Skip to main content

Advertisement

SpringerLink
Log in

Prospective, systematically recorded mycophenolate safety data in Graves’ orbitopathy

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Context

The antiproliferative mechanism of mycophenolate acid (MPA) suggests a beneficial effect in patients with Graves’ orbitopathy (GO).

Objective

To systematically analyze for the first time adverse events (AEs) during MPA treatment in GO.

Design

Prospective longitudinal study.

Setting

Academic tertiary referral center with a joint thyroid-eye clinic.

Patients

Fifty-three consecutive, unselected patients with clinically active and moderate-to-severe GO.

Methods

MPA 0.720 g was given once daily for 24-weeks in GO patients. AEs were documented and coded according to the standardized medical dictionary for regulatory activities (MedDRA). AE were followed up and seriousness as defined by ICH-guideline E6 was documented. All AEs were analyzed regarding a possible underlying cause and if not, graded as side effect (SE).

Results

Fifty GO patients (93 %) had Graves’ disease, 37 (70 %) and 29 (54.7 %) were female and smoker, respectively. Thirty-six patients (68 %) reported at least one AE. A total of 88 AEs were documented, most frequent AEs were insomnia (N = 6), fatigue (N = 5) and optic neuropathy (N = 5), while other AEs occurred in up to three patients (5.6 %), only. In 12 (23 %) patients, at least one SE occurred. All 17 reported SE, i.e. mild infections and gastrointestinal intolerance were within the known safety profile of MPA. No patient dropped MPA medication because of drug-induced SE. Most AEs showed a recovered (76 %) or recovering (16 %) outcome. Seven (13 %) patients were hospitalized, five (62 %) due to optic neuropathy, none of these events was graded as SE.

Conclusions

MedDRA-coded data documented the good tolerance of a moderate MPA dose in GO patients.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bartalena L, Macchia PE, Marcocci C, Salvi M, Vermiglio F (2015) Effects of treatment modalities for Graves’ hyperthyroidism on Graves’ orbitopathy: a 2015 Italian Society of Endocrinology Consensus Statement. J Endocrinol Invest 38(4):481–487. doi:10.1007/s40618-015-0257-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bartalena L, Fatourechi V (2014) Extrathyroidal manifestations of Graves’ disease: a 2014 update. J Endocrinol Invest 37(8):691–700. doi:10.1007/s40618-014-0097-2

    Article  CAS  PubMed  Google Scholar 

  3. Bartalena L (2013) Graves’ orbitopathy: imperfect treatments for a rare disease. Eur Thyroid J 2(4):259–269. doi:10.1159/000356042

    Article  PubMed  PubMed Central  Google Scholar 

  4. Stan MN, Garrity JA, Bahn RS (2012) The evaluation and treatment of graves ophthalmopathy. Med Clin North Am 96(2):311–328. doi:10.1016/j.mcna.2012.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kahaly GJ, Pitz S, Hommel G, Dittmar M (2005) Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 90(9):5234–5240. doi:10.1210/jc.2005-0148

    Article  CAS  PubMed  Google Scholar 

  6. Zang S, Ponto KA, Pitz S, Kahaly GJ (2011) Dose of intravenous steroids and therapy outcome in Graves’ orbitopathy. J Endocrinol Invest 34(11):876–880

    Article  CAS  PubMed  Google Scholar 

  7. Menconi F, Leo M, Vitti P, Marcocci C, Marino M (2015) Total thyroid ablation in Graves’ orbitopathy. J Endocrinol Invest 38(8):809–815. doi:10.1007/s40618-015-0255-1

    Article  CAS  PubMed  Google Scholar 

  8. Salvi M, Vannucchi G, Curro N, Campi I, Covelli D, Dazzi D, Simonetta S, Guastella C, Pignataro L, Avignone S, Beck-Peccoz P (2015) Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves’ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab 100(2):422–431. doi:10.1210/jc.2014-3014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS (2015) Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J Clin Endocrinol Metab 100(2):432–441. doi:10.1210/jc.2014-2572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bartalena L (2010) What to do for moderate-to-severe and active Graves’ orbitopathy if glucocorticoids fail? Clin Endocrinol 73(2):149–152. doi:10.1111/j.1365-2265.2010.03783.x

    CAS  Google Scholar 

  11. Allison AC, Eugui EM (2000) Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47(2–3):85–118

    Article  CAS  PubMed  Google Scholar 

  12. Roche pharmaceuticals AG (2015) German summary of product characteristics. Cellcept

  13. Novartis pharmaceuticals GmbH (2015) German summary of product characteristics. Myfortic

  14. Allison AC (2002) Mechanisms of action of mycophenolate mofetil in preventing chronic rejection. Transpl Proc 34(7):2863–2866

    Article  CAS  Google Scholar 

  15. Allison AC, Eugui EM (2005) Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 80(2 Suppl):S181–S190

    Article  CAS  PubMed  Google Scholar 

  16. Eugui EM, Allison AC (1993) Immunosuppressive activity of mycophenolate mofetil. Ann N Y Acad Sci 685:309–329

    Article  CAS  PubMed  Google Scholar 

  17. Kuhn A, Bonsmann G, Anders HJ, Herzer P, Tenbrock K, Schneider M (2015) The diagnosis and treatment of systemic lupus erythematosus. Deutsches Arzteblatt international 112(25):423–432. doi:10.3238/arztebl.2015.0423

    PubMed  PubMed Central  Google Scholar 

  18. Kuhn A, Ruland V, Bonsmann G (2011) Cutaneous lupus erythematosus: update of therapeutic options part II. J Am Acad Dermatol 65(6):e195–e213. doi:10.1016/j.jaad.2010.06.017

    Article  PubMed  Google Scholar 

  19. Lee YH, Song GG (2015) Relative efficacy and safety of tacrolimus, mycophenolate mofetil, and cyclophosphamide as induction therapy for lupus nephritis: a Bayesian network meta-analysis of randomized controlled trials. Lupus. doi:10.1177/0961203315595131

    Google Scholar 

  20. Chen Y, Li Y, Yang S, Li Y, Liang M (2014) Efficacy and safety of mycophenolate mofetil treatment in IgA nephropathy: a systematic review. BMC Nephrol 15:193. doi:10.1186/1471-2369-15-193

    Article  PubMed  PubMed Central  Google Scholar 

  21. Grainge C, Jayasekera N, Dennison P, Rupani H, Kurukulaaratchy R, Howarth P (2013) Case series reporting the effectiveness of mycophenolate mofetil in treatment-resistant asthma. Eur Respir J 42(4):1134–1137. doi:10.1183/09031936.00026413

    Article  CAS  PubMed  Google Scholar 

  22. Olejarz W, Bryk D, Zapolska-Downar D (2014) Mycophenolate mofetil—a new atheropreventive drug? Acta Pol Pharm 71(3):353–361

    PubMed  Google Scholar 

  23. Prabhakar BS, Bahn RS, Smith TJ (2003) Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr Rev 24(6):802–835. doi:10.1210/er.2002-0020

    Article  CAS  PubMed  Google Scholar 

  24. Shan SJ, Douglas RS (2014) The pathophysiology of thyroid eye disease. J Neuro Ophthalmol 34(2):177–185. doi:10.1097/WNO.0000000000000132

    Article  Google Scholar 

  25. Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marino M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM, European Group on Graves O (2008) Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol Eur Fed Endocr Soc 158(3):273–285. doi:10.1530/EJE-07-0666

    Article  CAS  Google Scholar 

  26. Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits MP, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krassas G, Lane CM, Lazarus JH, Marino M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM (2008) Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 18(3):333–346. doi:10.1089/thy.2007.0315

    Article  PubMed  Google Scholar 

  27. Riedl M, Kolbe E, Kampmann E, Kramer I, Kahaly GJ (2015) Prospectively recorded and MedDRA-coded safety data of intravenous methylprednisolone therapy in Graves’ orbitopathy. J Endocrinol Invest 38(2):177–182. doi:10.1007/s40618-014-0227-x

    Article  CAS  PubMed  Google Scholar 

  28. MSSO (2013) MedDRA Term selection: points to consider Release 4.6 Based on MedDRA Version 16.1

  29. ICH (2001) Data elements for transmission of individual case safety reports E2B. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

  30. ICH (1996) Guideline for good clinical practice E6(R1). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

  31. Dalal P, Grafals M, Chhabra D, Gallon L (2009) Mycophenolate mofetil: safety and efficacy in the prophylaxis of acute kidney transplantation rejection. Ther Clin Risk Manag 5(1):139–149

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Sigges J, Biazar C, Landmann A, Ruland V, Patsinakidis N, Amler S, Bonsmann G, Kuhn A, Co-Authors E (2013) Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus. Autoimmun Rev 12(7):694–702. doi:10.1016/j.autrev.2012.10.005

    Article  PubMed  Google Scholar 

  33. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group (1996) A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 61(7):1029–1037

    Article  Google Scholar 

  34. Sollinger HW (1995) Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 60(3):225–232

    Article  CAS  PubMed  Google Scholar 

  35. Salvadori M, Group ERLS (2005) Long-term administration of enteric-coated mycophenolate sodium in kidney transplant patients. Transpl Proc 37(2):909–911. doi:10.1016/j.transproceed.2005.01.063

    Article  CAS  Google Scholar 

  36. Kim JM, Kwon CH, Yun IJ, Lee KW, Yu HC, Suh KS, Joh JW, Cho BH (2014) A multicenter experience with generic mycophenolate mofetil conversion in stable liver transplant recipients. Ann Surg Treat Res 86(4):192–198. doi:10.4174/astr.2014.86.4.192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hardinger KL, Brennan DC, Lowell J, Schnitzler MA (2004) Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transpl Int 17(10):609–616. doi:10.1007/s00147-004-0768-6

    Article  PubMed  Google Scholar 

  38. Tierce JC, Porterfield-Baxa J, Petrilla AA, Kilburg A, Ferguson RM (2005) Impact of mycophenolate mofetil (MMF)-related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients. Clin Transpl 19(6):779–784. doi:10.1111/j.1399-0012.2005.00421.x

    Article  CAS  Google Scholar 

  39. European Mycophenolate Mofetil Cooperative Study Group (1995) Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 345(8961):1321–1325

    Article  Google Scholar 

  40. Pisoni CN, Sanchez FJ, Karim Y, Cuadrado MJ, D’Cruz DP, Abbs IC, Khamasta MA, Hughes GR (2005) Mycophenolate mofetil in systemic lupus erythematosus: efficacy and tolerability in 86 patients. J Rheumatol 32(6):1047–1052

    CAS  PubMed  Google Scholar 

  41. Pisoni CN, Karim Y, Cuadrado MJ (2005) Mycophenolate mofetil and systemic lupus erythematosus: an overview. Lupus 14(Suppl 1):s9–11

    Article  CAS  PubMed  Google Scholar 

  42. Karim MY, Alba P, Cuadrado MJ, Abbs IC, D’Cruz DP, Khamashta MA, Hughes GR (2002) Mycophenolate mofetil for systemic lupus erythematosus refractory to other immunosuppressive agents. Rheumatology 41(8):876–882

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This paper includes parts of the doctorate thesis of M. Riedl. The authors are grateful to E. Kampmann, M. Pirkl and M. Lehman (JGU Thyroid Lab) for data collection.

Author information

Authors and Affiliations

  1. Departments of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany

    M. Riedl, E. Kolbe & G. J. Kahaly

  2. Interdisciplinary Center for Clinical Trials, Johannes Gutenberg University Medical Center, Mainz, Germany

    M. Riedl & A. Kuhn

  3. Pharmacy Department, Johannes Gutenberg University Medical Center, Mainz, Germany

    I. Krämer

Authors
  1. M. Riedl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Krämer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Kolbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. J. Kahaly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. J. Kahaly.

Ethics declarations

Conflict of interest

The authors have nothing to declare.

Ethical approval

The authors confirm that the performance of this prospective study and the research involving human participants was compliant with ethical standards. The study protocol was consistent with the principles of the Declaration of Helsinki.

Informed consent

Written informed consent to be included in the database and to draw blood was obtained from all participants and approval by the local Ethics Committee was obtained.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Riedl, M., Kuhn, A., Krämer, I. et al. Prospective, systematically recorded mycophenolate safety data in Graves’ orbitopathy. J Endocrinol Invest 39, 687–694 (2016). https://doi.org/10.1007/s40618-016-0441-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-016-0441-9

Keywords

Search

Navigation