Management of Patients under Treatment with Monoclonal Antibodies and New Biological Therapies

: Objective: The aim of this study is to know the biological therapy drugs that are related to adverse events, what dental treatments are associated with the appearance of these events, their severity, and how they are resolved. Study design: Analysis of cases described in the literature on patients undergoing treatment with biological therapies who have developed adverse effects associated with these drugs. Results: Of the 62 articles reviewed, 49 describe 68 cases of MRONJ, most of which appeared in the jaw and received surgical and/or conservative treatment. Conclusions: Biological therapies can potentially develop adverse effects in the oral cavity, so strict monitoring by the dentist is necessary.


Introduction
Biological therapies are a new method of treating some autoimmune diseases and cancer. They were defined by the FDA (Food and Drugs Administration) as any virus, therapeutic serum, toxin, antitoxin, or similar product applicable to the prevention and treatment of human diseases. These biologics include vaccines, blood and blood-derived preparations, antitoxins, growth hormones, human insulin, gene therapies, recombinant therapies, proteins, and allergens, along with the newer biologics: cytokines, monoclonal antibodies, and fusion proteins [1,2].
Cytokines are immunomodulators that regulate the host's response to inflammation and infections. In this way they work by signaling molecules that will bind to protein receptors on cells, generating a physiological change in them.
Monoclonal antibodies are synthetic molecules that activate against certain antigens to improve immune recognition. They are divided into four subgroups: murine, chimeric, humanized, and human.
Fusion proteins are composed of transmembrane proteins connected to another molecule through the Fc portion of human immunoglobulin.
The mechanisms of action of biological therapies involve a series of physiological changes that can trigger side effects in the patient. One of these mechanisms is the inhibition of molecules such as TNFα, which are essential in the inflammatory response. This produces a change in the immune system that can lead to these patients having a greater predisposition to infections [1].
Other mechanisms of action to take into account, due to their physiological repercussions, are antiresorptive and antiangiogenic, influencing osteoclasts and vascular endothelial growth factor (VEGF), respectively [2,3].
Despite the efficacy and safety of these drugs in the vast majority of patients, there is a significant risk of producing adverse effects such as mucositis, hyperkeratotic lesions, mucosal dyschromia, geographic tongue, dysgeusia, lichenoid lesions, telangiectasias, xerostomia, dysesthesia, and, the most prominent, osteonecrosis of the jaw, due to its antiangiogenic and/or antiresorptive power [4]. This osteonecrosis will be considered related to these medications when the following characteristics described by the AAOMS (American Association of Oral and Maxillofacial Surgeons) are present in a patient: -Previous or current treatment with antiresorptive or antiangiogenic agents. -Exposed bone or bone that can be probed through an intra-or extra-oral fistula in the maxillofacial region, which has persisted for more than 8 weeks. -Absence of radiotherapy or previous metastasis in the jaw [2].
In 2014, the AAOMS changed the term "Bisphosphonate-Related Osteonecrosis of the Jaws" (BRONJ) to "Medication-related Osteonecrosis of the Jaws" (MRONJ) to include all other drugs related to osteonecrosis. However, since 2017 there are only three monoclonal antibodies officially recognized by the FDA as causing MRONJ: denosumab, bevacizumab, and sunitinib. The rest of the reported drugs have not yet been recognized as such due to the lack of scientific evidence [5].
The objective of this study is to know the drugs related to adverse events in oral surgery, what effects they produce, and to record how they have been resolved according to the available literature.

Material and Methods
An electronic search was carried out in the National Library of American Medicine (MEDLINE) through Pubmed, with the combination of the following terms: "MRONJ"; "Adverse effect" AND "dental disease" AND "targeted therapy", applying the results filters by year between 2005 and 2020, in humans, and with the full text available.
The following inclusion criteria were established: articles published since 2005, but due to the lack of described literature on the subject, the search was extended to those published since 2005; in English or Spanish; performed in humans; patients being treated with biological therapies; and in relation to the objective of this review. Following the exclusion criteria, those articles published prior to 2005 were eliminated from the search; in a language other than Spanish or English; performed on animals; those duplicates; and those that, after reading the abstract, were not related to the main objective of this review.

Results
A total of 374 articles were obtained, to which the criteria described above were applied, going to read full text 83 articles, and finally selecting a total of 54 for this review ( Figure 1).
Regarding the treatment carried out for osteonecrosis, in a total of 38 cases a surgical treatment was carried out, in 23 cases a conservative treatment was carried out, and in seven of them the treatment followed was not specified.
The surgical act is the triggering factor reported in most cases, with a total of 27; this is followed by a poor fit of the prostheses, mentioned in five cases; finally, in 31 the triggering factor for osteonecrosis is not described and in the remaining five cases a factor other than those previously mentioned is related. Oral complications related to biological therapies have been found, such as lesions at the mucosal level as described in the reviews of the literature by Vigarios et al. [4] (2017) and Watter et al. [23] (2011). Cases of infections at the oral level have been reported in patients treated with adalimumab and infliximab, as described by Cillo et al. [24] (2019) and Filler et al. [25] (2005), as well as a case of exudative erythema multiforme (EEM) in a patient treated with infliximab as described by Edwards et al. [26] (2013). Within the literature, the complication of which more cases have been found is osteonecrosis of the jaws, in patients receiving one or more biological therapies ( Figure 2). Within our search, 49 articles containing a total of 68 cases establish a possible relationship of biological therapies with osteonecrosis of the jaws (Table 1). In 62.69% of the cases, osteonecrosis was related to denosumab (16.42%), an antiresorptive agent; bevacizumab (28.36%) or sunitib (17.91%), both antiangiogenic agents, coinciding with the three drugs described in 2014 by the AAOMS as producers of MRONJ.  Among them, it can be observed that there are more cases of osteonecrosis in the mandible (83.58%) than in the maxilla, as well as a higher frequency in men, with 53.73%. Regarding the treatment carried out for osteonecrosis, it can be observed that a surgical treatment was carried out in 55.22% of the cases, which consists in the majority of them in a mandibular sequestrectomy or resection. Conservative treatment consists mainly of antibiotic therapy, antimicrobial rinses, strict oral hygiene measures, as well as modifications in biological therapy.

Discussion
Although osteonecrosis is the most studied complication due to its severity, there are also references to other complications at the oral level. Although these complications do not involve such a high risk for the patient, they require treatment to control and improve their quality of life.
These drugs can be difficult to identify clinically by their brand names. A table (Table 2) is presented with the drugs and their most common commercial name to facilitate their identification for the professional, as well as a series of recommendations on the management of patients with biological therapy.

Management of Patients Undergoing Treatment with Biological Therapies
The management of patients undergoing treatment with these biological therapies requires monitoring and special measures by the dentist to avoid the adverse effects previously described.
Before starting therapy, it is essential to carry out a complete dental treatment. Dental treatment includes a comprehensive dental examination with orthopantomography and intraoral radiographs, extraction of teeth with impossible prognosis, conservative dental treatments and periodontal interventions, prosthesis adjustment, factor control risks such as tobacco and diabetes, as well as patient education on the importance of oral care.
Infection is one of the most important adverse effects, but not enough scientific evidence has been found to support the use of antibiotic prophylaxis in these patients when performing surgery. The considerations prior to a surgical treatment that we will have to take into account are [1]: Complete blood count if the procedure involves bleeding. Prothrombin time (PT) and INR, if the patient has liver damage. This is one of the possible adverse effects in long-term treatment with biological therapies [57].
Interruption of treatment with biological agents before the procedure. The so-called drug holiday is a subject of controversy between different authors. With bisphosphonates, drug holiday protocols exist before performing invasive surgical treatment, although continuing with the controversy, a recent study in Japan [58] suggests that the withdrawal of BPs would not reduce the risk of developing adverse effects after surgery such as osteonecrosis [59]. This may be due to the fact that BPs have a long-lasting skeletal retention, while biological drugs such as denosumab have a reversible effect. For this reason, the use of drug holiday in patients receiving denosumab could be endorsed. However, the temporary suspension of medications must be compatible with the underlying pathology and be authorized by the prescriber. To date, there is insufficient scientific evidence to confirm the effectiveness of the drug holiday [60,61].
Regarding the surgical technique used in this type of patients, it should be as atraumatic as possible and can be accompanied by the use of plasma rich in growth factors (PRGF) to promote bone and soft tissue regeneration after surgery, reducing thus the risk of infection, and the time of exposure of the wound to bacteria. After surgery, experts recommend the use of antimicrobial rinses and systemic antibiotics.

Management of Complications Associated with Biological Therapies
Oral toxicities are one of the adverse effects in treatment with biological therapies. The management of these oral toxicities consists of: Mucositis, stomatitis, and aphthous lesions: Basic oral care, corticosteroids (topical, intralesional, or oral), morphine rinses, systemic analgesics, LLLT (Low Level Laser Therapy), and change in medication and interruption of previously agreed radiotherapy sessions with the oncologist.
Hyperkeratotic lesions and dyschromia of the mucosa: Monthly reviews and biopsy in case of suspicion.
Geographic tongue: Avoidance of irritants, rinsing with corticosteroids in painful lesions.
Dysgeusia: Nutritional recommendations such as abundant consumption of liquids and cold meals; Changes in the medication previously agreed with the dentist can be proposed.
Lichenoid lesions: Topical corticosteroids for painful lesions and periodic reviews, as well as change in medication.
Telangiectasias and mucosal bleeding: Basic oral care and change in medication. Xerostomía: Basic oral care, hydration, use of sialogogues such as pilocarpine or artificial salivary substitutes (palliative).
Dysestesia: Basic oral care, avoidance of irritants and symptomatic treatment with analgesics. In case of neuropathy, use drugs such as clonazepam or gabapentin.
MRONJ: This complication is divided by the AAOMS into four grades with a specific treatment for each of them [2]. (Table 3) Table 3. Complication grades divided by the AAOMS and specific treatment. Complication grades according to AAOMS and recommended treatment are shown.

Grade Treatment
Risk: No apparent necrotic bone Treatment not indicated, patient education Grade 0: No clinical evidence of bone necrosis, but nonspecific clinical findings, radiographic changes, and symptoms.
Systemic management, including the use of analgesics and antibiotic. Grade 1: Exposure and bone necrosis, or fistulas that can be probed to bone in asymptomatic patients without evidence of infection. Antibacterial rinses, clinical follow-up, patient education.
Grade 2: Exposure and bone necrosis, or fistulas that can be probed to the bone, associated with infection with pain or erythema in the region of exposed bone with or without purulent drainage.
Symptomatic treatment with oral antibiotics, antibacterial rinses, pain control, debridement to relieve soft tissue irritation and control infection. Grade 3: Presence of one of the following signs: bone exposure and necrosis that extends beyond the alveolar region, pathological fractures, extraoral fistulas, oro-nasal or oro-antral communication, osteolysis that extends to the lower border of the mandible or floor of the breast.
Antibacterial rinses, antibiotic therapy and pain control, surgical debridement or resection to alleviate infection and long-lasting pain.
It has been observed that the use of hyperbaric oxygen therapy as an adjunct to surgical and non-surgical treatment produces improvements in wound healing, pain, and quality of life. However, there are no statistically significant differences with respect to the control group [2,62].
Other studies mention the use of low-frequency lasers, parathyroid hormone and BMPs (Bone Morphogenetic Protein) as strategies in non-surgical treatment, but more studies are needed to verify their efficacy [2].

Study Limitations
The present study meets a series of limitations: There is a lack of scientific evidence about the possible adverse effects that these drugs may present at the oral level, in addition, it is difficult to relate them to a single drug in polymedicated patients. Likewise, in most cases, the adverse event is not easily related to dental treatment due to the time elapsed until it appears.
Despite this, this review presents all the oral adverse events reported to date in relation to these drugs.

Conclusions
The biological drugs that, according to the literature described, have the greatest relationship with adverse events in the dental field are bevacizumab, denosumab and sunitinib. The main adverse event is osteonecrosis of the jaws (MRONJ), resolved in most of the cases described with surgical treatment.
It is necessary to take into account the oral complications associated with these therapies and the importance of monitoring by the dentist from the beginning, in order to prevent or reduce the appearance of these.
Despite the reported cases, more studies are needed to describe in a more exhaustive way the appearance of complications that could be related to these treatments.