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Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors
YIJOM-4263; No of Pages 8
Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2019.08.007, available online at https://www.sciencedirect.com
Clinical Paper Clinical Pathology
Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors
K. Brijs1,2, I. Miclotte1,2, S. Vermeire3, V. Darche4, C. Politis1,2 1 OMFS IMPATH Research Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; 2Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium; 3Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; 4Oral and Maxillofacial Surgery, CHR-Namur, Namur, Belgium
K. Brijs, I. Miclotte, S. Vermeire, V. Darche, C. Politis: Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2019 The Author(s). Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Abstract. Previous reports have suggested a possible association between tumour necrosis factor alpha (TNF-a) inhibitors, used in the treatment of immune-mediated inflammatory diseases, and medication-related osteonecrosis of the jaw (MRONJ). However, a comprehensive assessment of the frequency and severity of MRONJ caused by these agents is lacking. The aim of this cohort study was to investigate the occurrence of MRONJ in a population of patients with inflammatory bowel disease (IBD) treated with TNF-a inhibitors at a tertiary care medical centre. A total of 2701 IBD patients under current or former treatment with TNF-a inhibitors were identified in an IBD registry covering the period 1994–2018. These patients were cross-matched with all patients diagnosed with MRONJ. This resulted in three patients with a definite diagnosis of MRONJ, without concomitant treatment with bisphosphonates. All three patients required surgical treatment with sequestrectomy. Mucosal healing occurred at 4–15 months and one patient developed recurrence. In conclusion, this study identified and described anti-TNFa-related MRONJ occurring in a large cohort of IBD patients, and reported the severity and treatment strategies used.
Medication-related osteonecrosis of the jaw (MRONJ) is a disabling condition with increasing incidence, a high burden on quality of life, and poor outcomes. Only 50–60% of patients make a full 0901-5027/000001+08
recovery with mucosal healing1–4. Typically, bisphosphonates and denosumab have been associated with this disease, although anti-angiogenic agents have also been reported to cause MRONJ4,5. More
Key words: osteonecrosis of the jaw; MRONJ; inflammatory bowel disease; TNF-a inhibitors. Accepted for publication
recently, a number of reports have described the occurrence of MRONJ in patients treated with tumour necrosis factor alpha (TNF-a) inhibitors6–9. However, a comprehensive assessment of the
ã 2019 The Author(s). Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
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frequency and severity of MRONJ in these patients has not yet been performed. Since receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-a share some biological features and RANKL inhibition by denosumab is associated with MRONJ, TNF-a inhibition may also be associated with MRONJ (Fig. 1). Denosumab is a monoclonal antibody directed against RANKL, a molecule that normally binds to the RANK receptor on (pre-)osteoclasts and thereby induces the maturation of pre-osteoclasts to osteoclasts and the activation and survival of osteoclasts10. Inhibition of this interaction subsequently blocks bone degradation. This drug is used as an antiresorptive agent in the treatment of osteoporosis and malignancies4,5. RANKL and TNF-a both belong to the TNF superfamily and play a role in immune homeostasis and bone degradation11,12. TNF-a is an important cytokine involved in the pathogenesis of chronic immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis, and rheumatoid arthritis. Neutralizing TNF-a through the use of TNF-a inhibitors reduces disease activity in these autoimmune diseases12. Since a comprehensive assessment of MRONJ in patients treated with TNF-a inhibitors has not been performed to date, the aim of this study was to investigate the occurrence and severity of MRONJ in a large IBD population treated with these drugs. Materials and methods
A retrospective cohort study was performed at the University Hospitals Leuven, Belgium. First, all patients with IBD
who had received treatment with TNF-a inhibitors were identified in an IBD registry covering the period 1994–February 2018 at the study institution and were included in the study. The medical history of all patients with IBD was obtained from this registry, including age, sex, type of IBD, and types of TNF-a inhibitor used. These patients were then cross-matched with all patients diagnosed with MRONJ in the Oral and Maxillofacial Surgery Department between January 2000 and February 2018. These patients were identified by a selection of key words in their medical records, including ‘osteonecrosis’, ‘MRONJ’, ‘ONJ’, ‘BRONJ’, ‘jaw necrosis’, ‘osteochemonecrosis’, and ‘osteomyelitis’. Furthermore, to identify additional patients with possible MRONJ, all medical files from patients with IBD were searched for the key words ‘ONJ’, ‘MRONJ’, ‘BRONJ’, ‘exposed bone’, ‘osteonecrosis’, and ‘osteochemonecrosis’. For the IBD patients diagnosed with MRONJ, the location and the stage of MRONJ, predisposing and precipitating factors, the initial symptoms (infection, pain, hypoesthesia, and bone sequestra), the treatment, and the outcome were recorded. Predisposing factors were poor oral health, smoking behaviour, alcohol use, treatment with steroids or bisphosphonates, and diabetes. Regarding patient characteristics, continuous variables were recorded as the mean standard deviation or as the number (percentage). Results
The study cohort consisted of 2701 IBD patients treated with at least one TNF-a inhibitor. The IBD diagnosis was classified into three categories: Crohn’s disease, ulcerative colitis, and IBD unclassified (IBDU). IBDU is a term to describe
IBD restricted to the colon than cannot be assigned to Crohn’s disease or ulcerative colitis13. The baseline characteristics of all IBD patients and the distribution of patients according to their disease (Crohn’s disease, ulcerative colitis, or IBDU) are shown in Table 1. The majority of patients in this study population had Crohn’s disease (1842 patients, 68.2%). No patients with microscopic colitis were included in the IBD registry. The mean age of the study population was 44.4 years and 1215 patients were male. Three monoclonal antibodies were used as TNF-a inhibitors: infliximab and adalimumab (both for ulcerative colitis and Crohn’s disease), and golimumab (only for ulcerative colitis). Infliximab is administered intravenously, and adalimumab and golimumab are administered subcutaneously. The majority of the patients in the study cohort (85.1%) were treated with infliximab, alone or in sequential combination with other TNF-a inhibitors. On cross-matching the IBD patients with 1519 possible cases of MRONJ, six patients with IBD and possible MRONJ were identified. Revision of the individual patient records showed that three patients did not have a definite diagnosis of MRONJ, resulting in three confirmed cases of MRONJ in patients treated with TNF-a inhibitors (Fig. 2). All three cases were registered between 2013 and 2016. The additional search in the medical files of patients with IBD for the key words ‘ONJ’, ‘MRONJ’, ‘BRONJ’, ‘exposed bone’, ‘osteonecrosis’, and ‘osteochemonecrosis’ did not result in the identification of additional patients with possible MRONJ. The baseline characteristics of the three patients are shown in Table 2. MRONJ in
Fig. 1. Receptor interaction and signalling. As members of the TNF superfamily, RANKL and RANK functionally resemble TNF-a and TNF-R. As denosumab causes MRONJ by interrupting the interaction between RANKL and RANK, TNF-a inhibitors may also induce MRONJ. (MRONJ, medication-related osteonecrosis of the jaw; RANK(L), receptor activator of nuclear factor kappa-B (ligand); TNF-a(R), tumour necrosis factor alpha (receptor).
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
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Table 1. Patient characteristics of the whole sample and by IBD subtype. Whole sample N = 2701 Age (years), mean SD Sex, n (%) Male Female IBD diagnosis, n (%) Crohn’s disease Ulcerative colitis IBD unclassified TNF-a inhibitor used, n (%) Infliximab Adalimumab Golimumab Infliximab + adalimumab Infliximab + golimumab Adalimumab + golimumab Infliximab + adalimumab + golimumab
IBD Crohn’s disease
Ulcerative colitis
IBD unclassified
764 327 0 751 0 0 0
467 56 14 208 31 3 21
41 3 0 15 0 0 0
44.4 15.7 1215 (45.0%) 1486 (55.0%) 1842 (68.2%) 800 (29.6%) 59 (2.2%) 1272 (47.1%) 386 (14.3%) 14 (0.5%) 974 (36.1%) 31 (1.1%) 3 (0.1%) 21 (0.8%)
IBD, inflammatory bowel disease; SD, standard deviation; TNF-a, tumour necrosis factor alpha.
Fig. 2. Flowchart of the search procedure, identifying cases of medication-related osteonecrosis of the jaw (MRONJ) in patients with inflammatory bowel disease (IBD) and treated with tumour necrosis factor alpha (TNF-a) inhibitors.
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
Risk factors Poor oral health Smoking Alcohol use Bisphosphonate use Corticosteroid use Diabetes Complaint at presentation Type of complaint Period between precipitating factor and complaint Stage of MRONJ at presentationa Treatment Conservative Surgery HBO therapy Cessation of anti-TNF-a therapy/ other immune modulating drugs Follow-up, time to healing Recurrence
Case 1
Case 2
Case 3
Female CD, for 9 years Infliximab, adalimumab 23 Extraction of molars in upper jaw
Female UC, for 7 years Infliximab 57 Extraction of one molar in lower jaw
Male CD, for 22 years Infliximab, adalimumab 46 Extraction of multiple teeth in lower jaw; local trauma caused by prosthesis
Yes No No Not mentioned No, never No
Yes Yes No Not mentioned In the past No
Yes Yes Not mentioned Not mentioned Yes No
OAC Development of OAC at time of extraction
Pain Persistent pain since extraction 10 days before 1
Pain and hypoesthesia of the inferior alveolar nerve Development of symptoms 5 months after extraction
Antibiotics, mouth rinse Sequestrectomy No No cessation; continuation of infliximab and mesalazine
Antibiotics, mouth rinse Sequestrectomy, incision of abscess No Currently not on anti-TNF-a therapy; continuation of vedolizumab; interruption of steroids
Mucosal healing after 4 months No
Mucosal healing after 15 months No
3; OAC Antibiotics, mouth rinse Debridement of osteomyelitis, sequestrectomy Yes Currently not on anti-TNF-a therapy; interruption of other immunosuppressive drugs for 16 months Mucosal healing after 7 months Yes, 4 years later Treatment with palatal rotation flap after failure of mucoperiosteal flap
2; with development of abscess
CD, Crohn’s disease; HBO, hyperbaric oxygen; IBD, inflammatory bowel disease; MRONJ, medication-related osteonecrosis of the jaw; OAC, oro-antral communication; TNF-a, tumour necrosis factor alpha; UC, ulcerative colitis. a Stage 1: Exposed and necrotic bone or a fistula that probes to bone; asymptomatic patients with no evidence of infection. Stage 2: Exposed and necrotic bone or a fistula that probes to bone; symptomatic patients with evidence of infection. Stage 3: Exposed and necrotic bone or a fistula that probes to bone with complications6.
Brijs et al.
Sex Type of IBD TNF-a inhibitor ever received Age (years) Precipitating factor
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Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
Table 2. Characteristics of the three confirmed cases of MRONJ in patients treated with TNF-a inhibitors.
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Fig. 3. Case 1. (a) Preoperative panoramic radiograph showing apical translucencies in multiple elements, including the molars of the right upper jaw. (b) Clinical picture 5 months after the extraction of the right upper molars, showing a large persisting oro-antral communication in the first quadrant (osteonecrosis lesion, stage 3).
these patients occurred within the 9 years after anti-TNF-a drug exposure. The severity of the lesion, conventional risk factors for MRONJ (including poor oral health, diabetes, smoking behaviour, and corticosteroid or bisphosphonate use), treatment, and recurrence are reported. There was no bisphosphonate use in the medical history of these three patients. The patient in case 1 had had Crohn’s disease for 9 years. She had been treated with infliximab for 7 years, followed by adalimumab for 8 months. She finally participated in two short trials (with ustekinumab and vedolizumab) because of unsatisfactory disease control and adverse events. The development of a severe stage 3 MRONJ lesion occurred 1 year after the cessation of therapy with TNF-a inhibi-
tors (Fig. 3). The patient required debridement and sequestrectomy, and mucosal healing was obtained after 7 months. However, the patient developed recurrence after 4 years. The patient in case 2 had had ulcerative colitis for 7 years and was being treated with infliximab. She had previously been treated with corticosteroids and mesalazine for microscopic colitis. At the time of MRONJ occurrence, she was still on treatment with infliximab and mesalazine (Fig. 4). The patient required sequestrectomy for the stage 1 MRONJ lesion, and mucosal healing was obtained after 4 months. The patient in case 3 had had Crohn’s disease for 22 years. He had been treated consecutively with infliximab for 4 years, adalimumab for 3 years, and abatacept for
9 months, and had participated in two trials: with ustekinumab (10 months) and vedolizumab (5 years). Meanwhile, corticosteroids had frequently been used because of multiple episodes of disease exacerbation. There was an interval of 9 years between the last administration of adalimumab and the occurrence of a stage 2 osteonecrosis lesion (Fig. 5). The patient required abscess incision and sequestrectomy, and mucosal healing was only obtained after 15 months. Discussion
MRONJ has been associated with the use of bisphosphonates and RANKL inhibitors, but the occurrence and severity of MRONJ in patients treated with TNF-a
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
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Fig. 4. Case 2. (a) Panoramic radiograph after the extraction of the right molar in the lower jaw showing the extraction socket and multiple other teeth with carious lesions. (b) Clinical picture showing an osteonecrosis lesion (stage 1) at the alveolar ridge.
inhibitors has not been investigated. This study is novel in reporting the occurrence and severity of MRONJ in a large cohort of 2701 IBD patients treated with TNF-a inhibitors. The main finding of this study is the development of MRONJ in three patients. Two out of the three patients had severe and extensive lesions, and all three patients underwent surgical treatment for their MRONJ. The time to a complete response ranged from 4 to 15 months and one patient relapsed 4 years later. These findings correspond to the few cases already published in the literature, reporting high-grade osteonecrosis lesions of the jaw after tooth extractions, necessitating a surgical approach to induce healing6–8. Pathophysiologically, there is supporting evidence for a potential association of MRONJ with TNF-a inhibitors. As well as its protective function in immunity, TNFa is also a mediator of bone destruction. It is an osteoclast-stimulating molecule and sti-
mulates osteoclastogenesis both directly, by acting on osteoclast precursors, and indirectly, by promoting the production and secretion of RANKL10,12. As TNF-a influences bone metabolism in the same way as RANKL, TNF-a inhibition may also cause an inhibition of bone turnover resulting in the development of MRONJ. Moreover, anti-TNF-a treatment makes people prone to infectious complications by inducing immune dysfunction. MRONJ may be seen in this context5–8. We recognize a number of limitations to this study. First, as a single-centre study, some cases of MRONJ may have been missed if the patients had not been treated for the MRONJ at the study centre. However, in the case of oral symptoms in IBD patients, they would have been referred at least once to the oral surgeon at the institution to establish a diagnosis. Moreover, all medical files of patients with IBD were cross-searched for a number of key words related to osteonecrosis in order not to miss
any diagnosis. Second, the registry did not include detailed data on the duration of the treatment with TNF-a inhibitors. Therefore, the occurrence of MRONJ could not be related to the TNF-a inhibitor exposure time. Third, the patients identified were also treated with concomitant therapies such as corticosteroids or other biological agents (Table 2). It was not possible to adjust for these confounding factors using this study design. Fourth, it remains unknown to what extent TNF-a inhibitors can cause MRONJ after discontinuation of the biological agent. For denosumab, unlike bisphosphonates, the effect on bone metabolism dissipates after 6 months because it is not retained in the bone5. Like denosumab, TNF-a inhibitors are monoclonal antibodies and their effect on bone metabolism is probably also explained by temporal interactions with their receptor. As a consequence, it would seem that an association between TNF-a inhibitors and MRONJ can only be assumed when the patient is on
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
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Fig. 5. Case 3. (a) Preoperative panoramic radiograph showing advanced tooth decay. (b) Clinical picture taken 5 months after extraction of the teeth in the lower jaw showing an osteonecrosis lesion (stage 2) in the third quadrant.
current treatment with a TNF-a inhibitor, or has been on treatment in the past few months. Of the three patient cases presented, only two patients were currently being treated with TNF-a inhibitors or had been on treatment recently. Together with the retrospective nature of this study, these results are merely descriptive, without defining causality between TNF-a inhibitors and MRONJ. In summary, this study is novel in reporting the occurrence of severe MRONJ in a large registry of IBD patients treated with TNF-a inhibitors. Future studies should continue to register the occurrence of MRONJ in patients treated with biologicals in order to further establish the incidence and investigate causality.
Funding
No funding.
Competing interests
No competing interests. Ethical approval
Ethical approval was obtained from the Ethics Committee of the University of Leuven (reference number MP005848). Patient consent
Not required. References 1. Bast F, Groß A, Hecht L, Schrom T. Etiology and treatment of osteonecrosis of the mandible. Wspolczensa Onkol 2013;17:281–5. http://dx.doi.org/10.5114/wo.2013.35275. 2. Grisar K, Schol M, Schoenaers J, Dormaar T, Coropciuc R, Vander Poorten V, Politis C. Osteoradionecrosis and medication-related
osteonecrosis of the jaw: similarities and differences. Int J Oral Maxillofac Surg 2016;45:1592–9. http://dx.doi.org/10.1016/ j.ijom.2016.06.016. 3. Coropciuc RG, Grisar K, Aerden T, Schol M, Schoenaers J, Politis C. Medication-related osteonecrosis of the jaw in oncological patients with skeletal metastases: conservative treatment is effective up to stage 2. Br J Oral Maxillofac Surg 2017;55:787–92. 4. Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O. Interventions for managing medication-related osteonecrosis of the jaw (Review). Cochrane Database Syst Rev ) 2017;(10)CD012432. http://dx.doi.org/ 10.1002/14651858.CD012432.pub2. 5. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F. American Association of Oral and Maxillofacial Surgeons Position Paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg http://dx.doi.org/ 2014;72:1938–56. 10.1016/j.joms.2014.04.031.
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
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6. Preidl RHM, Ebker T, Raithel M, Wehrhan F, Neukam FW, Stockmann P. Osteonecrosis of the jaw in a Crohn’s disease patient following a course of bisphosphonate and adalimumab therapy: a case report. BMC Gastroenterol 2014;14:1–6. 7. Cassoni A, Romeo U, Terenzi V, Della Monaca M, Rajabtork Zadeh OR, Raponi I, Fadda MT, Polimeni A, Valentini V. Adalimumab: another medication related to osteonecrosis of the jaws? Case Rep Dent 2016;2016:1–6. http://dx.doi.org/10.1155/2016/2856926. 8. Favia G, Tempesta A, Limongelli L, Crincoli V, Iannone F, Lapadula G, Maiorano E. A case of osteonecrosis of the jaw in a patient with Crohn’s disease treated with infliximab. Am J Case Rep 2017;18:1351–6. http://dx. doi.org/10.12659/AJCR.905355. 9. Ebker T, Rech J, von Wilmowsky C, Neukam FW, Stockmann P. Fulminant course of
osteonecrosis of the jaw in a rheumatoid arthritis patient following oral bisphosphonate intake and biologic therapy. Rheumatology (Oxford) 2013;52:218–20. http://dx. doi.org/10.1093/rheumatology/kes351. 10. Boyce BF, Li P, Yao Z, Zhang Q, Badell IR, Schwarz EM, O’Keefe RJ, Xing L. TNFalpha and pathologic bone resorption. Keio J Med 2005;54:127–31. http://dx.doi.org/ 10.2302/kjm.54.127. 11. Hehlgans T, Pfeffer K. The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 2005;115:1–20. http://dx.doi.org/10.1111/ j.1365-2567.2005.02143.x. 12. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008;117:244–79.
http://dx.doi.org/10.1016/j. pharmthera.2007.10.001. 13. Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H. Differential diagnosis in inflammatory bowel disease colitis: state of the art and future perspectives. World J Gastroenterol 2015;21:21–46. http://dx.doi. org/10.3748/wjg.v21.i1.21.
Address: Constantinus Politis Department of Oral and Maxillofacial Surgery University Hospitals Leuven Campus Sint-Rafae¨l Kapucijnenvoer 33 3000 Leuven Belgium E-mail: [email protected]
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2019.08.007, available online at https://www.sciencedirect.com
Clinical Paper Clinical Pathology
Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors
K. Brijs1,2, I. Miclotte1,2, S. Vermeire3, V. Darche4, C. Politis1,2 1 OMFS IMPATH Research Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; 2Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium; 3Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; 4Oral and Maxillofacial Surgery, CHR-Namur, Namur, Belgium
K. Brijs, I. Miclotte, S. Vermeire, V. Darche, C. Politis: Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2019 The Author(s). Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Abstract. Previous reports have suggested a possible association between tumour necrosis factor alpha (TNF-a) inhibitors, used in the treatment of immune-mediated inflammatory diseases, and medication-related osteonecrosis of the jaw (MRONJ). However, a comprehensive assessment of the frequency and severity of MRONJ caused by these agents is lacking. The aim of this cohort study was to investigate the occurrence of MRONJ in a population of patients with inflammatory bowel disease (IBD) treated with TNF-a inhibitors at a tertiary care medical centre. A total of 2701 IBD patients under current or former treatment with TNF-a inhibitors were identified in an IBD registry covering the period 1994–2018. These patients were cross-matched with all patients diagnosed with MRONJ. This resulted in three patients with a definite diagnosis of MRONJ, without concomitant treatment with bisphosphonates. All three patients required surgical treatment with sequestrectomy. Mucosal healing occurred at 4–15 months and one patient developed recurrence. In conclusion, this study identified and described anti-TNFa-related MRONJ occurring in a large cohort of IBD patients, and reported the severity and treatment strategies used.
Medication-related osteonecrosis of the jaw (MRONJ) is a disabling condition with increasing incidence, a high burden on quality of life, and poor outcomes. Only 50–60% of patients make a full 0901-5027/000001+08
recovery with mucosal healing1–4. Typically, bisphosphonates and denosumab have been associated with this disease, although anti-angiogenic agents have also been reported to cause MRONJ4,5. More
Key words: osteonecrosis of the jaw; MRONJ; inflammatory bowel disease; TNF-a inhibitors. Accepted for publication
recently, a number of reports have described the occurrence of MRONJ in patients treated with tumour necrosis factor alpha (TNF-a) inhibitors6–9. However, a comprehensive assessment of the
ã 2019 The Author(s). Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007
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frequency and severity of MRONJ in these patients has not yet been performed. Since receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-a share some biological features and RANKL inhibition by denosumab is associated with MRONJ, TNF-a inhibition may also be associated with MRONJ (Fig. 1). Denosumab is a monoclonal antibody directed against RANKL, a molecule that normally binds to the RANK receptor on (pre-)osteoclasts and thereby induces the maturation of pre-osteoclasts to osteoclasts and the activation and survival of osteoclasts10. Inhibition of this interaction subsequently blocks bone degradation. This drug is used as an antiresorptive agent in the treatment of osteoporosis and malignancies4,5. RANKL and TNF-a both belong to the TNF superfamily and play a role in immune homeostasis and bone degradation11,12. TNF-a is an important cytokine involved in the pathogenesis of chronic immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis, and rheumatoid arthritis. Neutralizing TNF-a through the use of TNF-a inhibitors reduces disease activity in these autoimmune diseases12. Since a comprehensive assessment of MRONJ in patients treated with TNF-a inhibitors has not been performed to date, the aim of this study was to investigate the occurrence and severity of MRONJ in a large IBD population treated with these drugs. Materials and methods
A retrospective cohort study was performed at the University Hospitals Leuven, Belgium. First, all patients with IBD
who had received treatment with TNF-a inhibitors were identified in an IBD registry covering the period 1994–February 2018 at the study institution and were included in the study. The medical history of all patients with IBD was obtained from this registry, including age, sex, type of IBD, and types of TNF-a inhibitor used. These patients were then cross-matched with all patients diagnosed with MRONJ in the Oral and Maxillofacial Surgery Department between January 2000 and February 2018. These patients were identified by a selection of key words in their medical records, including ‘osteonecrosis’, ‘MRONJ’, ‘ONJ’, ‘BRONJ’, ‘jaw necrosis’, ‘osteochemonecrosis’, and ‘osteomyelitis’. Furthermore, to identify additional patients with possible MRONJ, all medical files from patients with IBD were searched for the key words ‘ONJ’, ‘MRONJ’, ‘BRONJ’, ‘exposed bone’, ‘osteonecrosis’, and ‘osteochemonecrosis’. For the IBD patients diagnosed with MRONJ, the location and the stage of MRONJ, predisposing and precipitating factors, the initial symptoms (infection, pain, hypoesthesia, and bone sequestra), the treatment, and the outcome were recorded. Predisposing factors were poor oral health, smoking behaviour, alcohol use, treatment with steroids or bisphosphonates, and diabetes. Regarding patient characteristics, continuous variables were recorded as the mean standard deviation or as the number (percentage). Results
The study cohort consisted of 2701 IBD patients treated with at least one TNF-a inhibitor. The IBD diagnosis was classified into three categories: Crohn’s disease, ulcerative colitis, and IBD unclassified (IBDU). IBDU is a term to describe
IBD restricted to the colon than cannot be assigned to Crohn’s disease or ulcerative colitis13. The baseline characteristics of all IBD patients and the distribution of patients according to their disease (Crohn’s disease, ulcerative colitis, or IBDU) are shown in Table 1. The majority of patients in this study population had Crohn’s disease (1842 patients, 68.2%). No patients with microscopic colitis were included in the IBD registry. The mean age of the study population was 44.4 years and 1215 patients were male. Three monoclonal antibodies were used as TNF-a inhibitors: infliximab and adalimumab (both for ulcerative colitis and Crohn’s disease), and golimumab (only for ulcerative colitis). Infliximab is administered intravenously, and adalimumab and golimumab are administered subcutaneously. The majority of the patients in the study cohort (85.1%) were treated with infliximab, alone or in sequential combination with other TNF-a inhibitors. On cross-matching the IBD patients with 1519 possible cases of MRONJ, six patients with IBD and possible MRONJ were identified. Revision of the individual patient records showed that three patients did not have a definite diagnosis of MRONJ, resulting in three confirmed cases of MRONJ in patients treated with TNF-a inhibitors (Fig. 2). All three cases were registered between 2013 and 2016. The additional search in the medical files of patients with IBD for the key words ‘ONJ’, ‘MRONJ’, ‘BRONJ’, ‘exposed bone’, ‘osteonecrosis’, and ‘osteochemonecrosis’ did not result in the identification of additional patients with possible MRONJ. The baseline characteristics of the three patients are shown in Table 2. MRONJ in
Fig. 1. Receptor interaction and signalling. As members of the TNF superfamily, RANKL and RANK functionally resemble TNF-a and TNF-R. As denosumab causes MRONJ by interrupting the interaction between RANKL and RANK, TNF-a inhibitors may also induce MRONJ. (MRONJ, medication-related osteonecrosis of the jaw; RANK(L), receptor activator of nuclear factor kappa-B (ligand); TNF-a(R), tumour necrosis factor alpha (receptor).
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Table 1. Patient characteristics of the whole sample and by IBD subtype. Whole sample N = 2701 Age (years), mean SD Sex, n (%) Male Female IBD diagnosis, n (%) Crohn’s disease Ulcerative colitis IBD unclassified TNF-a inhibitor used, n (%) Infliximab Adalimumab Golimumab Infliximab + adalimumab Infliximab + golimumab Adalimumab + golimumab Infliximab + adalimumab + golimumab
IBD Crohn’s disease
Ulcerative colitis
IBD unclassified
764 327 0 751 0 0 0
467 56 14 208 31 3 21
41 3 0 15 0 0 0
44.4 15.7 1215 (45.0%) 1486 (55.0%) 1842 (68.2%) 800 (29.6%) 59 (2.2%) 1272 (47.1%) 386 (14.3%) 14 (0.5%) 974 (36.1%) 31 (1.1%) 3 (0.1%) 21 (0.8%)
IBD, inflammatory bowel disease; SD, standard deviation; TNF-a, tumour necrosis factor alpha.
Fig. 2. Flowchart of the search procedure, identifying cases of medication-related osteonecrosis of the jaw (MRONJ) in patients with inflammatory bowel disease (IBD) and treated with tumour necrosis factor alpha (TNF-a) inhibitors.
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Risk factors Poor oral health Smoking Alcohol use Bisphosphonate use Corticosteroid use Diabetes Complaint at presentation Type of complaint Period between precipitating factor and complaint Stage of MRONJ at presentationa Treatment Conservative Surgery HBO therapy Cessation of anti-TNF-a therapy/ other immune modulating drugs Follow-up, time to healing Recurrence
Case 1
Case 2
Case 3
Female CD, for 9 years Infliximab, adalimumab 23 Extraction of molars in upper jaw
Female UC, for 7 years Infliximab 57 Extraction of one molar in lower jaw
Male CD, for 22 years Infliximab, adalimumab 46 Extraction of multiple teeth in lower jaw; local trauma caused by prosthesis
Yes No No Not mentioned No, never No
Yes Yes No Not mentioned In the past No
Yes Yes Not mentioned Not mentioned Yes No
OAC Development of OAC at time of extraction
Pain Persistent pain since extraction 10 days before 1
Pain and hypoesthesia of the inferior alveolar nerve Development of symptoms 5 months after extraction
Antibiotics, mouth rinse Sequestrectomy No No cessation; continuation of infliximab and mesalazine
Antibiotics, mouth rinse Sequestrectomy, incision of abscess No Currently not on anti-TNF-a therapy; continuation of vedolizumab; interruption of steroids
Mucosal healing after 4 months No
Mucosal healing after 15 months No
3; OAC Antibiotics, mouth rinse Debridement of osteomyelitis, sequestrectomy Yes Currently not on anti-TNF-a therapy; interruption of other immunosuppressive drugs for 16 months Mucosal healing after 7 months Yes, 4 years later Treatment with palatal rotation flap after failure of mucoperiosteal flap
2; with development of abscess
CD, Crohn’s disease; HBO, hyperbaric oxygen; IBD, inflammatory bowel disease; MRONJ, medication-related osteonecrosis of the jaw; OAC, oro-antral communication; TNF-a, tumour necrosis factor alpha; UC, ulcerative colitis. a Stage 1: Exposed and necrotic bone or a fistula that probes to bone; asymptomatic patients with no evidence of infection. Stage 2: Exposed and necrotic bone or a fistula that probes to bone; symptomatic patients with evidence of infection. Stage 3: Exposed and necrotic bone or a fistula that probes to bone with complications6.
Brijs et al.
Sex Type of IBD TNF-a inhibitor ever received Age (years) Precipitating factor
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Table 2. Characteristics of the three confirmed cases of MRONJ in patients treated with TNF-a inhibitors.
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Fig. 3. Case 1. (a) Preoperative panoramic radiograph showing apical translucencies in multiple elements, including the molars of the right upper jaw. (b) Clinical picture 5 months after the extraction of the right upper molars, showing a large persisting oro-antral communication in the first quadrant (osteonecrosis lesion, stage 3).
these patients occurred within the 9 years after anti-TNF-a drug exposure. The severity of the lesion, conventional risk factors for MRONJ (including poor oral health, diabetes, smoking behaviour, and corticosteroid or bisphosphonate use), treatment, and recurrence are reported. There was no bisphosphonate use in the medical history of these three patients. The patient in case 1 had had Crohn’s disease for 9 years. She had been treated with infliximab for 7 years, followed by adalimumab for 8 months. She finally participated in two short trials (with ustekinumab and vedolizumab) because of unsatisfactory disease control and adverse events. The development of a severe stage 3 MRONJ lesion occurred 1 year after the cessation of therapy with TNF-a inhibi-
tors (Fig. 3). The patient required debridement and sequestrectomy, and mucosal healing was obtained after 7 months. However, the patient developed recurrence after 4 years. The patient in case 2 had had ulcerative colitis for 7 years and was being treated with infliximab. She had previously been treated with corticosteroids and mesalazine for microscopic colitis. At the time of MRONJ occurrence, she was still on treatment with infliximab and mesalazine (Fig. 4). The patient required sequestrectomy for the stage 1 MRONJ lesion, and mucosal healing was obtained after 4 months. The patient in case 3 had had Crohn’s disease for 22 years. He had been treated consecutively with infliximab for 4 years, adalimumab for 3 years, and abatacept for
9 months, and had participated in two trials: with ustekinumab (10 months) and vedolizumab (5 years). Meanwhile, corticosteroids had frequently been used because of multiple episodes of disease exacerbation. There was an interval of 9 years between the last administration of adalimumab and the occurrence of a stage 2 osteonecrosis lesion (Fig. 5). The patient required abscess incision and sequestrectomy, and mucosal healing was only obtained after 15 months. Discussion
MRONJ has been associated with the use of bisphosphonates and RANKL inhibitors, but the occurrence and severity of MRONJ in patients treated with TNF-a
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Fig. 4. Case 2. (a) Panoramic radiograph after the extraction of the right molar in the lower jaw showing the extraction socket and multiple other teeth with carious lesions. (b) Clinical picture showing an osteonecrosis lesion (stage 1) at the alveolar ridge.
inhibitors has not been investigated. This study is novel in reporting the occurrence and severity of MRONJ in a large cohort of 2701 IBD patients treated with TNF-a inhibitors. The main finding of this study is the development of MRONJ in three patients. Two out of the three patients had severe and extensive lesions, and all three patients underwent surgical treatment for their MRONJ. The time to a complete response ranged from 4 to 15 months and one patient relapsed 4 years later. These findings correspond to the few cases already published in the literature, reporting high-grade osteonecrosis lesions of the jaw after tooth extractions, necessitating a surgical approach to induce healing6–8. Pathophysiologically, there is supporting evidence for a potential association of MRONJ with TNF-a inhibitors. As well as its protective function in immunity, TNFa is also a mediator of bone destruction. It is an osteoclast-stimulating molecule and sti-
mulates osteoclastogenesis both directly, by acting on osteoclast precursors, and indirectly, by promoting the production and secretion of RANKL10,12. As TNF-a influences bone metabolism in the same way as RANKL, TNF-a inhibition may also cause an inhibition of bone turnover resulting in the development of MRONJ. Moreover, anti-TNF-a treatment makes people prone to infectious complications by inducing immune dysfunction. MRONJ may be seen in this context5–8. We recognize a number of limitations to this study. First, as a single-centre study, some cases of MRONJ may have been missed if the patients had not been treated for the MRONJ at the study centre. However, in the case of oral symptoms in IBD patients, they would have been referred at least once to the oral surgeon at the institution to establish a diagnosis. Moreover, all medical files of patients with IBD were cross-searched for a number of key words related to osteonecrosis in order not to miss
any diagnosis. Second, the registry did not include detailed data on the duration of the treatment with TNF-a inhibitors. Therefore, the occurrence of MRONJ could not be related to the TNF-a inhibitor exposure time. Third, the patients identified were also treated with concomitant therapies such as corticosteroids or other biological agents (Table 2). It was not possible to adjust for these confounding factors using this study design. Fourth, it remains unknown to what extent TNF-a inhibitors can cause MRONJ after discontinuation of the biological agent. For denosumab, unlike bisphosphonates, the effect on bone metabolism dissipates after 6 months because it is not retained in the bone5. Like denosumab, TNF-a inhibitors are monoclonal antibodies and their effect on bone metabolism is probably also explained by temporal interactions with their receptor. As a consequence, it would seem that an association between TNF-a inhibitors and MRONJ can only be assumed when the patient is on
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Fig. 5. Case 3. (a) Preoperative panoramic radiograph showing advanced tooth decay. (b) Clinical picture taken 5 months after extraction of the teeth in the lower jaw showing an osteonecrosis lesion (stage 2) in the third quadrant.
current treatment with a TNF-a inhibitor, or has been on treatment in the past few months. Of the three patient cases presented, only two patients were currently being treated with TNF-a inhibitors or had been on treatment recently. Together with the retrospective nature of this study, these results are merely descriptive, without defining causality between TNF-a inhibitors and MRONJ. In summary, this study is novel in reporting the occurrence of severe MRONJ in a large registry of IBD patients treated with TNF-a inhibitors. Future studies should continue to register the occurrence of MRONJ in patients treated with biologicals in order to further establish the incidence and investigate causality.
Funding
No funding.
Competing interests
No competing interests. Ethical approval
Ethical approval was obtained from the Ethics Committee of the University of Leuven (reference number MP005848). Patient consent
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Address: Constantinus Politis Department of Oral and Maxillofacial Surgery University Hospitals Leuven Campus Sint-Rafae¨l Kapucijnenvoer 33 3000 Leuven Belgium E-mail: [email protected]
Please cite this article in press as: Brijs K, et al. Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.08.007