Aktuelle Neurologie 2018; 45(01): 44-51
DOI: 10.1055/s-0043-118528
Aktuelle Diagnostik
© Georg Thieme Verlag KG Stuttgart · New York

Die Post-Alemtuzumab-Therapie-induzierte Schilddrüsendysfunktion bei schubförmig-remittierender MS (RRMS) – ein variantenreiches Krankheitsbild auf einem interdisziplinären Terrain

Alemtuzumab Treatment-Induced Thyroid Dysfunction in Relapsing Remitting MS (RRMS): a Varied Clinical Picture in an Interdisciplinary Terrain
Hans-Klaus Goischke
Further Information

Publication History

Publication Date:
28 September 2017 (online)

Zusammenfassung

Alemtuzumab-induzierte Schilddrüsendysfunktionen (engl.: Alemtuzumab-induced thyroid dysfunction; AITD) können die Lebensqualität von MS-Patienten wesentlich beeinträchtigen, wenn diese Nebenwirkung nicht rechtzeitig erkannt und adäquat von allen Fachrichtungen reagiert wird. Vor Alemtuzumab-Therapie sollten der TSH-Spiegel und die Schilddrüsen-AK untersucht werden. Bei Nachweis von TPO-AK vor Beginn der Behandlung betrug das Risiko 69 %, eine AITD zu entwickeln im Vergleich zu TPO-negativen Patienten mit nur 31 %.

Trotzdem waren 85 %, die eine AITD später entwickelten, vor Therapie TPO-AK-negativ, sodass AK-Negativität basal kein Schutz vor AITD darstellt. Deshalb müssen die periodischen Tests streng durchgeführt werden. Eine interdisziplinäre Zusammenarbeit von Neurologen, Internisten (Endokrinologen) und Gynäkologen führt zum rechtzeitigen Erkennen des variantenreichen klinischen Verlaufes bei wechselnden biochemischen Befunden mit entsprechenden diagnostischen und therapeutischen Konsequenzen. Da die klinischen Symptome der Hypothyreose/Hyperthyreose sich mit denen der MS überschneiden können, ist die Bestimmung von laborchemischen Parametern auch im Verlauf rechtzeitig unerlässlich, insbesondere bei graviden Patientinnen. Durch die kostengünstige und gut verträgliche Add-on-Therapie mit Vitamin D mit multiplen Zielwirkungen – 1. auf die AITD, 2. auf die Reduktion der Krankheitsaktivität und 3. auf die positive Beeinflussung einer Gravidität (Verringerung einer niedrigen Geburtsgewichts-, Eklampsie- und Frühgeburtenrate, Reduktion der Übertragung der MS auf die Nachkommenschaft) – sollte trotz noch offener Fragen den Betroffenen die Chance zur Minderung der Progression nicht verwehrt werden. Der Arzt spielt eine wichtige Rolle in der Stärkung der Fähigkeit der Patienten, ihre eigene Krankheit zu managen, um die Krankheitsprogression zu vermindern. Im Arzt-Patienten-Gespräch sollte die Reduzierung von Risikofaktoren (z.B. Vit.-D-Mangel) thematisiert werden. Ein Engagement für ein optimales interdisziplinäres Management mit Therapieindividualisierung und Reduzierung von Arzneimittelnebenwirkungen verbessert die Lebensqualität von MS-Patienten.

Abstract

Alemtuzumab-induced thyroid dysfunction (AITD) can significantly affect the quality of life of MS patients if this side effect is not recognized in time and adequately responded to by all specialist disciplines. Before alemtuzumab therapy, the TSH level and the thyroid gland should be examined. In the detection of TPO-AK before the start of treatment, the risk of developing an AITD was 69 % compared to TPO-negative patients with only 31 % risk. 85 %, of patients who developed AITD later were TPO-AK-negative before therapy, so that baseline AK-negativity is no protection from AITD. Therefore, periodic tests must be carried out strictly. An interdisciplinary collaboration between neurologists, internists (endocrinologists) and gynecologists leads to the timely recognition of the varied clinical course with varying biochemical findings with corresponding diagnostic and therapeutic consequences. Since the clinical symptoms of hypothyroidism/hyperthyroidism can overlap with those of MS, determination of laboratory chemical parameters is also essential over time, especially in the case of pregnant patients. Through the cost-effective and well-tolerated add-on therapy with vitamin D with multiple targets – 1. AITD, 2. reduction of disease activity and 3. positive influence on pregnancy (reduction of low birth weight, eclampsia and premature birth rate, reduction of transmission of MS to the offspring), the chances of reducing progression should not be denied to those affected. The physician has an important role in strengthening the ability of patients to shape and manage their own illness and to influence disease progression. Acceptance of reduction of risk factors (vitamin D deficiency) by patients can undoubtedly be achieved during physician-patient conversation. A commitment to optimal interdisciplinary management with therapy individualization and reduction of drug side effects improves the quality of life of MS patients.

 
  • Literatur

  • 1 Tuchy O, Costelloe L, Hill-Cawthorne G. et al. Alemtuzumab treatment of multiple sclerosis: longterm safety and efficacy. J Neurol Neurosurg Psychiatry 2015; 86: 208-215
  • 2 Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinien (AM-RL): Anlage IV – Therapiehinweis Alemtuzumab. Dtsch Ärztebl 2017; 114: C86-C92
  • 3 Coles AJ, Fox E, Vladic A. et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012; 78: 1069-1078
  • 4 Daniels GB, Vladic A, Brinar V. et al. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metabol 2014; 99: 80-89
  • 5 Havrdova E, Horakova D, Kovarova I. Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use. Adv Neurol Disord 2015; 8: 31-45
  • 6 Mahzari M, Arnaout A, Freedman MS. Alemtuzumab induced thyroid disease in multiple sclerosis: A review and approach to management. Can J Neurol Sci 2015; 42: 284-291
  • 7 Obermann M, Ruck T, Pfeuffer S. et al. Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis. Mult Scler 2016; 22: 1235-1241
  • 8 Cuker A, Coles AJ, Sullivan H. et al. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood 2011; 118: 6299-6305
  • 9 Cohen JA, Coles AJ, Arnold DL. et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 2012; 380: 1819-1828
  • 10 Cuker A, Palmer J, Oyuela P. et al. Successful detection and management of immune thrombocytopenia in alemtuzumab-treated patients with active relapsing-remitting multiple sclerosis. Neurology 2014; 82 (10 Suppl): P2.198
  • 11 Clatworthy MR, Wallin EF. Anti-glomerular basement membrane disease after alemtuzumab. N Engl J Med 2008; 359: 768-769
  • 12 Wynn DR, Arnold D, Cohen J. et al. Detection, incidence and management of glomerulonephritis in the alemtuzumab clinical development programme. ECTRIMS Meeting; 2–5 Oct 2013. Copenhagen. Denmark: P597
  • 13 Meyer D, Coles A, Oyuela P. et al. Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2013; 2: 60-63
  • 14 Krull I, Brändle M. Hyperthyreose: Diagnostik und Therapie. Schweiz Med Forum 2013; 47: 954-960
  • 15 Tsourdi E, Gruber M, Rauner M. et al. Gravesʼ disease after treatment with alemtuzumab for multiple sclerosis. Hormones 2015; 14: 148-153
  • 16 Cossburn M, Pace AA, Jones J. et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 2011; 77: 573-579
  • 17 CAMMS223 Trial Investigators. Coles AJ, Compston DA. et al. Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-1801
  • 18 Samuels MH. Subacute, silent, and postpartum thyroidits. Med Clin North Am 2012; 96: 223-233
  • 19 Instanes JT, Halmoy A, Engeland A. et al. Attention-deficit/hyperactivity disorder in offspring of mother with inflammatory and immune system disease. Biol Psychiatry 2017; 81: 452-459
  • 20 Ghassabian A, Bongers-Schokking JJ, Rijke YB. et al. Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: The Generation R Study. Thyroid 2012; 22: 178-186
  • 21 Zivadinov R, Raj B, Ramanathan M. et al. Autoimmune comorbidities are associated with brain injury in multiple sclerosis. Am J Neuroradiol 2016; 37: 1010-1016
  • 22 Zimmermann A, Weber MM. Schilddrüsenerkrankungen in der Schwangerschaft. J Gynäkol Endokrinol 2012; 22: 6-12
  • 23 Grünwald F, Derwahl K-M. Diagnostik und Therapie von Schilddrüsenerkrankungen. Berlin: Lehmanns Media; 2014
  • 24 Chan S, Boelaert K. Optimal management of hypothyroidism, hypothyroxinaemie and euthyroid TPO antibody positivity preconception and in pregnancy. Clin Endocrin 2015; 82: 313-326
  • 25 Maraka S, Mwangi R, McCoy G. et al. Thyroid hormone treatment among pregnancy women with subclinical hypothyroidism: US national assessment. BMJ 2017; DOI: 10.1136/bmj.i6865.
  • 26 Unuane D, Velkeniers B, Bravenboer B. et al. Impact of thyroid autoimmunity in euthyroid women on live birth rate after IUI. Hum Reprod 2017; 32: 915-922
  • 27 Meena M, Chopra S, Jain V. The effect of anti-thyroid peroxidase antibodies on pregnancy outcomes in euthyroid women. J Clin Diagn Res 2016; 19: Qc04-QC07
  • 28 Mceldfuff A, Morris J. Thyroid function tests and thyroid autoantibodies in an unselected population of women undergoing first trimester screening for aneuploidy. Aust N Z J Obstet Gynaecol 2008; 5: 478-480
  • 29 De-Regil LM, Palacios C, Lombardo LK. et al. Vitamin D supplementation for women during pregnancy. Sao Paulo Med J 2016; 134: 274-275
  • 30 Laursen JH, Sondergaard HB, Sorensen PS. et al. Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab. Mult Scler Rel Disord 2016; 10: 169-173
  • 31 Sandberg L, Biström M, Salzer J. et al. Vitamin D and axonal injury in multiple sclerosis. Mult Scler 2016; 22: 1027-1031
  • 32 Muris AH, Rolf L, Broen K. et al. A low vitamin D status at diagnosis is associated with an early conversion to secondary progressive multiple sclerosis. J Steroid Biochem Mol Biol 2016; 164: 254-257
  • 33 Mirzaei F, Michels KB, Munger K. et al. Gestational vitamin D and risk of multiple sclerosis in the offspring. Ann Neurol 2011; 7: 30-40
  • 34 Munger KL, Aivo J, Hongell K. et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the finnish maternity cohort. JAMA Neurol 2016; 73: 515-519
  • 35 Nielsen NM, Munger KL, Koch-Henriksen N. et al. Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-controll study. Neurology 2017; 88: 44-51
  • 36 Bhargava P, Steele SU, Waubant E. et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. Mult Scler 2016; 22: 753-760
  • 37 Wagner CL, Hollis BW, Kotsa K. et al. Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications. Rev Endocr Meta Disord 2017; 18: 307-322
  • 38 Stubbs G, Henley K, Green J. Autism: Will vitamin D supplementation during pregnancy and early childhood reduce the recurrence rate of autism in newborn siblings?. Med Hypotheses 2016; 88: 74-78
  • 39 Bizzaro G, Shoenfeld Y. Vitamin D and autoimmune thyroid diseases: facts and unresolved questions. Immun Res 2015; 61: 46-52
  • 40 Ma J, Wu D, Li CH. et al. Lower serum 25-hydroxyvitamin D level is associated with 3 types of autoimmune thyroid diseases. Medicine (Baltimore) 2015; 94: e1639
  • 41 Kivity S, Agmon-Levin N, Zisappl M. et al. Vitamin D and autoimmune thyroid disease. Cell Mol Immunol 2011; 8: 243-247
  • 42 Tamer G, Arik S, Tamer I. et al. Relative vitamin D insufficiency in Hashimotoʼs thyroiditis. Thyroid 2011; 21: 891-896
  • 43 Mackawy AM, Al-Ayed BM, Al-Rashidi BM. Vitamin D deficiency and its association with thyroid disease. Int J Health Sci (Qassim) 2013; 7: 267-275
  • 44 Wang X, Zynat J, Guo Y. et al. Low serum vitamin D is associated with anti-thyroid-globulin antibody in female individuals. Int J Endocrinol 2015; 2015: 285290 doi:10.1155/2015/285290
  • 45 Goswami R, Marwaha RK, Gupta N. et al. Prevalence of vitamin D deficiency and its relationships with thyroid autoimmunity in Asian Indians: a community-based survey. Br J Nutr 2009; 102: 382-386
  • 46 Chailurkit LO, Aekplakorn W, Ongphiphadhanakul B. High vitamin D status in younger individuals is associated with low circulation thyrotropin. Thyroid 2013; 23: 25-30
  • 47 Hupperts R. et al. High dose cholecalciferol (vitamin D3) oil as add-on therapy in subjects with RRMS receiving subcutaneous interferon ß1a. 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, London 14.–17.9.2016. Free communications1; 16.09.2016
  • 48 Sotirchos ES, Bhargava P, Eckstein CH. et al. Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology 2016; 86: 382-390
  • 49 Robien K, Oppeneer SJ, Kelly JA. et al. Drug-vitamin D interactions: a systematic review of the literature. Nutr Clin Pract 2013; 28: 194-208
  • 50 Holmoy T, Torkildsen O. Can vitamin D reduce inflammation in relapsing-remitting multiple sclerosis?. Expert Rev Neurother 2016; 16: 233-235
  • 51 Pierrot-Deseilligny CH, Souberbielle JC. Vitamin D and multiple sclerosis: An update. Mult Scler Relat Disord 2017; 14: 35-45
  • 52 Hempel S, Graham G, Fu N. et al. A systematic review of the effects of modifiable risk factor interventions on the progression of multiple sclerosis. Mult Scler 2017; 23: 513-524
  • 53 Dècard BF, Ahsen N, Grundwald T. et al. Low vitamin D and elevated immunoreactivity against Epstein-Barr virus before first clinical manifestation of multiple sclerosis. J Neurol Neurosurg Psychiatry 2012; 83: 1170-1173
  • 54 Unholzer S, Rothmund A, Haen E. Alleskönner Vitamin D?. Nervenarzt 2017; 88: 489-494
  • 55 Institute of Medicine (US). Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. In: Ross AC, Taylor CL, Yaktine AL, Del Valle HB. (eds). Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011
  • 56 Ascherio A, Munger KL. Epidemiology of multiple sclerosis: from risk factors to prevention-an update. Semin Neurol 2016; 36: 103-114
  • 57 Grant WB, Whiting SJ, Schwalfenberg GK. et al. Estimated economic benefit of increasing 25-hydroxyvitamin D concentrations of Canadians to or above 100 nmol/l. Dermatoendocrinol 2016; 8: e1248324
  • 58 Hempel S, Graham GD, Fu N. et al. A systematic review of modifiable risk factors in the progression of multiple sclerosis. Mult Scler 2017; 23: 525-533
  • 59 Coetzee T, Thompson A. When are we going to take modifiable risk factors more seriously in multiple sclerosis?. Mult Scler 2017; 23: 494-495
  • 60 Gafson A, Craner MJ, Matthews PM. Personalised medicine for multiple sclerosis care. Mult Scler 2017; 23: 362-369
  • 61 Topliss JD. Clinical update in aspects of the management of autoimmune thyroid disease. Endocrinol Metab (Seoul) 2016; 31: 493-499
  • 62 Sormani MP, Bruzzi P. Can we measure long-term treatment effects in multiple sclerosis?. Nat Rev Neurol 2015; 11: 176-182
  • 63 Kalincik T, Butzkueven H. Observational data: understanding the real MS world. Mult Scler 2016; 22: 1642-1648
  • 64 Trojano M, Tintore M, Montalban X. et al. Treatment decisions in multiple sclerosis – insights from real-world observational studies. Nat Rev Neurol 2017; 13: 105-108
  • 65 Mowry E. Vitamin D supplementation as disease modifying therapy. ACTRIMS Forum 2017; 23: 2-90
  • 66 Baker D, Herrod SS, Alvarez-Gonzalez C. Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of alemtuzumab. JAMA Neurol 2017; 74: 961-969
  • 67 Steinman L. Induction of new autoimmune diseases after alemtuzumab therapy for multiple sclerosis. JAMA Neurol 2017; 74: 907-908