Abstract
BACKGROUND & AIMS
Vitamin D levels have been associated with disease activity in patients with ulcerative colitis (UC), but it is unclear whether they affect the risk of disease relapse. We sought to determine the association between baseline vitamin D levels during a period of clinical remission and risk of subsequent UC relapse.
METHODS
We performed a physician-blinded prospective study of 70 patients with UC in clinical remission followed after a surveillance colonoscopy at a tertiary academic medical center. Serum samples were collected at the time of colonoscopy and baseline endoscopic and histologic activity were determined. Levels of 25-hydroxy-vitamin D were measured using an ELISA. The primary outcome was rate of clinical relapse, determined over 12 months.
RESULTS
The mean baseline vitamin D level was lower among patients with relapse (29.5 ng/mL) than without (50.3 ng/mL) (P=.001). Remission vitamin D level (≤ 35 ng/mL) was associated with risk of clinical relapse (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.01–1.56; P=.044) over 12 months, independent of endoscopic or histologic grade at enrollment. A receiver operating characteristic curve of vitamin D levels for the outcome of relapse had an area under the curve of 0.72; a serum level ≤ 35 ng/mL had a sensitivity of 70% (95% CI 46%–88%) and specificity of 74% (95% CI 57%-83%) for predicting risk of clinical relapse.
CONCLUSIONS
Serum levels of vitamin D ≤ 35 ng/mL during periods of clinical remission increase the risk of UC relapse. Clinical trials to obtain vitamin D levels above this threshold should be considered.
Keywords: IBD, Biomarker, Relapse Prevention
INTRODUCTION
Ulcerative colitis (UC) and Crohn’s disease are inflammatory bowel diseases (IBD) that are chronic, idiopathic disorders of the gastrointestinal tract that are believed to result from a complex interplay between genetic, environmental, immune, and microbial factors [1,2]. Vitamin D has an emerging role as an environmental factor in the pathogenesis of autoimmune disorders including IBD [3,4]. The clinical significance of vitamin D has extended beyond its function in calcium homeostasis and bone metabolism with mounting evidence supporting its role in regulating immune responses. [5,6]. Vitamin D receptors are found to be expressed on a variety of immune cells and indeed vitamin D has numerous and multifaceted effects on the immune system. Vitamin D decreases the generation of pro-inflammatory Th1 responses and increases the levels of anti-inflammatory Th2 cells. [7] Vitamin D promotes self-tolerance by inhibition of dendritic cell differentiation and maturation [8,9] and increases the number and function of T regulatory cells [10,11]. Vitamin D has also been implicated in modulating the ability of human macrophages to kill intracellular bacteria [12] as well as protecting the epithelial mucosal barrier in intestinal inflammation. [13]
Genetic polymorphisms in the vitamin D receptor (VDR) have been associated with susceptibility and disease severity in patients with ulcerative colitis and Crohn’s disease. [14,15]. In mice models of experimental colitis, VDR knockout mice developed severe inflammation of the gastrointestinal tract and administration of the active form of Vitamin D (1,25D3) attenuated this effect of VDR deficiency on the development of severe colitis. [16] In human studies, vitamin D levels are inversely related to disease severity in patients with IBD. In two cross-sectional studies, vitamin D deficiency was associated with disease activity in both ulcerative colitis and Crohn’s disease. [17,18] One retrospective study demonstrated the association between vitamin D deficiency and lower quality of life indices and increased disease activity in patients with Crohn’s disease, but not in patients with UC. [19] Several other studies in Crohn’s disease patients have shown that higher vitamin D status was associated with reduced risk of disease development, normalization of vitamin D levels reduced risk of surgery, and that vitamin D levels increase and are responsive to treatment with biologics. [20,21,22]
Prospective studies exploring the effects of vitamin D on clinical outcomes and relapse are lacking, especially in patients with ulcerative colitis. One small prospective cohort of patients with mild to moderate Crohn’s disease demonstrated that raising the serum Vitamin D levels to normal levels was associated decreased disease index scores. [23] In a randomized clinical trial of vitamin D supplementation in Crohn’s disease patients, there was a trend towards reduced risk of clinical relapse, but was ultimately not significant. [24] Although vitamin D status has been implicated to correlate with disease severity, the clinical significance of low vitamin D levels among patients with ulcerative colitis in clinical remission is unclear. We thus aimed to explore the effect of vitamin D levels on risk of relapse in patients with UC in clinical remission. We also assessed the correlation between vitamin D levels and presence of baseline endoscopic and histologic inflammation.
MATERIALS AND METHODS
Study Design and Patient Enrollment
We conducted a prospective study of patients with UC in clinical remission, Simple Clinical Colitis Activity Index (SCCAI) ≤ 2, (Supplementary Figure 1) [25,26] who were recruited after a surveillance colonoscopy from the Inflammatory Bowel Disease Center at Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA from 2009–2012. The study was approved by the BIDMC institutional review board (IRB) under protocol # 2009P000314. From a cohort of 170 enrolled subjects, 70 had a baseline serum sample collected at the time of index colonoscopy. After the study follow-up period was completed, blinded investigators (JG, SM) measured serum vitamin D levels in these de-identified samples. Age, gender, ethnicity, smoking status, creatinine, duration of disease, extent of disease, relevant medications (current NSAIDs, current 5-ASA, current 6MP/AZA, current anti-TNF-α, steroids in the past year, and vitamin D supplementation), and season of enrollment were recorded for each patient. Baseline laboratory values (white blood cell count, hematocrit, erythrocyte sedimentation rate, and C-reactive protein) were also obtained. We did not assess for baseline dietary vitamin D intake, assess for initiation of vitamin D supplementation during the period of follow-up, or actively supplement patients with vitamin D based on baseline levels.
Assessment of Baseline Endoscopic and Histologic Inflammation and Clinical Relapse
Each enrolled patient had a clinically-indicated surveillance colonoscopy. During the index colonoscopy, endoscopic activity was classified using the sigmoidoscopy sub-score of the Mayo activity index based on the most inflamed segment of the colon. [27] Histological activity in all segments was classified using the Geboes score by a GI pathologist blinded to endoscopic scores. [28] For each patient, a total Geboes score was assigned to biopsies from each colonic segment and the highest score (most inflamed segment) was used as the cumulative histologic score. In our study, we defined endoscopic inflammation as a Mayo endoscopic score (MES) ≥ 2 Histologic inflammation was defined as a Geboes histologic score ≥ 3. “Clinical relapse” during the follow-up period was defined as a SCCAI score > 2, medication intensification, or UC-related hospitalization at any time during our follow-up period of 12 months. Medication intensification was defined by an increase in dose of current regimen, addition of another medication, or change in class of medication due to symptom relapse.
Vitamin D Measurement and Receiver Operator Characteristic Curve
Serum vitamin D levels (25(OH)D) were measured by using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Calbiotech, San Diego, CA) according the manufacturer’s instructions. A Receiver Operating Characteristic (ROC) curve of vitamin D levels for the outcome of clinical relapse was constructed. A vitamin D level threshold of ≤ 35 ng/mL was determined to have the greatest association for risk of clinical relapse in univariate and multivariate analysis (Supplementary Table 1) and thus chosen as our threshold level for further analyses. We compared risk of clinical relapse among patients with vitamin D level ≤ 35 ng/mL vs level > 35 ng/mL. To account for seasonal variations in vitamin D in New England, the year was dichotomized to a “low sunlight season” (September to February) and a “high sunlight season” (March to August). Sunlight season was included as a co-variate in our univariate analysis for risk of clinical relapse.
Data Analysis
The rate of clinical relapse, predictive value of clinical variables on the primary outcome, odds ratio (OR) with its 95 % confidence interval (CI), and p-values were assessed using JMP 11.0 (SAS Institute Inc., North Carolina). Dichotomous variables were analyzed for outcomes using χ2 test or Fisher’s exact test where appropriate, and continuous variables analyzed using t-test if normally distributed, or Wilcoxon test for non-normal data. Correction for multiple testing was included. All variables were initially analyzed in a univariate fashion to determine their association to clinical relapse. P-values of factors that showed evidence of an effect on clinical relapse (P < 0.05) were then analyzed on the multivariate regression analysis. Given that mucosal healing been associated with risk of clinical relapse in patients with ulcerative colitis [29,30], we constructed models accounting for the individual effects of endoscopic and histologic inflammation. We also performed a subgroup analysis restricted to patients with both clinical (SCCAI ≤ 2) and endoscopic (MES ≤1) remission while accounting for the confounding effects of underlying histologic inflammation (Geboes grade ≥ 3). Finally, we also performed a time to event analysis to detect a difference in time to clinical relapse among patients with vitamin D ≤ 35 ng/mL vs vitamin D > 35 ng/mL. For our multivariate analysis, model building was based on forward stepwise logistic regression, with a p value of 0.05 required for entry. All figures were generated using GraphPad Prism (version 5.0; GraphPad Software Inc., La Jolla, CA).
RESULTS
Baseline Patient Characteristics
Table 1 details the baseline phenotype of the enrolled cohort. The mean serum Vitamin D level in the cohort was 44 ng/mL (±29). Only 8 patients (11.4%) had steroid use in the past year. Vitamin D supplementation was reported by 42 patients (60%). Among the seventy patients enrolled, endoscopic inflammation was present in 9 patients (13%), while histologic inflammation was present in 32 patients (46%) at baseline. A multivariate analysis of the effects of clinical variables on the presence of baseline endoscopic or histologic inflammation highlighted that a vitamin D level ≤ 35 ng/mL was independently associated with increased presence of endoscopic inflammation (OR 1.29, 95% CI 1.07–1.85, P < 0.01) or histologic inflammation (OR 1.46, 95% CI 1.13–1.88, P = 0.005) at baseline.
TABLE 1.
Baseline Clinical Chacteristics of Cohort of Ulcerative Colitis Patients (N= 70 patients)
| Clinical Charactersitic | Number of Subjects (Percentage) |
|---|---|
| Demographics | |
| Average Age (years) | 48.6 (± 15.2) |
| Female Gender | 45 (64.3) |
| Caucasian Ethnicity | 65 (92.9) |
| Smoking (Current)a | 2 (2.9) |
| Average Creatinine (mg/dL) | 0.86 (± 0.19) |
| Season of Enrollment (Low Sunlight) b | 15 (21.4) |
| Ulcerative Colitis Characteristics | |
| Disease Duration (average years) | 12.0 (± 13.6) |
| Left-Sided Colitis | 27 (38.6) |
| Extenstive Colitis | 37 (52.9) |
| Duration of Remission ≥ 6 months | 57 (81.4) |
| Medications | |
| Current NSAIDs | 7 (10) |
| Current 5ASA | 52 (74.3) |
| Current 6MP/AZA | 13 (18.6) |
| Current anti-TNF-α | 4 (5.7) |
| Steroids in past year | 8 (11.4) |
| Vitamin D Supplement c | 42 (60) |
| Baseline Lab Values (Mean ± SD) | |
| White Blood Cell (K/uL) | 6.7 (± 2.3) |
| Hematocrit (%) | 41.0 (± 5.0) |
| Erythrocyte Sedimentation Rate (mm/hr) | 9.6 (± 9.3) |
| C-Reactive Protein (mg/L) | 3.2 (± 4.7) |
| Serum Vitamin D (ng/mL) d | 44.0 (±29) |
| Baseline Inflammation | |
| Endoscopic Inflammation e | 9 (12.9) |
| Histologic Inflammation f | 32 (45.7) |
There were only two patients who were current smokers at start of study, no patients were former smokers
Low sunlight season in Massachusetts (September to February), high sunlight season (March to August)
Includes patients who were on baseline Vitamin D supplements (including Multi-Vitamin) at time of enrollement in study
Baseline serum Vitamin D level at time of enrollement in study
Endoscopic Inflammation defined as Mayo Endoscopic Score ≥ 2
Histologic Inflammation defined as Geboes histologic score of ≥ 3
Vitamin D Levels and Receiver Operator Characteristic Curve
All patients who later relapsed had a SCCAI >2 at follow-up. Clinical relapse outcomes in our cohort included: SCCAI >2 alone (N= 5), SCCAI >2 with resulting medication intensification (N=13), and SCCAI >2 with resulting medication intensification and hospitalization (N= 2). As shown in Figure 1, mean baseline vitamin D level was lower in those who later relapsed (29.5 ng/mL), than those who did not (50.3 ng/mL, P = 0.001). A Receiver Operating Characteristic (ROC) curve of baseline serum vitamin D levels for the outcome of 12-month clinical relapse had an area under the curve (AUC) of 0.72 (p<0.01) (Figure 2). A serum vitamin D level of ≤ 35 ng/mL had a sensitivity of 70% (95% CI 46%-88%) and specificity of 74% (95% CI 57%-83%) for predicting subsequent risk of clinical relapse. An analysis of the effect of various serum vitamin D level thresholds on risk of subsequent of clinical relapse is summarized in Supplementary Table 1.
Figure 1.
Mean baseline Vitamin D level was lower among subsequent relapsers vs non-relapsers: 29.5 ng/mL vs 50.3 ng/mL (*p =0.001)
Figure 2.
A Receiver Operating Characteristic (ROC) curve of vitamin D levels for the outcome of relapse had an area under the curve (AUC) of 0.72 (p<0.01). Sensitivity 70.0% (95% CI 45.7%-88.1%), Specificity 73.5% (95% CI 56.7%-83.4), Likelihood Ratio 2.64.
Vitamin D Threshold and Risk of Clinical Relapse
The rate of clinical relapse over 12 months for patients with a vitamin D level ≤ 35 ng/mL vs patients with vitamin D level > 35 ng/mL was 20% vs 9 % (P = 0.003), respectively. Table 2 summarizes the univariate analysis of effect of clinical variables on clinical relapse; an increased risk of clinical relapse was associated with vitamin D level ≤ 35 ng/mL (OR 1.26, 95% CI 1.16–1.75, P =0.001), steroid use in the past year (OR 1.46, 95% CI 1.05–2.04, P = 0.026), and histologic inflammation (OR 1.52, 95% CI 1.22–1.89, P <0.001). Patients with vitamin D ≤ 35 ng/mL also had a shorter time to clinical relapse (P < 0.001, by Log Rank Mantel Cox) compared to UC patients with Vitamin D > 35 ng/mL (Figure 3). In our multivariate effects model, baseline vitamin D level ≤ 35 ng/mL was associated with increased risk of clinical relapse (OR 1.25, 95% CI 1.01–1.56, P =0.044) even after adjusting for the effects of baseline histologic inflammation (Table 3).
TABLE 2.
Univariate Factors Associated with Clinical Relapse over 12 months
| Clinical Variables | Odds Ratio | 95% CI | p Value | |
|---|---|---|---|---|
| Age (per year) | 0.99 | 0.99 | 1.00 | 0.146 |
| Female Gender | 1.06 | 0.84 | 1.34 | 0.601 |
| Caucasian Ethnicity | 1.15 | 0.90 | 1.46 | 0.257 |
| Smoking (Current) | 1.24 | 0.64 | 2.40 | 0.513 |
| Creatinine | 0.88 | 0.90 | 2.47 | 0.107 |
| Season (Low Sunlight)a | 1.22 | 0.98 | 1.51 | 0.079 |
| Vitamin D Supplements | 1.42 | 0.70 | 2.01 | 0.244 |
| Vitamin D level ≤ 35 ng/mL | 1.26 | 1.16 | 1.75 | 0.001 |
| Current NSAIDs | 1.00 | 0.69 | 1.44 | 0.980 |
| Current 5ASA | 1.26 | 0.98 | 1.61 | 0.073 |
| Current 6MP/AZA | 1.12 | 0.85 | 1.49 | 0.411 |
| Current anti-TNF-α | 0.96 | 0.60 | 1.54 | 0.859 |
| Steroids in past year | 1.46 | 1.05 | 2.04 | 0.026 |
| Erythrocyte Sedimentation Rate (ESR) | 1.00 | 0.98 | 1.01 | 0.569 |
| C-Reactive Protein (CRP) | 0.98 | 0.96 | 1.01 | 0.204 |
| Endoscopic Inflammationb | 1.35 | 0.98 | 1.87 | 0.066 |
| Histologic Inflammationc | 1.52 | 1.22 | 1.89 | <0.001 |
Low sunlight season in Massachusetts (September to February) , high sunlight season (March to August)
Includes patients with Endoscopic Inflammation (Mayo Endoscopic Score ≥ 2)
Includes patients with Histologic Inflammation (Geboes histologic score of ≥ 3)
Figure 3.
Time to Event Analysis of Effect of Vitamin D Levels on Risk of Clinical Relapse in Patients with Ulcerative Colitis in Remission. Patients with vitamin D ≤ 35 ng/mL had a shorter time to clinical relapse (p< 0.001, by Log Rank Mantel Cox) compared to UC patients with Vitamin D > 35 ng/mL.
TABLE 3.
Multivariate Analysis of Factors Associated with Clinical Relapse over 12 months
| Clinical Variables | Odds Ratio | 95% CI | p Value | |
|---|---|---|---|---|
| ENDOSCOPIC INFLAMMATION MODEL a | ||||
| Vitamin D level ≤ 35 ng/mL | 1.32 | 1.05 | 1.66 | 0.020 |
| Steroids in past year | 1.29 | 0.93 | 1.79 | 0.131 |
| Endoscopic Inflammation | 1.13 | 0.81 | 1.56 | 0.475 |
| HISTOLOGIC INFLAMMATION MODEL b | ||||
| Vitamin D level ≤ 35 ng/mL | 1.27 | 1.03 | 1.57 | 0.026 |
| Steroids in past year | 1.20 | 0.87 | 1.64 | 0.264 |
| Histologic Inflammation | 1.37 | 1.10 | 1.71 | 0.007 |
| CLINICAL AND ENDOSCOPIC REMISSION MODEL c | ||||
| Vitamin D level ≤ 35 ng/mL | 1.25 | 1.01 | 1.56 | 0.044 |
| Histologic Inflammation | 1.40 | 1.13 | 1.74 | 0.003 |
Analysis included UC patients in clinical remisssion, model adjusted for the confounding effects of endoscopic inflammation
Analysis included UC patients in clinical remisssion, model adjusted for the confounding effects of histologic inflammation
Analysis was restricted to patients in clinical remission (SCCA I≤ 2) and endoscopic remission (Mayo endoscopic score ≤ 1), N= 61 patients, in univariate analysis steroid use in past year was no longer associated with risk of clinical relapse
DISCUSSION
In this prospective cohort study of seventy patients with ulcerative colitis, we demonstrate for the first time that vitamin D levels are associated with baseline endoscopic and histologic inflammation severity during clinical remission, and are independently associated with the longitudinal risk of clinical relapse. These results suggest that vitamin D status is not only linked to current disease severity, but also has an impact on future risk of clinical relapse.
To our knowledge, this is the first prospective study demonstrating the effect of vitamin D levels during remission on clinical outcomes among ulcerative colitis patients. There have been no previous clinical trials and few prospective studies exploring the role of vitamin D on ulcerative colitis clinical outcomes. One analysis of an epidemiological cohort by Ananthakrishnan et al [21] demonstrated that low vitamin D levels was associated with clinical relapse in the form of increased risk of hospitalizations and surgeries. The results of our study are consistent with their finding that low vitamin D predisposes patients to clinical relapse. However, their study did not control for UC disease severity or account for the effect of baseline inflammation in their multivariate analysis. Our study differs in that we restricted enrollment only to patients in clinical remission and adjusted for confounding effects of endoscopic and histologic inflammation in our analyses.
Previous studies have also shown that vitamin D levels are inversely related to UC disease activity. These studies of disease activity were based mainly on symptom scores and quality of life surveys. [18,19,31] Our study supports these previous findings that vitamin D is a marker of disease activity in UC and adds further to the literature by demonstrating that vitamin D levels also reflect inflammatory activity at the endoscopic and histologic level beyond the clinical phenotype. Taken together, low serum vitamin D levels may be a useful biomarker for the detection of inflammation in UC patients in the absence of significant clinical symptoms.
Our finding that low vitamin D levels increases risk of clinical relapse in UC patients in remission may be interpreted in several ways. One explanation is that the immunoprotective and anti-inflammatory properties of vitamin D diminishes with lower levels and this directly leads to subsequent inflammation and clinical relapse. Another explanation is that low vitamin D levels was an effect of increased disease activity and that the risk of clinical relapse was mediated through the effects of baseline inflammation. Low baseline vitamin D levels measured in our cohort was not due to clinical disease activity as the patients enrolled in our study were in clinical remission. Although a subset of patients in our cohort had endoscopically and histologically active disease, our models adjusted for the effect of this baseline inflammation in our analysis. We also performed a subgroup analysis restricted only to patients in clinical and endoscopic remission and after adjusting for histologic inflammation in our multivariate analysis, low vitamin D was still associated with risk of clinical relapse. Thus, our results demonstrate that low vitamin D impacts risk of clinical relapse independent of subclinical inflammation.
Our study has several major strengths. First, our study was prospective and provided clarity of temporal sequence regarding our exposure of low vitamin D levels and outcome of clinical relapse. Second, our study was blinded: investigators measuring baseline serum vitamin D levels were blinded to subsequent relapse status to avoid selection bias at time of analysis and likewise, our investigators assessing relapse during followup periods were blinded to baseline vitamin D levels. Third, our cohort was limited to UC patients in clinical remission, which allowed us to isolate the independent effects of vitamin D levels on risk of clinical relapse. Fourth, vitamin D status was based on direct vitamin D measurements from serum obtained at time of enrollment rather than from ICD-9 codes for vitamin D deficiency, random vitamin D values from the medical record, or from estimates of serum vitamin D calculated from diet, physical activity, and other predictors of vitamin D levels. Finally, our study focused solely on UC patients, a population that warrants greater attention regarding the clinical role of vitamin D. Generalizations regarding the effect of vitamin D on inflammatory bowel disease as a group may not be appropriate as there genetic and immunologic differences in the pathogenesis of ulcerative colitis and Crohn’s disease.
Our study has several limitations that merit attention. First, our sample size was small and may not be representative of the general UC population. Furthermore, the generalizability of our findings is limited only to UC patients in remission. Second, our study was based on a single measurement of serum vitamin D at time of enrollment, which may not reflect a patient’s baseline levels and does not take into account the possibility of fluctuations over the course of 12 months. One large scale epidemiological study by Jorde et al [32] involving long term tracking of serum vitamin D levels acknowledged that although there are fluctuations in serum vitamin D levels, they are unlikely to have substantial improvements over time. Their study supported the use of a single serum vitamin D measurement to predict future health outcomes. Third, our study is observational and thus is limited by the inability to account for potential unmeasured confounders. In particular, our study did not take into account baseline dietary vitamin D intake, BMI, physical activity, parathyroid hormone levels, malabsorptive conditions, medications that affect vitamin D levels, or adherence to medical therapy. Finally, although our cohort enrolled patients with clinically quiescent UC, we did not restrict our enrollment to patients with endoscopic and histologic remission, which raises the possibility that subclinical inflammation rather than low vitamin D levels is contributing to risk of relapse. However, we adjusted for the confounding effects of baseline endoscopic and histologic inflammation in our subgroup analysis and multivariate models.
The results of our study have several clinical implications. First, although currently not part of regular surveillance and standard of care in ulcerative colitis patients, our findings support the need for routine measurement of serum vitamin D levels. Second, our study suggest a role of low vitamin D as a maker of endoscopic and histologic inflammation in the absence of significant clinical symptoms which may in turn be used to risk-stratify patients. Third, our findings provide a rationale for vitamin D supplementation in maintenance therapy in patients with ulcerative colitis. Maintaining serum vitamin D levels above specified thresholds during periods of clinical remission may be protective against subsequent clinical relapse.
In conclusion, our study provides evidence that low vitamin D levels (≤ 35 ng/mL) correlate with endoscopic and histologic inflammation and are associated with increased risk of subsequent clinical relapse during periods of clinical remission. Vitamin D is an affordable, accessible, and relatively nontoxic supplement that may have protective effects in the maintenance of clinical remission in patients with ulcerative colitis. Clinical trials of vitamin D therapy to obtain vitamin D levels above this threshold should be considered to definitively establish its impact on ulcerative colitis outcomes.
Supplementary Material
Acknowledgments
ACM is supported by NIH grant K23DK084338 and Rabb Research Award. We are grateful to Adam Cheifetz MD, Kenneth Falchuk MD, and Jacqueline Wolf MD for allowing us to enroll their patients.
Abbreviations
- IBD
Inflammatory bowel disease
- UC
ulcerative colitis
- ELISA
Enzyme-linked Immunosorbent Assay
- SCCAI
Simple Colitis Clinical Activity Index
- OR
Odds Ratio
- ROC
receiver operating characteristic
- AUC
area under the curve
- NSAIDs
nonsteroidal anti-inflammatory drugs
- 5ASA
5-aminosalicylic acid
- 6MP/AZA
6-mercaptopurine/azathioprine
- anti-TNF-α
anti-tumor necrosis factor-α
Footnotes
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Disclosures: Authors have no conflicts of interests or financial disclosures relevant to this manuscript.
Writing Assistance: None
Author Contributions: John Gubatan and Alan Moss planned and designed the study and analyzed the data; John Gubatan and Shuji Mitsuhashi measured serum vitamin D levels; Talia Zenlea and Laura Rosenberg enrolled patients and collected clinical data, , Simon Robson provided the laboratory support, John Gubatan drafted the manuscript; all authors interpreted the results and contributed to critical review of the manuscript; John Gubatan had full access to all of the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.
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