- Email: [email protected]
Vitamin D and Autoimmune Rheumatologic Disorders
Autoimmunity Reviews 9 (2010) 507–510
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Vitamin D and Autoimmune Rheumatologic Disorders Christina F. Pelajo ⁎, Jorge M. Lopez-Benitez, Laurie C. Miller Division of Pediatric Rheumatology, Floating Hospital for Children, Tufts Medical Center, United States
a r t i c l e
i n f o
Available online 8 February 2010 Keywords: Vitamin D Autoimmunity Rheumatology Immunology
a b s t r a c t Vitamin D levels depend on many variables, including sun exposure, age, ethnicity, body mass index, use of medications and supplements. A much higher oral vitamin D intake than the current guidelines is necessary to maintain adequate circulating 25(OH)D levels in the absence of UVB radiation of the skin. In addition to the traditional known metabolic activities, vitamin D has been shown to modulate the immune system, and its deficiency has been linked to the development of several autoimmune disorders including type 1 diabetes and multiple sclerosis. Experimental use of vitamin D has revealed a novel role in the immunopathogenesis of autoimmune diseases. Disorders such as systemic lupus erythematosus, rheumatoid arthritis, Behçet's, polymyositis/dermatomyositis and systemic scleroderma have all been associated to some extent to vitamin D deficiency. If vitamin D deficiency occurs at a higher rate in patients with autoimmune disorders, then appropriate supplementation may be indicated. © 2010 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sources of vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . Factors related to vitamin D levels . . . . . . . . . . . . . . . . . . 3.1. Ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Body mass index . . . . . . . . . . . . . . . . . . . . . . . 3.3. Geography and seasonal factors . . . . . . . . . . . . . . . . 3.4. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Identifying and treating vitamin D deficiency . . . . . . . . . . . . . 5. Inadequacy of current guidelines regarding vitamin D . . . . . . . . . 6. Vitamin D role in the immune system . . . . . . . . . . . . . . . . . 7. Animal models of vitamin D and autoimmunity . . . . . . . . . . . . 8. Clinical vitamin D deficiency and autoimmune rheumatologic disorders . 8.1. Rheumatoid arthritis. . . . . . . . . . . . . . . . . . . . . . 8.2. Systemic lupus erythematosus . . . . . . . . . . . . . . . . . 8.3. Behçet's. . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Childhood rheumatologic disorders . . . . . . . . . . . . . . . 9. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home . messages . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
507 508 508 508 508 508 508 508 508 508 508 508 508 509 509 509 509 509 509 509
1. Introduction
⁎ Corresponding author. 800 Washington Street, Box # 190, Boston, MA 02111, United States. Tel.: + 617 636 7286; fax: + 617 671 1263. E-mail address: [email protected] (C.F. Pelajo). 1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.02.011
Vitamin D plays an essential role in calcium homeostasis. Vitamin D regulates intestinal absorption of dietary calcium, renal excretion of calcium, and calcium ion flux in bones. In addition to these important metabolic activities, vitamin D also contributes to the regulation of the immune system. In this survey, basic vitamin D physiology will be
508
C.F. Pelajo et al. / Autoimmunity Reviews 9 (2010) 507–510
reviewed, and some of the pitfalls in interpreting vitamin D levels will be highlighted. In addition, the effects of vitamin D on the immune system will be summarized, with a focus on the contributions of vitamin D deficiency to autoimmune disorders. 2. Sources of vitamin D Vitamin D may be acquired from three main sources: food, sun exposure, or dietary supplements. However, dietary intake can provide only ∼ 20% of the body's daily requirements of vitamin D [1,2]. Sun exposure is necessary for humans to maintain adequate vitamin D levels. Vitamin D is synthesized in the skin after ultraviolet B (UVB) radiation induces the conversion of 7-dehydrocholesterol to previtamin D3, which is rapidly converted to vitamin D3 [3]. One minimal erythema dose of UVB radiation (i.e., slight redness of the skin) to the whole body produces between 10,000 and 25,000 IU of vitamin D [3–5]. Because regular ultraviolet exposure ages the skin and increases the risk of non-melanoma skin cancers [6], and incidental sun exposure from daily activity may not be sufficient to achieve adequate serum 25-hydroxyvitamin D levels for all individuals, dietary supplements are a good source of vitamin D which avoid these risks and optimize serum levels of vitamin D. Dietary supplements contain either vitamin D2 or D3. Vitamin D3 is three times more effective in raising 25-hydroxyvitamin D [25(OH) D] than D2 [6]. Vitamin D kinetics is not linear, and the response to a given oral dose of vitamin D is inversely related to the starting level of 25(OH)D [7].
4. Identifying and treating vitamin D deficiency Although there is no consensus on optimal levels of vitamin D, most experts define levels of less than 20 ng/ml (50 nmol/L) as vitamin D deficiency, levels from 20–29 ng/ml (50–72 nmol/L) as vitamin D insufficiency, and levels of 30 ng/ml (75 nmol/L) or above as adequate [3,5]. Levels greater than 150 ng/ml (375 nmol/L) are considered toxic [3,5]. Recommended treatment for vitamin D deficiency is 2000 IU of vitamin D3 daily or 50,000 IU of vitamin D2 weekly for 8–16 weeks, followed by maintenance treatment with 50,000 IU each 2 to 4 weeks [3,4,6]. Higher doses may be needed for some patients, depending on baseline levels and risk factors for vitamin D deficiency. 5. Inadequacy of current guidelines regarding vitamin D
Interpretation of vitamin D levels is complicated by many factors. Understanding the contributions these factors make is important in interpreting research regarding vitamin D in health and pathologic conditions.
The American Academy of Pediatrics recommends 400 IU of vitamin D daily for every child soon after birth [10]. This recommendation is based on the high prevalence of vitamin D deficiency even among otherwise healthy children. Most over-the-counter multivitamins also contain 400 IU of vitamin D. This dose does not effectively prevent vitamin D deficiency [6]. Besides, most studies that showed benefits of vitamin D in relation to prevention of autoimmune disorders used doses much higher than that. For example, a large prospective study of children in Finland (n = 10,366) evaluated individuals who were given 2000 IU of vitamin D3 daily during the first year of life. After N30 years of follow-up, the risk of type 1 diabetes was reduced by 80%. Among children with vitamin D deficiency the risk was increased by 200% [11]. In 1997, the Institute of Medicine's Food and Nutrition Board recommended an upper limit of 2000 IU per day for unsupervised intake of vitamin D3 by adults and children (N1 year old), and for infants 1000 IU [4,6,8]. However, such limits may limit effective treatment [6]. Vitamin D toxicity has not been reported, even in adults chronically consuming up to 10,000 IU of vitamin D3 per day [4,6,12].
3.1. Ethnicity
6. Vitamin D role in the immune system
Higher amounts of melanin diminishes the rate of vitamin D synthesis, thus African Americans are at higher risk for vitamin D deficiency [4,6].
1,25-dihydroxyvitamin D [1,25(OH)2D] has many roles in the immune system (Table 1). The overall effect of vitamin D is immunosuppressive [13].
3.2. Body mass index
7. Animal models of vitamin D and autoimmunity
Obesity is a risk factor for lower levels of vitamin D, as this vitamin is stored in fat [8]. Serum levels of vitamin D in obese subjects increase only about 50% as much as the levels in non-obese subjects when both groups are exposed to the same intake of vitamin D [5].
3.4. Age
Because of its immunosuppressive activity, the effect of Vitamin D has been investigated in various experimental models of autoimmunity. For example, in the MRL-lpr/lpr mice models of spontaneous lupus, vitamin D supplementation improves longevity and reduces proteinuria, diminishes knee arthritis [14], and prevents dermatological lesions [25]. Administration of 1,25(OH)2D3 prior to the expression of disease can even prevent lupus in these mice models [25]. In the murine model of collagen-induced arthritis, vitamin D receptor agonists prevent disease expression, and also suppress established disease [25,26]. In murine experimental autoimmune encephalomyelitis (EAE), 1,25(OH)2D3 analogs protected against the development of disease, especially when combined with other immunosuppressants [22].
Ageing is associated with reduced synthesis of vitamin D in the skin, as the content of 7-dehydrocholesterol decreases [4,6].
8. Clinical vitamin D deficiency and autoimmune rheumatologic disorders
3.5. Drugs
There are many difficulties in establishing a solid relationship between vitamin D deficiency and autoimmune rheumatologic disorders in humans. Different cut-offs for vitamin D deficiency and insufficiency are used in different studies; some studies are based on the reported intake rather than on serum levels; the rarity of the
3. Factors related to vitamin D levels
3.3. Geography and seasonal factors In areas in latitudes above about 37° north or below 35° south there is marked decrease in UVB incidence during winter months, increasing the risk of vitamin D deficiency [3,5,9]. Peak of vitamin D level usually occurs in late summer, and nadir in the beginning of spring [6].
Several drugs alter vitamin D levels. Anticonvulsants, corticosteroids, cimetidine, antituberculosis agents, theophylline and orlistat decrease vitamin D levels, while thiazide diuretics may increase it [6].
C.F. Pelajo et al. / Autoimmunity Reviews 9 (2010) 507–510 Table 1 Vitamin D actions in the immune system. 1,25 dihydroxyvitamin D: Decreases the antigen-presenting activity of macrophages to lymphocytes [8,14] Increases apoptosis induced by dendritic cells and T lymphocytes — tolerance [15–17] Inhibits the maturation of monocytes into dendritic cells [18,19] Induces activation of T reg and natural killer T cells [2,13] Inhibits the Th1 profile [13,18–20] •Decreases IL-2 and IFN-γ synthesis [8,14,18,19,21] Stimulates the Th2 dominance [13,18–20] •Increases IL-4, IL-5 and IL-10 synthesis [14,15,18] Inhibits the synthesis of IL-12, IL-1, IL-6 and TNFα [6,8,21,22] Inhibits B cell proliferation, plasma cell differentiation, and antibodies production [14,18,19,23,24]
diseases makes it difficult to obtain large samples of subjects; there are many confounding factors associated with those diseases, as prednisone intake, photosensitivity and recommended use of sunscreen; and the outdated limit for unsupervised intake impair doseappropriate interventional research. Nonetheless, here we present some evidence of autoimmune rheumatologic disorders and vitamin D deficiency. The hypothesis that vitamin D relates to autoimmune disorders emerged from the observation that people living near the equator were at a decreased risk of developing common autoimmune diseases [9]. Furthermore, several surveys of rheumatology populations found reduced levels of vitamin D. For example, 1029 patients with different autoimmune disorders, including scleroderma, polymyositis and dermatomyositis, antiphospholipid syndrome, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), had lower levels of 25(OH)D than controls [19]. 8.1. Rheumatoid arthritis There are different types of evidence linking RA with vitamin D deficiency. Like the latitude-related prevalence of RA, which coincides with areas where vitamin D deficiency is more prevalent [1,2,26]. Vitamin D has also been related to disease activity in RA; 25(OH)D values showed a significant negative correlation with RA clinical status [2], and low 1,25(OH)2D3 levels were associated with higher RA disease activity [18]. Although intake report is not the ideal way of evaluating vitamin D status, greater intake of vitamin D inversely related to the risk of developing RA in a prospective cohort study of 29,368 women [27]. On the other hand, not all studies confirm this relationship. In a small sample of patients with RA (n = 29), 25(OH)D levels corresponded to controls [28]. 8.2. Systemic lupus erythematosus Several studies have addressed vitamin D deficiency in SLE patients [2,24,28–32]. In 37 SLE patients serum levels of 25(OH)D were b80 nmol/L (32 ng/ml) in 65% and b47.7 nmol/L (19 ng/ml) in 20% [2]. Similar rates were found in a sample of 92 patients in Spain, 75% had vitamin D insufficiency (b30 ng/ml) and 15% vitamin D deficiency (b10 ng/ml) [29]. Also 67% of 123 recently diagnosed SLE patients had lower 25(OH)D levels than controls [30]. Because of the high rates of vitamin D deficiency in SLE patients, Carvalho investigated the possibility that this was due to autoantibodies against vitamin D. However, only 4% of 171 SLE patients had measurable anti-vitamin D antibodies, and the presence of these antibodies did not relate to serum levels of 25(OH)D [16]. Regarding disease activity, results published are controversial. Borba et al. found lower levels of 25(OH)D in 12 SLE patients with high activity compared to 24 patients with minimal activity and 26
509
controls [31]. Confirming these results, in Germany, 34 of 57 SLE patients had low 25(OH)D levels and levels correlated with disease activity [32]. In contrast, in Copenhagen, SLE patients had lower levels of 25(OH)D than healthy or osteoarthritis controls, but vitamin D levels did not correlate with disease activity [28]. No relation between deficiency or insufficiency and SLE severity was found either in the sample of 92 patients from Spain [29]. As mentioned before, not all studies prove a definitive relationship between vitamin D deficiency, RA and SLE. In a prospective analysis involving over 180,000 women followed for up to 22 years, vitamin D intake (based on dietary recall) did not relate to the risk of developing SLE or RA [33]. Nevertheless, only a minority of subjects were taking more than 400 IU of vitamin D per day, which is considered a low dose for the prevention of autoimmunity. Although there is no consensus regarding low levels of vitamin D and SLE activity, the possibility of an association suggests that repletion of vitamin D may have benefits beyond bone health for those patients [34]. 8.3. Behçet's Serum 25(OH)D levels of 41 patients with Behçet's disease tended to be lower in active patients [35]. 8.4. Childhood rheumatologic disorders Despite extensive evidence of vitamin D deficiency associated with autoimmune rheumatologic disorders in adults, little information is available relating to children. In 7/12 adolescents with SLE, subnormal serum levels of 1,25(OH)2D3 were found [36]. Among 113 children with chronic rheumatic diseases (juvenile idiopathic arthritis, juvenile SLE and juvenile dermatomyositis), 25(OH)D levels were not reduced [37]. 9. Conclusion A much higher oral vitamin D intake than recommended in current guidelines is safe and necessary to maintain adequate circulating 25 (OH)D levels, especially in the absence of UVB radiation of the skin. There is strong evidence of an association between SLE and RA and vitamin D deficiency, although other autoimmune rheumatologic disorders might also have an association. Further studies on the topic are needed to clarify these preliminary findings. In the meantime, if vitamin D deficiency is occurring at a higher rate in patients with autoimmune disorders, appropriate supplementation is indicated. Take-home messages • 25(OH)D should be assessed for the evaluation of vitamin D status. • A much higher oral vitamin D intake than the current guidelines is necessary to maintain adequate circulating 25(OH)D levels in the absence of UVB radiation of the skin. • Vitamin D has an immunosuppressive effect and it can suppress experimental autoimmunity. • Repletion of vitamin D may have benefits beyond bone health for patients with certain autoimmune disorders, such as SLE. • Prevention of hypovitaminosis D may reduce the prevalence of some autoimmune disorders. References [1] Cutolo M, Otsa K, Paolino S, Yprus M, Veldi T, Seriolo B. Vitamin D involvement in rheumatoid arthritis and systemic lupus erythaematosus. Ann Rheum Dis 2009;68:446–7. [2] Cutolo M. Vitamin D and autoimmune rheumatic diseases. Rheumatology (Oxford) 2009;48:210–2. [3] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.
510
C.F. Pelajo et al. / Autoimmunity Reviews 9 (2010) 507–510
[4] Heaney RP. The vitamin D requirement in health and disease. J Steroid Biochem Mol Biol 2005;97:13–9. [5] Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80:1678S–88S. [6] Cannell JJ, Hollis BW, Zasloff M, Heaney RP. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother 2008;9:107–18. [7] Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int 2005;16:713–6. [8] Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 2003;89:552–72. [9] Holick MF. Vitamin D: a millennium perspective. J Cell Biochem 2003;88:296–307. [10] Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122:1142–52. [11] Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500–3. [12] Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006;84:18–28. [13] Cantorna MT, Yu S, Bruce D. The paradoxical effects of vitamin D on type 1 mediated immunity. Mol Aspects Med 2008;29:369–75. [14] Shoenfeld N, Amital H, Shoenfeld Y. The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease. Nat Clin Pract Rheumatol 2009;5:99–105. [15] van Etten E, Mathieu C. Immunoregulation by 1, 25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 2005;97:93–101. [16] Carvalho JF. Anti-vitamin D, vitamin D in SLE. Ann N Y Acad Sci 2007;1109:550–7. [17] van Halteren AG, Tysma OM, van Etten E, Mathieu C, Roep BO. 1alpha, 25dihydroxyvitamin D3 or analogue treated dendritic cells modulate human autoreactive T cells via the selective induction of apoptosis. J Autoimmun 2004;23:233–9. [18] Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137–42. [19] Orbach H, Zandman-Goddard G, Amital H, Barak V, Szekanecz Z, Szucs G, et al. Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci 2007;1109:385–400. [20] Jirapongsananuruk O, Melamed I, Leung DY. Additive immunosuppressive effects of 1, 25-dihydroxyvitamin D3 and corticosteroids on TH1, but not TH2, responses. J Allergy Clin Immunol 2000;106:981–5. [21] Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1, 25dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 1995;125: 1704S–8S. [22] van Etten E, Branisteanu DD, Verstuyf A, Waer M, Bouillon R, Mathieu C. Analogs of 1, 25-dihydroxyvitamin D3 as dose-reducing agents for classical immunosuppressants. Transplantation 2000;69:1932–42.
[23] Lemire J. 1, 25-dihydroxyvitamin D3 — a hormone with immunomodulatory properties. Z Rheumatol 2000;59(Suppl 1):24–7. [24] Chen S, Sims GP, Chen XX, Gu YY, Lipsky PE. Modulatory effects of 1, 25dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007;179:1634–47. [25] Adorini L. Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cell Immunol 2005;233:115–24. [26] Cantorna MT. Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc Soc Exp Biol Med 2000;223:230–3. [27] Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 2004;50:72–7. [28] Muller K, Kriegbaum NJ, Baslund B, Sorensen OH, Thymann M, Bentzen K. Vitamin D3 metabolism in patients with rheumatic diseases: low serum levels of 25hydroxyvitamin D3 in patients with systemic lupus erythematosus. Clin Rheumatol 1995;14:397–400. [29] Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C. Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology (Oxford) 2008;47:920–3. [30] Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 2006;5:114–7. [31] Borba VZ, Vieira JG, Kasamatsu T, Radominski SC, Sato EI, Lazaretti-Castro M. Vitamin D deficiency in patients with active systemic lupus erythematosus. Osteoporos Int 2009;20:427–33. [32] Becker A, Fischer R, Schneider M. Bone density and 25-OH vitamin D serum level in patients with systemic lupus erythematosus. Z Rheumatol 2001;60:352–8. [33] Costenbader KH, Feskanich D, Holmes M, Karlson EW, Benito-Garcia E. Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann Rheum Dis 2008;67:530–5. [34] Kamen D, Aranow C. Vitamin D in systemic lupus erythematosus. Curr Opin Rheumatol 2008;20:532–7. [35] Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease. Rheumatology (Oxford) 2008;47:840–8. [36] O'Regan S, Chesney RW, Hamstra A, Eisman JA, O'Gorman AM, Deluca HF. Reduced serum 1, 25-(OH)2 vitamin D3 levels in prednisone-treated adolescents with systemic lupus erythematosus. Acta Paediatr Scand 1979;68:109–11. [37] Reed A, Haugen M, Pachman LM, Langman CB. Abnormalities in serum osteocalcin values in children with chronic rheumatic diseases. J Pediatr 1990;116:574–80.
Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). (Clifford DB, et al. Lancet Neurol. 2010;9:438-446). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients. The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6-80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase the risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML. Diagnosis of natalizumab-associated PML requires optimized clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimizing the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Vitamin D and Autoimmune Rheumatologic Disorders Christina F. Pelajo ⁎, Jorge M. Lopez-Benitez, Laurie C. Miller Division of Pediatric Rheumatology, Floating Hospital for Children, Tufts Medical Center, United States
a r t i c l e
i n f o
Available online 8 February 2010 Keywords: Vitamin D Autoimmunity Rheumatology Immunology
a b s t r a c t Vitamin D levels depend on many variables, including sun exposure, age, ethnicity, body mass index, use of medications and supplements. A much higher oral vitamin D intake than the current guidelines is necessary to maintain adequate circulating 25(OH)D levels in the absence of UVB radiation of the skin. In addition to the traditional known metabolic activities, vitamin D has been shown to modulate the immune system, and its deficiency has been linked to the development of several autoimmune disorders including type 1 diabetes and multiple sclerosis. Experimental use of vitamin D has revealed a novel role in the immunopathogenesis of autoimmune diseases. Disorders such as systemic lupus erythematosus, rheumatoid arthritis, Behçet's, polymyositis/dermatomyositis and systemic scleroderma have all been associated to some extent to vitamin D deficiency. If vitamin D deficiency occurs at a higher rate in patients with autoimmune disorders, then appropriate supplementation may be indicated. © 2010 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sources of vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . Factors related to vitamin D levels . . . . . . . . . . . . . . . . . . 3.1. Ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Body mass index . . . . . . . . . . . . . . . . . . . . . . . 3.3. Geography and seasonal factors . . . . . . . . . . . . . . . . 3.4. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Identifying and treating vitamin D deficiency . . . . . . . . . . . . . 5. Inadequacy of current guidelines regarding vitamin D . . . . . . . . . 6. Vitamin D role in the immune system . . . . . . . . . . . . . . . . . 7. Animal models of vitamin D and autoimmunity . . . . . . . . . . . . 8. Clinical vitamin D deficiency and autoimmune rheumatologic disorders . 8.1. Rheumatoid arthritis. . . . . . . . . . . . . . . . . . . . . . 8.2. Systemic lupus erythematosus . . . . . . . . . . . . . . . . . 8.3. Behçet's. . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Childhood rheumatologic disorders . . . . . . . . . . . . . . . 9. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home . messages . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
507 508 508 508 508 508 508 508 508 508 508 508 508 509 509 509 509 509 509 509
1. Introduction
⁎ Corresponding author. 800 Washington Street, Box # 190, Boston, MA 02111, United States. Tel.: + 617 636 7286; fax: + 617 671 1263. E-mail address: [email protected] (C.F. Pelajo). 1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.02.011
Vitamin D plays an essential role in calcium homeostasis. Vitamin D regulates intestinal absorption of dietary calcium, renal excretion of calcium, and calcium ion flux in bones. In addition to these important metabolic activities, vitamin D also contributes to the regulation of the immune system. In this survey, basic vitamin D physiology will be
508
C.F. Pelajo et al. / Autoimmunity Reviews 9 (2010) 507–510
reviewed, and some of the pitfalls in interpreting vitamin D levels will be highlighted. In addition, the effects of vitamin D on the immune system will be summarized, with a focus on the contributions of vitamin D deficiency to autoimmune disorders. 2. Sources of vitamin D Vitamin D may be acquired from three main sources: food, sun exposure, or dietary supplements. However, dietary intake can provide only ∼ 20% of the body's daily requirements of vitamin D [1,2]. Sun exposure is necessary for humans to maintain adequate vitamin D levels. Vitamin D is synthesized in the skin after ultraviolet B (UVB) radiation induces the conversion of 7-dehydrocholesterol to previtamin D3, which is rapidly converted to vitamin D3 [3]. One minimal erythema dose of UVB radiation (i.e., slight redness of the skin) to the whole body produces between 10,000 and 25,000 IU of vitamin D [3–5]. Because regular ultraviolet exposure ages the skin and increases the risk of non-melanoma skin cancers [6], and incidental sun exposure from daily activity may not be sufficient to achieve adequate serum 25-hydroxyvitamin D levels for all individuals, dietary supplements are a good source of vitamin D which avoid these risks and optimize serum levels of vitamin D. Dietary supplements contain either vitamin D2 or D3. Vitamin D3 is three times more effective in raising 25-hydroxyvitamin D [25(OH) D] than D2 [6]. Vitamin D kinetics is not linear, and the response to a given oral dose of vitamin D is inversely related to the starting level of 25(OH)D [7].
4. Identifying and treating vitamin D deficiency Although there is no consensus on optimal levels of vitamin D, most experts define levels of less than 20 ng/ml (50 nmol/L) as vitamin D deficiency, levels from 20–29 ng/ml (50–72 nmol/L) as vitamin D insufficiency, and levels of 30 ng/ml (75 nmol/L) or above as adequate [3,5]. Levels greater than 150 ng/ml (375 nmol/L) are considered toxic [3,5]. Recommended treatment for vitamin D deficiency is 2000 IU of vitamin D3 daily or 50,000 IU of vitamin D2 weekly for 8–16 weeks, followed by maintenance treatment with 50,000 IU each 2 to 4 weeks [3,4,6]. Higher doses may be needed for some patients, depending on baseline levels and risk factors for vitamin D deficiency. 5. Inadequacy of current guidelines regarding vitamin D
Interpretation of vitamin D levels is complicated by many factors. Understanding the contributions these factors make is important in interpreting research regarding vitamin D in health and pathologic conditions.
The American Academy of Pediatrics recommends 400 IU of vitamin D daily for every child soon after birth [10]. This recommendation is based on the high prevalence of vitamin D deficiency even among otherwise healthy children. Most over-the-counter multivitamins also contain 400 IU of vitamin D. This dose does not effectively prevent vitamin D deficiency [6]. Besides, most studies that showed benefits of vitamin D in relation to prevention of autoimmune disorders used doses much higher than that. For example, a large prospective study of children in Finland (n = 10,366) evaluated individuals who were given 2000 IU of vitamin D3 daily during the first year of life. After N30 years of follow-up, the risk of type 1 diabetes was reduced by 80%. Among children with vitamin D deficiency the risk was increased by 200% [11]. In 1997, the Institute of Medicine's Food and Nutrition Board recommended an upper limit of 2000 IU per day for unsupervised intake of vitamin D3 by adults and children (N1 year old), and for infants 1000 IU [4,6,8]. However, such limits may limit effective treatment [6]. Vitamin D toxicity has not been reported, even in adults chronically consuming up to 10,000 IU of vitamin D3 per day [4,6,12].
3.1. Ethnicity
6. Vitamin D role in the immune system
Higher amounts of melanin diminishes the rate of vitamin D synthesis, thus African Americans are at higher risk for vitamin D deficiency [4,6].
1,25-dihydroxyvitamin D [1,25(OH)2D] has many roles in the immune system (Table 1). The overall effect of vitamin D is immunosuppressive [13].
3.2. Body mass index
7. Animal models of vitamin D and autoimmunity
Obesity is a risk factor for lower levels of vitamin D, as this vitamin is stored in fat [8]. Serum levels of vitamin D in obese subjects increase only about 50% as much as the levels in non-obese subjects when both groups are exposed to the same intake of vitamin D [5].
3.4. Age
Because of its immunosuppressive activity, the effect of Vitamin D has been investigated in various experimental models of autoimmunity. For example, in the MRL-lpr/lpr mice models of spontaneous lupus, vitamin D supplementation improves longevity and reduces proteinuria, diminishes knee arthritis [14], and prevents dermatological lesions [25]. Administration of 1,25(OH)2D3 prior to the expression of disease can even prevent lupus in these mice models [25]. In the murine model of collagen-induced arthritis, vitamin D receptor agonists prevent disease expression, and also suppress established disease [25,26]. In murine experimental autoimmune encephalomyelitis (EAE), 1,25(OH)2D3 analogs protected against the development of disease, especially when combined with other immunosuppressants [22].
Ageing is associated with reduced synthesis of vitamin D in the skin, as the content of 7-dehydrocholesterol decreases [4,6].
8. Clinical vitamin D deficiency and autoimmune rheumatologic disorders
3.5. Drugs
There are many difficulties in establishing a solid relationship between vitamin D deficiency and autoimmune rheumatologic disorders in humans. Different cut-offs for vitamin D deficiency and insufficiency are used in different studies; some studies are based on the reported intake rather than on serum levels; the rarity of the
3. Factors related to vitamin D levels
3.3. Geography and seasonal factors In areas in latitudes above about 37° north or below 35° south there is marked decrease in UVB incidence during winter months, increasing the risk of vitamin D deficiency [3,5,9]. Peak of vitamin D level usually occurs in late summer, and nadir in the beginning of spring [6].
Several drugs alter vitamin D levels. Anticonvulsants, corticosteroids, cimetidine, antituberculosis agents, theophylline and orlistat decrease vitamin D levels, while thiazide diuretics may increase it [6].
C.F. Pelajo et al. / Autoimmunity Reviews 9 (2010) 507–510 Table 1 Vitamin D actions in the immune system. 1,25 dihydroxyvitamin D: Decreases the antigen-presenting activity of macrophages to lymphocytes [8,14] Increases apoptosis induced by dendritic cells and T lymphocytes — tolerance [15–17] Inhibits the maturation of monocytes into dendritic cells [18,19] Induces activation of T reg and natural killer T cells [2,13] Inhibits the Th1 profile [13,18–20] •Decreases IL-2 and IFN-γ synthesis [8,14,18,19,21] Stimulates the Th2 dominance [13,18–20] •Increases IL-4, IL-5 and IL-10 synthesis [14,15,18] Inhibits the synthesis of IL-12, IL-1, IL-6 and TNFα [6,8,21,22] Inhibits B cell proliferation, plasma cell differentiation, and antibodies production [14,18,19,23,24]
diseases makes it difficult to obtain large samples of subjects; there are many confounding factors associated with those diseases, as prednisone intake, photosensitivity and recommended use of sunscreen; and the outdated limit for unsupervised intake impair doseappropriate interventional research. Nonetheless, here we present some evidence of autoimmune rheumatologic disorders and vitamin D deficiency. The hypothesis that vitamin D relates to autoimmune disorders emerged from the observation that people living near the equator were at a decreased risk of developing common autoimmune diseases [9]. Furthermore, several surveys of rheumatology populations found reduced levels of vitamin D. For example, 1029 patients with different autoimmune disorders, including scleroderma, polymyositis and dermatomyositis, antiphospholipid syndrome, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), had lower levels of 25(OH)D than controls [19]. 8.1. Rheumatoid arthritis There are different types of evidence linking RA with vitamin D deficiency. Like the latitude-related prevalence of RA, which coincides with areas where vitamin D deficiency is more prevalent [1,2,26]. Vitamin D has also been related to disease activity in RA; 25(OH)D values showed a significant negative correlation with RA clinical status [2], and low 1,25(OH)2D3 levels were associated with higher RA disease activity [18]. Although intake report is not the ideal way of evaluating vitamin D status, greater intake of vitamin D inversely related to the risk of developing RA in a prospective cohort study of 29,368 women [27]. On the other hand, not all studies confirm this relationship. In a small sample of patients with RA (n = 29), 25(OH)D levels corresponded to controls [28]. 8.2. Systemic lupus erythematosus Several studies have addressed vitamin D deficiency in SLE patients [2,24,28–32]. In 37 SLE patients serum levels of 25(OH)D were b80 nmol/L (32 ng/ml) in 65% and b47.7 nmol/L (19 ng/ml) in 20% [2]. Similar rates were found in a sample of 92 patients in Spain, 75% had vitamin D insufficiency (b30 ng/ml) and 15% vitamin D deficiency (b10 ng/ml) [29]. Also 67% of 123 recently diagnosed SLE patients had lower 25(OH)D levels than controls [30]. Because of the high rates of vitamin D deficiency in SLE patients, Carvalho investigated the possibility that this was due to autoantibodies against vitamin D. However, only 4% of 171 SLE patients had measurable anti-vitamin D antibodies, and the presence of these antibodies did not relate to serum levels of 25(OH)D [16]. Regarding disease activity, results published are controversial. Borba et al. found lower levels of 25(OH)D in 12 SLE patients with high activity compared to 24 patients with minimal activity and 26
509
controls [31]. Confirming these results, in Germany, 34 of 57 SLE patients had low 25(OH)D levels and levels correlated with disease activity [32]. In contrast, in Copenhagen, SLE patients had lower levels of 25(OH)D than healthy or osteoarthritis controls, but vitamin D levels did not correlate with disease activity [28]. No relation between deficiency or insufficiency and SLE severity was found either in the sample of 92 patients from Spain [29]. As mentioned before, not all studies prove a definitive relationship between vitamin D deficiency, RA and SLE. In a prospective analysis involving over 180,000 women followed for up to 22 years, vitamin D intake (based on dietary recall) did not relate to the risk of developing SLE or RA [33]. Nevertheless, only a minority of subjects were taking more than 400 IU of vitamin D per day, which is considered a low dose for the prevention of autoimmunity. Although there is no consensus regarding low levels of vitamin D and SLE activity, the possibility of an association suggests that repletion of vitamin D may have benefits beyond bone health for those patients [34]. 8.3. Behçet's Serum 25(OH)D levels of 41 patients with Behçet's disease tended to be lower in active patients [35]. 8.4. Childhood rheumatologic disorders Despite extensive evidence of vitamin D deficiency associated with autoimmune rheumatologic disorders in adults, little information is available relating to children. In 7/12 adolescents with SLE, subnormal serum levels of 1,25(OH)2D3 were found [36]. Among 113 children with chronic rheumatic diseases (juvenile idiopathic arthritis, juvenile SLE and juvenile dermatomyositis), 25(OH)D levels were not reduced [37]. 9. Conclusion A much higher oral vitamin D intake than recommended in current guidelines is safe and necessary to maintain adequate circulating 25 (OH)D levels, especially in the absence of UVB radiation of the skin. There is strong evidence of an association between SLE and RA and vitamin D deficiency, although other autoimmune rheumatologic disorders might also have an association. Further studies on the topic are needed to clarify these preliminary findings. In the meantime, if vitamin D deficiency is occurring at a higher rate in patients with autoimmune disorders, appropriate supplementation is indicated. Take-home messages • 25(OH)D should be assessed for the evaluation of vitamin D status. • A much higher oral vitamin D intake than the current guidelines is necessary to maintain adequate circulating 25(OH)D levels in the absence of UVB radiation of the skin. • Vitamin D has an immunosuppressive effect and it can suppress experimental autoimmunity. • Repletion of vitamin D may have benefits beyond bone health for patients with certain autoimmune disorders, such as SLE. • Prevention of hypovitaminosis D may reduce the prevalence of some autoimmune disorders. References [1] Cutolo M, Otsa K, Paolino S, Yprus M, Veldi T, Seriolo B. Vitamin D involvement in rheumatoid arthritis and systemic lupus erythaematosus. Ann Rheum Dis 2009;68:446–7. [2] Cutolo M. Vitamin D and autoimmune rheumatic diseases. Rheumatology (Oxford) 2009;48:210–2. [3] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.
510
C.F. Pelajo et al. / Autoimmunity Reviews 9 (2010) 507–510
[4] Heaney RP. The vitamin D requirement in health and disease. J Steroid Biochem Mol Biol 2005;97:13–9. [5] Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80:1678S–88S. [6] Cannell JJ, Hollis BW, Zasloff M, Heaney RP. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother 2008;9:107–18. [7] Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int 2005;16:713–6. [8] Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 2003;89:552–72. [9] Holick MF. Vitamin D: a millennium perspective. J Cell Biochem 2003;88:296–307. [10] Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122:1142–52. [11] Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500–3. [12] Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006;84:18–28. [13] Cantorna MT, Yu S, Bruce D. The paradoxical effects of vitamin D on type 1 mediated immunity. Mol Aspects Med 2008;29:369–75. [14] Shoenfeld N, Amital H, Shoenfeld Y. The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease. Nat Clin Pract Rheumatol 2009;5:99–105. [15] van Etten E, Mathieu C. Immunoregulation by 1, 25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 2005;97:93–101. [16] Carvalho JF. Anti-vitamin D, vitamin D in SLE. Ann N Y Acad Sci 2007;1109:550–7. [17] van Halteren AG, Tysma OM, van Etten E, Mathieu C, Roep BO. 1alpha, 25dihydroxyvitamin D3 or analogue treated dendritic cells modulate human autoreactive T cells via the selective induction of apoptosis. J Autoimmun 2004;23:233–9. [18] Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137–42. [19] Orbach H, Zandman-Goddard G, Amital H, Barak V, Szekanecz Z, Szucs G, et al. Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci 2007;1109:385–400. [20] Jirapongsananuruk O, Melamed I, Leung DY. Additive immunosuppressive effects of 1, 25-dihydroxyvitamin D3 and corticosteroids on TH1, but not TH2, responses. J Allergy Clin Immunol 2000;106:981–5. [21] Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1, 25dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 1995;125: 1704S–8S. [22] van Etten E, Branisteanu DD, Verstuyf A, Waer M, Bouillon R, Mathieu C. Analogs of 1, 25-dihydroxyvitamin D3 as dose-reducing agents for classical immunosuppressants. Transplantation 2000;69:1932–42.
[23] Lemire J. 1, 25-dihydroxyvitamin D3 — a hormone with immunomodulatory properties. Z Rheumatol 2000;59(Suppl 1):24–7. [24] Chen S, Sims GP, Chen XX, Gu YY, Lipsky PE. Modulatory effects of 1, 25dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007;179:1634–47. [25] Adorini L. Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cell Immunol 2005;233:115–24. [26] Cantorna MT. Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc Soc Exp Biol Med 2000;223:230–3. [27] Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 2004;50:72–7. [28] Muller K, Kriegbaum NJ, Baslund B, Sorensen OH, Thymann M, Bentzen K. Vitamin D3 metabolism in patients with rheumatic diseases: low serum levels of 25hydroxyvitamin D3 in patients with systemic lupus erythematosus. Clin Rheumatol 1995;14:397–400. [29] Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C. Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology (Oxford) 2008;47:920–3. [30] Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 2006;5:114–7. [31] Borba VZ, Vieira JG, Kasamatsu T, Radominski SC, Sato EI, Lazaretti-Castro M. Vitamin D deficiency in patients with active systemic lupus erythematosus. Osteoporos Int 2009;20:427–33. [32] Becker A, Fischer R, Schneider M. Bone density and 25-OH vitamin D serum level in patients with systemic lupus erythematosus. Z Rheumatol 2001;60:352–8. [33] Costenbader KH, Feskanich D, Holmes M, Karlson EW, Benito-Garcia E. Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann Rheum Dis 2008;67:530–5. [34] Kamen D, Aranow C. Vitamin D in systemic lupus erythematosus. Curr Opin Rheumatol 2008;20:532–7. [35] Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease. Rheumatology (Oxford) 2008;47:840–8. [36] O'Regan S, Chesney RW, Hamstra A, Eisman JA, O'Gorman AM, Deluca HF. Reduced serum 1, 25-(OH)2 vitamin D3 levels in prednisone-treated adolescents with systemic lupus erythematosus. Acta Paediatr Scand 1979;68:109–11. [37] Reed A, Haugen M, Pachman LM, Langman CB. Abnormalities in serum osteocalcin values in children with chronic rheumatic diseases. J Pediatr 1990;116:574–80.
Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). (Clifford DB, et al. Lancet Neurol. 2010;9:438-446). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients. The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6-80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase the risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML. Diagnosis of natalizumab-associated PML requires optimized clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimizing the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.