Discussion and Conclusions
Several new medications have been added to the potential-cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as agent therapy and one in association with denosumab.12,18 As far as literature reports, MRONJ onset in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib and cobimetinib –the other chemotherapy drugs taken by the patient- have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of Head & Neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and three days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis”.19 Still, as a matter of fact, most recent meta-analyses show that AO therapy should be more symptomatic19,20 rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self-limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.19,20 As reported in literature, after the diagnosis, AO , regardless of the therapy, tends to remit in a period of days or weeks, most commonly20, whilst there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a non-healing post-extraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ (which was possibly a stage 1 rather than a stage 0, as we evaluated during our first visit) rather than AO.
As reported before, amongst the various anticancer therapies agents administered to the patient, ipilimumab was the only drug which could be related to MRONJ.
Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.12 Ipilimumab is a humanized monoclonal antibody against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is expressed both in activated T-cells and in suppressor T-regulatory cells, binding to antigen presenting cells and therefore diminishing T-cell responses. The block of the CTLA-4 is able to improve the antitumor responses of activated T-cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.18,21 The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature there are reported cases of ipilimumab -related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T-cells presence. CTLA4 deficient activated T-cells have been shown to be associated with osteonecrosis, as activated T-cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.22 Trauma from regular oral activity or oral surgery (e.g. tooth extraction) could increase the demand on this vulnerable bone to mend itself, resulting in localized bone necrosis.12
Ipilimumab is known to have a 14.7 day blood half-life23 while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long-term efficacy with about 20% of patients alive at 5, 7 and 10 years after treatment completion. This long term efficacy is due to the immune-responses induced by checkpoint inhibitors. Still, just like the anti-cancer effects, side effects can last for many years.12 It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co-caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF-mutant melanoma can lead to an immune stimulatory microenvironment by enhancing expression of immune stimulatory molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor-antigen spreading, re-stimulating T-CELL activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti-BRAF therapy enhances the reactivity and cytotoxicity of T cells24,25. The re-activation of such empowered T-CELL clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.