麻豆果冻传媒影音

In March 2016, a 49-year-old female patient presents to the clinic's Oral Surgery Unit with significant mouth pain associated with exposed bone in the body of her lower jaw.

She notes that three teeth were extracted in this area about 5 months previously. She says she has no history of antiresorptive, antiangiogenic, or steroid therapies. Her clinical history does not include any comorbidities or risk factors, such as smoking or alcohol abuse.

Examination reveals a large necrotic lesion, with bone exposed, inside her mouth as well as externally; she also has swelling beneath her jaw and pus discharge.

More detailed clinical examination identifies a painful bone exposure of about 3 cm, extending from the 3.2 to 4.1 at post-extractive sites, with pus discharge. Clinicians note saliva leaking from an external ulcer beneath her jaw. Using dental probes, they diagnose an intra-extra-oral fistula in the area of the exposed bone.

Clinicians perform a radiological exam orthopantomography (Rx OPT) (Figure 1), which shows a poorly defined radiolucency in the area of bone exposure (3.2, 3.1, and 4.1 post-extraction sites). A subsequent enhanced multi-slice spiral computed tomography with 3D reconstruction (Figure 2) reveals an area of osteolysis of the alveolar process in the anterior mandible. The lingual cortical plate is involved up to the inferior margin. However, imaging shows preservation of the facial cortical plate.

Medical History

In 2003, the patient is diagnosed with Crohn's disease. She is treated with salazopyrin (500 mg orally, three times a day) and mesalazine (800 mg orally, three times a day).

In February 2004, her Crohn's disease symptoms persist despite the prescribed treatments. Physicians prescribe infliximab (250 mg intravenous every 6 weeks).

In December 2015, the patient has three teeth (3.2, 3.1, and 4.1) extracted due to periodontal disease. She continues treatment for her Crohn's disease. For about 2 months after the extractions, she experiences pain and swelling of her lower jaw.

Two months later, in February 2016, the patient is referred to the clinic's Oral Surgery Unit after her mouth pain and mandibular swelling worsen, prompting a follow-up examination that reveals the onset of skin ulceration with extraoral necrotic bone exposure of the anterior mandibular area.

Differential diagnosis of the patient's necrosis of the jaw includes alveolar osteitis, which clinicians rule out based on her clinical presentation and the severity of her symptoms. Chronic sclerosing osteomyelitis is deemed unlikely given the associated pus discharge. Leukemia is ruled out based on results of routine blood tests. Other neoplastic malignant etiologies such as osteosarcoma and lymphoma are dismissed, based on the fact that the clinical symptoms developed immediately following the extractions of the teeth.

The provisional diagnosis is medication-related osteonecrosis of the jaw (MRONJ), based on clinical and radiological findings. The lesion is classified as stage 3 according to the American Association of Oral and Maxillofacial Surgeons (AAOMS) staging system.

Treatment

Treatment with infliximab is discontinued. The patient receives three cycles of antibiotic therapy with ceftriaxone (1 g/once a day by intramuscular injection) and metronidazole (500 mg/twice a day orally) for 8 days, followed by 10 days of suspension.

Following antibiotic treatment cycles, the patient undergoes surgical therapy with wide bone resection and debridement of the cutaneous area.

The facial cortical plate is preserved, and mandibular fracture is prevented. After resection, a piezoelectric device is used to remove residual infected and necrotic tissues, with the aim of preventing a MRONJ recurrence.

To shorten healing time, a gel compound of sodium hyaluronate and amino acids is applied to the bone defect, and an iodoform gauze is applied to the external wound. Previous antibiotic therapy is resumed for an additional cycle.

Analysis of the surgical specimen confirms the clinical diagnosis of MRONJ.

The wounds heal without complications and with no recurrence during 16 months of clinical and radiological follow-up. Rehabilitation involves a removable prosthesis for optimal function and aesthetics, with good stabilization of the surgical sites.

Discussion

The clinicians reporting this ¹ write that while ONJ related to treatment with bisphosphonates has been "extensively characterized over the last 13 years," the ONJ in this Crohn's disease patient is uncharacteristic: the symptoms developed after tooth extraction and initial treatment with salazopyrin/mesalazine, followed by several years of infliximab treatment, and in the absence of any history of antiresorptive/antiangiogenic therapies.

AAOMS MRONJ as "the presence of exposed necrotic bone or bone that can be probed through an intraoral or extra-oral fistula in the maxillofacial region, that has persisted for longer than 8 weeks, occurring in patients undergoing treatment with antiresorptive or antiangiogenic agents with no history of radiation therapy or obvious metastatic disease to the jaws."²

The condition used to be known as bisphosphonate-related osteonecrosis of the jaw, but the terminology was changed in 2014¹ due to increasing cases found to be associated with other antiresorptive and antiangiogenic drugs.³

Current medications that have been identified in distinct case series of MRONJ include inhibitors of receptor activator of nuclear factor kappa-Β ligand (RANKL) (denosumab),⁴ of angiogenesis (bevacizumab and rituximab),^5,7,15,16 of tyrosine kinase receptors (sunitinib),^6,11 and of TNF (adalimumab),⁷ and the list may be expected to continue growing, the authors of this case noted.

Tumor necrosis factor (TNF)-α plays a central role in mucosal inflammation, and increased levels of TNF-α have been noted in numerous inflammatory conditions, including inflammatory bowel disease, several inflammatory types of arthritis, and psoriasis. Importantly, it also affects systemic bone loss and turnover, due to its ability to promote osteoclasts and osteoblasts activity.⁸

The authors note that infliximab, a genetically engineered chimeric human/mouse monoclonal antibody,⁹ binds with high affinity to both the soluble and the transmembrane forms of human TNF-α. Anti-TNF-α antibody treatments such as infliximab inhibit induction of interleukins, enhancement of leukocyte migration, and expression of adhesion molecules. As such, infliximab is increasingly used to treat a range of these inflammatory conditions.¹⁰

A similar case of MRONJ similar to this patient's case was reported in a patient with rheumatoid arthritis; however, it involved concurrent treatment with both infliximab and bisphosphonates.¹¹

The case authors note that the potential implications of infliximab treatment in the setting of oral surgery have yet to be fully described in the literature.¹² According to findings of one long-term , use of anti-TNF agents may enhance mucosal healing but as noted, also may interfere with bone physiology and turnover, and with wound repair.¹³

The authors note that immunosuppression related to anti-TNF-α treatments may facilitate infectious complications, and hence, result in MRONJ due to "spreading of ongoing infections."¹⁴

Dentists are well positioned to detect or prevent, and manage MRONJ, and have published ¹⁵ to support the process. While the role of infliximab in MRONJ has yet to be confirmed, these case authors advise all prescribers of biologics to ensure that patients have a preventive dental check-up before and during treatment with infliximab and other biologics.

References

1. Favia G, et al: Infliximab-related osteonecrosis of the jaw. Am J Case Rep 2017; 18: 1351-1356.

2. Ruggiero SL, et al: American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaws – 2014 update. J Oral Maxillofac Surg 2014; 72(10): 1938-1956.

3. Ramirez L, et al: New non-bisphosphonate drugs that produce osteonecrosis of the jaws. Oral Health Prev Dent 2015; 13(5): 385-893.

4. Pichardo SE, van Merkesteyn JP: Evaluation of a surgical treatment of denosumab-related osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol 2016; 122(3): 272-278.

5. Santos-Silva AR, et al: Osteonecrosis of the mandible associated with bevacizumab therapy. Oral Surg Oral Med Oral Pathol Ora Radiol 2013; 115(6): e32–e36.

6. Fleissig Y, et al: Sunitinib related osteonecrosis of jaw: A case report. Oral Surg Oral Med Oral Pathol Oral Radiol 2012; 113(3): e1e3.

7. Cassoni A, et al: Adalimumab: Another medication related to osteonecrosis of the jaws? Case Rep Dent 2016; 2016: 2856926.

8. Sivolella S, et al: Denosumab and anti-angiogenetic drug-related osteonecrosis of the jaw: An uncommon but potentially severe disease. Anticancer Res 2013; 33(5): 1793-1797.

9. Sandborn WJ, Hanauer SB: Antitumor necrosis factor therapy for inflammatory bowel disease: A review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 1999; 5: 119-133.

10. Ciantar M, Adlam DM: Treatment with infliximab: Implications in oral surgery? A case report. Br J Oral Maxillofac Surg 2007; 45(6): 507-510.

11. Ebker T et al: Fulminant course of osteonecrosis of the jaw in a rheumatoid arthritis patient following oral bisphosphonate intake and biologic therapy. Rheumatology, 2013; 52(1): 218–20.

12. Ciantar M, Adlam DM: Treatment with infliximab: Implications in oral surgery? A case report. Br J Oral Maxillofac Surg 2007; 45(6): 507-510.

13. Rutgeerts P, et al: Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: Data from the EXTEND trial. Gastroenterology 2012; 142: 1102-1111.

14. Preidl RHM, et al: Osteonecrosis of the jaw in a Crohn's disease patient following a course of Bisphosphonate and Adalimumab therapy: A case report. BMC Gastroenterology 2014; 14: 6.

15. Nicolatou-Galitis O, et al. Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 2019; 127(2): 117–135.

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