Photodynamic therapy for the successful management of cyclosporine-related gum hypertrophy: A novel therapeutic option.

Background: Drug-induced gingival overgrowth is associated with the intake of three classes of drugs: anticonvulsants, immunosuppressants, and calcium channel blockers. It is clinically characterized by hyperplasia of the gingival connective tissue which appears edematous, bloody, and purplish-red in color. In more severe cases, drug-induced gingival hyperplasia negatively affects the patient's quality of life, making it difficult to eat and practice good oral hygiene. Drug-induced gingival overgrowth therapy is controversial and, in fact, no studies in the literature highlight a well-defined therapeutic protocol. The therapies that are described provide primarily for non-surgical periodontal treatment and second-line surgical treatment. The aim of this work is to highlight a case of drug-induced gingival hyperplasia which was completely resolved thanks to photodynamic therapy which is completely free from side effects. Design and
Methods: Photodynamic therapy was performed on an 18 year-old female patient with LEDs at a power of 450-470 nm and 5500 mW/cm2 + 7500 mW/cm2, combined with a Curcuma longa-based photosensitizer. A single session was performed, with applications of approximately 30 s for each interdental papilla.
Results: The patient improved markedly after only one cycle of PDT. There was an absence of clinically detectable inflammation, edema, and rubor of the involved dental papillae. At the 4, 6, and 12 week follow-ups there were no recurrences. Conclusions: This case report highlights the first case of drug-induced gingival hypertrophy entirely treated with photodynamic therapy to be described in the literature. Therefore, although it is only a case report, this therapy which is free from side effects should be investigated as an alternative to current therapies.

Introduction

Drug-induced gingival overgrowth (DIGO) is a well-known clinical condition. DIGO is clinically characterized by hyperplasia of the gingival connective tissue which appears edematous, bloody, and purplish-red in color.[1] Furthermore, the most commonly affected site is keratinized mucosa on the maxillary and anterior mandibular vestibular sides.[1] In severe cases, DIGO can cover the entire surface of the teeth compromising chewing, occlusion and esthetics, as well as adequate maintenance of oral hygiene practices.[2,3] The literature shows that three types of drugs are mainly associated with DIGO:

- anticonvulsants (phenytoin);

- immunosuppressants (cyclosporine A);

- calcium channel blockers (Nifedipine, Verapamil, diltiazem).[4]

In particular, cyclosporine induced gingival overgrowth affects 25%–81% of patients and usually occurs within 6 months of starting treatment.[5,6] Another problem is the high recurrence rate of this condition.[6] Although numerous studies have been performed, the etiopathogenetic mechanisms underlying drug-induced gingival hyperplasia are still unclear.[7] Some studies have shown an increase in the proliferation of gingival fibroblasts and keratinocytes, an over-regulation of some salivary inflammatory cytokines including interleukin (IL) -1α, IL-6, and IL-8, and an increase in cellular apoptotic processes.[1,5] Furthermore, chronic irritative factors including tartar and dental plaque are determinants in the most severe and massive pictures of drug-induced gingival hyperplasia.[8] DIGO therapy is controversial and, in fact, there are no studies in the literature that highlight a well-defined therapeutic protocol. In some cases, it may be useful to suspend the drug and replace it, with all the complications that may arise.[8] In the literature, numerous studies have shown that scaling and root planing have given good results.[9-11] The rationale behind this therapy is the reduction in inflammation and the mechanical removal of plaque and tartar.[12] Often, when non-surgical periodontal therapy does not lead to an effective reduction in DIGO, surgical treatment follows, that is, the removal of the hyperplasic gingiva with a cold or electric scalpel.[13,14] Unfortunately, such treatments are not well tolerated by patients because of the adverse effects such as local bleeding, surgery times, post-operative pain, infectious complications, and adherence to a liquid and cold diet in the following weeks.[15,16] It would therefore be interesting to evaluate the clinical efficacy of other unconventional therapies. The light-emitting diode (LED) was developed in 1962 by an American electrical engineer called Nick Holonyak JR. It is a special type of diode capable of emitting a small amount of light when passed through an electric current. Starting from this technological innovation, researchers have been able to develop LEDs with different wavelengths and with a photon density clinically useful for the treatment of an extended area of   the target tissue. They are also characterized by high reliability, long life, high efficiency, and low consumption. The use of LEDs at certain wavelengths allows the activation of specific photosensitizers, which is known as photodynamic therapy (PDT). Today, technology has led us to have increasingly high-performance and small-sized LED lamps with tips specifically designed to work in limited environments such as those within the oral cavity.[17] There are many fields of application of PDT in dentistry,[18] for example, in the treatment of periodontitis,[19] Herpes simplex infections,[20,21] oral lichen planus,[22,23] leukoplakia,[24,25] as well as squamous cell carcinoma.[26] The aim of this work is thus to illustrate a case of drug-induced hyperplasia healing in a patient with rheumatoid arthritis by means of PDT.

Design and methods

An 18 year-old patient suffering from gingival swelling was brought to our attention (Figures 1 and 2). She had been suffering for 5 months from increasing gingival enlargement in maxillary and mandibular teeth and also gingival bleeding while brushing her teeth or eating. She had a history of rheumatoid arthritis localized in her left knee, which had been treated with oral cyclosporine (10 mg once daily) for the past 5 years. The patient also has good control of home oral hygiene. It was decided to try treatment with PDT with the aim of reducing inflammation and the bacterial load on the sites involved. PDT was performed with LED at a power of 450–470 nm and 5500 mW/cm2 + 7500 mW / cm2 (lumina max lad, Dentalica, Italy), combined with a Curcuma longa-based photosensitizer (Figure 3). A single session was performed, with applications of about 30 s for each interdental papilla between 1.3 and 2.3, and between 3.3 and 4.3 (Figure 4) after the introduction of the photosensitizer (both in the pocket and on the vestibular side of the papillae). The latter consisted of 3% H2O2 + Curcuma longa powder, mixed with distilled water to reach a volume of 1.5 ml. The product was shaken and used after a few minutes, sprinkling the sites to be treated. The light was emitted by a long blunt 8 mm tip and then activated at a distance of 0.5 cm from the lesion. At the end of the application, the dye was removed with the aid of a sterile gauze and physiological solution.

Figure 1.

Initial clinical condition of the patient in frontal view.

Figure 2.

Initial clinical condition of the patient in lateral view.

Figure 3.

Application of the photosensitizer.

Figure 4.

Expert categorizations of violin and saxophone videos.

Results

The patient improved markedly after only one cycle of PDT. There was an absence of clinically-detectable inflammation, edema, and rubor of the involved dental papillae (Figures 5 and 6). At the 4, 6, and 12 week follow-ups there were no recurrences. A noteworthy aspect is that the patient was not subjected to any oral hygiene practices in the outpatient setting and therefore the therapeutic effects are entirely attributable to PDT.

Figure 5.

Clinical condition after photodynamic therapy in frontal view.

Figure 6.

Clinical condition after photodynamic therapy in lateral view.

Discussion

PDT is an unconventional therapy used in numerous branches of medicine.[27] PTD’s mechanism of action is based on the application of a photosensitive compound called photosensitizer which has a high affinity for damaged or infected cells. The photosensitizer absorbs light at a certain wavelength, activating itself, and leading to the selective elimination of damaged cells.[28] In fact, during this phase, reaction processes take place involving molecular oxygen with the consequent formation of reactive oxygen species (ROS) capable of stimulating the cell death circuits of microorganisms and infected cells.[29] The great advantage of PDT is that the photosensitizer only accumulates in damaged tissues, resulting in selective destruction.[30] The causes of the high affinity to damaged tissues could be justified by the high affinity of the photosensitizer to low density lipoproteins (LDL). These have the role of providing the cholesterol necessary to build cell membranes during cell division.[31] Clinically, this affinity translates into a complete absence of PTD side effects.[32,33] In addition, PDT is painless, extremely practical, repeatable and simple to perform, making it particularly suitable for outpatient clinical practice. In fact, these properties are the reason why PDT is widely used in oral medicine and dentistry,[34-40] but the search for new PTs effective against the most common oral pathologies remains however worthy of note. The photosensitizer used in this case report was curcumin. In particular, curcumin, extracted from the rhizomes of the Curcuma longa plant, is emerging in the literature on account of its anti-inflammatory, antibacterial, antiviral, and anticancer properties.[41-43] Furthermore, numerous studies in the literature have highlighted the immunomodulating properties of curcumin in patients with HIV, Alzheimer’s disease, and multiple sclerosis.[44-50] A key property for its use as a photosensitizer is that the light absorption peak of curcumin is around 400–500 nm.[51] The uniqueness of this study is the lack of any studies on the application of PDT in the treatment of DIGOs. In fact, only one work in the literature used PDT with a diode laser (810 nm) only after having performed Er: YAG laser-assisted gingivectomy & gingivoplasty (2940 nm).[52] Based on the evidence available from RCTs and recent meta-analyses, a very recent narrative review by Sculean et al. found that the combination of scaling and root planing and PDT in patients with mild to moderate periodontitis can lead to clinical improvements that are significantly greater than root planning alone in non-surgical treatment. In cases of stage III and grade IV periodontitis, PDT provides clinical improvements, although PDT cannot be replaced with systemic antibiotic therapy (based on amoxicillin and metronidazole). Furthermore, it is noted that PDT may be indicated as a useful tool for the treatment of moderate residual periodontal pockets during maintenance therapy.[53] In particular, Sreedhar et al. also demonstrated that photodynamic therapy with curcumin has been shown to be useful as an adjunct to non-surgical periodontal therapy. Furthermore, multiple cycles of PDT are more beneficial for the improvement of clinical and microbiological parameters than a single application.[54] It is important to emphasize that rheumatoid arthritis is an autoimmune disease that has long been associated with periodontal disease and recent studies on the oral microbiome have highlighted its role in arthritis.[55-57] An association was clearly demonstrated between the abundance of oral Porphyromonas gingivalis in patients with rheumatoid arthritis compared to healthy controls.[58] The study by Mahdi et al. found that PDT using only/just curcumin, hydrogen peroxide, and erythrosine as photosensitizers exerted a moderate bactericidal effect on P. gingivalis which greatly improved in conjugation with visible light.59 The survival rate of P. gingivalis reached zero percent when the suspension was exposed to blue-light-activated curcumin and hydrogen peroxide for 2 min. Furthermore, curcumin exerted a notable antibacterial activity against F. nucleatum compared to erythrosine and hydrogen peroxide (p = 0.00). Therefore, in this specific case, PDT with curcumin could have also determined significant therapeutic effects on the systemic pathology. Therefore, although this is only a case report, with all the limitations present, it is important not to underestimate PDT with curcumin in the treatment of DIGOs precisely because of the results obtained and the absence of comorbidities and side effects that would have been obtained by changing the drug.