The Role of Vitamin D in Anti-Tumor Necrosis Factor-Alpha-Induced Response in Patients with Inflammatory Bowel Disease

Abstract

Vitamin D is an important immunomodulator of the immune system and has been suggested to play a role in the pathogenesis of inflammatory bowel disease (IBD). Drugs targeting TNF-alpha are effective IBD therapies, and vitamin D has been demonstrated to suppress TNF-alpha as well as work synergistically with infliximab to reduce TNF-alpha in vitro. As a result, vitamin D may play a role in anti-TNF-induced response. The objectives of this study were to first compare the proportion of patients who achieved a clinical response in the normal vitamin D group to the proportion of patients who achieved a clinical response in the low vitamin D group at week 14; and to secondly compare clinical response rates at week 22, after the low vitamin D group was supplemented at week 14. Secondary outcomes included assessing clinical remission, C-reactive protein normalization, cytokine responses, health related quality of life, and depression at these time points. Adult Crohn’s disease and ulcerative colitis patients initiating anti-TNF therapy were invited to participate. Prior to starting anti-TNF therapy and at week 14, blood samples were collected to measure serum vitamin D, C-reactive protein, and cytokines levels and questionnaires were administered to assess clinical disease activity, depression, and quality of life. Patients low in vitamin D (serum 25(OH)D levels <75 nmol/L) were then administered a high dose (250,000-500,000 IU) of vitamin D intramuscularly within 2 weeks of their week 14-dose. Patients with normal vitamin D levels were not supplemented. Measurements of vitamin D, C-reactive protein, cytokines, clinical disease activity, depression, and quality of life were repeated 8 weeks later, prior to the patient’s week 22- dose. Clinical response at week 14 and week 22 was defined as a decrease of ≥ 3 points in the clinical disease activity scores from baseline. The proportion of patients who clinically responded at week 14 was similar between the two vitamin D groups (67% (14/21) vs. 65% (15/23), p=0.92). However, after stratifying by disease severity, there was a clinically significant higher proportion of patients in the low vitamin D group who responded at week 14 compared to the normal vitamin D group, if patients had severe disease (79% (11/14) vs. 53% (9/17), p=0.14). On the contrary, there was a trend to a higher proportion of patients in the normal vitamin D group who responded at week 14 compared to the low vitamin D group, if patients had non-severe disease (100% (4/4) vs. 44% (4/9), p=0.11). Clinical response results at week 22 were similar. Patients with low vitamin D levels and severe disease had higher serum levels of TNF-alpha, IL-6, and IL-1beta at baseline compared to patients with normal vitamin D levels and severe disease. By week 14 and week 22, cytokine levels were similar. Quality of life scores paralleled improvement in disease activity, and patients with low vitamin D levels had more cognitive depressive symptoms at the start of therapy. In conclusion, the inflammatory responses in patients with severe disease and low vitamin D levels are effectively treated with infliximab and adalimumab, and it may be that having inadequate levels of vitamin D before initiating anti-TNF therapy increases IBD patients’ sensitivity to this drug.