Alimentary Pharmacology and Therapeutics
Invited Editorials Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease B. Lebwohl*,† & J. F. Ludvigsson†,‡ *Department of Medicine, Coeliac Disease Center, Columbia University College of Physicians and Surgeons, New York, NY, USA. † Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. ‡ € € Department of Pediatrics, Orebro University Hospital, Orebro, Sweden. E-mail: [email protected] doi:10.1111/apt.12954
The study on histological recovery and gluten-free diet adherence by Galli et al. concludes that two in three adults with coeliac disease (CD) who adhere to a gluten-free diet (GFD) have a complete histological recovery after 1 year, and that severe histology at diagnosis predicts incomplete healing 1 year after diagnosis.1 The paper has several important strengths. This is a prospective study, using a validated adherence questionnaire,2 where assessors of histology and endoscopy were blinded. Dietary adherence was seen in 81.5%, consistent with earlier data.3, 4 The strict definition of complete histological recovery (Marsh 0 and ≤30/100 intraepithelial lymphocytes) is another strength, although the novelty of this definition means that some of these findings cannot be directly compared to that of earlier studies in which less stringent criteria were used. A limitation of this study is the number of study participants (n = 65); a resultant lack of statistical power may explain why certain factors could not be linked to degree of mucosal healing. In our earlier paper published in this journal,5 age was one factor strongly linked to mucosal healing, and this did not appear to be the case in the present study (although an adjusted odds ratio for age was not reported). Where the current and previous study agree is on the importance of degree of villous atrophy for later healing; both found that total villous atrophy on baseline biopsy is predictive of incomplete healing on follow-up.
Galli et al. found that incomplete mucosal recovery is still common even after 1 year of GFD in patients with CD. Earlier studies using less granular definitions of mucosal healing have reported histological recovery rates of 8–96% with most studies reporting a healing prevalence at follow-up of 57–76%.6 They also found that antibody seroconversion is not strongly predictive of mucosal healing, a finding with precedent in the literature.7 Of note, they also reported that osteoporosis was more common (P = 0.036) in those with lack of complete healing, supporting previous data from our group that persistent villous atrophy increases the risk of future hip fracture.8 Incomplete healing was also associated with lower cholesterol (P = 0.008) in this paper; hypocholesterolaemia may counter the negative effect of long-term inflammation in CD and partly explain why persistent villous atrophy has not been linked to an increased risk of cardiovascular death,9 despite a higher baseline rate of cardiovascular disease in CD.10 Considering recent evidence of the importance of mucosal healing for future risk of both lymphoproliferative malignancy,11 and fractures8 the findings of Galli et al. linking dietary adherence to healing need to be considered in the follow-up of patients with CD.
ACKNOWLEDGEMENTS Declaration of personal interests: None. Declaration of funding interests: BL: The American Scandinavian Foundation, the Coeliac Sprue Association and the National Center for Research Resources, a component of the National Institutes of Health (KL2 RR024157). JFL: Karolinska Institutet, the Swedish Society of Medicine, the Swedish Research Council – Medicine 522-2A09-195 and the Swedish Coeliac Society. REFERENCES 1. Galli G, Esposito G, Lahner E, et al. Histological recovery and gluten-free diet adherence: a prospective 1-year follow-up study of adult patients with coeliac disease. Aliment Pharmacol Ther 2014; 40: 639–47.
AP&T invited editorial columns are restricted to discussing papers that have been published in the journal. An editorial must have a maximum of 300 words, may contain one table or figure, and should have no more than 10 references. It should be submitted electronically to the Editors via http://mc.manuscriptcentral.com/apt.
ª 2014 John Wiley & Sons Ltd
1241
Invited Editorials 2. Biagi F, Andrealli A, Bianchi PI, Marchese A, Klersy C, Corazza GR. A glutenfree diet score to evaluate dietary compliance in patients with coeliac disease. Br J Nutr 2009; 102: 1–6. 3. Leffler DA, Edwards-George J, Dennis M, et al. Factors that influence adherence to a gluten-free diet in adults with celiac disease. Dig Dis Sci 2008; 53: 1573–81. 4. Ludvigsson JF, Brandt L, Montgomery SM, Granath F, Ekbom A. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009; 9: 19. 5. Lebwohl B, Murray JA, Rubio-Tapia A, Green PH, Ludvigsson JF. Predictors of persistent villous atrophy in coeliac disease: a population-based study. Aliment Pharmacol Ther 2014; 39: 488–95. 6. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 2014; 63: 1210–28.
Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease – authors’ reply G. Galli, G. Esposito, E. Lahner & B. Annibale Department of Digestive and Liver Disease, Ospedale Sant’Andrea, University Sapienza, Rome, Italy. E-mail: [email protected] doi:10.1111/apt.12975
We thank Drs Lebwohl and Ludvigsson for their interest and the comments about our work.1, 2 We are aware that our strict definition of complete histological recovery (Marsh 0 and ≤30/100 intraepithelial lymphocytes) makes difficult the comparison with other earlier studies on histological findings during gluten-free diet (GFD). However we believe that, according to Marsh classification,3 minimal histological lesions are truly to be considered coeliac disease because they represent intestinal damage, especially considering its immunological nature. We agree that the number of study participants (n = 65) could be a limitation of the study, decreasing statistical power. We support the idea that age is probably an important biological factor linked with mucosal healing.4 In fact our multivariate analysis (OR = 8.74) showing positive association between risks factors and mucosal healing has been adjusted for age over/under 45 years.2 Unfortunately, due to the relatively low sample size, no statistically significant results were found between mucosal healing and age at time of diagnosis. Considering our findings of hypocholesterolaemia and increased frequency of osteoporosis in patients without complete healing, we want to specify that these findings are related to the diagnosis time and not to 1 year of 1242
7. Hopper AD, Hadjivassiliou M, Hurlstone DP, et al. What is the role of serologic testing in celiac disease? A prospective, biopsyconfirmed study with economic analysis Clin Gastroenterol Hepatol 2008; 6: 314–20. 8. Lebwohl B, Michaelsson K, Green PH, Ludvigsson JF. Persistent mucosal damage and risk of fracture in celiac disease. J Clin Endocrinol Metab 2014; 99: 609–16. 9. Lebwohl B, Granath F, Ekbom A, et al. Mucosal healing and mortality in coeliac disease. Aliment Pharmacol Ther 2013; 37: 332–9. 10. Ludvigsson JF, James S, Askling J, Stenestrand U, Ingelsson E. Nationwide cohort study of risk of ischemic heart disease in patients with celiac disease. Circulation 2011; 123: 483–90. 11. Lebwohl B, Granath F, Ekbom A, et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 2013; 159: 169–75.
gluten-free diet (GFD) as discussed by Lebwohl et al. These results probably reflect that their presence is associated with more severe initial histological damage of intestinal mucosa as previously observed in patients with lack of complete healing.5 We are convinced that an optimal management of coeliac patients in the first year of GFD should include diet adherence assessment by means of validated tools linked to evaluation of an accurate histological recovery. This approach could be useful to reduce the future risk of both lymphoproliferative malignancy and fractures as pointed out by Lebwohol et al.5, 6
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Lebwohl B, Ludvigsson JF. Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease. Aliment Pharmacol Ther 2014; 40: 1241–2. 2. Galli G, Esposito G, Lahner E, et al. Histological recovery and gluten-free diet adherence: a prospective 1-year follow-up study of adult patients with coeliac disease. Aliment Pharmacol Ther 2014; 40: 639–47. 3. Marsh MN. Gluten major histocompatibility complex and the small intestine. A molecular approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 1992; 102: 330–54. 4. Lebwohl B, Murray JA, Rubio-Tapia A, Green PH, Ludvigsson JF. Predictors of persistent villous atrophy in coeliac disease: a population-based study. Aliment Pharmacol Ther 2014; 39: 488–95. 5. Lebwohol B, Michaelsson K, Green PH, et al. Persistent mucosal damage risk of fracture in celiac disease. J Clin Endocrinol Metab 2014; 99: 609–16. 6. Lebwohl B, Granath F, Ekbom A, et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 2013; 159: 169–75.
Aliment Pharmacol Ther 2014; 40: 1241-1249 ª 2014 John Wiley & Sons Ltd
Invited Editorials Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease B. Lebwohl*,† & J. F. Ludvigsson†,‡ *Department of Medicine, Coeliac Disease Center, Columbia University College of Physicians and Surgeons, New York, NY, USA. † Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. ‡ € € Department of Pediatrics, Orebro University Hospital, Orebro, Sweden. E-mail: [email protected] doi:10.1111/apt.12954
The study on histological recovery and gluten-free diet adherence by Galli et al. concludes that two in three adults with coeliac disease (CD) who adhere to a gluten-free diet (GFD) have a complete histological recovery after 1 year, and that severe histology at diagnosis predicts incomplete healing 1 year after diagnosis.1 The paper has several important strengths. This is a prospective study, using a validated adherence questionnaire,2 where assessors of histology and endoscopy were blinded. Dietary adherence was seen in 81.5%, consistent with earlier data.3, 4 The strict definition of complete histological recovery (Marsh 0 and ≤30/100 intraepithelial lymphocytes) is another strength, although the novelty of this definition means that some of these findings cannot be directly compared to that of earlier studies in which less stringent criteria were used. A limitation of this study is the number of study participants (n = 65); a resultant lack of statistical power may explain why certain factors could not be linked to degree of mucosal healing. In our earlier paper published in this journal,5 age was one factor strongly linked to mucosal healing, and this did not appear to be the case in the present study (although an adjusted odds ratio for age was not reported). Where the current and previous study agree is on the importance of degree of villous atrophy for later healing; both found that total villous atrophy on baseline biopsy is predictive of incomplete healing on follow-up.
Galli et al. found that incomplete mucosal recovery is still common even after 1 year of GFD in patients with CD. Earlier studies using less granular definitions of mucosal healing have reported histological recovery rates of 8–96% with most studies reporting a healing prevalence at follow-up of 57–76%.6 They also found that antibody seroconversion is not strongly predictive of mucosal healing, a finding with precedent in the literature.7 Of note, they also reported that osteoporosis was more common (P = 0.036) in those with lack of complete healing, supporting previous data from our group that persistent villous atrophy increases the risk of future hip fracture.8 Incomplete healing was also associated with lower cholesterol (P = 0.008) in this paper; hypocholesterolaemia may counter the negative effect of long-term inflammation in CD and partly explain why persistent villous atrophy has not been linked to an increased risk of cardiovascular death,9 despite a higher baseline rate of cardiovascular disease in CD.10 Considering recent evidence of the importance of mucosal healing for future risk of both lymphoproliferative malignancy,11 and fractures8 the findings of Galli et al. linking dietary adherence to healing need to be considered in the follow-up of patients with CD.
ACKNOWLEDGEMENTS Declaration of personal interests: None. Declaration of funding interests: BL: The American Scandinavian Foundation, the Coeliac Sprue Association and the National Center for Research Resources, a component of the National Institutes of Health (KL2 RR024157). JFL: Karolinska Institutet, the Swedish Society of Medicine, the Swedish Research Council – Medicine 522-2A09-195 and the Swedish Coeliac Society. REFERENCES 1. Galli G, Esposito G, Lahner E, et al. Histological recovery and gluten-free diet adherence: a prospective 1-year follow-up study of adult patients with coeliac disease. Aliment Pharmacol Ther 2014; 40: 639–47.
AP&T invited editorial columns are restricted to discussing papers that have been published in the journal. An editorial must have a maximum of 300 words, may contain one table or figure, and should have no more than 10 references. It should be submitted electronically to the Editors via http://mc.manuscriptcentral.com/apt.
ª 2014 John Wiley & Sons Ltd
1241
Invited Editorials 2. Biagi F, Andrealli A, Bianchi PI, Marchese A, Klersy C, Corazza GR. A glutenfree diet score to evaluate dietary compliance in patients with coeliac disease. Br J Nutr 2009; 102: 1–6. 3. Leffler DA, Edwards-George J, Dennis M, et al. Factors that influence adherence to a gluten-free diet in adults with celiac disease. Dig Dis Sci 2008; 53: 1573–81. 4. Ludvigsson JF, Brandt L, Montgomery SM, Granath F, Ekbom A. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009; 9: 19. 5. Lebwohl B, Murray JA, Rubio-Tapia A, Green PH, Ludvigsson JF. Predictors of persistent villous atrophy in coeliac disease: a population-based study. Aliment Pharmacol Ther 2014; 39: 488–95. 6. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 2014; 63: 1210–28.
Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease – authors’ reply G. Galli, G. Esposito, E. Lahner & B. Annibale Department of Digestive and Liver Disease, Ospedale Sant’Andrea, University Sapienza, Rome, Italy. E-mail: [email protected] doi:10.1111/apt.12975
We thank Drs Lebwohl and Ludvigsson for their interest and the comments about our work.1, 2 We are aware that our strict definition of complete histological recovery (Marsh 0 and ≤30/100 intraepithelial lymphocytes) makes difficult the comparison with other earlier studies on histological findings during gluten-free diet (GFD). However we believe that, according to Marsh classification,3 minimal histological lesions are truly to be considered coeliac disease because they represent intestinal damage, especially considering its immunological nature. We agree that the number of study participants (n = 65) could be a limitation of the study, decreasing statistical power. We support the idea that age is probably an important biological factor linked with mucosal healing.4 In fact our multivariate analysis (OR = 8.74) showing positive association between risks factors and mucosal healing has been adjusted for age over/under 45 years.2 Unfortunately, due to the relatively low sample size, no statistically significant results were found between mucosal healing and age at time of diagnosis. Considering our findings of hypocholesterolaemia and increased frequency of osteoporosis in patients without complete healing, we want to specify that these findings are related to the diagnosis time and not to 1 year of 1242
7. Hopper AD, Hadjivassiliou M, Hurlstone DP, et al. What is the role of serologic testing in celiac disease? A prospective, biopsyconfirmed study with economic analysis Clin Gastroenterol Hepatol 2008; 6: 314–20. 8. Lebwohl B, Michaelsson K, Green PH, Ludvigsson JF. Persistent mucosal damage and risk of fracture in celiac disease. J Clin Endocrinol Metab 2014; 99: 609–16. 9. Lebwohl B, Granath F, Ekbom A, et al. Mucosal healing and mortality in coeliac disease. Aliment Pharmacol Ther 2013; 37: 332–9. 10. Ludvigsson JF, James S, Askling J, Stenestrand U, Ingelsson E. Nationwide cohort study of risk of ischemic heart disease in patients with celiac disease. Circulation 2011; 123: 483–90. 11. Lebwohl B, Granath F, Ekbom A, et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 2013; 159: 169–75.
gluten-free diet (GFD) as discussed by Lebwohl et al. These results probably reflect that their presence is associated with more severe initial histological damage of intestinal mucosa as previously observed in patients with lack of complete healing.5 We are convinced that an optimal management of coeliac patients in the first year of GFD should include diet adherence assessment by means of validated tools linked to evaluation of an accurate histological recovery. This approach could be useful to reduce the future risk of both lymphoproliferative malignancy and fractures as pointed out by Lebwohol et al.5, 6
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Lebwohl B, Ludvigsson JF. Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease. Aliment Pharmacol Ther 2014; 40: 1241–2. 2. Galli G, Esposito G, Lahner E, et al. Histological recovery and gluten-free diet adherence: a prospective 1-year follow-up study of adult patients with coeliac disease. Aliment Pharmacol Ther 2014; 40: 639–47. 3. Marsh MN. Gluten major histocompatibility complex and the small intestine. A molecular approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 1992; 102: 330–54. 4. Lebwohl B, Murray JA, Rubio-Tapia A, Green PH, Ludvigsson JF. Predictors of persistent villous atrophy in coeliac disease: a population-based study. Aliment Pharmacol Ther 2014; 39: 488–95. 5. Lebwohol B, Michaelsson K, Green PH, et al. Persistent mucosal damage risk of fracture in celiac disease. J Clin Endocrinol Metab 2014; 99: 609–16. 6. Lebwohl B, Granath F, Ekbom A, et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 2013; 159: 169–75.
Aliment Pharmacol Ther 2014; 40: 1241-1249 ª 2014 John Wiley & Sons Ltd
