Die Rolle von Vitamin D bei entzündlichen Erkrankungen

Zusammenfassung

Neben skelettalen Endokrinen Effekten gewinnen nichtskelettale Vitamin D3-Wirkungen bei chronischen Erkrankungen, wie denen des Immunsystems, gewinnen an Bedeutung. 1α-Hydroxylase (CYP27B1) und der Vitamin-D-Rezeptor (VDR) wurden in diversen Immunzellen nachgewiesen. Diese Zellen haben damit die Fähigkeit zur Konversion von 25-(OH)-Vitamin-D3 zu 1,25-(OH)₂-Vitamin-D3, das lokal autokrin wirkt. Darüber erfolgt am Immunsystem eine Immunmodulation, die zu einer Verstärkung der angeborenen Immunität mit Stärkung der antibakteriellen Wirkung sowie einer vielfältigen Regulation der erworbenen Immunantwort führt. Vitamin-D-Mangel wird mit der Entwicklung verschiedener Autoimmunerkrankungen, z. B., Diabetes mellitus Typ I, multiple Sklerose, rheumatoide Arthritis (RA), systemischer Lupus erythematodes (SLE), in Verbindung gebracht. Dies gewinnt angesichts des Nachweises einer unzureichenden Vitamin-D-Versorgung in der ganzen Welt an Bedeutung. Bei fast allen rheumatologischen Erkrankungen, wie RA, SLE, systemische Sklerose, ankylosierende Spondylitis sowie M. Behçet, finden sich teils sehr niedrige 25-(OH)-Vitamin D3-Serumspiegel. Bei diesen Erkrankungen lässt sich eine inverse Beziehung zwischen dem 25-(OH)-Vitamin D3-Serumspiegel und der Krankheitsaktivität nachweisen. Bislang ist unklar, ob die hohe Krankheitsaktivität den niedrigen 25-(OH)-Vitamin D3-Serumspiegel bedingt oder umgekehrt. Es lässt sich nicht sicher belegen, dass eine ungünstige Vitamin-D-Versorgung die Inzidenz von RA oder SLE erhöht. Angesichts der immunmodulatorischen Wirkung liegt es nahe, Vitamin D3 als Komedikation in der Behandlung der Autoimmunerkrankungen einzusetzen. Die Ergebnisse teils offener, teils randomisierter Studien (RCT) zeigen bislang keine sicher überzeugenden Wirkungen. Weitere RCT, die sich am individuellen 25-(OH)-Vitamin D3-Serumspiegel ausrichten, höhere 25-(OH)-Vitamin D3-Serumspiegel erreichen und länger dauern, sind erforderlich.

Abstract

Over the last decades, non-skeletal effects of vitamin D3 in several chronic diseases, such as immune-mediated diseases, have gained increasing attention. 1α-hydroxylase (CYP27B1) and vitamin D receptor (VDR) have been found to be expressed by different cell types of the immune system. These cells are thus able to convert 25-(OH)-vitamin D3 to 1,25-(OH)2-vitamin D3, which act locally in an autocrine fashion, without being subject to control by the endocrine system. Consequently, different immunomodulating effects can be exerted through vitamin D3 including strengthening of the innate immune response, with an amplification of antibacterial effects, and also different regulatory effects of the adaptive immune response. A lack of vitamin D is regarded to be associated with the development of different autoimmune diseases such as type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This is of importance considering the growing evidence of an insufficient alimentary supply of vitamin D world-wide. Low and even very low 25-(OH)-vitamin D3 levels can be found in almost all rheumatic diseases including RA, SLE, systemic sclerosis, ankylosing spondylitis and Behçet’s disease. In all of these diseases an inverse correlation between 25-(OH)-vitamin D3 levels and disease activity can be found. Until now, the underlying cause of this inverse correlation is unclear. Whether high disease activity induces low 25-(OH)-vitamin D3 levels or vice versa remains to be clarified. So far it is not proven that an insufficient supply of vitamin D increases the incidence of RA or SLE. However, considering the immunomodulatory effects of vitamin D on the cells of the immune system, the use of vitamin D3 as a combination partner in the immunosuppressive treatment of autoimmune diseases would be conceivable. Yet, the results of some open-label studies and few randomised controlled trials (RCT) have not revealed any convincing effect so far. Nevertheless, it cannot be excluded that the vitamin D3 dosages and the duration of the trials, both of which were based on the endocrine effects of vitamin D3, were insufficient to achieve autocrine immunomodulatory efficacy. In order to answer this question further RCT are required which use dosages adjusted to individual 25-(OH)-vitamin D3 serum levels, achieve higher systemic levels of 25-(OH)-Vitamin D3 and are of longer duration.

Schlüsselwörter

Vitamin D - Vitamin-D-Mangel - Immunsystem - Autoimmunerkrankung - Behandlung

Key words

vitamin D - vitamin D deficiency - immune system - autoimmune disease - treatment

• Literatur

• 1 Heaney RP.. Vitamin D in Health and Disease. Clin J Am Soc Nephrol 2008; 3: 1535-1541
• 2 Hewison M. Vitamin D, Immunity and Human Disease. Clinic Rev Bone Miner Metab 2010; 8: 32-39
• 3 Deluca HF, CANTORNA MT. Vitamin D: its role and uses in immunology. The FASEB Journal 2001; 15: 2579-2585
• 4 Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005; 289: F8-F28
• 5 Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc 2011; 18: 1-12
• 6 Marcinkowska E. A run for a membrane vitamin D receptor. Biol Signals Recept 2001; 10: 341-349
• 7 Rode von Essen M, Kongsbak M, Schjerling P et al. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nature Immunology 2010; 11: 344-349
• 8 Williams CJB. On the use and administration of cod-liver oil in pulmonary consumption. London Journal of Medicine 1849; 1: 1-18
• 9 Finsen NR Nobel prize presentation speech by professor the count K.A.H. Morner, Rector of the Royal Caroline Institute on December 10, 1903. Im Internet: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1903/press.html . Stand: 23.12.2011
• 10 Geiges ML. „…Und am höchsten das Licht“: Heliotherapie in der Schweiz. In: Graf F, Wolff E. Zauber Berge: die Schweiz als Kraftraum und Sanatorium. Baden: hier+jetzt; 2010: 110-121
• 11 Rook GA, Steele J, Fraher L et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986; 57: 159-163
• 12 Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med 2010; 88: 441-450
• 13 Cross HS. Extrarenal vitamin D hydroxylase expression and activity in normal and malignant cells: modification of expression by epigenetic mechanisms and dietary substances. Nutr Rev 2007; 65: 108-112
• 14 Baeke F, Gysemans C, Korf H et al. Vitamin D insufficiency: implications for the immune system. Pediatr Nephrol 2010; 25: 1597-1606
• 15 Maruotti N, Cantatore FP. Vitamin D and the Immune System. J Rheumatol 2010; 37: 491-495
• 16 Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 2008; 4: 404-412
• 17 Ross AC, Manson JE, Abrams ST et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to know. J Clin Endocrinol Metab 2011; 96: 53-58
• 18 Cherniack EP, Florez H, Roos BA et al. Hypovitaminosis D in the elderly: from bone to brain. J Nutr Health Aging 2008; 12: 366-373
• 19 Priemel M, von Domarus C, Klatte TO et al. Bone Mineralization Defects and Vitamin D Deficiency: Histomorphometric Analysis of Iliac Crest Bone Biopsies and Circulating 25-Hydroxyvitamin D in 675 Patients. J Bone Miner Res 2010; 25: 305-312
• 20 Nationale Verzehrsstudie II Max Rubner-Institut Bundesforschungsinstitut für Ernährung und Lebensmittel 2008. Im Internet: http://www.was-esse-ich.de/uploads/media/NVSII_Abschlussbericht_Teil_2.pdf . Stand: 11.02.2012
• 21 Hintzpeter B, Mensink GB, Thierfelder W et al. Vitamin D status and health correlates among German adults. Eur J Clin Nutr 2008; 62: 1079-1089
• 22 Ginde AA, Liu MC, Camargo Jr CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Arch Intern Med 2009; 169: 626-632
• 23 Webb AR, Pilbeam C, Hanafin N et al. Annevaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr 1990; 51: 1075-1081
• 24 Holick MF. Environmental factors that influence the cutaneous production of vitamin D1. Am J Clin Nutr 1995; (suppl) 61: S638-S645
• 25 Mouyis M, Ostor AJK, Crisp AJ et al. Hypovitaminosis D among rheumatology outpatients in clinical Practice. Rheumatology 2008; 47: 1348-1351
• 26 Kerr GS, Sabahi I, Richards JS et al. Prevalence of vitamin d insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 2011; 38: 53-59
• 27 Kamen DL, Cooper GS, Bouali H et al. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 2006; 5: 114-117
• 28 Mok CC, Birmingham DJ, Leung HW et al. Vitamin D levels in Chinese patients with systemic lupus erythematosus: relationship with disease activity, vascular risk factors and atherosclerosis. Rheumatology. 2012; 51
• 29 Vacca A, Cormier C, Piras M et al. Vitamin D Deficiency and Insufficiency in 2 Independent Cohorts of Patients with Systemic Sclerosis. J Rheumatol 2009; 36: 1924-1929
• 30 Zold E, Szodoray P, Gaal J et al. Vitamin D deficiency in undifferentiated connective tissue disease. Arthritis Res Ther 2008; 10: R123
• 31 Hamzaoui K, Ben Dhifallah I, Karray E et al. Vitamin D modulates peripheral immunity in patients with Behçet’s disease. Clin Exp Rheumatol 2010; 28 (Suppl. 60) S50-S57
• 32 Lange U, Teichmann J, Strunk J et al. Association of 1.25 vitamin D3 deficiency, disease activity and low bone mass in ankylosing spondylitis. Osteoporos Int 2005; 16: 1999-2004
• 33 Merlino LA, Curtis J, Mikuls TR et al. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum 2004; 50: 72-77
• 34 Costenbader KH, Feskanich D, Holmes M et al. Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann Rheum Dis 2008; 67: 530-535
• 35 Racovan M, Walitt B, Collins CE et al. Calcium and vitamin D supplementation and incident rheumatoid arthritis: the Women’s Health Initiative Calcium plus Vitamin D trial. Rheumatol Int Dec 22 2011;
• 36 Nielen MM, van Schaardenburg D, Lems WF et al. Vitamin D deficiency does not increase the risk in vitamin D levels at any time point: 1 year, 2 years or at least 5 years prior to diagnosis of rheumatoid arthritis: comment on the article by Merlino et al. Arthritis Rheum 2006; 54: 3719-3720
• 37 Cutolo M, Otsa K, Laas K et al. Circannual vitamin D serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clinical and Experimental Rheumatology 2006; 24: 702-704
• 38 Oelzner P, Müller A, Deschner F et al. Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif Tissue Int 1998; 62: 193-198
• 39 Rossini M, Bongi SM, La Montagna G et al. Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Research Ther 2010; 12: R216
• 40 Patel S, Farragher T, Berryet J et al. Association between Serum Vitamin D Metabolite Levels and Disease Activity in Patients With Early Inflammatory Polyarthritis. Arthritis Rheum 2007; 56: 2143-2149
• 41 Lange U, Jung O, Teichmann J et al. Relationship between disease activity and serum levels of vitamin D metabolites and parathyroid hormone in ankylosing spondylitis. Osteoporos Int 2001; 12: 1031-1035
• 42 Caramaschi P, Dalla Gassa A, Ruzzenente O et al. Very low levels of vitamin d in systemic sclerosis patients. Clin Rheumatol 2010; 29: 1419-1425
• 43 Colin EM, Asmawidjaja PS, van Hamburg JP et al. 1,25-Dihydroxyvitamin D3 Modulates Th17 Polarization and Interleukin-22 Expression by Memory T Cells From Patients With Early Rheumatoid Arthritis. Arthritis Rheum 2010; 62: 132-142
• 44 Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxycholecalciferol Inhibits the Progression of Arthritis in Murine Models of Human Arthritis. J Nutr 1998; 128: 68-72
• 45 Zwerina K, Baum W, Axmann R et al. Vitamin D receptor regulates TNF-mediated arthritis. Ann Rheum Dis 2011; 70: 1122-1129
• 46 Yamauchi Y, Tsunematsu T, Konda S et al. A double blind trial of alfacalcidol on patients with rheumatoid arthritis (RA). Ryumachi 1989; 29: 11-24
• 47 Hein G, Oelzner P. Vitamin D metabolites in rheumatoid arthritis: findings-hypotheses-consequences. Z Rheumatol 2000; 59: 28-32
• 48 Andjelkovic Z, Vojinovic J, Pejnovic N et al. Disease modifying and immunomodulatory effects of high dose 1 alpha (OH) D3 in rheumatoid arthritis patients. Clin Exper Rheumatol 1999; 17: 453-456
• 49 Gopinath K, Danda D. Supplementation of 1,25 dihydroxy vitamin D3 in patients with treatment naive early rheumatoid arthritis: a randomised controlled trial. Int J Rheum Dis 2011; 14: 332-339
• 50 Salesi M, Farajzadegan Z.. Efficacy of Vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy. Rheumatol Int 2011; 27 [Epub ahead of print]