Pain Severity and Vitamin D Deficiency in IBD Patients

Round 1

Reviewer 1 Report

This paper purports to find a relationship between circulating hypo-Vit D and pain as reported by IBD patients. However, the results have not supported the assumption.

GENERAL OBSERVATIONS

Vit D is accredited with multiple complex functions. Its structure similar to a seco-steroid would encourage to understand it as a sort of immune suppressor, and its indications for IBD are not unanimously shared in the scientific community.

SPECIFIC

This background anticipates the unlikelyhood to readily demonstrate a link between Vit D levels and a complex/elusive variable such as pain in the protean condition of IBD. Perhaps this task is made even more difficult by the choice to include heavily treated hospitalized patients wherein any effect from Vit D might get blurred by potent medication. From this point of view I wonder whether including less medicated ambulatory patients could be more rewarding.

CONCLUSION

The study is well written and well conducted. Needless to say, the negative findings may detract from publication priority.

Author Response

Thank you for your valuable feedback. The comment that an association between vitamin D level and pain severity may be blurred by potent medication is highly relevant. This has been thoroughly discussed in the 'Discussion' chapter in the paragraph concerning limitiations. We still think that our sample may be considered representative of IBD patients treated in specialist care settings, and that any potential association of vitamin D deficiency to patient reported outcomes like pain severity were worth exploring. Further studies in different populations may shed further light on any possible associations and interventions. 

Reviewer 2 Report

Comments on the manuscript entitled " Pain severity and vitamin D deficiency in IBD patients"

Patients with Inflammatory bowel disease (IBD) frequently experience abdominal as well as extra-abdominal pain, which becomes severe as the disease activity increases in Ulcerative colitis (UC) and Crohn’s disease (CD). Besides multiple factors, like socio-demographic and psychological variables, vitamin D deficiency could also be responsible for severity of pain in IBD patients. The vitamin D deficiency is frequently observed in IBD patients and has been known to be associated with musculoskeletal pain and headache in general practice. Based on these known facts, Frigstad et al. group aimed to investigate the association between vitamin D deficiency and pain severity in IBD patients. Authors also investigated the anxiety and depressed state of patients with pain severity in IBD. The study revealed no significant association of vitamin deficiency with pain severity in IBD patients in multivariate analysis. However, univariate analyses demonstrated a link between depression and anxiety with pain severity only in UC patients. Although the negative findings are often neglected and mostly not propounded for publication, authors results hold significance by shifting the direction towards other possible pain modulating factors in IBD disease activity. Overall, the results are adequately represented and well discussed. However, the quality of this study could be highly enhanced if they can incorporate following minor revisions:

(1) Authors should include one table representing the cohorts with different Vitamin-D levels and showing their correlation with average levels of CRP, FC, SCCAI, HBI and Hospital Anxiety and depression score

(2) In order to improve the significance of their study authors should perform Pearson correlation analysis (r-values) to establish if there is any relationship between Vitamin D levels and pain severity in IBD patients, Vit. D and CRP or FCP and Vit. D and HADS-A or HADS-D score in IBD patients.

(3) Authors findings suggest no significant association of vit. D deficiency with pain severity in IBD patients altogether. However, their findings may provide different outcome if they distinguish CD and UC patients into mild-to-moderate and moderate-to-severe category.

(4) Prostaglandin E2 has direct association with inflammatory pain (PMID:21804201) and Vit. D inhibits the synthesis of this lipid mediator (PMID:23941558). Knowing the fact that authors have procured serum samples for 229 CD and 178 UC patients, it would be interesting to evaluate serum PGE2 levels in them. Probably, Vit. D deficiency may not be affecting PGE2 levels in Norwegian population. May be some other factors are contributing to reduced PGE2 levels, acting antagonistically to Vit. D deficiency (besides Vit. D supplement intake).

(5) It is quite possible that other inflammatory marker like serum amyloid A for IBD activity (PMID:3121351) has more close association with vit D deficiency and pain severity in Norwegian population.

Author Response

Thank you so much for your valuable feedback. The advice has helped to improve the manuscript in the submitted revision.

A table 2 has been added to show disease activity as well as depressive and anxiety symptoms with different vitamin D levels. A clarification has been added under results, summarizing earlier published findings in the same cohort on the associations between vitamin D deficiency and disease activity in IBD. Results from Pearson correlation analyses have been added to the results section, showing no significant association between 'pain interference' and vitamin D deficiency. For 'pain severity', analysis of this association is already included in the univariate analyses presented, and further analysis has not been done. The main outcome variables were 'pain severity' and 'vitamin D deficiency'. For the statistical analyses, three patient groups were formed: i) no pain, ii) mild pain and iii) moderate or severe pain. These groups were considered the most relevant approach from a clinical perspective, but also statistically, as relatively few patients reported moderate and severe pain. This is the reason for not distinguishing patients into other alternative categories. This has been clarified in the 'Methods' section. A reference to vitamin D and prostaglandin E has been added in the 'Discussion' section. Unfortunately we are not able to do further analysis of blood tests as no biobank exists, and the results are based on samples taken in clinical practice, with only vitamin D concentrations measured in a central laboratory.  No reference have been made to Amyloid E as exploration of other inflammatory markers was beyond the scope of our study. All new changes has been clearly highlighted in the revised manuscript. Please note changes in references and Table 2.

Round 2

Reviewer 1 Report

The changes made have significantly added to the priority of this paper