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Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-α) inhibitors: a systematic review
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ScienceDirect British Journal of Oral and Maxillofacial Surgery xxx (2019) xxx–xxx
Review
Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review R. Sacco a,b,c,∗ , S. Shah c , R. Leeson d , V. Moraschini e,f , C.F. de Almeida Barros Mourão g , O. Akintola c , A. Lalli h a
Oral Surgery Department, Barts and the London School of Medicine and Dentistry, London E1 2AT, UK Eastman Dental Institute – University College of London, London, WC1X 8LT, UK c King’s College Hospital, London, SE5 9RW, UK d Eastman Dental Institute, London WC1X 8LT, UK e Fulminense Federal University, Rio De Janeiro, Brazil f Salgado de Oliveira University, R. Lambari, 10 – Trindade, São Gon¸ calo, RJ, Rio De Janeiro, 24456-570, Brazil g Estácio de Sá University, R. Raul Pompéia, 231 - Copacabana, Rio de Janeiro - RJ, 22080-000, Rio de Janeiro, Brazil h Centre for Oral Immunobiology and Regenerative Medicine Barts and The London School of Medicine and Dentistry, London, E1 4NS, UK b
Abstract Tumour necrosis factor-␣ (TNF-␣) inhibitors are increasingly being used as immunomodulators to manage inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. Reported serious side effects include an increased incidence of lymphoma and greater susceptibility to infections such as tuberculosis. The aim of this systematic review was to find out whether there is an associated risk of medication-related osteonecrosis of the jaw (MRONJ). Three authors independently searched PubMed, MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials for published reports of oral osteonecrosis (ONJ) or osteomyelitis (OM) in patients who took anti TNF-␣ drugs and had no history of antiangiogenic agents or antiresorptive treatment. All types of studies on humans treated with TNF-␣ inhibitors were considered. Only six were eligible for analysis, and all were independently assessed for risk of bias. They included six patients with ONJ or OM that was attributed solely to TNF-␣ inhibitors. The most common site of ONJ was the posterior mandible (n = 5). The mean (SD) duration of anti-TNF-␣ treatment before the development of bony lesions was 62.5 (47.4) months. Invasive surgery was reported as a precipitating factor in five cases, and the ONJ/OM resolved with conservative management in five. Although all the studies were judged to be at high risk of bias, the limited data suggest that some patients will potentially develop ONJ/OM as a result of treatment with TNF-␣ inhibitors. Studies of higher quality are now needed to establish the relative risk of MRONJ in patients who take them. Crown Copyright © 2019 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved. Keywords: Osteonecrosis; osteonecrosis of the jaw; osteomyelitis; tumournecrosis factor- ␣ (TNF- ␣) inhibitors; ankylosing spondylitis; Crohn’s disease
∗ Corresponding author at: King’s College Hospital, London, UK, SE5 9RW; Barts and The London School of Medicine and Dentistry, London E1 2AT, UK; Eastman Dental Institute, London, UK, WC1X 8LT. E-mail addresses: [email protected] (R. Sacco), [email protected] (S. Shah), [email protected] (R. Leeson), [email protected] (V. Moraschini), [email protected] (C.F. de Almeida Barros Mourão), [email protected] (O. Akintola), [email protected] (A. Lalli).
https://doi.org/10.1016/j.bjoms.2019.09.023 0266-4356/Crown Copyright © 2019 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved.
Please cite this article in press as: R. Sacco, S. Shah, R. Leeson et al.. Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review. Br J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.bjoms.2019.09.023
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Introduction Inhibitors of tumour necrosis factor-alpha (TNF- ␣) are important treatments for a number of inflammatory conditions, including rheumatoid arthritis (RA), spondyloarthritis, psoriasis, and inflammatory bowel disease (IBD), and they offer a targeted strategy that contrasts with the non-specific immunosuppressive agents traditionally used.1 TNF-␣ is a proinflammatory cytokine that was first cloned in the mid-eighties. It is released predominantly by macrophages that appear early during the response to trauma or bacterial infection,2,3 and is synthesised primarily by activated macrophages and T cells as a transmembrane precursor protein. The cytoplasmic tail of this precursor is then cleaved to release soluble TNF-␣. Initially it was reported to have two important properties: the induction of haemorrhagic necrosis of tumours in vivo, and the ability to kill tumour cells in vitro.4 Its biological activity requires the aggregation of three TNF-␣ monomers to form a trimer, which then acts by
binding either TNFR1 or TNFR2 receptors, also known as p55 and p75, respectively.5–7 Both receptors have multiple effects on the immune system. These include stimulation of the release of the inflammatory cytokines interleukin IL-1β, IL-6, IL-8, and GM-CSF; upregulation of the expression of endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin) and chemokines (MCP-1, MIP-2, RANTES and MIP-1α); and the coordination of the migration of leukocytes to targeted organs.8 TNF-␣ is important for the activation of macrophages and phagosomes, the differentiation of monocytes into macrophages, the recruitment of neutrophils and macrophages, and the formation of granulomas.9 Currently, five approved biological treatments are known to interfere with its activity: adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab (Table 1). Infliximab, adalimumab, and golimumab are monoclonal antibodies. Etanercept is a soluble, bivalent TNF-␣ receptor,
Table 1 Anti-TNF-␣ drugs used to treat inflammatory diseases. Drug
Formulation
Route of administration
Indication
Frequency
Etanercept
50 mg bottle 25 mg bottle
Subcutaneous
50 mg once a week or 25 mg twice a week
Infliximab
100 mg bottle
Intravenous
Adalimumab
40 mg bottle
Subcutaneous
Certolizumab pegol
200 mg bottle
Subcutaneous
Rheumatoid arthritis Juvenile idiopathic arthritis Psoriatic arthritis Ankylosing spondylitis Plaque psoriasis Pediatric plaque psoriasis Rheumatoid arthritis Crohn’s disease in adults Crohn’s disease in children Ulcerative colitis Ulcerative colitis in children Ankylosing spondylitis Psoriatic arthritis Psoriasis Rheumatoid arthritis Polyarticular juvenile idiopathic arthritis Axial spondyloarthritis Ankylosing spondylitis Psoriatic arthritis Psoriasis Crohn’s disease Crohn’s disease in children Ulcerative colitis Rheumatoid arthritis
Golimumab
50 mg solution for injection in prefilled syringe 50 mg solution for injection in prefilled pen
Intravenous Subcutaneous
Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis
Initially: intravenous infusion at a dose of 3-5 mg/kg (according to body weight) at weeks 0, 2, and 6 Maintenance: IV infusions every 8 weeks. Dose may be increased to 5-10 mg/kg and frequency increased to every 4 weeks 40 mg every other week as a self-administered subcutaneous injection
200 mg every 2 weeks or 400 mg every 4 weeks Initially: given at the clinic or at an infusion centre as an IV at a dose of 2 mg/kg (according to body weight) at weeks 0 and 4 Maintenance: IV infusions every 8 weeks or 50 mg once/month as a self-administered subcutaneous injection
IV: intravenous.
Please cite this article in press as: R. Sacco, S. Shah, R. Leeson et al.. Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review. Br J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.bjoms.2019.09.023
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while certolizumab pegol is the antigen-binding fragment (Fab) of a humanised monoclonal antibody coupled to polyethylene glycol. Highly similar forms of some of these molecules termed “biosimilars” are now being developed, and have been licensed for use in some countries.10 With regards to therapeutic use, infliximab and adalimumab have both been approved for a broader clinical spectrum of activity than etanercept. For example, the former are effective in many cases of IBD, uveitis, and sarcoidosis, as well as RA, psoriatic arthritis, and the seronegative spondyloarthropathies. In contrast, etanercept does not seem to be effective in cases of IBD or sarcoidosis. Certolizumab pegol, which was first approved for use in Crohn’s disease, is now available in many countries for use in rheumatoid and psoriatic arthritis, and ankylosing spondylitis or spondyloarthritis.11–14 A number of adverse events (most commonly related to infections) have been reported in patients treated with anti TNF-␣ drugs (Table 2).15 More recently, non-biological immunosuppressants used in the treatment of RA have also been implicated in the development of medication-related osteonecrosis of the jaws (MRONJ).16,17 Currently, only MRONJ that is related to antiresorptive and antiangiogenic treatment has been well described.18 After tooth extraction in patients with cancer, its incidence in those treated with bisphosphonates intravenously has been estimated to range from 1.6% - 14.8%, compared with 1.3% - 15.6% in those treated with denosumab.19–22 When patients on specific drug regi-
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mens, which do not include agents known to cause MRONJ, present with clinically exposed bone intraorally and radiographic changes associated with osteonecrosis, it is essential to find out if they are at risk. The aim of this systematic review therefore was to analyse all published evidence related to osteonecrosis of the jaw (ONJ) and osteomyelitis (OM) in patients treated with TNF-␣ inhibitors and no history of antiangiogenic or antiresorptive treatment. To our knowledge, this is the first systematic review to investigate the possibility that anti TNF-␣ drugs may also cause MRONJ.
Material and methods This systematic review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1).23 The following databases were used: PubMed, MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials (CENTRAL). A three-stage screening approach was used to ensure the precision and quality of the search, and three authors (RS, SS, and OA) independently checked the titles and abstracts. Disagreements were resolved by discussion. A data screening and abstraction form was used to verify the eligibility of the studies, assess the methods, and extract data on the characteristics and outcomes of those selected.
Table 2 Summary of adverse effects issued by the US Food and Drug Administration (FDA) (Lis et al 2014).15 Drug
Common adverse effects
EtanerceptAdalimumabInfliximabCertolizumabGolimumab
Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Drugs should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: • Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have commonly presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before and during anti TNF-␣ treatment. Treatment for latent infection should be started before anti TNF-␣. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localised, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empirical antifungal treatment should be considered in patients who develop severe systemic illness and are at risk of invasive fungal infections. • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with anti TNF-␣ should be carefully considered before treatment is started in patients with chronic or recurrent infections. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment, including the possible development of tuberculosis in those who tested negative for latent tuberculosis infection before treatment began. Lymphoma and other malignancies, some fatal, have been reported in children and adolescents treated with TNF blockers.
Please cite this article in press as: R. Sacco, S. Shah, R. Leeson et al.. Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review. Br J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.bjoms.2019.09.023
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PubMed 225
Eligible
EMBASE 8
Medline 47
CINAHL 9
CENTRAL 8
Screened papers aer removing duplicates 233
Screening
Idenficaon
R. Sacco, S. Shah, R. Leeson et al. / British Journal of Oral and Maxillofacial Surgery xxx (2019) xxx–xxx
Excluded by titles/abstract 223
Manual Search 0
Screened Full text 10
Included
Excluded arcles 4
Final selecon 6
Fig. 1. Flow diagram of selection process.
Authors of studies that were eligible but lacked sufficient information were contacted directly.
cess rates. We also aimed to identify the type and rate of complications and side effects of the ONJ/OM intervention.
Criteria for inclusion
Data
The studies selected were published or unpublished randomised controlled trials, case-controlled trials, case series, retrospective studies, and case reports. Papers were obtained from January 1985 to March 2019. Animal studies, reviews, and studies that included patients who had previously had radiation therapy to the head and neck, and those who were taking, or had a history of, antiangiogenic and antiresorptive drugs, were excluded. There were no language restrictions. All the studies involved patients who had developed ONJ or OM after taking TNF-␣ inhibitors. There was no restriction to age, sex, or ethnic origin, or to the minimum number of patients included. The objective of the study was to assess the risk of developing ONJ or OM in patients exposed to anti TNF-␣ drugs.
Data included the number of patients, sex, age, risk factors (for example, concurrent steroid therapy, diabetes, and latent infections), causes that triggered ONJ/OM, site of ONJ/OM; type, regimen, and cumulative dose of TNF-␣ inhibitor; clinical indication, type of ONJ/OM intervention, associated complications, and follow up time. All selected papers were carefully read to identify the author(s), year of publication, study design, population, and treatment characteristics. In the case of missing information, we contacted the authors and waited six weeks for a reply. If there was no response, data were recorded as “not reported” (NR).
Outcome measures The primary outcome measure was to assess the type of causeevent association for the development of ONJ and OM in patients treated with TNF-␣ inhibitors. The secondary outcomes were to identify the time-toevent for the development of ONJ or OM after the initiation of anti TNF-␣ treatment and the most common TNF-␣ inhibitor associated with their development; the most likely intraoral site for lesions to occur, the most effective treatment for patients with intraoral bony lesions, and the relative suc-
Quality assessment Two authors (RS, AL) appraised the risk of bias in randomised controlled trials with the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions. For case-control studies they used the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I).24,25 The authors also used the CARE checklist for case reports and the Modified Delphi checklist for the case series.26,27 Instances of disagreement about risk of bias assessments were referred to one of the other members of the review team (RL) and resolved by discussion. Levels of evidence were assessed according to the levels of evidence for prognostic studies adapted from the American Society of Plastic Surgeons.28
Please cite this article in press as: R. Sacco, S. Shah, R. Leeson et al.. Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review. Br J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.bjoms.2019.09.023
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Type of study
No. of patients
Ciantar 200729 Cassoni 201630 Tsuchiya 201631 Aghaloo 201732 Favia 2017 33 Cillo 201934
Case report Case report Case report Case study Case report Case report
1 1 1 1* 1 1
∗
5
Risk of bias and assessment of quality All five case reports lacked clarity in many of the 13 domains of the CARE checklist with information missing on patients’ details, timeline, and follow up. We therefore concluded that the level of bias was high. In the only case series, a consistent lack of clarity in some of the seven domains of the Modified Delphi checklist (predominantly outcome measures) led us to consider that the level of bias was also high.
6 patients but only 1 fitted the criteria for this review.
Discussion Results Six studies were included. Four of them reported patients with ONJ and two included patients with OM. All the published data described patients treated between 2006 and 2019. There were five case reports and one case series (Table 3).29–34 Results were expressed as descriptive statistics because of the heterogeneity of the data. A total of six patients (mean (range) age of 62.5 (25 - 63) years) were included (five female and one male). The reported indications for treatment with TNF-␣ inhibitors were juvenile idiopathic arthritis (n = 1), ulcerative colitis (n = 1), rheumatoid arthritis (n = 1), Crohn’s disease (n = 2), and idiopathic arthritis (n = 1). ONJ/OM affected the mandible in five patients and the maxilla in one. Four patients had ONJ. The most common cause was an invasive procedure (n=5) such as exodontia or placement of implants. The drug most commonly reported to be responsible was infliximab (n = 3) followed by adalimumab (n = 2). The mean (range) time of onset of ONJ/OM was 63 (24-130) months after the drugs were started (Tables 4 and 5). Patients were followed for a mean (range) of 17 (5 – 48) months. Management was conservative in three cases, and at the end of follow up the lesions had completely resolved in five. In the other, resolution was not clear (Table 6). Excluded studies We originally considered 10 studies, but after inspection of the full papers, four were excluded (Table 7).35–38
ONJ is a well-known adverse effect of antiresorptive and antiangiogenic medications, particularly when they are used in the treatment of primary or metastatic bone cancers.18,20 TNF-␣ inhibitors are new medications that bind specifically to TNF receptors to reduce the severe inflammatory response produced by autoimmune diseases. Early clinical trials on infliximab, adalimumab, and etanercept have not shown any substantial risks of OM or ONJ,39,40 and a large retrospective study concluded that anti TNF-␣ drugs were not important risk factors for infection or osteonecrosis.41 Another, however, showed a strong association with infective complications after orthopaedic surgery.42 As there is a lack of clinical randomised trials or prospective large cohort studies, it is not clear whether patients who are prescribed anti TNF-␣ medications are more susceptible to ONJ or OM than those treated with other medications such as traditional disease-modifying antirheumatic drugs (DMARDS).43 The purpose of this systematic review was to analyse the current evidence and assess the associated risk of the development of ONJ or OM, or both, in patients treated with TNF-␣ inhibitors.29–34 Our findings suggest that some who take these drugs will develop ONJ even if they do not have the conventional risk factors for MRONJ. Despite the low quality and high risk of bias in the studies, ONJ/OM resolved completely in five cases, and in some, TNF-␣ inhibitors were discontinued and then restarted after complete resolution.29,30 The limited data make it difficult to draw a definitive conclusion about the most appropriate management of patients who require TNF-␣ inhibitors (Table 8). We therefore think that multicentre studies, case-controlled studies, or ran-
Table 4 Epidemiological data. First author, date, and reference
Age (years) and sex
Triggering factor
Site of MRONJ/ osteomyelitis
Clinical presentation
MRONJ stage
Ciantar 200729 Cassoni 201630 Tsuchiya 201631 Aghaloo 201732 Favia 2017 33 Cillo 2019 34
25 F 63 F 29 M 42 F 49 F 55 F
Dental extraction Dental implants Spontaneous Dental extraction Dental extraction Dental implants
Mandible Mandible Mandible Maxilla Mandible Mandible
Pain with no bone exposed Pain, unhealed socket Ongoing pain Pain with bone exposed Pain with bone exposed Purulent drainage
NA 0 NA 2 3 NR
MRONJ: medication-related osteonecrosis of the jaw; M: male; F: female; NR: not reported; NA: not applicable.
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Table 5 Anti TNF-␣ drugs and concurrent medications used for the management of inflammatory diseases. First author, date, and reference
TNF-␣ inhibitor
Indication for drug treatment
Concurrent medications
Time of exposure to drug (months)
Ciantar 200729
Infliximab
Juvenile idiopathic arthritis
NR
Cassoni 201630 Tsuchiya 201631
Adalimumab Infliximab
Idiopathic arthritis Crohn’s disease
Aghaloo 201732
Etanercept
Rheumatoid arthritis
Favia 2017 33 Cillo 201934
Infliximab Adalimumab
Crohn’s disease Ulcerative colitis
Prednisolone Levothyroxine Morphine Dicolofenac Fluoxetine – Flunitrazepam Mirtazapine Lorazepam Pentazocine Prednisolone Trazodone Tramadol Diclofenac Duloxetine – Atenolol Atorvastatin Lisinopril Levothyroxine Sucralfate Tramadol
36 NR 24
130 60
Table 6 Reported management strategies and outcomes. First author, date, and reference
Management of MRONJ/ osteomyelitis
Follow-up time (months)
Type of special investigation used during follow up
Complications during the study
MRONJ outcome after treatment/end of follow up
Ciantar 200729
Conservative management (multiple antibiotics) Conservative management (antibiotics and pain relief). Dental extraction Antibiotics and chlorhexidine for 1 year then debridement of bony sequestrum Antibiotics and partial resection Debridement of necrotic bone and removal of implant
5
DPT
NR
Complete resolution
8
CT
NR
NR
48 18
CT, MRI CBCT
NR NR
Complete resolution Complete resolution
16
CT
–
Complete resolution
5
NR
NR
Complete resolution
Cassoni 201630
Tsuchiya 201631 Aghaloo 201732
Favia 2017 33 Cillo 201934
MRONJ: medication-related osteonecrosis of the jaw; DPT: dental panoramic tomography; CT: computed tomography; MRI: magnetic resonance imaging; CBCT: cone-beam computed tomography; NR: not reported.
domised controlled trials that show a high level of evidence are necessary if we are to understand and quantify the risk of MRONJ in these patients. We suggest that, in general, the following rules should be applied in future research protocols:
• Diagnosis and staging of the bony disease should be assessed with standard reproducible scales and all clinicians involved in the study should use them
(histopathological and microbiological assessment are required to confirm the aetiology). • If randomisation is feasible, it should be described in sufficient detail to allow an assessment of comparable groups – for example, a TNF-␣ inhibitor drug compared with a DMARD. • Common, quantifiable and clinically-relevant endpoints (time to complete wound healing, pain, investigations, acceptability of treatment, and participants’ satisfaction) should be described in sufficient detail.
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Table 7 List of excluded studies. First author, year, and reference
Type of study
No. of patients
Reason for exclusion
Lescaille 201335
112
All patients given bisphosphonates
Marí 201436
Retrospective cohort study Case report
1
Beattie 201537
Case report
1
Di Fede 201638
Multicentre retrospective cohort study
18
Patient initially treated by free-flap microvascular reconstruction for diffuse sclerosing osteomyelitis. Eventually a diagnosis of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis,and osteitis) was made and treated with TNF-␣ inhibitor Patient with rheumatoid arthritis and drug history of adalimumab injections together with alendronic acid, who developed a squamous cell carcinoma Patients with rheumatoid arthritis and drug history including bisphosphonates or denosumab, or both
Table 8 Summary data. Data are number unless otherwise stated.
Ethics statement/confirmation of patients’ permission
Variable
No.
Mean (range) age (years) Sex: Male Female Presenting symptom: Pain with no bone exposed Pain with bone exposed Purulent drainage Site: Mandible Maxilla Type of human monoclonal TNF-␣ antibody drugs Etanercept Infliximab Adalimumab Certolizumab pegol Golimumab Predisposing factors: Exodontia Dental implants Spontaneous Management: Conservative Surgical Other Resolution of treatment: Complete Incomplete Not clear
43.8 (25-63) 1 5 2 3 1 5 1 1 3 2 0 0
Not applicable.
Authors’ contributions All the authors of this manuscript have substantial contributions to the conception or design of the work; to the acquisition, analysis, or interpretation of data for the work; to draft of the paper and revising it critically and finally approved the version to be published.
Conflict of interests statement This study was not supported by any companies and all the authors have no conflict of interest.
3 2 1
CRediT authorship contribution statement 3 2 1 5 0 1
• The follow-up period for patients with established ONJ should be at least 18 months. In conclusion, ONJ is potentially a serious iatrogenic complication in patients treated with antiresorptive and antiangiogenic agents, and it is now clear that other newlydeveloped drugs may cause similar intraoral symptoms. To our knowledge this is the first systematic review to report the potential association between ONJ and TNF-␣ inhibitors, and to highlight the absence of high-level reported evidence. The limited data, however, suggest the need for further welldesigned clinical studies to quantify the risk.
R. Sacco: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. S. Shah: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. R. Leeson: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing original draft, Writing - review & editing. V. Moraschini: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing original draft, Writing - review & editing. C.F. de Almeida Barros Mourão: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration,
Please cite this article in press as: R. Sacco, S. Shah, R. Leeson et al.. Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review. Br J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.bjoms.2019.09.023
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Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. O. Akintola: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. A. Lalli: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing original draft, Writing - review & editing.
References 1. Rider P, Carmi Y, Cohen I. Biologics for targeting inflammatory cytokines, clinical uses, and limitations. Int J Cell Biol 2016;2016:9259646. 2. Wang AM, Creasey AA, Ladner MB, et al. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science 1985;228:149–54. 3. Shirai T, Yamaguchi H, Ito H, et al. Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. Nature 1985;313:803–6. 4. Ghezzi P, Cerami A. Tumor necrosis factor as a pharmacological target. Mol Biotechnol 2005;31:239–44. 5. Beutler B, Cerami A. The biology of cachectin/TNF — a primary mediator of the host response. Annu Rev Immunol 1989;7:625–55. 6. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001;19:163–96. 7. Zhang G. Tumor necrosis factor family ligand-receptor binding. Curr Opin Struct Biol 2004;14:154–60. 8. Roach DR, Bean AG, Demangel C, et al. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002;168:4620–7. 9. Koo S, Marty FM, Baden LR. Infectious complications associated with immunomodulating biologic agents. Infect Dis Clin North Am 2010;24:285–306. 10. World Health Organization. Expert Committee on Biological Standardization: Geneva, 19–23 October 2009. Guidelines on evaluation of similar biotherapeutic products (SBPs). Available from URL: https:// www.who.int/biologicals/areas/biological therapeutics/BIOTHERAP EUTICS FOR WEB 22APRIL2010.pdf (last accessed 25 September 2019). 11. Brezinski EA, Armstrong AW. An evidence-based review of the mechanism of action, efficacy, and safety of biologic therapies in the treatment of psoriasis and psoriatic arthritis. Curr Med Chem 2015;22:1930–42. 12. Atreya R, Zimmer M, Bartsch B, et al. Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14+ macrophages. Gastroenterology 2011;141:2026–38. 13. Papoutsaki M, Costanzo A. Treatment of psoriasis and psoriatic arthritis. BioDrugs 2013;27:3–12. 14. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001;121:1088–94. 15. Lis K, Kuzawi´nska O, Bałkowiec-Iskra E. Tumor necrosis factor inhibitors — state of knowledge. Arch Med Sci 2014;10:1175–85. 16. Alsalleeh F, Keippel J, Adams L, et al. Bisphosphonate-associated osteonecrosis of jaw reoccurrence after methotrexate therapy: a case report. J Endod 2014;40:1505–7. 17. Horie N, Kawano R, Kaneko T, et al. Methotrexate-related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis. Aust Dent J 2015;60:408–11.
18. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw — 2014 update. J Oral Maxillofac Surg 2014;72:1938–56. 19. Yamazaki T, Yamori M, Ishizaki T, et al. Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. Int J Oral Maxillofac Surg 2012;41:1397–403. 20. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012;23:1341–7. 21. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012;48:3082–92. 22. Kajizono M, Sada H, Sugiura Y, et al. Incidence and risk factors of osteonecrosis of the jaw in advanced cancer patients after treatment with zoledronic acid or denosumab: a retrospective cohort study. Biol Pharm Bull 2015;38:1850–5. 23. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. BMJ 2009;339:b2700. 24. Higgins JP, Green S, editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration; 2011. Available from URL: https://training.cochrane.org/handbook (last accessed 25 September 2019). 25. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919. 26. Riley DS, Barber MS, Kienle GS, et al. CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol 2017;89:218–35. 27. Moga C, Guo B, Schopflocher D, et al. Development of a quality appraisal tool for case series studies using a modified Delphi technique; 2012. Available from URL: https: file:///C:/Users/User/Downloads/development of a quality appraisal tool for case series studies using a modified delphi technique.pdf. (last accessed 25 September 2019). 28. ASPS evidence rating scales. American Society of Plastic Surgeons. Available from URL: https://www.plasticsurgery.org/documents/ medical-professionals/health-policy/evidence-practice/ASPS-RatingScale-March-2011.pdf (last accessed 26 September 2019). 29. Ciantar M, Adlam DM. Treatment with infliximab: implications in oral surgery? a case report. Br J Oral Maxillofac Surg 2007;45:507–10. 30. Cassoni A, Romeo U, Terenzi V, et al. Adalimumab: another medication related to osteonecrosis of the jaws? Case Rep Dent 2016;2016: 2856926. 31. Tsuchiya S, Sugimoto K, Omori M, et al. Mandibular osteomyelitis implicated in infliximab and periapical periodontitis: a case report. J Oral Maxillofacial Surg Med Pathol 2016;28:410–5. 32. Aghaloo TL, Tetradis S. Osteonecrosis of the jaw in the absence of antiresorptive or antiangiogenic exposure: a series of 6 cases. J Oral Maxillofac Surg 2017;75:129–42. 33. Favia G, Tempesta A, Limongelli L, et al. 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. 34. Cillo Jr JE, Barbosa N. Adalimumab-related dental implant infection. J Oral Maxillofac Surg 2019;77:1165–9. 35. Lescaille G, Coudert AE, Baaroun V, et al. Osteonecrosis of the jaw and nonmalignant disease: is there an association with rheumatoid arthritis? J Rheumatol 2013;40:781–6. 36. Marí A, Morla A, Melero M, et al. Diffuse sclerosing osteomyelitis (DSO) of the mandible in SAPHO syndrome: a novel approach with anti-TNF therapy. Systematic review. J Craniomaxillofac Surg 2014;42:1990–6.
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41. den Broeder AA, Creemers MC, Fransen J, et al. Risk factors for surgical site infections and other complications in elective surgery in patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: a large retrospective study. J Rheumatol 2007;34:689–95. 42. Giles JT, Bartlett SJ, Gelber AC, et al. Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis Rheum 2006;55:333–7. 43. da Cunha BM, Maria Henrique da Mota L, Dos Santos-Neto LL. Risk of orthopedic surgical site infections in patients with rheumatoid arthritis treated with antitumor necrosis factor alfa therapy. Int J Rheumatol 2012;2012:369565.
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Review
Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review R. Sacco a,b,c,∗ , S. Shah c , R. Leeson d , V. Moraschini e,f , C.F. de Almeida Barros Mourão g , O. Akintola c , A. Lalli h a
Oral Surgery Department, Barts and the London School of Medicine and Dentistry, London E1 2AT, UK Eastman Dental Institute – University College of London, London, WC1X 8LT, UK c King’s College Hospital, London, SE5 9RW, UK d Eastman Dental Institute, London WC1X 8LT, UK e Fulminense Federal University, Rio De Janeiro, Brazil f Salgado de Oliveira University, R. Lambari, 10 – Trindade, São Gon¸ calo, RJ, Rio De Janeiro, 24456-570, Brazil g Estácio de Sá University, R. Raul Pompéia, 231 - Copacabana, Rio de Janeiro - RJ, 22080-000, Rio de Janeiro, Brazil h Centre for Oral Immunobiology and Regenerative Medicine Barts and The London School of Medicine and Dentistry, London, E1 4NS, UK b
Abstract Tumour necrosis factor-␣ (TNF-␣) inhibitors are increasingly being used as immunomodulators to manage inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. Reported serious side effects include an increased incidence of lymphoma and greater susceptibility to infections such as tuberculosis. The aim of this systematic review was to find out whether there is an associated risk of medication-related osteonecrosis of the jaw (MRONJ). Three authors independently searched PubMed, MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials for published reports of oral osteonecrosis (ONJ) or osteomyelitis (OM) in patients who took anti TNF-␣ drugs and had no history of antiangiogenic agents or antiresorptive treatment. All types of studies on humans treated with TNF-␣ inhibitors were considered. Only six were eligible for analysis, and all were independently assessed for risk of bias. They included six patients with ONJ or OM that was attributed solely to TNF-␣ inhibitors. The most common site of ONJ was the posterior mandible (n = 5). The mean (SD) duration of anti-TNF-␣ treatment before the development of bony lesions was 62.5 (47.4) months. Invasive surgery was reported as a precipitating factor in five cases, and the ONJ/OM resolved with conservative management in five. Although all the studies were judged to be at high risk of bias, the limited data suggest that some patients will potentially develop ONJ/OM as a result of treatment with TNF-␣ inhibitors. Studies of higher quality are now needed to establish the relative risk of MRONJ in patients who take them. Crown Copyright © 2019 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved. Keywords: Osteonecrosis; osteonecrosis of the jaw; osteomyelitis; tumournecrosis factor- ␣ (TNF- ␣) inhibitors; ankylosing spondylitis; Crohn’s disease
∗ Corresponding author at: King’s College Hospital, London, UK, SE5 9RW; Barts and The London School of Medicine and Dentistry, London E1 2AT, UK; Eastman Dental Institute, London, UK, WC1X 8LT. E-mail addresses: [email protected] (R. Sacco), [email protected] (S. Shah), [email protected] (R. Leeson), [email protected] (V. Moraschini), [email protected] (C.F. de Almeida Barros Mourão), [email protected] (O. Akintola), [email protected] (A. Lalli).
https://doi.org/10.1016/j.bjoms.2019.09.023 0266-4356/Crown Copyright © 2019 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved.
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Introduction Inhibitors of tumour necrosis factor-alpha (TNF- ␣) are important treatments for a number of inflammatory conditions, including rheumatoid arthritis (RA), spondyloarthritis, psoriasis, and inflammatory bowel disease (IBD), and they offer a targeted strategy that contrasts with the non-specific immunosuppressive agents traditionally used.1 TNF-␣ is a proinflammatory cytokine that was first cloned in the mid-eighties. It is released predominantly by macrophages that appear early during the response to trauma or bacterial infection,2,3 and is synthesised primarily by activated macrophages and T cells as a transmembrane precursor protein. The cytoplasmic tail of this precursor is then cleaved to release soluble TNF-␣. Initially it was reported to have two important properties: the induction of haemorrhagic necrosis of tumours in vivo, and the ability to kill tumour cells in vitro.4 Its biological activity requires the aggregation of three TNF-␣ monomers to form a trimer, which then acts by
binding either TNFR1 or TNFR2 receptors, also known as p55 and p75, respectively.5–7 Both receptors have multiple effects on the immune system. These include stimulation of the release of the inflammatory cytokines interleukin IL-1β, IL-6, IL-8, and GM-CSF; upregulation of the expression of endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin) and chemokines (MCP-1, MIP-2, RANTES and MIP-1α); and the coordination of the migration of leukocytes to targeted organs.8 TNF-␣ is important for the activation of macrophages and phagosomes, the differentiation of monocytes into macrophages, the recruitment of neutrophils and macrophages, and the formation of granulomas.9 Currently, five approved biological treatments are known to interfere with its activity: adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab (Table 1). Infliximab, adalimumab, and golimumab are monoclonal antibodies. Etanercept is a soluble, bivalent TNF-␣ receptor,
Table 1 Anti-TNF-␣ drugs used to treat inflammatory diseases. Drug
Formulation
Route of administration
Indication
Frequency
Etanercept
50 mg bottle 25 mg bottle
Subcutaneous
50 mg once a week or 25 mg twice a week
Infliximab
100 mg bottle
Intravenous
Adalimumab
40 mg bottle
Subcutaneous
Certolizumab pegol
200 mg bottle
Subcutaneous
Rheumatoid arthritis Juvenile idiopathic arthritis Psoriatic arthritis Ankylosing spondylitis Plaque psoriasis Pediatric plaque psoriasis Rheumatoid arthritis Crohn’s disease in adults Crohn’s disease in children Ulcerative colitis Ulcerative colitis in children Ankylosing spondylitis Psoriatic arthritis Psoriasis Rheumatoid arthritis Polyarticular juvenile idiopathic arthritis Axial spondyloarthritis Ankylosing spondylitis Psoriatic arthritis Psoriasis Crohn’s disease Crohn’s disease in children Ulcerative colitis Rheumatoid arthritis
Golimumab
50 mg solution for injection in prefilled syringe 50 mg solution for injection in prefilled pen
Intravenous Subcutaneous
Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis
Initially: intravenous infusion at a dose of 3-5 mg/kg (according to body weight) at weeks 0, 2, and 6 Maintenance: IV infusions every 8 weeks. Dose may be increased to 5-10 mg/kg and frequency increased to every 4 weeks 40 mg every other week as a self-administered subcutaneous injection
200 mg every 2 weeks or 400 mg every 4 weeks Initially: given at the clinic or at an infusion centre as an IV at a dose of 2 mg/kg (according to body weight) at weeks 0 and 4 Maintenance: IV infusions every 8 weeks or 50 mg once/month as a self-administered subcutaneous injection
IV: intravenous.
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while certolizumab pegol is the antigen-binding fragment (Fab) of a humanised monoclonal antibody coupled to polyethylene glycol. Highly similar forms of some of these molecules termed “biosimilars” are now being developed, and have been licensed for use in some countries.10 With regards to therapeutic use, infliximab and adalimumab have both been approved for a broader clinical spectrum of activity than etanercept. For example, the former are effective in many cases of IBD, uveitis, and sarcoidosis, as well as RA, psoriatic arthritis, and the seronegative spondyloarthropathies. In contrast, etanercept does not seem to be effective in cases of IBD or sarcoidosis. Certolizumab pegol, which was first approved for use in Crohn’s disease, is now available in many countries for use in rheumatoid and psoriatic arthritis, and ankylosing spondylitis or spondyloarthritis.11–14 A number of adverse events (most commonly related to infections) have been reported in patients treated with anti TNF-␣ drugs (Table 2).15 More recently, non-biological immunosuppressants used in the treatment of RA have also been implicated in the development of medication-related osteonecrosis of the jaws (MRONJ).16,17 Currently, only MRONJ that is related to antiresorptive and antiangiogenic treatment has been well described.18 After tooth extraction in patients with cancer, its incidence in those treated with bisphosphonates intravenously has been estimated to range from 1.6% - 14.8%, compared with 1.3% - 15.6% in those treated with denosumab.19–22 When patients on specific drug regi-
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mens, which do not include agents known to cause MRONJ, present with clinically exposed bone intraorally and radiographic changes associated with osteonecrosis, it is essential to find out if they are at risk. The aim of this systematic review therefore was to analyse all published evidence related to osteonecrosis of the jaw (ONJ) and osteomyelitis (OM) in patients treated with TNF-␣ inhibitors and no history of antiangiogenic or antiresorptive treatment. To our knowledge, this is the first systematic review to investigate the possibility that anti TNF-␣ drugs may also cause MRONJ.
Material and methods This systematic review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1).23 The following databases were used: PubMed, MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials (CENTRAL). A three-stage screening approach was used to ensure the precision and quality of the search, and three authors (RS, SS, and OA) independently checked the titles and abstracts. Disagreements were resolved by discussion. A data screening and abstraction form was used to verify the eligibility of the studies, assess the methods, and extract data on the characteristics and outcomes of those selected.
Table 2 Summary of adverse effects issued by the US Food and Drug Administration (FDA) (Lis et al 2014).15 Drug
Common adverse effects
EtanerceptAdalimumabInfliximabCertolizumabGolimumab
Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Drugs should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: • Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have commonly presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before and during anti TNF-␣ treatment. Treatment for latent infection should be started before anti TNF-␣. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localised, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empirical antifungal treatment should be considered in patients who develop severe systemic illness and are at risk of invasive fungal infections. • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with anti TNF-␣ should be carefully considered before treatment is started in patients with chronic or recurrent infections. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment, including the possible development of tuberculosis in those who tested negative for latent tuberculosis infection before treatment began. Lymphoma and other malignancies, some fatal, have been reported in children and adolescents treated with TNF blockers.
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PubMed 225
Eligible
EMBASE 8
Medline 47
CINAHL 9
CENTRAL 8
Screened papers aer removing duplicates 233
Screening
Idenficaon
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Excluded by titles/abstract 223
Manual Search 0
Screened Full text 10
Included
Excluded arcles 4
Final selecon 6
Fig. 1. Flow diagram of selection process.
Authors of studies that were eligible but lacked sufficient information were contacted directly.
cess rates. We also aimed to identify the type and rate of complications and side effects of the ONJ/OM intervention.
Criteria for inclusion
Data
The studies selected were published or unpublished randomised controlled trials, case-controlled trials, case series, retrospective studies, and case reports. Papers were obtained from January 1985 to March 2019. Animal studies, reviews, and studies that included patients who had previously had radiation therapy to the head and neck, and those who were taking, or had a history of, antiangiogenic and antiresorptive drugs, were excluded. There were no language restrictions. All the studies involved patients who had developed ONJ or OM after taking TNF-␣ inhibitors. There was no restriction to age, sex, or ethnic origin, or to the minimum number of patients included. The objective of the study was to assess the risk of developing ONJ or OM in patients exposed to anti TNF-␣ drugs.
Data included the number of patients, sex, age, risk factors (for example, concurrent steroid therapy, diabetes, and latent infections), causes that triggered ONJ/OM, site of ONJ/OM; type, regimen, and cumulative dose of TNF-␣ inhibitor; clinical indication, type of ONJ/OM intervention, associated complications, and follow up time. All selected papers were carefully read to identify the author(s), year of publication, study design, population, and treatment characteristics. In the case of missing information, we contacted the authors and waited six weeks for a reply. If there was no response, data were recorded as “not reported” (NR).
Outcome measures The primary outcome measure was to assess the type of causeevent association for the development of ONJ and OM in patients treated with TNF-␣ inhibitors. The secondary outcomes were to identify the time-toevent for the development of ONJ or OM after the initiation of anti TNF-␣ treatment and the most common TNF-␣ inhibitor associated with their development; the most likely intraoral site for lesions to occur, the most effective treatment for patients with intraoral bony lesions, and the relative suc-
Quality assessment Two authors (RS, AL) appraised the risk of bias in randomised controlled trials with the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions. For case-control studies they used the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I).24,25 The authors also used the CARE checklist for case reports and the Modified Delphi checklist for the case series.26,27 Instances of disagreement about risk of bias assessments were referred to one of the other members of the review team (RL) and resolved by discussion. Levels of evidence were assessed according to the levels of evidence for prognostic studies adapted from the American Society of Plastic Surgeons.28
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Type of study
No. of patients
Ciantar 200729 Cassoni 201630 Tsuchiya 201631 Aghaloo 201732 Favia 2017 33 Cillo 201934
Case report Case report Case report Case study Case report Case report
1 1 1 1* 1 1
∗
5
Risk of bias and assessment of quality All five case reports lacked clarity in many of the 13 domains of the CARE checklist with information missing on patients’ details, timeline, and follow up. We therefore concluded that the level of bias was high. In the only case series, a consistent lack of clarity in some of the seven domains of the Modified Delphi checklist (predominantly outcome measures) led us to consider that the level of bias was also high.
6 patients but only 1 fitted the criteria for this review.
Discussion Results Six studies were included. Four of them reported patients with ONJ and two included patients with OM. All the published data described patients treated between 2006 and 2019. There were five case reports and one case series (Table 3).29–34 Results were expressed as descriptive statistics because of the heterogeneity of the data. A total of six patients (mean (range) age of 62.5 (25 - 63) years) were included (five female and one male). The reported indications for treatment with TNF-␣ inhibitors were juvenile idiopathic arthritis (n = 1), ulcerative colitis (n = 1), rheumatoid arthritis (n = 1), Crohn’s disease (n = 2), and idiopathic arthritis (n = 1). ONJ/OM affected the mandible in five patients and the maxilla in one. Four patients had ONJ. The most common cause was an invasive procedure (n=5) such as exodontia or placement of implants. The drug most commonly reported to be responsible was infliximab (n = 3) followed by adalimumab (n = 2). The mean (range) time of onset of ONJ/OM was 63 (24-130) months after the drugs were started (Tables 4 and 5). Patients were followed for a mean (range) of 17 (5 – 48) months. Management was conservative in three cases, and at the end of follow up the lesions had completely resolved in five. In the other, resolution was not clear (Table 6). Excluded studies We originally considered 10 studies, but after inspection of the full papers, four were excluded (Table 7).35–38
ONJ is a well-known adverse effect of antiresorptive and antiangiogenic medications, particularly when they are used in the treatment of primary or metastatic bone cancers.18,20 TNF-␣ inhibitors are new medications that bind specifically to TNF receptors to reduce the severe inflammatory response produced by autoimmune diseases. Early clinical trials on infliximab, adalimumab, and etanercept have not shown any substantial risks of OM or ONJ,39,40 and a large retrospective study concluded that anti TNF-␣ drugs were not important risk factors for infection or osteonecrosis.41 Another, however, showed a strong association with infective complications after orthopaedic surgery.42 As there is a lack of clinical randomised trials or prospective large cohort studies, it is not clear whether patients who are prescribed anti TNF-␣ medications are more susceptible to ONJ or OM than those treated with other medications such as traditional disease-modifying antirheumatic drugs (DMARDS).43 The purpose of this systematic review was to analyse the current evidence and assess the associated risk of the development of ONJ or OM, or both, in patients treated with TNF-␣ inhibitors.29–34 Our findings suggest that some who take these drugs will develop ONJ even if they do not have the conventional risk factors for MRONJ. Despite the low quality and high risk of bias in the studies, ONJ/OM resolved completely in five cases, and in some, TNF-␣ inhibitors were discontinued and then restarted after complete resolution.29,30 The limited data make it difficult to draw a definitive conclusion about the most appropriate management of patients who require TNF-␣ inhibitors (Table 8). We therefore think that multicentre studies, case-controlled studies, or ran-
Table 4 Epidemiological data. First author, date, and reference
Age (years) and sex
Triggering factor
Site of MRONJ/ osteomyelitis
Clinical presentation
MRONJ stage
Ciantar 200729 Cassoni 201630 Tsuchiya 201631 Aghaloo 201732 Favia 2017 33 Cillo 2019 34
25 F 63 F 29 M 42 F 49 F 55 F
Dental extraction Dental implants Spontaneous Dental extraction Dental extraction Dental implants
Mandible Mandible Mandible Maxilla Mandible Mandible
Pain with no bone exposed Pain, unhealed socket Ongoing pain Pain with bone exposed Pain with bone exposed Purulent drainage
NA 0 NA 2 3 NR
MRONJ: medication-related osteonecrosis of the jaw; M: male; F: female; NR: not reported; NA: not applicable.
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Table 5 Anti TNF-␣ drugs and concurrent medications used for the management of inflammatory diseases. First author, date, and reference
TNF-␣ inhibitor
Indication for drug treatment
Concurrent medications
Time of exposure to drug (months)
Ciantar 200729
Infliximab
Juvenile idiopathic arthritis
NR
Cassoni 201630 Tsuchiya 201631
Adalimumab Infliximab
Idiopathic arthritis Crohn’s disease
Aghaloo 201732
Etanercept
Rheumatoid arthritis
Favia 2017 33 Cillo 201934
Infliximab Adalimumab
Crohn’s disease Ulcerative colitis
Prednisolone Levothyroxine Morphine Dicolofenac Fluoxetine – Flunitrazepam Mirtazapine Lorazepam Pentazocine Prednisolone Trazodone Tramadol Diclofenac Duloxetine – Atenolol Atorvastatin Lisinopril Levothyroxine Sucralfate Tramadol
36 NR 24
130 60
Table 6 Reported management strategies and outcomes. First author, date, and reference
Management of MRONJ/ osteomyelitis
Follow-up time (months)
Type of special investigation used during follow up
Complications during the study
MRONJ outcome after treatment/end of follow up
Ciantar 200729
Conservative management (multiple antibiotics) Conservative management (antibiotics and pain relief). Dental extraction Antibiotics and chlorhexidine for 1 year then debridement of bony sequestrum Antibiotics and partial resection Debridement of necrotic bone and removal of implant
5
DPT
NR
Complete resolution
8
CT
NR
NR
48 18
CT, MRI CBCT
NR NR
Complete resolution Complete resolution
16
CT
–
Complete resolution
5
NR
NR
Complete resolution
Cassoni 201630
Tsuchiya 201631 Aghaloo 201732
Favia 2017 33 Cillo 201934
MRONJ: medication-related osteonecrosis of the jaw; DPT: dental panoramic tomography; CT: computed tomography; MRI: magnetic resonance imaging; CBCT: cone-beam computed tomography; NR: not reported.
domised controlled trials that show a high level of evidence are necessary if we are to understand and quantify the risk of MRONJ in these patients. We suggest that, in general, the following rules should be applied in future research protocols:
• Diagnosis and staging of the bony disease should be assessed with standard reproducible scales and all clinicians involved in the study should use them
(histopathological and microbiological assessment are required to confirm the aetiology). • If randomisation is feasible, it should be described in sufficient detail to allow an assessment of comparable groups – for example, a TNF-␣ inhibitor drug compared with a DMARD. • Common, quantifiable and clinically-relevant endpoints (time to complete wound healing, pain, investigations, acceptability of treatment, and participants’ satisfaction) should be described in sufficient detail.
Please cite this article in press as: R. Sacco, S. Shah, R. Leeson et al.. Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review. Br J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.bjoms.2019.09.023
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Table 7 List of excluded studies. First author, year, and reference
Type of study
No. of patients
Reason for exclusion
Lescaille 201335
112
All patients given bisphosphonates
Marí 201436
Retrospective cohort study Case report
1
Beattie 201537
Case report
1
Di Fede 201638
Multicentre retrospective cohort study
18
Patient initially treated by free-flap microvascular reconstruction for diffuse sclerosing osteomyelitis. Eventually a diagnosis of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis,and osteitis) was made and treated with TNF-␣ inhibitor Patient with rheumatoid arthritis and drug history of adalimumab injections together with alendronic acid, who developed a squamous cell carcinoma Patients with rheumatoid arthritis and drug history including bisphosphonates or denosumab, or both
Table 8 Summary data. Data are number unless otherwise stated.
Ethics statement/confirmation of patients’ permission
Variable
No.
Mean (range) age (years) Sex: Male Female Presenting symptom: Pain with no bone exposed Pain with bone exposed Purulent drainage Site: Mandible Maxilla Type of human monoclonal TNF-␣ antibody drugs Etanercept Infliximab Adalimumab Certolizumab pegol Golimumab Predisposing factors: Exodontia Dental implants Spontaneous Management: Conservative Surgical Other Resolution of treatment: Complete Incomplete Not clear
43.8 (25-63) 1 5 2 3 1 5 1 1 3 2 0 0
Not applicable.
Authors’ contributions All the authors of this manuscript have substantial contributions to the conception or design of the work; to the acquisition, analysis, or interpretation of data for the work; to draft of the paper and revising it critically and finally approved the version to be published.
Conflict of interests statement This study was not supported by any companies and all the authors have no conflict of interest.
3 2 1
CRediT authorship contribution statement 3 2 1 5 0 1
• The follow-up period for patients with established ONJ should be at least 18 months. In conclusion, ONJ is potentially a serious iatrogenic complication in patients treated with antiresorptive and antiangiogenic agents, and it is now clear that other newlydeveloped drugs may cause similar intraoral symptoms. To our knowledge this is the first systematic review to report the potential association between ONJ and TNF-␣ inhibitors, and to highlight the absence of high-level reported evidence. The limited data, however, suggest the need for further welldesigned clinical studies to quantify the risk.
R. Sacco: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. S. Shah: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. R. Leeson: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing original draft, Writing - review & editing. V. Moraschini: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing original draft, Writing - review & editing. C.F. de Almeida Barros Mourão: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration,
Please cite this article in press as: R. Sacco, S. Shah, R. Leeson et al.. Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review. Br J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.bjoms.2019.09.023
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Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. O. Akintola: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. A. Lalli: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing original draft, Writing - review & editing.
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Please cite this article in press as: R. Sacco, S. Shah, R. Leeson et al.. Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-␣) inhibitors: a systematic review. Br J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.bjoms.2019.09.023