Red blood-cell disorders have many different entities, but it seems that only few have an impact on periodontal tissues. Severe periodontal destruction has been reported in patients with aplastic anemia, sickle cell anemia, acatalasia and pernicious anemia (1). Aplastic anemia is a rare hematological disorder characterized by hypocellular bone marrow that produces insufficient number of hematopoietic stem cells, resulting in deficient cellular components such as erythrocytes, thrombocytes, and granulocytes (2). According to the definition of pancytopenia, the most severely affected patients present neutrophil counts of <200/μL, platelet counts of <20,000/μL, and reticulocyte counts of <60,000/μL (3). Because of this, a patient with aplastic anemia has a higher risk of infections. That is the reason why in patients with aplastic anemia the most common causes of death are bacterial sepsis and fungal infections (2). Brennan et al. evaluated the prevalence of oral manifestations in 79 patients with aplastic anemia. Intraoral patechiae were found in 27% of patients, spontaneous gingival bleeding and gingival hyperplasia were reported in 16% of the patients (4).
The aim of this case report is to present a 5-year follow-up of periodontal and prosthodontic treatment in a cyclosporine treated aplastic anemia patient.
A 26-year-old female patient was referred to the Department of Periodontology, School of Dental Medicine, Zagreb due to a painful and swelling gingiva. She had been in therapy for aplastic anemia (Anemia aplastica gravis) from the age of 16, and was hospitalized on several occasions because of the disease remissions. She gets regular check-ups in a hematological clinic, with an occasional supportive transfusion therapy. In an acute phase of anemia she was treated with corticosteroids. She had been taking 100mg of cyclosporine (Ciklosporin, Alkaloid, Skopje, Macedonia) per day, and 1 ampulla of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor, Neupogen, Roche-Pharma AG, Switzerland) twice a week, for 10 years. However, she lacked a comprehensive dental and periodontal treatment for that period of time. Although her last hematological findings revealed a well regulated blood cells count (Table 1), periodontal treatment was planned to be performed with an antibiotic supportive therapy.
MCV=mean cell volume
During the oral and periodontal examination an exceptionally poor oral hygiene was found; there was a presence of supra- and subgingival calculus, and a hyperplastic gingiva, especially in the upper frontal teeth with spontaneous bleeding (Figure 1). Oral-medical findings were assessed as normal. Pocket probing depth on every tooth was greater than 4 mm, and up to 12 mm in the upper frontal teeth, which were considered the most critical and severely mobile teeth (Table 2). Radiological examination revealed circumscribed radiolucent lesions on several teeth, especially in the upper front (Figure 2). There were also a number of missing teeth (18, 15, 22, 25, 28, 38, 36, 35, 45, 46, 48), without any prosthodontic rehabilitation. The patient stated that the teeth spontaneously exfoliated during her hospitalization periods. On the basis of the periodontal and radiographic findings, a severe periodontitis associated with hematological disorders (aplastic anemia) was diagnosed (5). Cyclosporine therapy also contributed to the periodontal condition. The patient signed consent for the standard periodontal treatment.
A commercially available polymerase chain reaction (PCR) test (MicroDent test, Hain Lifescience, Nehren, Germany) was utilized for the detection of five periodontal pathogens: Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola (Table 3). To ascertain if there was a genetic predisposition for periodontitis, a interleukin-1 (IL-1) polymorphism risk test (GenoType PST, Hain Lifescience, Nehren, Germany) for IL1A-889 and IL1B+3953 was also done.
(< 103=neg, 103-104= +, 104-105=++, 105-106=+++)
Severely mobile teeth with deep pockets (12, 11, 21, 23, 24) were assessed as having a poor prognosis, and were extracted the day prior to initial periodontal treatment. According to the concept of full-mouth periodontal therapy, a non-surgical treatment was performed in 2 consecutive days, and was supplemented with an antibiotic therapy (amoxicillin 500 mg (Amoxicilin, Pliva, Zagreb, Croatia) and metronidazole 400 mg (Medazol, Belupo, Koprivnica, Croatia), 3 times a day, for 8 days, and antifibrinolytic therapy (tranexamic acid 500 mg (Cyklokapron, Pfizer, Zagreb, Croatia) 4 times a day, for 5 days. The antifibrinolytic and antibiotic therapy started 2 days prior to extractions and non-surgical therapy. In addition, the patient was given instructions to rinse twice daily with a 0.2% chlorhexidine solution (Corsodyl® mouthrinse, GlaxoSmithKline Consumer Healthcare, Zagreb, Croatia) for 1 minute, until the next control appointment. Following the 3 month re-evaluation (Figure 3), prosthodontic rehabilitation was done with removable partial dentures in both the upper (12-25) and lower jaw (36, 45-46). Although the patient was young, due to her poor financial situation, this type of prosthodontic appliance was primarily fabricated and the fixed prosthodontic appliances or implant borne fixed partial dentures had to be dismissed. Because of the advanced periodontal disease and continuous cyclosporine therapy, the patient was placed on a periodontal supportive program every 2 months but she was not very compliant.
Following non-surgical periodontal treatment supplemented with antibiotics and antifibrinolytic regimen, the periodontal conditions greatly improved and were successfully maintained over a period of five years (Table 2). Although the patient was not entirely compliant, she maintained shallow pocket probing depths and radiographically there was no evidence of further bone loss (Figure 4). By evaluating the panoramic radiograph, it could be noted that there was bone gain in the furcation area of tooth 37, and on the mesial and distal aspects of tooth 34. The patient maintained acceptable oral hygiene and was satisfied with the prosthetic solution (Figure 5). There was a concern that the removable partial dentures were going to induce further deterioration of periodontal conditions on abutment teeth, but there was no further loss of periodontal attachment on these teeth exhibited by shallow pocket probing depths.
Repeated microbiological PCR test after 5 years still revealed the presence of putative periodontal pathogens: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola (Table 3) in high counts, in spite of the antibiotic regimen putting the patient at risk of further periodontal attachment loss. The periodontitis IL-1 polymorphism risk test showed negative results because of only one positive allele for IL1A-889 and IL1B+3953, respectively (Table 4).
Over the past decades, a growing body of evidence documented a relationship between periodontal infection and systemic diseases (6). Anemia represents a condition with decreased concentration of oxygen-transporting system in a certain volume of blood. It has been suggested that lower concentration of oxygen available to the tissues could be a modifying factor in the periodontal immune response (7). Cyclosporine is the first choice in the treatment of acquired aplastic anemia in patients which do not need transfusion. Data showed that treatment with cyclosporine leads to the sustained disease remission in 40% of patients with aplastic anemia (8). However, cyclosporine is also the drug that can be associated with hyperplastic gingival overgrowth, which is also reported for phenytoin and calcium channel blockers. These alterations usually start on the labial papillae, and over time adjacent hyperplastic papillae tend to "merge", as recorded in this case. Gingival overgrowth is always limited to the zone of attached gingiva (9). Aimetti et al. evaluated the clinical efficacy of periodontal therapy in patients with transplanted kidneys, liver or heart, who took cyclosporine A and had severe gingival hyperplasia. They found that non-surgical periodontal treatment leads to significant reductions of all clinical parameters, including a degree of gingival overgrowth (10). Similarly to the mentioned study, in our case the causal periodontal treatment was successful in resolving the inflammation, thus eliminating the need for surgical intervention. Kantarci et al. found that almost 60% of patients with gingival hyperplasia induced by cyclosporine have a fibrotic component, but they also managed to avoid the need for surgical procedures in 47% of the patients (11). Several authors published papers describing the response of patients with aplastic anemia to periodontal therapy. Oyaizu et al. described periodontal therapy in severe aplastic anemia, and stressed the importance of appropriate antibiotic prophylaxis and precautions for potential bleeding. It is important to emphasize that the risk of systemic infection is significantly increased in patients with aplastic anemia (12, 13). In our case, subgingival instrumentation was supplemented with amoxicillin and metronidazole. Also, periodontal therapy was performed only after the approval of the hematologist, who suggested the administration of tranexamic acid for 5 days. At the 5 year follow-up, the microbiological status was still unsatisfactory, which can be attributed to inadequate patient compliance during the maintenance phase. Still, periodontal conditions remained stable with no further loss of periodontal support and shallow pocket probing depths.
Considering the periodontal diagnosis and in order to determine the possible hereditary component, the patient was referred to IL-1 gene polymorphism testing, since the IL-1 genotype positive non-smokers have a 19 times higher risk of alveolar bone loss (14). However, findings of genotype PST test were negative.
With the widespread use of dental implants the chosen prosthodontic treatment could be seen as somewhat out of date, and it is a well-known fact that patients with removable dentures tend to have further loss of periodontal support on abutment teeth (15). Although we realized that implant borne restorations in such a patient would be more interesting, the incidence of peri-implantitis in patients with periodontal disease is very high (16), and the repeated microbiological testing in our patient revealed a recurrence of a high count of periodontal pathogens. Bearing in mind that there is a high number of implants harboring periodontal pathogens and Staphylococcus aureus (17), this could pose an even greater threat of infection in patients with aplastic anemia.
On the basis of oral findings, it can be concluded that aplastic anemia is a disease with an increased risk of onset of severe forms of periodontitis, which can be additionally complicated by cyclosporine therapy. In such patients, periodontal therapy must start as soon as possible with mandatory antibiotic supplement. Apart from the regular recall appointments, a close collaboration between the periodontist and the hematologist is necessary. This case report shows that even in patients with such a severe systemic disease, over a period of 5 years, periodontitis can be well controlled without further periodontal support deterioration.