTMG). Significant associations were found between HLA DQB1*05:01 and TMG patients and between DQB1*05:02 and DRB1*16 alleles and LO-NTMG with anti-AChR Ab.

Conclusions

Two distinct cutoffs (< 41 and > 60 years) conveniently define EO-NTMG and LO-NTMG, with different characteristics. LO-NTMG is the most frequent disease subtype, with an increasing incidence. TMG patients reach higher clinical severity and higher antibody titers than NTMG patients. Moreover, TMG and LO-NTMG with anti-AChR Ab differ in their HLA-DQ association, providing further evidence that these two forms may have different etiologic mechanisms.

Keywords

Myasthenia gravis Disease subgroups Late-onset Early onset Thymoma HLA association 

Notes

Compliance with ethical standards

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standards

The study protocol was approved by the Independent Ethic Committee of PTV and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

All participating subjects signed an informed consent.

References

  1. 1.
    Carr A (2015) Actual world epidemiology of myasthenia gravis. In: Mineo TC (ed) Novel challenges in myasthenia gravis. Nova Science Publisher Inc, New York, pp 23–43Google Scholar
  2. 2.
    Casetta I, Groppo E, De Gennaro R et al (2010) Myasthenia gravis: a changing pattern of incidence. J Neurol 257:2015–2019CrossRefGoogle Scholar
  3. 3.
    Montomoli C, Citterio A, Piccolo G et al (2012) Epidemiology and geographical variation of myasthenia gravis in the province of Pavia, Italy. Neuroepidemiology 38:100–105CrossRefGoogle Scholar
  4. 4.
    Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Ströbel P (2013) The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 12:875–884CrossRefGoogle Scholar
  5. 5.
    Alkhawajah NM, Oger J (2013) Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing. Muscle Nerve 48:705–710CrossRefGoogle Scholar
  6. 6.
    Seldin MF, Alkhairy OK, Lee AT et al (2015) Genome-wide association study of late-onset myasthenia gravis: confirmation of TNFRSF11A and identification of ZBTB10 and three distinct HLA associations. Mol Med 21:769–781CrossRefGoogle Scholar
  7. 7.
    Renton AE, Pliner HA, Provenzano C et al (2015) A genome-wide association study of Myasthenia Gravis. JAMA Neurol 72:396–404CrossRefGoogle Scholar
  8. 8.
    Poulas K, Zagoriti Z, Kambpouris M, Lagoumintzis G (2015) Advanced Genetics in Myasthenia Gravis. In: Mineo TC (ed) Novel challenges in myasthenia gravis. Nova Science Publisher Inc, New York, pp 109–132Google Scholar
  9. 9.
    Testi M, Terracciano C, Guagnano A et al (2012) Association of HLA-DQB1*05:02 and DRB1*16 Alleles with Late-Onset, Nonthymomatous, AChR-Ab-Positive Myasthenia Gravis. Autoimmune Dis 2012:541760Google Scholar
  10. 10.
    Evoli A, Antonini G, Antozzi C et al (2019) Italian recommendations for the diagnosis and treatment of myasthenia gravis. Neurol Sci (in press)Google Scholar
  11. 11.
    Klein R, Marx A, Ströbel P, Schalke B, Nix W, Willcox N (2013) Autoimmune association and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis. Hum Immunol 74:1184–1193CrossRefGoogle Scholar
  12. 12.
    Evoli A, Caliandro P, Iorio R et al (2015) Poly-autoimmunity in patients with myasthenia gravis: a single-center experience. Autoimmunity 48:412–417CrossRefGoogle Scholar
  13. 13.
    Somnier FE (2005) Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis. Neurology 65:928–930CrossRefGoogle Scholar
  14. 14.
    Agius MA, Richman DP, Vincent A (2009) Autoantibody testing in the diagnosis and management of autoimmune disorders of neuromuscular transmission and related disorders. In: Kaminski HJ (ed) Myasthenia gravis and related disorders, 2nd edn. Humana Press, New York, pp 143–156CrossRefGoogle Scholar
  15. 15.
    Murai H, Yamashita N, Watanabe M et al (2011) Characteristics of myasthenia gravis according to onset-age: Japanese nationwide survey. J Neurol Sci 305:97–102CrossRefGoogle Scholar
  16. 16.
    Maniaol AH, Elsais A, Lorentzen AR et al (2012) Late Onset myasthenia gravis is associated with HLA DRB1*15:01 in the norwegian population. PLoS One 7:e36603CrossRefGoogle Scholar
  17. 17.
    Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B (2014) Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmunity 48–49:143–148CrossRefGoogle Scholar
  18. 18.
    Akaishi T, Yamaguchi T, Suzuki Y et al (2014) Insights into the classification of Myasthenia gravis. PloS ONE 9:e106757CrossRefGoogle Scholar
  19. 19.
    Howard FM Jr, Lennon VA, Finley J, Matsumoto J, Elveback LR (1987) Clinical correlations of antibodies that bind, block, or modulate human acetylcholine receptors in Myasthenia gravis. Ann N Y Acad Sci 505:526–538CrossRefGoogle Scholar
  20. 20.
    Kang SY, Oh JH, Song SK, Lee JS, Choi JC, Kang JH (2015) Both binding and blocking antibodies correlate with disease severity in myasthenia gravis. Neurol Sci 36:1167–1171CrossRefGoogle Scholar
  21. 21.
    Vandiedonck C, Raffoux C, Eymard B et al (2009) Association of HLA-A in autoimmune Myasthenia gravis with thymoma. J Neuroimmunol 210:120–123CrossRefGoogle Scholar
  22. 22.
    Bartoccioni E, Scuderi F, Augugliaro A et al (2009) HLA class II allele analysis in MuSK-positive myasthenia gravis suggests a role for DQ5. Neurology 72:195–197CrossRefGoogle Scholar
  23. 23.
    Nikolic AV, Andric ZP, Simonovic RB et al (2015) High frequency of DQB1*05 and absolute absence of DRB1*13 in muscle-specific tyrosine kinase positive myasthenia gravis. Eur J Neurol 22:59–63CrossRefGoogle Scholar
  24. 24.
    Baggi F, Antozzi C, Andreetta F et al (1998) Identification of a novel HLA class II association with DQB1∗0502 in an Italian myasthenic population. Ann N Y Acad Sci 841:355–359CrossRefGoogle Scholar
  25. 25.
    Saruhan-Direskeneli G, Hughes T, Yilmaz V et al (2016) Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis. Clin Immunol 166–167:81–88CrossRefGoogle Scholar
  26. 26.
    Ayyar BV, Atassi MZ (2017) Development of humanized scFv antibody fragment(s) that targets and blocks specific HLA alleles linked to myasthenia gravis. Appl Microbiol Biotechnol 101:8165–8179CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Roberto Massa
    • 1
    Email author
  • Giulia Greco
    • 1
  • Manuela Testi
    • 2
  • Emanuele Rastelli
    • 1
  • Chiara Terracciano
    • 1
  • Erica Frezza
    • 1
  • Matteo Garibaldi
    • 3
  • Girolama A. Marfia
    • 4
  • Franco Locatelli
    • 5
  • Nicola B. Mercuri
    • 4
  • Eugenio Pompeo
    • 6
  • Giovanni Antonini
    • 3
  • Marco Andreani
    • 5
  1. 1.Unit Malattie Neuromuscolari, Dipartimento Medicina dei SistemiUniversità di Roma Tor VergataRomeItaly
  2. 2.Unit Genetica MedicaAzienda Ospedaliera San Camillo-ForlaniniRomeItaly
  3. 3.Neurofisiopatologia, Dipartimento NESMOSOspedale S. Andrea, Sapienza Università di RomaRomeItaly
  4. 4.Neurologia, Dipartimento Medicina dei SistemiUniversità di Roma Tor VergataRomeItaly
  5. 5.Laboratorio d’Immunogenetica dei Trapianti, Dipartimento di Oncoematologia e Terapia Cellulare e GenicaIRCCS OPBGRomeItaly
  6. 6.Dipartimento Chirurgia ToracicaUniversità di Roma Tor VergataRomeItaly

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