DTAR Journal

In September 2021, the patient presented with a new outbreak of pain in the lower molar area. After the second COVID-19 vaccine (Pfizer) dose, she suffered a pseudo-outbreak of MS with loss of vision in the left eye and paraesthesia in the left hand lasting less than 24 h. The patient reported neglecting her healthy lifestyle during the summer, with less oral hygiene and greater social activity. Tooth polishing was performed with a brush and prophylaxis paste and rinsed with 0.12% chlorhexidine digluconate.

Fifteen days later (September 2021), a new periodontogram and panoramic radiograph were performed (Figure 1c), which detected greater bone loss in the areas of 2.6–2.7, 3.6–3.7, and 4.6–4.7 compared to the one performed 5 months earlier.

One week later, the patient presented with a new outbreak of gingiva. During this time, the patient commented that she had been under great stress with irregular rest periods.

On November 19, she received a new dose of ocrelizumab. Although the patient had received a third dose of the COVID-19 vaccine, she exhibited COVID-19 symptoms, and on Day 24, a positive diagnosis of COVID-19 was confirmed. On December 7, there was a worsening associated with the onset of fever (38.5^°), chills, and dyspnoea. The patient was hospitalized following a diagnosis of bilateral pneumonia due to COVID-19 in an immunocompromised patient. She was treated with azithromycin 500 mg, methylprednisolone, oxygen, and nonsteroidal antiinflammatory drugs (NSAIDs) and was discharged on January 5, 2022.

In January 2022, the patient’s gingiva had a coral-pink colour with orange peel stippling due to the absence of oedema and ulcerative gingival lesions, which were compatible with gingival health. New intraoral photographs were taken, a new periodontogram and panoramic radiograph were performed, and a periodontal maintenance session was conducted (Figures 1d, 2b and 3b).

In March 2022, the patient was again diagnosed with COVID-19. She had mild symptoms and was treated with three doses of remdesivir. A few days after being discharged, a new periodontal review was performed, the results of which were similar to those of the previous exam.

Discussion

MS progresses in an unpredictable manner, manifesting symptoms that vary from person to person [4]. Classically, MS has been considered a T-lymphocyte-mediated disease. However, the role of B lymphocytes has been speculated for decades. It is now known that activated B-lymphocyte-derived plasmablasts can remain in the cerebrospinal fluid of MS patients for very long periods.

The medication used for its treatment (immunomodulators) and to alleviate its symptoms (corticosteroids) can have effects on the oral mucosa (xerostomia, gingival hyperplasia, mucositis, aphthae, dysgeusia, candidiasis or angular cheilitis), which potentially contributes to worse oral health [5]. Cockburn et al. [6] indicated that up to 18 oral problems related to these drugs had been described, in addition to favouring the appearance of opportunistic infections.

Ocrelizumab is an IgG1 monoclonal antibody that selectively targets CD20+. The treatment causes a rapid decrease in circulating B cells and immunoglobulin levels without affecting lymphoid stem cells or plasma cells. Its effect was observed after 14 days, with a significant decrease in B lymphocytes (CD19+) in the lymph nodes. Measurement of CD19+ cells by flow cytometry is a surrogate measure of B lymphocytes in patients treated with anti-CD20 antibodies. Its effects persist between 6 and 18 months after the last dose.

Ocrelizumab has been studied in two pivotal clinical trials for relapsing MS: OPERA I and OPERA II. In both trials, ocrelizumab significantly reduced the rate of relapses and the progression of disability compared to an injectable disease-modifying therapy. Additionally, ocrelizumab significantly reduced the number of new or enlarging lesions on MRI scans compared to interferon beta-1a.

Overall, ocrelizumab has been shown to be an effective treatment for relapsing MS, with a significant reduction in relapses and disability progression. It is approved for treating both relapsing forms of MS and primary progressive MS.

In the case of periodontitis, it has been suggested that because both MS and periodontitis have an immune component, there could be some association between both diseases. However, Gustavsen et al. [7] indicated no significant association between MS and periodontitis after adjusting for smoking habits in their study. Sheu and Lin [8] found evidence of this association among women but not men.

Necrotizing periodontal diseases (NPDs) are characterized by the following main features: pain, necrosis of the papillae, and gingival bleeding [9].

Although their prevalence is low, NPDs importance lies in the severity and progression of the disease. Its aetiology is influenced by several factors that can condition the host’s response to the disease. These include immunodeficiencies, malnutrition, stress, and smoking. In addition to these factors, a specific bacterial association has been established, classically as a fuso-spirillary association [10].

Our patient had several predisposing factors, including immunosuppression, stress, smoking, poor oral hygiene, late periodontal treatment, and characteristic bacterial flora. Focusing on the factors present in the patient, we highlight significant contributing aspects below.

Immunosuppression Factor

As shown by April 2021 cytometry, the CD19/CD20+ B lymphocyte population was 0%, indicating effective humorall immunosuppression. We do not know if her humorall immunosuppression was maintained throughout the evolution of the case since the rest of the analyses were focused on the evaluation of T lymphocyte subpopulations (CD3+).

The patient also had 2 COVID-19 infections. The novel coronavirus (COVID-19) has been linked to an increased risk of exacerbation of MS symptoms. This is likely due to the fact that the virus causes inflammation and can affect the immune system. In people with MS, this can lead to a flare-up of symptoms or an exacerbation of existing disease. Additionally, people with MS are more susceptible to infections and may be more likely to contract COVID-19. Those with MS should take extra precautions to protect themselves, such as wearing a face mask, washing their hands frequently, and avoiding large gatherings.

Stress Factor

It is known that psychological stress affects human immune function [11]. For some authors, the combination of both periods of psychological stress and situations of immunosuppression are predisposing factors for the worsening of the disease [6,11], which leads to an increased risk of infections or their progression. These interconnections might be even more relevant in recurrent and aggressive cases of periodontal and peri-implant disease, often refractory to treatment [12].

Burtscher et al. [13] found that the isolation of people, in combination with the fear of contagion and quarantine, as well as a possible information overload, caused chronic stress and was associated with adverse effects on mental health.

Smoking Factor

It has been known for years that tobacco is the most important acquired risk factor in the treatment and prognosis of periodontal diseases [14]. Its content in various chemical products alters the inflammatory response, resulting in a potent toxicant for various cell types [15]. It should be noted that nicotine releases catecholamines both locally and systemically, which alters the vascular flow at the level of the gingival papillae, favouring papillary necrosis and increasing periodontal destruction [16].

In the present case, the patient was a smoker and did not begin treatment for smoking cessation until near the end of her evolution. This situation could have hindered treatment and favoured her relapses.

Poor oral Hygiene

The physical sequelae and the progressive deterioration produced by MS may imply greater difficulty in performing proper oral hygiene or accessing adequate oral care. Moreover, studies have demonstrated that smokers have higher plaque levels, more pathogenic flora, and less favourable responses to periodontal treatment [17].

Hatipoglu et al. [18] found higher values of the plaque index, probing depth, and gingival index in MS patients among patients with high levels of physical disability than among patients with low levels of disability.

Late Periodontal Treatment

Early diagnosis and prompt treatment of the disease prevents progression and cellular destruction and results in disease resolution [19].

The delay in treatment due to confinement and the fear of going to a dental office allowed subclinical evolution, with false periods of remission.

Microbiological Factor

It has been described that the rate of infections (mainly upper respiratory tract) is estimated at 75.6 per 100 patient-years (CI 95%: 73–78.2), although fortunately, the accumulated rate of severe infections in all the clinical trials was 1.3% for ocrelizumab [20].

NP is an opportunistic bacterial infection predominantly associated with Treponema spp., Selenomonas spp., Fusobacterium spp., and Prevotella intermedia. In our case, the predominant bacteria were Tannerella forsithia and Prebotella intermedia (Table 1).

According to the summary of the product characteristics of ocrelizumab and following its mechanism of action, inoculation with live or live attenuated vaccines is not recommended during treatment until B-cell repletion [20,21]. However, we have no information on mRNA-based vaccines.

To our knowledge, this is the first study to describe NP during RR-MS treatment. We found that NP is linked to treatment with immunomodulators, which cause a substantial decrease in humoral l immunity. This case highlights the need for an oral care protocol for patients who undergo immunomodulation.

Conclusion

Given the possible relationship between the immunomodulation of patients affected by RR-MS and the risk of presenting with NP, we recommend an evaluation and dental follow-up of patients with MS before, during, and after the administration of monoclonal antibodies.

We make three final recommendations to consider when elaborating on the general treatment regimen for NPDs: (A) early treatment often prevents sequelae and craters in soft tissues that will have new relapses; (B) treatment must be maintained even though the pain has disappeared following the application of the emergency measures; if not, relapses will occur more often; and (C) we must consider that a patient can fail to respond to this treatment, especially with advanced degrees of immunodepression.

Author Contributions:

Conceptualization, A.S.-P. and J.M.M.-C. ; methodology, A.S.-P. and A.J.-G. ; investigation, J.M.M.-C. and A.S.-P.; data curation, M.J.M.-V. and A.J.-G. ; writing—original draft preparation, J.M.M.-C. ; writing—review and editing, A.S.-P., A.J.-G., J.M.M.-C., M.J.M.V., and J.M.M.C. ; A.S.-P., supervision. and J.M.M.-C.

All authors have read and agreed to the published version of the manuscript.

Funding: This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

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