Using Plasma Vitamin D Concentration as a Surrogate Marker to Predict Drug Response: A New Chapter in the Management of Inflammatory Bowel Disease and Beyond? editorial
JPEN J Parenter Enteral Nutr 2014 38: 279 DOI: 10.1177/0148607114525470
Lingtak-Neander Chan, PharmD, BCNSP1; and Shirley C. Paski, MD, MSc2
1School of Pharmacy and Graduate Program in Nutritional Sciences, School of Public Health, University of Washington, Seattle, Washington;
2Department of Medicine, Division of Gastroenterology, University of Washington School of Medicine/VA Puget Sound Health Care System, Seattle, Washington.
Corresponding Author: Lingtak-Neander Chan, PharmD, BCNSP, School of Pharmacy, University of Washington, Box 357630, 1959 NE Pacific Street, HSC, H-361B, Seattle, WA 98195-7630, USA. Email: neander at u.washington.edu
Paradigms for the management of inflammatory bowel disease (IBD) have continued to evolve, yet the treatment response, especially for patients with moderate to severe disease, remains difficult to predict. Although the introduction of biologic agents, such as tumor necrosis factor alpha (TNFa) antagonists (eg, adalimumab, certolizumab, infliximab) and a4-integrin inhibitors (natalizumab and vedolizumab), has improved overall treatment outcome, clinical remission rate remains highly variable, ranging from 40% to 80%.1-6 In this issue of JPEN, the results from the cohort study by Zator and his colleagues showed that the pretreatment plasma vitamin D concentration may be an important marker in predicting the treatment outcomes of anti-TNFa therapy in patients with IBD.7 Specifically, using a baseline vitamin D concentration of 30 ng/mL as the cutoff, the investigators found that patients who were vitamin D deficient before treatment were more likely to experience early discontinuation of anti-TNFa therapy (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.03-4.39; P = .04). The results remained consistent after exclusion of patients who received concurrent systemic corticosteroid such as prednisone (HR, 2.80; 95% CI, 1.02-7.71). More important, the primary reason (72% of the cases) for early discontinuation of therapy was lack of efficacy, suggesting that pretreatment vitamin D deficiency is associated with suboptimal response to drug therapy.
It has long been suspected that vitamin D status may play a role in the pathogenesis and progression of IBD. Experimental models with the deletion of vitamin D receptor (VDR) were found to be more susceptible to develop colitis, to be less likely to recover from intestinal mucosal injury, and to experience worse prognosis compared with models that express VDR.8,9 In addition, a number of studies link vitamin D status and various aspects of IBD, ranging from the severity of illness to the development of long-term complications in patients.10-13 Vitamin D also appears to work in synergy with corticoste-roids, a relationship best demonstrated in childhood asthma.14 Steroid requirements and in vitro steroid responsiveness are significantly inversely associated with vitamin D status.15 Vitamin D enhances steroid-induced interleukin-10 secretion and MAPK phosphatase 1 expression to produce increased anti-inflammatory effects. Vitamin D also suppresses inflammation by enhancing both corticosteroid inhibition of proinflammatory chemokines such as RANTES (regulated upon activation normal T-cell expressed and secreted) and cor-ticosteroid induction of a tolerogenic dendritic cell pheno-type.16 But the current study by Zator et al is the first to specifically show the link between vitamin D status and anti-TNFa therapy. The finding of this study are supported by previously published papers demonstrating that vitamin D modulates the TNF-mediated proinflammatory pathway.17-20 What remains unclear is whether vitamin D independently decreases inflammatory response by suppressing TNF expression or works synergistically with anti-TNF agents through other mechanisms.
This study also may have opened a new chapter in the understanding of drug-nutrient interaction. Our existing knowledge leads us to think that the primary reason for us to monitor nutrient status with certain drug therapy is to prevent adverse events. For instance, we supplement a patient with pyridoxine during the course of therapy for tuberculosis with isoniazid to prevent neuropathy; we monitor plasma vitamin D concentrations in patients receiving enzyme-inducing antiepileptic agents such as phenytoin and carbamazepine because of the pharmacokinetic interactions through enzyme induction. But we have not seen any previous example where the treatment efficacy of a drug can be substantially augmented by targeting the plasma concentration of a micronutrient to a specific threshold. If the results are confirmed in future studies, this would likely be the most notable example of a drug-nutrient interaction showing that a micronutrient status can be used as a surrogate marker to predict the outcomes of pharmacotherapy.
Clearly, despite the potential of these results, they are of a pilot nature and must be validated and replicated with larger scale trials. A few important aspects that were not the aims of Zator's study should be addressed in future investigations.
- First, it is unclear whether the predictive value of treatment response of vitamin D concentration can be applied to other biologic agents such as natalizumab, which acts by inhibiting adhesion of leukocytes via integrin function instead of TNFa.
- Second, the investigators used 30 ng/mL as the single cutoff for vitamin D status.
The logical next question is to ask whether a dose-response relationship exists:
That is, is a higher plasma vitamin D concentration before treatment associated with better clinical response?
Does a ceiling effect exist for vitamin D status where no further treatment benefit can be observed?
- Third, in patients with severe disease who did not reach remission with prior anti-TNFa therapy,
is there a clinical benefit in titrating the plasma vitamin D concentration to 50 ng/mL or even higher before therapy?
- Fourth, among patients whose vitamin D status could not be effectively optimized before the initiation of anti-TNFa agents, would achieving the threshold plasma vitamin D concentration during drug therapy lead to a comparable treatment success rate?
The results from the authors' subgroup analysis suggest that it may be an option.
Among patients with hypovitaminosis D, those who received concurrent vitamin D supplementation with anti-TNFa treatment were less likely to experience early discontinuation of drug therapy compared with those who did not receive vitamin D.
But how much vitamin D should be given, and to what concentration should it be targeted?
- Fifth, would the optimal plasma vitamin D concentration vary for an individual anti-TNFa agent in order to achieve the best clinical response?
We are constantly being reminded by newer research data that not all drugs in the same class are created equal.
And we have evidence to indicate that this applies to anti-TNFa agents as well.
- Sixth, is the predictiveness of treatment response with vitamin D concentrations altered by the patient's other concurrent medications for IBD?
The authors have shown that it may be the case for systemic cor-ticosteroid.
What about other agents such as antimetabolites (eg, azathioprine, methotrexate) or other immunosuppres-sive agents (eg, cyclosporine) or monoclonal antibodies with targets other than TNFa (eg, ustekinumab, vedolizumab)?
- Seventh, what about using a threshold plasma vitamin D concentration of 20 ng/mL instead of 30 ng/mL?
This question will once again invoke heated debate regarding the optimal vitamin D plasma concentration.
But it is a fundamentally important question that may affect not only patient management but also policy and reimbursement.
In summary, unlike many other association studies between vitamin D and a disease state, the study by Zator and his colleagues is of significant potential because it may open a new chapter in targeted drug therapy for IBD and possibly other illnesses such as rheumatoid arthritis and multiple sclerosis. Nevertheless, it also raises many important questions that must be answered adequately before this approach becomes a real game changer.
- 1. Hanauer SB, Feagan BG, Lichtenstein GR, et al; ACCENT I Study Group. Maintenance infliximab for Crohn's disease. Lancet. 2002;359(9317):1541-1549.
- 2. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease. Gastroenterology. 2006;130:323-333.
- 3. Sandborn WJ, Feagan BG, Stoinov S, et al; PRECISE 1 Study Investigators. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med. 2007 ;357:228-238.
- 4. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn's disease. Gut. 2007;56(9):1232-1239.
- 5. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease. Gastroenterology. 2007;132:52-65.
- 6. Colombel JF, Sandborn WH, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. New Engl J Med. 2010;362:1383.
- 7. Zator ZA, Cantu SM, Konijeti GG, et al. Pretreatment 25-hydroxyvitamin D levels and durability of anti-tumor necrosis factor-a therapy in inflammatory bowel diseases. JPEN J ParenterEnteralNutr. 2014;38:385-391.
- 8. Froicu M, Cantorna MT. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol. 2007;8:5.
- 9. Liu W, Chen Y, Golan MA, et al. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. J Clin Invest. 2013;123(9): 3983-3996.
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- 11. Ananthakrishnan AN, Cagan A, Gainer VS, et al. Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in Crohn's disease. Inflamm Bowel Dis. 2013;19(9):1921-1927.
- 12. Samson CM, Morgan P, Williams E, et al. Improved outcomes with quality improvement interventions in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2012;55(6):679-688.
- 13. Juneja M, Baidoo L, Schwartz MB, et al. Geriatric inflammatory bowel disease: phenotypic presentation, treatment patterns, nutritional status, outcomes, and comorbidity. Dig Dis Sci. 2012;57(9):2408-2415.
- 14. Brehm JM, Schuemann B, Fuhlbrigge AL, et al. Childhood Asthma Management Program Research Group. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol. 2010;126(1):25-58e5.
- 15. Searing DA, Zhang Y, Murphy JR, et al. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol. 2010;125(5):996-1000.
- 16. Litonjua AA. Vitamin D and corticosteroids in asthma: synergy, interaction and potential therapeutic effects. Expert Rev Respir Med. 2013;7(2):101-104.
- 17. Bartels LE, J0rgensen SP, Bendix M, et al. 25-Hydroxy vitamin D3 modulates dendritic cell phenotype and function in Crohn's disease. Inflammopharmacology. 2013;21(3):177-186.
- 18. Karim Y, Turner C, Dalton N, et al. The relationship between proinflamma-tory cytokines and the effect of high dose vitamin D supplementation on their circulating concentrations. Int Immunopharmacol. 2013;17(3):693-697.
- 19. Kuo YT, Kuo CH, Lam KP, et al. Effects of vitamin D3 on expression of tumor necrosis factor-alpha and chemokines by monocytes. J Food Sci. 2010;75(6):H200-H204.
- 20. Kwon HJ, Won YS, Suh HW, et al. Vitamin D3 upregulated protein 1 suppresses TNF-a-induced NF-kB activation in hepatocarcinogenesis. J Immunol. 2010;185(7):3980-3989.
PDF is attached at the bottom of this page
VitaminDWiki wonders how many other drug responses would be improved when the patients have > 30 ng of vitamin D
- All items in category gut and vitamin D
- Inflammatory bowel diseases are helped by vitamin D – commissioned review Nov 2013
- IBD in Finland – 3X increase in 15 years, more prevalent further from equator – Nov 2012
- Overview Gut and vitamin D contains the following summary
- Gut problems result in reduced absorption of Vitamin D, Magnesium, etc.
- Celiac disease has a strong genetic component.
- Most, but not all, people with celiac disease have a gene variant.
- An adequate level vitamin D seems to decrease the probability of getting celiac disease.
- Celiac disease causes poor absorption of nutrients such as vitamin D.
- Bringing the blood level of vitamin D back to normal in patients with celiac disease decreases symptoms.
- The prevalence of celiac disease, not just its diagnosis, has increased 4X in the past 30 years, similar to the increase in Vitamin D deficiency.
- Review in Nov 2013 found that Vitamin D helped
Many intervention clinical trials with vitamin D for Gut problems (101 trials listed as of Sept 2019)
- All items in category gut and vitamin D
Overview Gut and Vitami D contains the following chart - notice the lower left section
Better response to Inflammatory Bowel Disease drug if more than 30 ng of vitamin D – March 2014
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