- Email: [email protected]
The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children
Journal of Crohn's and Colitis (2014) 8, 1730–1734
Available online at www.sciencedirect.com
ScienceDirect
The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children Mohamed Mutalib ⁎, Osvaldo Borrelli, Sarah Blackstock, Fevronia Kiparissi, Mamoun Elawad, Neil Shah, Keith Lindley Department of Paediatric Gastroenterology, Great Ormond Street Hospital for Sick Children NHS Foundation Trust, United Kingdom
Received 10 June 2014; received in revised form 24 August 2014; accepted 31 August 2014 KEYWORDS Inflammatory bowel disease; IBD; Crohn's disease; Ulcerative colitis; Sirolimus
Abstract Background: Management of refractory inflammatory bowel disease (IBD) in children is challenging and once response to conventional medical therapy deviates from the expected, options are often limited. Sirolimus is commonly used in post-transplantation management and is used sparsely as rescue therapy in refractory Crohn's disease. In the present study, we report the efficacy of sirolimus as an adjuvant immunosuppressive therapy in a retrospective case review of a selected group of IBD children who were refractory to the conventional treatments. Methods: Medical records of children with refractory IBD unresponsive to conventional therapy and started on sirolimus between 2006 and 2012 were retrospectively reviewed. Clinical response, through Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohn's Disease Activity Index (PCDAI), as well as intestinal inflammation, through specific histological scores, was evaluated. Results: The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully. Conclusion: Our data provide evidence that sirolimus seems to be effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing. © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
⁎ Corresponding author at: Department of Paediatric Gastroenterology, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, United Kingdom. Tel.: + 44 20 7405 9200; fax: + 44 20 7813 8258. E-mail address: [email protected] (M. Mutalib).
http://dx.doi.org/10.1016/j.crohns.2014.08.014 1873-9946/© 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
Sirolimus and pediatric IBD
1. Introduction Inflammatory bowel disease (IBD) is a relapsing and remitting chronic inflammatory condition that develops in genetically susceptible individuals often via immune dysregulated response to microorganisms.1 Based on clinical presentation, laboratory findings and radiology parameters and more definitively endoscopic and histological findings, IBD is broadly classified into three categories, i.e. Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBDU) in which the pattern and distribution of inflammation does not fall into neither of the two former categories.2 Management of IBD follows internationally recognized protocols to induce and maintain remission.3,4 Over the last decade, the use of anti-tumor necrosis factor alpha (anti-TNF-α) and other biological agents has transformed the medical therapy of IBD.5,6 They are considered disease modifying agents showing a complex mechanism of action that downregulate the mucosal production of TNF-α and interferon-Υ (IFN-Υ) and suppress proinflammatory cytokines7,8. Their use has facilitated withdrawal of steroids, reduced the need for surgery, improved patient's quality of life and most importantly in pediatric patients, their use has enabled optimum growth and development.8–10 However, over 25% of pediatric patients with IBD lose response to anti TNF with long term use.11 Achieving remission in individuals with pediatric IBD when the disease failed to respond to conventional medical therapies may be challenging and options are often limited. Sirolimus (rapamycin) is a macrocyclic antibiotic with immunosuppressive and antineoplastic properties with structural similarity to tacrolimus as it binds to the same family of intracellular FK 506 binding proteins but at a distinct site.12 It is commonly used in post-organ transplantation management. Although case reports on the use of sirolimus as rescue therapy in CD refractory to standard medical therapies have been published in adults,13 to the best of our knowledge there are no published data regarding the use of the drug in pediatric IBD. In this study we report the efficacy of sirolimus as an adjuvant immunosuppressive therapy in a retrospective case review of a selected group of IBD children who were refractory to the conventional treatments.
2. Patients and methods Sirolimus has been on the Great Ormond Street Hospital for Children NHS Foundation Trust formulary for use in treatment refractory IBD since 2006 and is used according to an in-house clinical guideline when appropriate. Children with a diagnosis of IBD who had been treated with sirolimus were identified through retrospective review of medical records between 2006 and 2012. Our data sources were the clinical and pharmacy patient databases within the Department of Gastroenterology at Great Ormond Street Hospital. Diagnosis of IBD was based on widely agreed endoscopic and histological criteria, as well as the exclusion of infectious and systemic disease, food allergies, and malabsorption.2 Clinical and histological disease activities were reviewed before and 3 months after the beginning of therapy with sirolimus, each child was followed up for a minimum of 3 months. All patients were started on 100 μg per kg of sirolimus initially then the
1731 dose was adjusted to achieve a trough level between 8 and 10 ng per milliliter. To assess clinical response we used the relevant disease activity indexes Pediatric Crohn's Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI). The index parameters were routinely recorded in our clinical practice by using a standard diary. Clinical remission is defined as the reduction of PCDAI or PUCAI to less than 10.14,15 A minimum of three biopsies was taken from different sites from the upper gastrointestinal tract and a minimum of five biopsies was taken from the ileum and different parts of the colon from all patients at the time of diagnosis and during follow-up. Biopsies were stained with hematoxylin and eosin and were examined by an experienced pediatric histopathologist with full knowledge of endoscopic and clinical features. We used a previously published grading system for scoring histology specimen for UC16 and Crohn's disease.17 It is not a routine practice in our institution for all patients to undergo endoscopy and biopsy three months after starting sirolimus irrespective to their clinical response, but rather the need for endoscopy was dictated by clinical necessity. For mucosal assessment in this study we used the first available endoscopy after three months of therapy with sirolimus, mostly done during clinical relapse. Patients were on a wide variety of medications before starting sirolimus (Table 1) the choice of these were directed by the clinical need of the individual child and their tolerance. Sirolimus was never used alone in this population of individuals with refractory IBD but in combination with other immunosuppressive therapies. Children on more than two types of immunosuppressant were given antibiotic prophylaxis according to our local microbiology protocol. The baseline characteristics of the patients were evaluated by means of descriptive analysis. For the treatment response analysis was performed using a Student t-test or Fisher exact test as appropriate. Wilcoxon signed rank test was applied to compare related samples. All statistical tests were 2-tailed and p b 0.05 was indicative of statistical significance. Analysis was performed using the Prism software version 5.00 (GraphPad, San Diego CA). Data are expressed as data were expressed as mean ± SD unless otherwise stated.
3. Results A total of 23 patients were identified. Of them, 9 children were excluded; two patients stopped sirolimus within a week because of persistent vomiting, two were transferred to another institution before they completed the period required for follow-up in our study, and five patients had incomplete records. Of the 14 patients analyzed, 11 patients had UC and 3 had ileo-colonic CD. Five were females and 9 were males, the mean age at diagnosis (±SD) was 9.1 (±3.8). Demographic data and clinical characteristics are summarized in (Table 1). Before commencement of sirolimus all 14 patients had failed a variety of standard medical therapies and all stayed on treatment while on sirolimus (Table 1). 8 patients had received steroid and 5-aminosalicylate (5-ASA), 5 had received thiopurines, 3 had received infliximab, 7 had received adalimumab, 5 had received methotrexate, and 1 was on tacrolimus. Of the UC patients 5 (45%) achieved clinical remission, 2 (18%) showed clinical response while 4 (36%) children did not
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Table 1 Demographic and disease characteristics before and after starting sirolimus. No. of children UC CD Males/females Age of diagnosis (years) (mean ± SD) Disease duration (months) (mean ± SEM) UC CD PUCAI (mean ± SD)
14 11 3 9/5 9.1 (± 3.8) 33.7 (± 9) 32 (± 8) Before 50.5 (± 20.7) After 27.7 (± 27.4) p value 0.04
PCDAI (mean ± SD) Before 30.8 (± 6.3) After 7.5 (± 2.5) p value 0.004 Hemoglobin (g/l) (mean ± SD) Before 110 (± 20.0) After 114 (± 20.2) p value 0.66
weaned off methotrexate. Endoscopy results did not correlate with clinical indexes; however these were not performed at standard intervals; many were performed during flare ups and well after the 3 month period when the scores were calculated. Five children (45%) with UC achieved histological mucosal healing (Fig. 2A); while six (55%) patients still had some disease activity. Five patients with UC had colectomy within 12 months of starting sirolimus. Of the CD patients two (67%) achieved mucosal healing while one (33%) showed ongoing mucosal inflammation in both terminal ileum and colonic diseases (Fig. 2B and C). In the majority of children clinical response to sirolimus occurred at least two weeks from starting treatment. Apart from minor gastrointestinal disturbances we did not encounter any serious side effect with sirolimus use in the studied population. Clinical response to sirolimus was observed two weeks after starting sirolimus onwards.
4. Discussion Sirolimus has been used successfully in a number of gastrointestinal inflammatory disorders. Yong et al. documented the successful use of sirolimus in children with IPEX and IPEX-like
C-reactive protein (mg/l) (mean ± SD) Before 22.7 (± 20.2) After 11.3 (± 13.4) p value 0.15 Histological score (mean ± SD) UC: Before 6.9 (± 0.9) After 4.3 (± 3.5) p value 0.029 CD: Terminal ileum
Colon
Before After p value Before After p value
9.3 (± 7.4) 5.3 (± 7.5) 0.54 14.3 (± 1.5) 8 (± 5.3) 0.12
Concurrent medications (no.) Steroid Thiopurine 5-ASA Infliximab Adalimumab Tacrolimus Methotrexate
8 5 8 3 7 1 5
UC: Ulcerative colitis, CD: Crohn's disease, PUCAI: Pediatric Ulcerative Colitis Activity Index, PCDAI: Pediatric Crohn's Disease Activity Index, SD: standard deviation, SEM: standard error of the mean.
respond to the addition of sirolimus (Fig. 1A). One patient was weaned off adalimumab after commencement on sirolimus. Of the patients with CD, all 3 showed a clinical remission assessed by their PCDAI (Fig. 1B). Two CD patients were successfully weaned off prednisolone and one was
Figure 1 Individual PUCAI (A) and PCDAI (B) values assessed before and at least three months after the beginning of therapy with sirolimus. PUCAI: Pediatric Ulcerative Colitis Activity Index, PCDAI: Pediatric Crohn's Disease Activity Index.
Sirolimus and pediatric IBD enteropathy with both clinical and histological improvements.18 Massey et al. used sirolimus to treat refractory Crohn's disease in an adult patient.13 Sirolimus acts by inhibiting mammalian target of rapamycin (mTOR), a protein kinase that plays an important role in cell division and proliferation.19 It also suppresses cytokine-mediated T cell proliferation and leads to T cell apoptosis.20 Moreover, it displays an antifibrotic effect by
Figure 2 Individual colonic histological scores (A) in UC children, and individual ileal (B) and colonic (C) histological scores in children with CD before and after the beginning of therapy with sirolimus. UC: Ulcerative colitis, CD: Crohn's disease.
1733 inhibiting extracellular matrix deposition and fibrogenesis and suppression of platelet derived growth factor induced fibroblast proliferation.21 Sirolimus is commonly used either alone or in combination with other calcineurin inhibitors in the prevention of graft rejection after solid organ transplantation and in the management of graft versus host disease (GVHD).21–23 In our study we provide evidence that the addition of sirolimus to conventional immunosuppressive therapies in a selected group of children with difficult to manage IBD leads to clinical and histological improvements in subset of patients. The apparent reduction in colectomy rate in responders to sirolimus did not reach statistical significance possibly because of the small numbers of patients (Fisher exact test 0.36). Moreover, in the patients responding to sirolimus it was sometimes possible to discontinue other treatments. One child with UC was weaned off adalimumab while 2 children with CD were weaned off prednisolone and 2 children with CD were able to stop methotrexate successfully. As this was not a prospective controlled study it is not possible to conclude that the weaning of these agents was as a consequence of the sirolimus therapy. None of the children on this cohort required additional steroid course while on sirolimus. Sirolimus shares some mechanisms of action and immunosuppressive effects with the calcineurin inhibitor cyclosporine. Although the efficacy of cyclosporine in the management of acute severe colitis is well documented,7–9,11 it is rarely used beyond rescue therapy due to significant side effects including nephrotoxicity, neurotoxicity, and hypertension.17,21,24 On the other hand sirolimus does not have the same serious side effects, and is proved to be as effective as cyclosporine in reducing active colitis in experimental studies and it is observed to reduce and alter leukocyte migration and adhesion in the gut mucosa.25 The role of immunoregulatory T cells in the prevention and suppression of the inflammatory process in IBD is well established.24 Interestingly, new evidence suggests that impaired autophagy, a catabolic pathway leading to recycling of proteins and macromolecular components, is directly implicated in a number of disease processes including inflammation and is associated with the risk of the development of Crohn's disease.26 It is well known that sirolimus plays an important role in promoting regulatory T cells and consequently favoring CD4+CD25+ T cell dependent immunoregulation, as well as in inducing autophagy through its blockade of mTOR.25,27 In our series, 45% of UC patient achieved mucosal healing defined by improving histological score adapted from previously published score (p value 0.029) (Table 1)16,17 and about two third of children with CD disease have achieved mucosal healing (p value 0.54 and 0.12 for ileal and colonic disease respectively). While clinical remission was achieved in 45% of UC patients (p value 0.04 for mean reduction of PUCAI) and 75% of CD patients (p value 0.004 for mean reduction of PCDAI). Two patients with UC showed an initial clinical response in their PUCAI in the first few months after starting sirolimus; however, they lost response with long term use. Moreover, the sirolimus group showed a reduction in inflammatory markers (measure by C-reactive protein) and improvement in anemia; however both parameters were not statistically significant. We were not able to demonstrate the exact correlation between activity indexes and histological disease activity,
1734 this could be explained by the fact that the two parameters were taken at different times. We calculated activity indexes around three months from starting sirolimus which was readily available from medical and nursing records, while endoscopy was only performed in symptomatic patients or in those having an annual mucosal assessment. Although all efforts were made to evaluate disease activity after major change in therapy, it is not always appropriate to subject children to invasive procedures such as endoscopy routinely if they are clinically well. Unfortunately, fecal calprotectin was not routinely available in our Institution at the time of the study period. Our study has some limitations. Firstly, this is a retrospective study embracing the well-known limitations of this type of methodology. Secondly, the concomitant treatment with other immunomodulatory agents is a likely confounding factor. However, it seems likely that adding sirolimus (a common denominator in all patients in this study) contributed to the success rate of other medications used. A well-designed randomized placebo-controlled study with long term outcome data is needed to definitively confirm the efficacy of sirolimus as concomitant immunosuppressive treatment in children with refractory IBD. In conclusion, our data provide compelling evidence that sirolimus is effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing. However, randomized placebo-controlled studies are warranted to extend our encouraging initial findings.
M. Mutalib et al.
9.
10.
11.
12.
13. 14.
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16.
17.
Conflict of interest None of the authors received any financial support from a third party and no conflict of interest is declared.
18. 19.
References 20. 1. Knights D, Lassen KG, Xavier RJ. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 2013;62:1505–10. 2. Levine A, Koletzko S, Turner D, Escher JC, Cucchiara S, de Ridder L, et al. Diagnosis of inflammatory bowel disease in children and adolescents: the Revised Porto Criteria. J Pediatr Gastroenterol Nutr. 2014;58(6):795–806. 3. Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571–607. 4. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000;119: 895–902. 5. Bradley GM, Oliva-Hemker M. Pediatric ulcerative colitis: current treatment approaches including role of infliximab. Biologics 2012;6:125–34. 6. Parashette KR, Makam RC, Cuffari C. Infliximab therapy in pediatric Crohn's disease: a review. Clin Exp Gastroenterol 2010;3(1):57–63. 7. Plevy SE, Landers CJ, Prehn J, Carramanzana NM, Deem RL, Shealy D, et al. A role for TNF alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease. J Immunol 1997;159:6276–82. 8. Ricciardelli I, Lindley KJ, Londei M, Quaratino S. Anti tumour necrosis-α therapy increases the number of FOX3+ regulatory T
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cell in children affected by Crohn's disease. Immunology 2008;125(2):178–83. Sandborn WJ. Current directions in IBD therapy: what goals are feasible with biological modifiers? Gastroenterology 2008;135: 1442–7. Borrelli O, Bascietto C, Cucchiara FS, Bueno de Mesquita M, Barbato M, Mancini V, et al. Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn's disease. Dig Liver Dis 2004;36(5):342–7. Oussalah A, Danese S, Peyrin-Biroulet L. Efficacy of TNF antagonists beyond one year in adult and pediatric inflammatory bowel diseases: a systematic review. Curr Drug Targets 2010;11:156–75. Weiwad M, Edlich F, Fischer G, Erdmann F, Jarczowski F, Dorn M, et al. Comparative analysis of calcineurin inhibition by complexes of immunosuppressive drugs with human FK506 binding proteins. Biochemistry 2006;45:15776–84. Massey DC, Bredin F, Parkes M. Use of sirolimus (rapamycin) to treat refractory Crohn's disease. Gut 2008;57(9):1294–6. Borrelli O, Cordischi L, Cirulli M, Pagallani M, Labalestra V, Uccini S, et al. Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn's disease: a randomized controlled open-label trial. Clin Gastroenterol Hepatol 2006;4(6):744–53. Turner D, Mack D, Leleiko N, Walters TD, Uusoue K, Leach ST, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology 2012;138:2282–91. Hanauer SB, Robinson M, Pruitt R, Lazenby AJ, Persson T, Nilsson LG, et al. Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study. U.S. Budesonide enema study group. Gastroenterology 1998;115:525–32. D'Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P, et al. Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998;114:262–7. Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol 2008;28:581–7. Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007;12:112–24. Abraham R, Wiederrecht G. Immunopharmacology of rapamycin. Annu Rev Immunol 1996;14:483–510. Abouelnasr A, Cohen S, Kiss T, Roy J, Lachance S. Defining the role of sirolimus in the management of graft-versus-host disease: from prophylaxis to treatment. Biol Blood Marrow Transplant 2013;19(1):12–21. Johnson RW. Sirolimus (Rapamune) in renal transplantation. Curr Opin Nephrol Hypertens 2002;11:603–7. Trotter JF. Sirolimus in liver transplantation. Transplant Proc 2003;35(Suppl 3):1935–2005. Pascual J. Concentration-controlled everolimus (Certican): combination with reduced dose calcineurin inhibitors. Transplantation 2005;79(Suppl 3):S76–9. Farkas S, Hornung M, Sattler C, Guba M, Steinbauer M, Anthuber M, et al. Rapamycin decreases leukocyte migration in vivo and effectively reduces experimentally induced chronic colitis. Int J Colorectal Dis 2006;21(8):747–53. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596–604. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntingdon disease. Nat Genet 2004;36:585–95.
Available online at www.sciencedirect.com
ScienceDirect
The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children Mohamed Mutalib ⁎, Osvaldo Borrelli, Sarah Blackstock, Fevronia Kiparissi, Mamoun Elawad, Neil Shah, Keith Lindley Department of Paediatric Gastroenterology, Great Ormond Street Hospital for Sick Children NHS Foundation Trust, United Kingdom
Received 10 June 2014; received in revised form 24 August 2014; accepted 31 August 2014 KEYWORDS Inflammatory bowel disease; IBD; Crohn's disease; Ulcerative colitis; Sirolimus
Abstract Background: Management of refractory inflammatory bowel disease (IBD) in children is challenging and once response to conventional medical therapy deviates from the expected, options are often limited. Sirolimus is commonly used in post-transplantation management and is used sparsely as rescue therapy in refractory Crohn's disease. In the present study, we report the efficacy of sirolimus as an adjuvant immunosuppressive therapy in a retrospective case review of a selected group of IBD children who were refractory to the conventional treatments. Methods: Medical records of children with refractory IBD unresponsive to conventional therapy and started on sirolimus between 2006 and 2012 were retrospectively reviewed. Clinical response, through Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohn's Disease Activity Index (PCDAI), as well as intestinal inflammation, through specific histological scores, was evaluated. Results: The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully. Conclusion: Our data provide evidence that sirolimus seems to be effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing. © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
⁎ Corresponding author at: Department of Paediatric Gastroenterology, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, United Kingdom. Tel.: + 44 20 7405 9200; fax: + 44 20 7813 8258. E-mail address: [email protected] (M. Mutalib).
http://dx.doi.org/10.1016/j.crohns.2014.08.014 1873-9946/© 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
Sirolimus and pediatric IBD
1. Introduction Inflammatory bowel disease (IBD) is a relapsing and remitting chronic inflammatory condition that develops in genetically susceptible individuals often via immune dysregulated response to microorganisms.1 Based on clinical presentation, laboratory findings and radiology parameters and more definitively endoscopic and histological findings, IBD is broadly classified into three categories, i.e. Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBDU) in which the pattern and distribution of inflammation does not fall into neither of the two former categories.2 Management of IBD follows internationally recognized protocols to induce and maintain remission.3,4 Over the last decade, the use of anti-tumor necrosis factor alpha (anti-TNF-α) and other biological agents has transformed the medical therapy of IBD.5,6 They are considered disease modifying agents showing a complex mechanism of action that downregulate the mucosal production of TNF-α and interferon-Υ (IFN-Υ) and suppress proinflammatory cytokines7,8. Their use has facilitated withdrawal of steroids, reduced the need for surgery, improved patient's quality of life and most importantly in pediatric patients, their use has enabled optimum growth and development.8–10 However, over 25% of pediatric patients with IBD lose response to anti TNF with long term use.11 Achieving remission in individuals with pediatric IBD when the disease failed to respond to conventional medical therapies may be challenging and options are often limited. Sirolimus (rapamycin) is a macrocyclic antibiotic with immunosuppressive and antineoplastic properties with structural similarity to tacrolimus as it binds to the same family of intracellular FK 506 binding proteins but at a distinct site.12 It is commonly used in post-organ transplantation management. Although case reports on the use of sirolimus as rescue therapy in CD refractory to standard medical therapies have been published in adults,13 to the best of our knowledge there are no published data regarding the use of the drug in pediatric IBD. In this study we report the efficacy of sirolimus as an adjuvant immunosuppressive therapy in a retrospective case review of a selected group of IBD children who were refractory to the conventional treatments.
2. Patients and methods Sirolimus has been on the Great Ormond Street Hospital for Children NHS Foundation Trust formulary for use in treatment refractory IBD since 2006 and is used according to an in-house clinical guideline when appropriate. Children with a diagnosis of IBD who had been treated with sirolimus were identified through retrospective review of medical records between 2006 and 2012. Our data sources were the clinical and pharmacy patient databases within the Department of Gastroenterology at Great Ormond Street Hospital. Diagnosis of IBD was based on widely agreed endoscopic and histological criteria, as well as the exclusion of infectious and systemic disease, food allergies, and malabsorption.2 Clinical and histological disease activities were reviewed before and 3 months after the beginning of therapy with sirolimus, each child was followed up for a minimum of 3 months. All patients were started on 100 μg per kg of sirolimus initially then the
1731 dose was adjusted to achieve a trough level between 8 and 10 ng per milliliter. To assess clinical response we used the relevant disease activity indexes Pediatric Crohn's Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI). The index parameters were routinely recorded in our clinical practice by using a standard diary. Clinical remission is defined as the reduction of PCDAI or PUCAI to less than 10.14,15 A minimum of three biopsies was taken from different sites from the upper gastrointestinal tract and a minimum of five biopsies was taken from the ileum and different parts of the colon from all patients at the time of diagnosis and during follow-up. Biopsies were stained with hematoxylin and eosin and were examined by an experienced pediatric histopathologist with full knowledge of endoscopic and clinical features. We used a previously published grading system for scoring histology specimen for UC16 and Crohn's disease.17 It is not a routine practice in our institution for all patients to undergo endoscopy and biopsy three months after starting sirolimus irrespective to their clinical response, but rather the need for endoscopy was dictated by clinical necessity. For mucosal assessment in this study we used the first available endoscopy after three months of therapy with sirolimus, mostly done during clinical relapse. Patients were on a wide variety of medications before starting sirolimus (Table 1) the choice of these were directed by the clinical need of the individual child and their tolerance. Sirolimus was never used alone in this population of individuals with refractory IBD but in combination with other immunosuppressive therapies. Children on more than two types of immunosuppressant were given antibiotic prophylaxis according to our local microbiology protocol. The baseline characteristics of the patients were evaluated by means of descriptive analysis. For the treatment response analysis was performed using a Student t-test or Fisher exact test as appropriate. Wilcoxon signed rank test was applied to compare related samples. All statistical tests were 2-tailed and p b 0.05 was indicative of statistical significance. Analysis was performed using the Prism software version 5.00 (GraphPad, San Diego CA). Data are expressed as data were expressed as mean ± SD unless otherwise stated.
3. Results A total of 23 patients were identified. Of them, 9 children were excluded; two patients stopped sirolimus within a week because of persistent vomiting, two were transferred to another institution before they completed the period required for follow-up in our study, and five patients had incomplete records. Of the 14 patients analyzed, 11 patients had UC and 3 had ileo-colonic CD. Five were females and 9 were males, the mean age at diagnosis (±SD) was 9.1 (±3.8). Demographic data and clinical characteristics are summarized in (Table 1). Before commencement of sirolimus all 14 patients had failed a variety of standard medical therapies and all stayed on treatment while on sirolimus (Table 1). 8 patients had received steroid and 5-aminosalicylate (5-ASA), 5 had received thiopurines, 3 had received infliximab, 7 had received adalimumab, 5 had received methotrexate, and 1 was on tacrolimus. Of the UC patients 5 (45%) achieved clinical remission, 2 (18%) showed clinical response while 4 (36%) children did not
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Table 1 Demographic and disease characteristics before and after starting sirolimus. No. of children UC CD Males/females Age of diagnosis (years) (mean ± SD) Disease duration (months) (mean ± SEM) UC CD PUCAI (mean ± SD)
14 11 3 9/5 9.1 (± 3.8) 33.7 (± 9) 32 (± 8) Before 50.5 (± 20.7) After 27.7 (± 27.4) p value 0.04
PCDAI (mean ± SD) Before 30.8 (± 6.3) After 7.5 (± 2.5) p value 0.004 Hemoglobin (g/l) (mean ± SD) Before 110 (± 20.0) After 114 (± 20.2) p value 0.66
weaned off methotrexate. Endoscopy results did not correlate with clinical indexes; however these were not performed at standard intervals; many were performed during flare ups and well after the 3 month period when the scores were calculated. Five children (45%) with UC achieved histological mucosal healing (Fig. 2A); while six (55%) patients still had some disease activity. Five patients with UC had colectomy within 12 months of starting sirolimus. Of the CD patients two (67%) achieved mucosal healing while one (33%) showed ongoing mucosal inflammation in both terminal ileum and colonic diseases (Fig. 2B and C). In the majority of children clinical response to sirolimus occurred at least two weeks from starting treatment. Apart from minor gastrointestinal disturbances we did not encounter any serious side effect with sirolimus use in the studied population. Clinical response to sirolimus was observed two weeks after starting sirolimus onwards.
4. Discussion Sirolimus has been used successfully in a number of gastrointestinal inflammatory disorders. Yong et al. documented the successful use of sirolimus in children with IPEX and IPEX-like
C-reactive protein (mg/l) (mean ± SD) Before 22.7 (± 20.2) After 11.3 (± 13.4) p value 0.15 Histological score (mean ± SD) UC: Before 6.9 (± 0.9) After 4.3 (± 3.5) p value 0.029 CD: Terminal ileum
Colon
Before After p value Before After p value
9.3 (± 7.4) 5.3 (± 7.5) 0.54 14.3 (± 1.5) 8 (± 5.3) 0.12
Concurrent medications (no.) Steroid Thiopurine 5-ASA Infliximab Adalimumab Tacrolimus Methotrexate
8 5 8 3 7 1 5
UC: Ulcerative colitis, CD: Crohn's disease, PUCAI: Pediatric Ulcerative Colitis Activity Index, PCDAI: Pediatric Crohn's Disease Activity Index, SD: standard deviation, SEM: standard error of the mean.
respond to the addition of sirolimus (Fig. 1A). One patient was weaned off adalimumab after commencement on sirolimus. Of the patients with CD, all 3 showed a clinical remission assessed by their PCDAI (Fig. 1B). Two CD patients were successfully weaned off prednisolone and one was
Figure 1 Individual PUCAI (A) and PCDAI (B) values assessed before and at least three months after the beginning of therapy with sirolimus. PUCAI: Pediatric Ulcerative Colitis Activity Index, PCDAI: Pediatric Crohn's Disease Activity Index.
Sirolimus and pediatric IBD enteropathy with both clinical and histological improvements.18 Massey et al. used sirolimus to treat refractory Crohn's disease in an adult patient.13 Sirolimus acts by inhibiting mammalian target of rapamycin (mTOR), a protein kinase that plays an important role in cell division and proliferation.19 It also suppresses cytokine-mediated T cell proliferation and leads to T cell apoptosis.20 Moreover, it displays an antifibrotic effect by
Figure 2 Individual colonic histological scores (A) in UC children, and individual ileal (B) and colonic (C) histological scores in children with CD before and after the beginning of therapy with sirolimus. UC: Ulcerative colitis, CD: Crohn's disease.
1733 inhibiting extracellular matrix deposition and fibrogenesis and suppression of platelet derived growth factor induced fibroblast proliferation.21 Sirolimus is commonly used either alone or in combination with other calcineurin inhibitors in the prevention of graft rejection after solid organ transplantation and in the management of graft versus host disease (GVHD).21–23 In our study we provide evidence that the addition of sirolimus to conventional immunosuppressive therapies in a selected group of children with difficult to manage IBD leads to clinical and histological improvements in subset of patients. The apparent reduction in colectomy rate in responders to sirolimus did not reach statistical significance possibly because of the small numbers of patients (Fisher exact test 0.36). Moreover, in the patients responding to sirolimus it was sometimes possible to discontinue other treatments. One child with UC was weaned off adalimumab while 2 children with CD were weaned off prednisolone and 2 children with CD were able to stop methotrexate successfully. As this was not a prospective controlled study it is not possible to conclude that the weaning of these agents was as a consequence of the sirolimus therapy. None of the children on this cohort required additional steroid course while on sirolimus. Sirolimus shares some mechanisms of action and immunosuppressive effects with the calcineurin inhibitor cyclosporine. Although the efficacy of cyclosporine in the management of acute severe colitis is well documented,7–9,11 it is rarely used beyond rescue therapy due to significant side effects including nephrotoxicity, neurotoxicity, and hypertension.17,21,24 On the other hand sirolimus does not have the same serious side effects, and is proved to be as effective as cyclosporine in reducing active colitis in experimental studies and it is observed to reduce and alter leukocyte migration and adhesion in the gut mucosa.25 The role of immunoregulatory T cells in the prevention and suppression of the inflammatory process in IBD is well established.24 Interestingly, new evidence suggests that impaired autophagy, a catabolic pathway leading to recycling of proteins and macromolecular components, is directly implicated in a number of disease processes including inflammation and is associated with the risk of the development of Crohn's disease.26 It is well known that sirolimus plays an important role in promoting regulatory T cells and consequently favoring CD4+CD25+ T cell dependent immunoregulation, as well as in inducing autophagy through its blockade of mTOR.25,27 In our series, 45% of UC patient achieved mucosal healing defined by improving histological score adapted from previously published score (p value 0.029) (Table 1)16,17 and about two third of children with CD disease have achieved mucosal healing (p value 0.54 and 0.12 for ileal and colonic disease respectively). While clinical remission was achieved in 45% of UC patients (p value 0.04 for mean reduction of PUCAI) and 75% of CD patients (p value 0.004 for mean reduction of PCDAI). Two patients with UC showed an initial clinical response in their PUCAI in the first few months after starting sirolimus; however, they lost response with long term use. Moreover, the sirolimus group showed a reduction in inflammatory markers (measure by C-reactive protein) and improvement in anemia; however both parameters were not statistically significant. We were not able to demonstrate the exact correlation between activity indexes and histological disease activity,
1734 this could be explained by the fact that the two parameters were taken at different times. We calculated activity indexes around three months from starting sirolimus which was readily available from medical and nursing records, while endoscopy was only performed in symptomatic patients or in those having an annual mucosal assessment. Although all efforts were made to evaluate disease activity after major change in therapy, it is not always appropriate to subject children to invasive procedures such as endoscopy routinely if they are clinically well. Unfortunately, fecal calprotectin was not routinely available in our Institution at the time of the study period. Our study has some limitations. Firstly, this is a retrospective study embracing the well-known limitations of this type of methodology. Secondly, the concomitant treatment with other immunomodulatory agents is a likely confounding factor. However, it seems likely that adding sirolimus (a common denominator in all patients in this study) contributed to the success rate of other medications used. A well-designed randomized placebo-controlled study with long term outcome data is needed to definitively confirm the efficacy of sirolimus as concomitant immunosuppressive treatment in children with refractory IBD. In conclusion, our data provide compelling evidence that sirolimus is effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing. However, randomized placebo-controlled studies are warranted to extend our encouraging initial findings.
M. Mutalib et al.
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Conflict of interest None of the authors received any financial support from a third party and no conflict of interest is declared.
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