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Original Article
Awareness of Complications of Dental Treatment in Patients Treated
with Drugs Affecting the Immune System:
A Nationwide Questionnaire Survey of Dental Practitioners in Japan
Hitomi Nishizaki
a§, Yoshinari Morimoto
a,b＊§, Shin-ichi Yamada
b,c, Hiroshi Kurita
b,c,
Akira Tanaka
b,d, Akira Yamaguchi
b,e, Masaru Miyata
b,f, Hiromasa Yoshikawa
b,g,
Souichi Yanamoto
b,h, and Yutaka Imai
b,iaDepartment of Critical Care Medicine and Dentistry, Graduate School of Dentistry, Kanagawa Dental University,
Yokosuka-city, Kanagawa 238-8580, Japan, bThe survey and research-planning committee,
Japanese Society for Dentistry of Medically Compromised Patient, Kita-ku, Tokyo 115-0055, Japan,
cDepartment of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto-city, Nagano 390-8621, Japan,
Department of Oral and Maxillofacial Surgery, dThe Nippon Dental University School of Life Dentistry at Niigata, eThe Nippon Dental University Niigata Hospital, Niigata-city, Niigata 951-8580, Japan,
fDepartment of Dentistry and Oral Surgery, Ishikawa Prefectural Central Hospital, Kanazawa-city 920-8530, Japan, gDepartment of Oral and Maxillofacial Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan, hDepartment of Clinical Oral Oncology, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences,
Nagasaki 852-8501, Japan,
iDokkyo Medical University School of Medicine, Shimotsuga-gun, Tochigi 321-0293, Japan
The aim of this study was to investigate the awareness and experience, among dental practitioners, of adverse events resulting from dental treatment of patients undergoing therapy with drugs that affect the immune system [angiogenesis inhibitors, biological agents, immunosuppressants, and disease-modifying anti-rheumatic drugs (DMARDs)]. For this purpose, a nationwide questionnaire survey was conducted. Questionnaires were sent to 2,050 dentists, of which 206 (10.1%) were completed and returned. The results showed that most den-tists were aware of complications associated with dental treatment of patients treated with drugs that affect the immune system, and about half had actually experienced such complications. Delayed wound healing, osteo-necrosis of the jaw (ONJ), and postoperative infections were reported. Whereas approximately 50% of dentists did not discontinue the drugs during dental treatment, about 18% did. During temporary drug discontinua-tion, some patients experienced aggravation of the primary disease, such as worsening of rheumatism, growth of tumors, and rejection reactions of transplanted organs. As for medical cooperation, only less than half of the dentists were asked for oral hygiene management by a physician prior to starting the drug treatment. Prospective studies are needed because evidence for dental treatments in patients treated with these drugs remains limited.
Key words: angiogenesis inhibitor, biological agent, disease-modifying antirheumatic drug (DMARD),
immuno-suppressant, medication-related osteonecrosis of the jaw (MRONJ)
Received May 8, 2020 ; accepted October 13, 2020.
＊Corresponding author. Phone : +81-46-845-3168; Fax : +81-46-845-3139 E-mail : [email protected] (Y. Morimoto)
O
steonecrosis of the jaw related to drugs (called medication-related osteonecrosis of the jaw: MRONJ) has often been reported in patients taking antiresorptive agents, such as bisphosphonates (BPs) and anti-receptor activator of nuclear factor κB ligand (anti-RANKL) denosumab. The prevalence of ONJ in Asian patients prescribed oral BPs for osteoporosis has been found to range from 0% to 0.094%, and that of low-dose intravenous BPs was 0-0.348% [1,2]. The incidence of ONJ in patients receiving oral BPs and iv BPs was 1.04-69 per 100,000 patient-years and 0-90 per 100,000 patient-years, respectively [2]. However, Taguchi et al. reported a high incidence of Stage 0 or Stage 1 ONJ of 6.14 per 1000 patient-years in osteopo-rosis patients with good oral health receiving mino-dronic acid [3]. The incidence of ONJ in patients pre-scribed denosumab ranged from 0 to 30.4 per 100,000 patient-years [2].Numerous studies have been conducted on the onset of osteonecrosis of the jaw (ONJ) and its prevention and treatment during oral and maxillofacial surgical proce-dures (e.g., tooth extractions) in patients with osteopo-rosis or malignant tumors receiving treatment with drugs such as antiresorptive agents. Position papers have been published in the United States and Japan [4,5]. Both of these papers suggested that antiresorp-tive drugs do not have to be discontinued before tooth extraction, or they can be discontinued for 2 months before tooth extraction when needed [4,5]. In addition to these drugs, corticosteroid hormones and new drugs (e.g., disease-modifying antirheumatic drugs [DMARDs], biological agents, immunosuppressants, angiogenesis inhibitors) have been used in rheumatic medicine, transplantation therapy, and the treatment of tumors in recent years, and reports of complications associated with dental treatments related to infections, delayed wound healing, and ONJ have occasionally been reported [6-8]. The United States Food and Drug Administration (FDA) published a warning on the risk of MRONJ with the use of the angiogenesis inhibitors bevacizumab and sunitinib [4-6,8,9]. There are reports of other drugs causing complications such as ONJ; however, there is currently a lack of evidence about complications associated with dental treatments in patients undergoing therapy with drugs that affect the immune system [7].
In order to suppress the occurrence of complications related to dental treatment in patients receiving these
drugs, cooperation between medical physicians and dentists is necessary. Dental practitioners are generally thought to be well-informed regarding bone resorptive inhibitors, based on the position papers cited above and the curricula of dental practitioner programs. However, a questionnaire survey targeting physicians reported that there is insufficient cooperation between physicians and dentists, and some complications (such as fracture) were observed [10]. At the same time, dentists have not been actively informed about drugs other than bone resorptive inhibitors.
The aim of the present study was to investigate the awareness of and experience with adverse events result-ing from dental treatment of patients receivresult-ing these new drugs that affect the immune system. For this pur-pose, a questionnaire survey was conducted targeting dental practitioners, including oral and maxillofacial surgeons and general dental practitioners. The out-comes could contribute to the establishment of new strategies to disseminate management policies about these complications to all dentists. The findings of this questionnaire survey are reported in the present study.
Materials and Methods
This study was conducted in accordance with the Helsinki Declaration. The present questionnaire survey was planned by the survey and research-planning com-mittee of the Japanese Society of Dentistry for Medically Compromised Patients and was conducted after obtain-ing approval from the Society’s ethics committee (No. 6) and Board of Directors. An outline of the items in the questionnaire survey is presented below.
1. The items consisted of the following questions: (1) To what affiliation and division do you belong? (2) What are your major specialties?
2. Did you know that complications associated with dental treatment can occur in patients treated with drugs that affect the immune system? 3. Have you ever seen complications associated with
dental treatments in patients treated with drugs that affect the immune system?
4. Could you describe the cases you have seen? (1) What kind of drugs that affect the immune
system were used?
(2) For how long were the drugs that affect the immune system used before the dental treat-ments?
(3) What kinds of complications were observed? (4) What kinds of dental treatments contributed to
the complications?
(5) How long after the dental treatments were per-formed were the complications observed? 5. Did you ask the physician to discontinue or change
the drugs that affect the immune system before the dental treatments?
(1) What kinds of drugs that affect the immune system did you ask the physicians to discon-tinue or change?
(2) For how long were the drugs that affect the immune system discontinued?
(3) What kinds of complications did you observe during the discontinuation of drugs that affect the immune system?
(4) Were the drugs restarted after the dental treat-ments?
(5) If you did not ask to discontinue the drugs, please provide the reasons.
6. During tooth extractions, were any findings of acute inflammation observed around the teeth? (1) Did you prescribe antibiotics when you
per-formed invasive treatments?
(2) What kinds of antibiotics did you prescribe? 7. Is it your experience that physicians consult with
dentists about oral hygiene treatment before medical treatment?
8. Is it your experience that patients treated with drugs that affect the immune system ask about the complications associated with dental treatments? 9. Do dentists cooperate with physicians in regard to
the medical care in your region?
10. Do you cooperate with physicians in regard to this medical care?
The questionnaire survey targeted 2,050 dentists who were members of the Japanese Society of Dentistry for Medically Compromised Patients and the Japanese Society of Hospital Dentistry and Oral-Maxillofacial Surgery. The study period was between December 2017 and February 2018. The questionnaires were mailed by the Society’s Secretariat, and the completed question-naires were returned by mail in the enclosed self- addressed stamped envelopes. Database entry of the collected questionnaires was conducted by the Department of Dentistry and Oral Surgery at Shinshu University School of Medicine, and the data were pro-cessed in the Department of Critical Care Medicine and
Dentistry at Kanagawa Dental University Graduate School of Dentistry. The drugs that were studied (drugs affecting the immune system) were angiogenesis inhib-itors and other molecular targeted drugs, anticancer drugs, DMARDs, biological agents, immunosuppres-sants, sulfonamides, corticosteroid hormones, and antiresorptive agents (e.g., BPs, anti-RANKL drugs). Since the number of responses varied for each question, the percentage (%) of the total number of responses was calculated for each response. Statistical analysis was conducted using SPSS (ver. 16.0; SPSS Japan Inc., Tokyo). Most items were analyzed using descriptive analysis.
The questionnaires included the following message: “Return of the completed questionnaire will be consid-ered consent to participate”. Since this was an anony-mous questionnaire that did not require the partici-pants’ names or sex or the names of the affiliated institutions, it was not considered necessary to obtain consent regarding the protection of personal informa-tion.
Results
Questionnaire collection and the characteristics of the respondents. Of the 2,050 mailed questionnaires, 206 were completed and returned (10.1% response rate). A total of 112 dentists (56.3%) were affiliated with the Department of Oral and Maxillofacial Surgery, while 68 (33.8%) worked in dental clinics and 17 (8.6%) worked in departments of periodontology or gerodontology. No responses were given by 5 dentists (Fig.1).
The reported drugs that affect the immune system are listed in Table 1.
Knowledge of and experience with complications associated with dental treatments in patients undergo-ing therapy with drugs that affect the immune system.
Overall, 193 dentists (97.0%) were aware of the possi-bility of complications (such as postoperative wound infections, delayed wound healing, and ONJ) associ-ated with dental treatments in patients undergoing therapy with drugs that affect the immune system. Six dentists (3.0%) had no awareness. A total of 96 dentists (48.2%) saw patients with complications, whereas 103 (51.8%) did not. The numbers of patients with compli-cations that dentists saw were as follows: 1 patient (9 dentists), 2 patients (4 dentists), 3 patients (6 dentists), 4 patients (1 dentist), 5 patients (3 dentists), and 6 or more patients (4 dentists).
Complications associated with dental treatments in patients undergoing therapy with drugs that affect the immune system. Table 2 shows the number of reported cases for each drug that affects the immune system. The duration of drug treatments prior to dental treatment is shown in Table 3; approximately half of participants (133 dentists; 48%) reported durations of less than 1 month.
Figure 2A shows the complications associated with dental treatment. Delayed wound healing (35%), ONJ (33%), and postoperative wound infection (14%) were the most common. While the relationship with dental treatments was weak, cases of intractable stomatitis and oral ulcers (8%) and lymphoproliferative diseases (4%) were observed.
Figure 2B shows the factors associated with
compli-cations. The dental treatments thought to be associated with complications were mainly tooth extractions (79 dentists; 61%).
Table 4 shows the detailed associations between the drugs and complications. Delayed wound healing (31 dentists) and ONJ (25 dentists) were mainly observed with single-drug therapies. Delayed wound healing and ONJ were observed with combination therapies of
47 (35%)
44 (33%) 18 (14%)
10 (8%)
6 (4%) 8 (6%) Delay of wound healing Osteonecrosis of the jaw
Postoperative infection Intractable stomatitis and ulcer Lymphoproliferative disease Others 79 (61%) 7 (6%) 4 (3%) 3 (2%) 27 (21%) 9 (7%) Tooth extraction Other oral surgery Denture treatment Conservative treatment None Undetermined
A
B
Fig. 2 Complications of dental treatment and factors associated with them. A, Complications of dental treatment; B, Factors asso-ciated with the complications. The numbers indicate the number of dentists (percentage). 25 (13%) 19 (10%) 17 (8%) 68 (34%) 68 (34%) 2 (1%) OMFS in MUH OMFS in DUH Dentistry in DUH OMFS in GH Dental clinic Others
Fig. 1 Affiliations of the responders. The numbers indicate the number of dentists (percentage).
OMFS, Department of Oral and Maxillofacial Surgery; Dentistry, Department of Dentistry; MUH, Medical University Hospital; DUH, Dental University Hospital; GH, General Hospital.
Table 1 The list of reported drugs
Classification Drugs
▪ Molecular targeted drugs
Angiogenesis inhibitor (mammalian target of rapamycin inhibitor) Everolimus Angiogenesis inhibitor (vascular endothelial growth factor inhibitor) Bevacizumab Angiogenesis inhibitor (Multi-kinase inhibitor) Sorafenib, Sunitinib
Anti-CD20 monoclonal antibody Rituximab
▪ Anticancer drugs Cyclophosphamide
▪ Disease modified anti-rheumatic-drugs (DMARDs) Methotrexate, Iguratimod, Sodium aurothiomalate, Bucillamine
▪ Biological agents Infliximab, Tocilizumab, Golimumab, Etanercept, Adalimumab, Abatacept
▪ Immunosuppressants Everolimus, Cyclosporin, Azathioprine, Tacrolimus
▪ Sulfonamide Salazosulfapyridine
DMARDs (methotrexate or bucillamine) with various other drugs (infliximab or tocilizumab: 5 dentists; cyclosporine: 2; prednisolone: 1; bisphosphonates: 1).
The onset period of complications associated with dental treatments for postoperative wound infections and delayed wound healing was less than 1 month (7 dentists), 1 month (23 dentists), or 3, 4, and 5 months (1 dentist each). ONJ was observed in less than 1 month (1 dentist), 1 month (5 dentists), 2 months (1 dentist), or 4 months (2 dentists).
Drug discontinuation. A total of 30 dentists (18.1%) asked the attending physicians to discontinue these drugs prior to oral and maxillofacial surgeries; 85 (51.2%) did not make such requests. While 44 dentists (26.5%) saw both kinds of cases (cases in which a dis-continuation request was made and cases in which it
was not made), 7 (4.2%) requested a change to another medication.
The drugs directed by the attending physician for discontinuation prior to dental treatment were metho-trexate, immunosuppressants, biological agents, angiogenesis inhibitors, and corticosteroid hormones (Table 5). Relatively few requests were made for dis-continuation of BPs and anti-RANKL drugs (3 dentists; 3%) and other DMARDs (1 dentist; 1%). One dentist (1%) performed dental treatment between drug inter-vals.
The most common discontinuation period prior to the dental procedure was less than 4 months (Table 6). The discontinued drugs were reported to have been
Table 2 Drugs that affect the immune system
Drugs Number of dentists Percentage(%)
Methotrexate 50 26.2
Corticosteroid hormone 36 18.9
Angiogenesis inhibitor 28 14.7
Biological agents 23 12.0
Bisphosphonate and denosumab 20 10.5
Immunosuppressants 18 9.4
Molecular target drugs 13 6.8
Other DMARDs 2 1.0
Anticancer drugs 1 0.5
DMARDs, Disease-modifying antirheumatic drugs.
Table 3 Duration of drug therapy prior to dental treatment Duration of treatment prior
to dental treatment Number of dentists Percentage (%)
≤1 month 133 48.5 >1 month, ≤2 months 39 14.2 >2 months, ≤3 months 21 7.7 >3 months, ≤4 months 21 7.7 >4 months, ≤5 months 10 3.7 >5 months, ≤6 months 10 3.7 >6 months, ≤7 months 13 4.7 >7 months, ≤12 months 12 4.4 >1 year 15 5.4
There were overlapping numbers, because multiple dental treat-ments were performed by a dentist.
Table 4 Complications after dental treatment associated with drugs that affect the immune system
Drugs None wound healingDelayed Osteonecrosisof the jaw Postoperativeinfection Others complicationsTotal
Disease-modifying antirheumatic drugs (DMARDs) 13 9 5 4 0 18
Corticosteroid hormone 2 6 4 3 0 13
Angiogenesis inhibitor 4 8 5 1 1 15
Biological agents 1 3 4 2 0 9
Bisphosphonate agents and denosumab 0 1 6 0 0 7
Immunosuppressants 1 3 1 0 0 4
Others 0 1 0 0 0 1
Total complications - 31 25 10 1
-Each category includes some drugs described below.
Disease-modifying antirheumatic drugs (DMARDs): methotrexate, iguratimod, sodium aurothiomalate, bucillamine; Corticosteroid hormone: prednisolone;
Angiogenesis inhibitors: bevacizumab, sorafenib, everolimus, sunitinib; Immunosuppressants: everolimus, cyclosporine, azathioprine, tacrolimus;
Biological agents: infliximab, tocilizumab, golimumab, etanercept, adalimumab, abatacept; Bisphosphonate drugs: zoledronate, alendronate;
restarted after the dental treatment by 44 dentists (60.3%) and terminated by 4 (5.5%), while the status of the discontinued drugs is unknown for 25 dentists (34.3%). The timing of resuming the drug after the dental treatment was usually less than 3 months (Table 6). All discontinuations and resumptions were deter-mined by the attending physicians. The following adverse effects were observed during the drug discon-tinuation period: worsened rheumatism in 3 patients (methotrexate in 2 and methotrexate+immunosup-pressant in 1), enlarged tumor in 1 patient (a patient on bevacizumab), rejection reaction of the transplanted organ in 1 patient (a patient on immunosuppressants), no adverse effects in 48 patients, and unknown in 1 patient.
The reasons for not needing to discontinue the drugs were: “impedes the treatment of the primary disease” (53 dentists; 50%); “low occurrence of infections, etc.” (23 dentists; 22%); “no evidence” (17 dentists; 16%); “impedes dental treatment” (6 dentists; 6%); and “no reason” (6 dentists; 6%).
Administration of antibiotics. Prior to tooth extraction, 33 patients (58.9%) observed acute
inflam-mation surrounding the tooth to be extracted, and 23 (41.1%) observed no acute inflammation. As for the administration of antibiotics for invasive dental treat-ments such as tooth extractions, 86 dentists (94.5%) administered antibiotics, 3 (3.3%) did not, and 2 were uncertain about whether antibiotics had been adminis-tered (2.2%). The types of antibiotics used were as fol-lows: penicillin-based (48 dentists; 43%), cephalo-sporin-based (46 dentists; 41%), quinolone-based (12 dentists; 11%), macrolide-based (5 dentists; 4%), and clindamycin (1 dentist; 0.9%). Quinolones and clinda-mycin were used following penicillin and/or cephalo-sporin-based antibiotics in all reported cases.
Medical cooperation. A total of 75 dentists (46.3%) were asked to provide oral hygiene manage-ment by physicians prior to starting treatmanage-ments with drugs that affect the immune system, whereas 86 (53.1%) did not receive such requests, and 1 (0.6%) was uncertain about whether such a request had been made. A total of 72 dentists (40.2%) were asked by patients about complications associated with dental treatments when undergoing therapy with these drugs, 100 (55.9%) were not asked, and 7 (3.9%) were uncertain whether they had been asked.
As for the community’s involvement pertaining to complications associated with dental treatments related to these drugs, 71 dentists (38.0%) responded that there was cooperation between physicians and dentists, 65 (35.9%) said that there was no such cooperation, and 51 (28.2%) were uncertain as to whether cooperation took place. Moreover, 142 dentists (75.9%) said that they were personally involved in cooperating with phy-sicians regarding the patients undergoing treatments with these drugs, 19 (10.2%) were planning to do so, and 26 (13.9%) were not involved in such cooperation.
Table 5 Drugs discontinued prior to dental treatment
Drugs Number of dentists Percentage(%)
Methotrexate 34 37.8
Biological agents 14 15.6
Immunosuppressants 14 15.6
Angiogenesis inhibitor 13 14.4
Corticosteroid hormone 10 11.1
Bisphosphonates and denosumab 3 3.3
Other DMARDs 1 1.1
Dental treatment between drug
intervals 1 1.1
DMARDs, Disease-modifying antirheumatic drugs.
Table 6 Drug discontinuation or resumption periods prior to/after dental treatment
Duration Number of dentists for duration of drugdiscontinuation (%) Number of dentists for duration of drugresumption (%)
≤1 month 6 (13.3) 3 (12.0) >1 month, ≤2 months 13 (28.9) 16 (64.0) >2 months, ≤3 months 10 (22.2) 4 (16.0) >3 months, ≤4 months 10 (22.2) 1 (4.0) >4 months, ≤5 months 1 (2.2) 0 >5 months, ≤6 months 0 0 >6 months, ≤7 months 3 (6.7) 0 >7 months 2 (4.5) 1 (4.0)
Discussion
The results of the present survey showed that most dentists were aware of the possible complications (such as postoperative wound infection, delayed wound heal-ing, and ONJ) associated with dental treatments caused by drugs such as DMARDs, biological agents, immu-nosuppressants, and angiogenesis inhibitors. In fact, about half of the dentists had actually seen such compli-cations. A questionnaire survey of general dental prac-titioners (GDPs) in the United Kingdom found that over 90% of dentists were not aware that antiresorptive agents other than BPs (e.g., denosumab) and angiogen-esis inhibitors may cause MRONJ [11]. According to another study, 33.6% of GDPs, 48.5% of dental radiol-ogists, and 84.4% of oral and maxillofacial surgeons (OMSs) were aware that antiresorptive agents and angiogenesis inhibitors may cause MRONJ [12]. It is not surprising that the level of awareness among the OMSs was high, because most of the OMSs worked in hospitals in collaboration with physicians. Awareness of the complications was also high in the present study, because the majority of the respondents were OMSs. This suggested the importance of increasing awareness and experience levels related to this matter among den-tists in all specialties.
In regard to the period of drug use prior to dental treatment, approximately half of the dentists had per-formed dental treatments either before or immediately after patients started the drug treatments (less than 1 month: 48%): in other words, during a time period when the drugs were considered to have a minimal effect. According to Pimolbutr et al., the average treat-ment period with angiogenesis inhibitors prior to developing MRONJ was 6.5 months with intravenous drugs and 16 months with oral drugs, and undertaking dental treatments prior to starting the drug treatment or in the early stages was considered reasonable [13].
In the present study, complications associated with dental treatments were delayed wound healing (35%), ONJ (33%), and postoperative wound infection (14%), and these accounted for 82% of all complications. Tooth extraction was the most frequent dental treat-ment associated with complications, accounting for approximately 60% of the cases with complications. Pimolbutr et al. reported that the causes of MRONJ were tooth extraction (37%) and damage to the oral mucosa due to dentures, dental and periodontal
inflammation, and the placing of implants (23%) [13]. Fusco et al. observed a high rate of ONJ (52%) in those taking a combination of primarily zoledronic acid and sunitinib, and the main causes were dental and peri-odontal infection (34%), tooth extraction (30%), and undetermined cause (28%) [14]. Ghidini et al. found that, in many cases, tooth extraction and jaw surgeries were the cause of ONJ with single-drug therapy with BP, and with combination therapy with BP and angiogene-sis inhibitors, there were many spontaneous occur-rences [15]. In the present study, tooth extraction was a slightly more common cause of complications than reported in previous studies. No cause or undeter-mined cause was seen in 28% of cases, which was simi-lar to the rate in previous studies. A certain number of spontaneous occurrences of complications were also observed.
Previous reports have found that MRONJ occurs frequently with the combined use of BP and angiogene-sis inhibitors [13,14]. In the present study, there were no reported cases of the combined use of BP and angio-genesis inhibitors; however, delayed wound healing, ONJ, and postoperative infection were commonly observed in most cases of single-drug and multiple drug combination therapies with each of the drugs that affect the immune system. The FDA and past studies have reported that there is a high risk of developing MRONJ with single-drug treatments of BP or anti-RANKL drugs, and with combination-drug treatments of bevacizumab or sunitinib with BP/anti-RANKL drugs [4,5,8,13,14]. As in earlier reports, in the present study, delayed wound healing and ONJ were observed with not only angiogenesis inhibitors, but also drugs such as DMARDs (methotrexate, etc. ), immunosuppressants, and biological agents [4,5,8,12,16-22]. Dental treat-ments require a careful approach, since there may be drugs other than those with an FDA warning that pose a risk of delayed wound healing and ONJ.
As for the period of onset of complications associ-ated with dental treatments, the majority of postopera-tive wound infections and delayed wound healing occurred within less than 1 month, whereas a large number of ONJ cases occurred at 1 month. Pimolbutr
et al. reported that MRONJ after tooth extraction
developed during a period of 3 months, and a similar tendency was observed in the present study [13]. In terms of the use of antibiotics, the majority of patients undergoing invasive dental treatment, such as tooth
extraction, were given antibiotics. The majority of cases used penicillin- and cephalosporin-based antibiotics, and their use was considered appropriate based on the guideline for preventing postoperative infection pub-lished by the Japanese Society of Chemotherapy and Japan Society for Surgical Infection [Japanese Society of Chemotherapy: http://www.chemotherapy.or.jp/ guideline/ jyutsugo_shiyou_jissen.pdf].
Only about 18% of the dentists contacted the attend-ing physician to request the temporary discontinuation of these drugs affecting the immune system prior to the dental treatments. A previous questionnaire survey that targeted physicians reported that approximately 60% of respondents had received discontinuation requests from dentists, and they had seen 30 adverse events. About 16% of respondents had patients who discontinued osteoporosis treatment following a requested drug dis-continuation. Moreover, dentists requested discontin-uation for many medications that were not associated with the incidence of ONJ [10]. According to the posi-tion paper on MRONJ, there is no evidence that the discontinuation of drugs before dental treatment inhib-its the development of ONJ [4,5]. Thus, there were very few requests for the discontinuation of BPs and anti-RANKL drugs, but requests to discontinue other drugs were made by some dentists (18% of respon-dents), which was similar to the finding in the previous questionnaire survey [4,5,10]. Education on manage-ment policies in regard to these drugs is necessary for all dentists when dental treatments are necessary.
When drugs were discontinued, the most prevalent discontinuation periods were 1-4 months prior to and 1-3 months after the procedures, almost the same as in the previous report [10]. In the majority of cases, the drugs were re-introduced, perhaps because of the posi-tion paper on MRONJ pertaining to drug discontinua-tion, which outlines that drug discontinuation should occur 2 months before and administration should resume 2 months after dental treatments [4,5]. On the other hand, the drugs were not discontinued in over 50% of the cases; this was because a majority of the respondents were OMSs who could easily collaborate with physicians in the hospital. A previous study sug-gested that a long waiting period (≥2 months) before tooth extraction for stopping the antiresorptive medica-tions may be a risk factor for delayed wound healing beyond 8 weeks after extraction in osteoporosis patients ≥60 years of age [23]. Similar to the situation of BPs
and anti-RANKL drugs in relation to ONJ, many den-tists did not discontinue the drugs in their patients with MRONJ, taking into account the adverse effects of drug discontinuation on the primary disease. While there were not many, some serious adverse events were seen during the drug discontinuation period, such as a worsening of rheumatism, enlarged tumors, and rejec-tion reacrejec-tions of transplanted organs. Since a previous questionnaire survey that targeted physicians reported that the respondents experienced 30 adverse events, including 10 fractures, 1 ONJ, and 4 cases of worsen-ing symptoms [10], a careful approach to drug discon-tinuation is necessary.
With respect to medical-dental cooperation, about half of the dentists were approached by physicians to discuss oral hygiene management prior to starting treatment with these drugs that affect the immune sys-tem. Approximately 85% of the dentists said that they were already cooperating with physicians, or that they were planning to do so. A questionnaire survey that targeted physicians reported that approximately 76% of respondents had never requested oral health care from dentists before osteoporosis treatment [10], which was different from our present result. The reported study was published in 2014, and cooperation between dental and medical professionals may have improved in the ensuing 5 years. However, 72% of respondents reported that there is no cooperation between dentists and med-ical professionals in their region, which would corre-spond with the incidence in the present study (the existence of cooperation with physicians remained at about 35% in the community) [10]. About 70% of the dentists had been asked by their patients about compli-cations associated with dental treatments when under-going therapy with these drugs, confirming that the risk of complications with these drugs is widely known. In the future, dentists will need to promote medical coop-eration and dissemination of information in the com-munity in regard to drugs, other than antiresorptive agents, that confer a risk of developing MRONJ.
A limitation of the present study was the fact that this was a questionnaire survey with a low response rate (10.1%). The low response rate may have been due to the large number of items in the questionnaire and the need to provide detailed information for each response. However, the dentists’ awareness of and experience with adverse events associated with dental treatment in patients receiving drugs that affect the immune system
were clarified. In the future, the Society as a whole will need to conduct an investigation of actual conditions through the prospective enrollment of cases.
In conclusion, the present questionnaire survey showed that most dentists were aware of the possibility of complications associated with dental treatment in patients undergoing therapy with drugs that affect the immune system. Nearly half of the dentists had actually seen these complications. Delayed wound healing, osteonecrosis of the jaw (ONJ), and postoperative infections were mainly reported. It was also found that the majority of dentists were undertaking dental treat-ments in cooperation with physicians. However, the level of cooperation among dentists and physicians in the community was low. Thus, there is a need for den-tists to provide sufficient information to physicians about dental and medical cooperation.
Acknowledgments. This research was financially supported in part by a grant from the Japanese Association for Dental Science Federation, JDSF-DSP1-2018-202-2.
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