Case Report/Clinical Technique
A Case of SAPHO Syndrome with Endodontic Implications and Treatment with Biologic Drugs Elisabetta Cotti, DDS, MS,* Roberto Careddu, DDS,* Elia Schirru, DDS,† Silvia Marongiu, MD,‡ Maria Pina Barca, MD,‡ Paolo Emilio Manconi, MD,‡ and Giuseppe Mercuro, MD‡ Abstract Introduction: SAPHO syndrome (SS) is an autoinflammatory disease characterized by synovitis, acne, pustulosis, hyperostosis, and osteitis. Among the sites affected by the osteoarticular manifestations of SS are the anterior chest wall and the mandible. The etiology of SS is still unknown; theories advocate a genetic predisposition and an infectious cause in association with disorders of the immune system. Methods: We report a case of SS in which there was the involvement of the mandible with a lesion of endodontic origin. A 44-year-old white woman diagnosed with SS at the university hospital was referred to the Department of Conservative Dentistry and Endodontics for a consultation. She reported spontaneous pain localized to the periapical area of tooth #19 with a history of multiple restorative and endodontic treatments. It was diagnosed as a previously treated tooth with symptomatic apical periodontitis (AP) at the time of the endodontic evaluation. A second retreatment was then performed in 1 appointment under local anesthesia. During retreatment, a separated instrument and a ledge were found in the mesiobuccal canal, and attempts to bypass it were not successful; the canal was then obturated to the reachable length. Within the same month, the patient was also administered an anti–tumor necrosis factor alpha biologic medication in association with a disease-modifying antirheumatic drugs for the treatment of SS. Within 3 months, the overall therapy had led to a marked improvement of the systemic and mandibular symptoms, and a periapical radiograph showed almost complete healing of the lesion. Medical examinations have shown a total remission of signs and symptoms starting 6 months after the initiation of treatment. After 5 years, the disease is under control, and tooth #19 is symptom free and shows absence of AP. Conclusions: The endodontists need to be aware of
the existence of SS and the possible effects of the use of disease-modifying antirheumatic drugs and biologic medications on the treatment of persistent AP. (J Endod 2015;-:1–6)
Key Words Apical periodontitis, biologic medications, SAPHO syndrome
S
APHO is the acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis and is used to define a rare syndrome characterized by chronic inflammatory cutaneous and musculoskeletal disorders (1). There are not sufficient data to assess the prevalence of SAPHO syndrome (SS) and its distribution in different countries, but some authors estimate it to be approximately 1 in 10,000 in whites (2, 3); it predominantly occurs in young females (4, 5). The current classification for SS is primitive inflammatory osteitides in the spectrum of autoinflammatory diseases (6), and its etiology is still relatively unknown; current theories include a genetic predisposition (6–8) and an infectious (9, 10) or postinfectious cause in possible association with disorders of the immune system (11, 12). Microorganisms isolated from the lesions include Propionibacterium acnes and Staphylococcus aureus; however, P. acnes is the most prevalent (13, 14). The typical onset of SS is accompanied by the gradual and episodic appearance of skeletal pain, which is usually localized in the anterior chest wall and is sometimes associated with unilateral or bilateral swelling of the sternoclavicular area (1, 15–17). The characteristic lesions of SS can be divided into osteoarticular manifestations, skin manifestations, and ‘‘other’’ manifestations (Table 1). Osteoarticular manifestations are represented by synovitis, hyperostosis, and osteitis. The sites more often affected are the anterior chest wall (70%–90%), the rachis (30%–60%), the sacroiliac joints (30%–40%), the peripheral joints (30%) (18), and the mandible (10%) (19, 20). The clinical features of mandibular involvement of SS include ankylosis of the temporomandibular joint and, more frequently, chronic osteitis (20). The lesions, which are often quite extensive and can affect the entire jaw, may present with pain and swelling of the bone but without suppurative events (21–23). Bone lesions of SAPHO do not belong to any specific class of osteomyelitis (24); therefore, it is difficult to make a differential diagnosis with other types of bone lesions (25). Cutaneous manifestations characteristic of SS are palmoplantar pustulosis and acne in different variants such as acne fulminans or acne conglobata; other cutaneous
From the Departments of *Conservative Dentistry and Endodontics and ‡Department of Medical Sciences, University of Cagliari, Cagliari, Italy; and †Department of Endodontology, King’s College Dental Institute, London, United Kingdom. Address requests for reprints to Dr Elisabetta Cotti, Department of Conservative Dentistry and Endodontics, University of Cagliari, Via Roma 149, 09124 Cagliari, Italy. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2015 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2015.04.005
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TABLE 1. Manifestations of the SAPHO Syndrome Body systems Osteoarticular
Skin
Other manifestations
Manifestations Hyperostosis Osteitis Limitation of motion Swelling Palmoplantar pustulosis Acne fulminans Acne conglobate Hydradenitis suppurativa Pyoderma gangrenosum Pustular psoriasis Crohn disease Ulcerative colitis
lesions are represented by Hidradenitis suppurativa and Pyoderma gangrenosum (15, 26). The radiographic patterns of mandibular lesions in SS have been classified as an ‘‘osteolytic pattern’’ characterized by bone resorption and a ‘‘mixed pattern’’ characterized by areas of both osteolysis and osteosclerosis and often accompanied by important resorptive defects (27). The diagnosis of SS is based on a correct medical history report with a careful examination of clinical signs and symptoms. Radiographic examinations are a fundamental complement to finalize the diagnosis. Regular radiographs can reveal the presence of bone lesions in more advanced stages of the syndrome (18). Bone scintigraphy with technetium-99m (m99Tc) is useful to disclose bone lesions (including in the mandible) and to evaluate, through the uptake of the radioactive tracer, the areas of most intense bone activity (26). 18F-Fluoro-deoxyglucose positron emission tomographic/computed tomographic (CT) imaging or magnetic resonance imaging can be alternatively used to monitor the activity of the lesions. CT imaging is often used for guided bone biopsies, which are important for making a differential diagnosis with neoplastic lesions and to verify the presence of bacteria within the lesion (18, 26, 28–30). A classification of the criteria used to differentially diagnose SS is represented in Table 2 (9, 31). To date, the therapy for SS is based on the use of nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs), corticosteroids, antibiotics, bisphosphonates, and biologic drugs. In some cases, a surgical approach may be necessary (32). We report a case of SAPHO syndrome in which there was involvement of the mandible with a concomitant lesion of endodontic origin.
In October 2009, a 44-year-old white woman was brought to the Department of Internal Medicine, University of Cagliari Hospital, Cagliari, Italy. She had marked asthenia and reported recent weight loss; a daily low-grade fever, and the progressive appearance of a hard, painful swelling in the left clavicle in the last month. She also reported pain in the left mandible (in the molar area), which irradiated to the neck and left shoulder. The clinical examination of the patient confirmed the chief complaints. Routine blood examination showed the presence of mild anemia (hemoglobin = 10.5 g/dL) and human leukocyte antigen B, increased erythrocyte sedimentation rate, and C-reactive protein. CT examination of the left clavicle revealed a complex bone pattern with ‘‘areas of hyperostosis and erosion of the cortical plate, sclerosis with obliteration of the medullary canal, presence of irregularly shaped bone lesions alternated with areas of newly formed bone tissue of variable density’’ as reported by the radiologist. CT imaging of the chest showed large and bilateral areas of erosion in the sternoclavicular joints. Whole-body bone scintigraphy showed areas of hypercaptation in the sternum, left clavicle, and left mandible (Fig. 1). After cardiovascular assessment, the patient underwent CT-guided biopsy in the left clavicle, which revealed the presence of reactive tissue of non-neoplastic origin with bone thickening and remodeling; no bacteria were isolated. The tentative diagnosis was SAPHO syndrome. While the patient was undergoing further examinations, she was referred to the Department of Conservative Dentistry and Endodontics at the university hospital for a consultation.
TABLE 2. Classification Criteria for SAPHO Syndrome Inclusion
Exclusion
Bone and/or joint involvement + PPP and PV Bone and/or joint involvement + severe acnes Chronic multifocal osteomyelitis in children Sterile hyperostosis in adults Bone and/or joint involvement + chronic bowel diseases
Bone tumors Noninflammatory condensing lesions of bone Osteitis
PPP, Palmoplantar pustulosis; PV, Pyoderma vegetans. Data from Govoni M, Colina M, Massara A, et al. Sapho syndrome and infections. AutoimmunRev 2009;8:256–9 (9) and Benhamou CL, Chamot AM, Kahn MF. Synovitis-acne-pustulosis hyperostosisosteomyelitis syndrome (SAPHO). A new syndrome among the spondyloarthropathies? Clin Exp Rheumatol 1988;6:109–12 (31). Based on a presentation by Kahn MF, ACR 67th Annual Scientific Meeting, 2003.
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Figure 1. Bone scintigraphy performed in 2009 shows areas of ipercaptation in the sternum, left clavicle, and left mandible (arrows).
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Case Report/Clinical Technique The patient reported the presence of moderate pain in the left mandible localized in the buccal periapical area corresponding to tooth #19. She also mentioned that tooth #19 had a history of multiple treatments over the past years. According to the patient’s records, in the last 10 years, tooth #19 had been restored twice because of recurrent caries, and, subsequently, after strong pain, the tooth received a root canal treatment. Six months after the first endodontic treatment, the symptoms had worsened, and retreatment had been performed. One year after retreatment, symptoms had not subsided, and at the same time, the patient had started to present the other systemic symptoms described previously. Because the patient had kept some dental records over the years, it was possible to verify most of the reported history of tooth #19. A panoramic radiograph dated 1998 showed an extensive restoration in tooth #19 (Fig. 2A), which was also visible in a second radiograph dated 2001 (Fig. 2B). At the time of the endodontic consultation (2009), the oral examination showed a hard swelling sensitive to palpation in the buccal mucosa around tooth #19 that was also tender to percussion. The panoramic radiograph revealed a periapical lesion corresponding to tooth #19 that appeared endodontically treated and restored (Fig. 2C). Ecographic examination showed an ‘‘echogenic,’’ solid, and vascularized lesion indicative of a possible granuloma (33) (Fig. 2D). The endodontic diagnosis was a previously treated tooth with symptomatic apical periodontitis. Together with the patient, it was decided to attempt a second retreatment after discussing the alternative options (surgery or extraction). The retreatment was performed in 1 appointment. A mandibular nerve block anesthesia using 1 carpule of lidocaine with adrenaline 1:100,000 was administered; the rubber dam was placed, and the access cavity was made using high speed with a round diamond bur and continuous water cooling. Upon opening the access cavity, the
internal part of a composite core was removed, and 3 canal orifices were localized. Gutta-percha was removed from the canals using a solvent (Endosolv E; Septodont, Saint Maur des Fosses, France), Gates Glidden burs #1 to #4, and hand instrumentation with K files #10 to #25 in a crown-down mode. During the removal of the gutta-percha and sealer from the canals, a ledge was localized in the apical third of the mesiobuccal canal, and a separated instrument was found (Fig. 3A). Attempts to bypass the instrument and the ledge were not successful; it was then decided to complete the retreatment and consider the future possibility of a surgery. The preparation of the root canals was completed with hand instrumentation using K files (K Flex Files; SybronEndo, Orange, CA), copious irrigation with 5% sodium hypochlorite, and a final rinse of 15% EDTA. The canals were dried and obturated using gutta-percha cones, sealer (Pulp Canal Sealer, SybronEndo), and a warm vertical compaction technique. The mesiobuccal canal was obturated to the length that was possible to reach; the access cavity was restored with dentinal adhesive and composite resin (Estelite; Tokuyama, Tokyo, Japan) (Fig. 3B). Because of the presence of symptoms and hard swelling, the patient was medicated with ibuprofen 600 mg every 6 hours for 48 hours and amoxicillin 500 mg every 6 hours for 7 days. The patient was contacted every day, and she explained that she had felt an exacerbation of the pain (even under the medications) the day after the treatment was completed and that she gradually felt better. Within the next month, based on further clinical findings and laboratory tests, the diagnosis of SAPHO syndrome was confirmed, and the treatment was based on the administration of an anti–tumor necrosis factor alpha (TNF-a) biologic medication in association with a DMARD (adalimumab [Humira, AbbVie, North Chicago, IL], 40 mg fortnightly; methotrexate [Rheumatrex, Dava, Fort Lee, NJ], 10 mg weekly). At the
Figure 2. (A) Detail from a panoramic radiograph dated 1998; it shows the presence of an extensive mesio-occlusal-distal restoration on tooth #19 (arrow). (B) Detail from a panoramic radiograph dated 2001; the restoration on tooth #19 is still visible, and there are no signs of AP. (C) October 2009: detail from a panoramic radiograph (at the time of our first evaluation). It discloses the presence of a new restoration on tooth# 19; the tooth has been treated endodontically, and there are signs of apical periodontitis (arrow). (D) October 2009: the echographic examination performed in the periapical area of tooth #19 (circled) displays an echogenic, solid, and vascularized lesion indicative of a possible granuloma.
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Figure 3. (A) October 2009: the intraoperative radiograph shows a separated instrument in the mesiobuccal canal (arrow) and confirms the presence of AP. (B) October 2009: a radiograph showing the retreatment completed in tooth #19. (C) February 2010: an intraoral radiograph of tooth #19 at the 3-month followup showing healing of apical periodontitis. (D) April 2014: an intraoral radiograph of tooth #19 at the 4-year follow-up showing a healthy periapical bone.
1-month follow-up, she was experiencing a diminished tenderness to palpation and percussion, and the hard swelling in the mandible was reduced. Within 3 months, the overall therapy had led to a marked improvement of the systemic symptoms with attenuation of the osteoarticular pain, disappearance of the skin lesions, and normalization of the inflammatory markers. The mandibular swelling had disappeared, and the patient was symptom free. An intraoral radiograph showed almost complete healing of the lesion at the 3-month recall (Fig. 3C). Six months after initiation of the therapy, the patient reported a subjective state of well-being, and clinical examinations showed a total remission of signs and symptoms. All instrumental investigations performed in the medical follow-up showed that conditions had considerably improved compared with the initial state. The investigations performed both clinically and radiographically in tooth #19 showed an absence of symptoms, which was associated with radiographic healing of the lesion in the mandible despite the impossibility to complete successful retreatment (Fig. 3D). The patient has been kept under treatment for SS for the last 5 years; although she has experienced times of new exacerbation of general symptoms, her state is considered stabilized. The latest recall on tooth #19 showed an absence of symptoms and healing of the apical periodontitis.
Discussion SAPHO syndrome is a disease that associates osteoarticular manifestations with other clinical signs, mainly skin lesions. Its etiology is still unknown although the most likely hypothesis is that SS is an autoinflammatory disease triggered in genetically predisposed subjects by an infectious event caused by a low virulence pathogen (1–12, 15–27). 4
Cotti et al.
The close interaction between infection and rheumatic diseases has extensively been studied; infectious agents may be the basis of a phenomenon called molecular mimicry that leads to the creation of a crossreactive immune response that affects self-structures (11, 34). To date, P. acnes is the microorganism most strongly related to SS; it has been isolated in cutaneous lesions and 42%–67% of bone biopsies of patients with the syndrome (9, 10, 26, 34, 35). It was stipulated that P. acnes could be the cause of the immune stimulation against the self-structures in this syndrome (36–38). Studies on P. acnes have shown its ability to stimulate the production of interleukin (IL)-1, IL-8, and TNF-a by PMNs, which in patients with SS are less concentrated (because of a desensitization probably linked to the chronic infection by P. acnes) (12, 39). In addition, components of P. acnes have immune modulatory activity modulated by Toll-like receptor 9 (34, 38). It has also been shown that P. acnes can trigger a nonspecific activation of cell-mediated immunity; the immune response that follows may be an attempt to remove the bacterium, potentially promoting continuation of the inflammation (9). Because P. acnes has not been consistently isolated from all biopsies from SAPHO patients, it can be speculated that this microorganism can survive in forms that are noncultivable in common culture media or that the body is actually able to remove it (9, 39). P. acnes has been associated with other bacteria with the persistence of endodontic infections that are resistant to treatment (40–42). In the present case report, the patient was able to provide us with most of her dental records, which made it possible to follow the history of tooth #19 from early restoration to development of an apical periodontitis that was refractory to the first endodontic treatment. When it was decided to perform a second retreatment because of the persistence of symptoms, the timing coincided with the appearance of systemic symptoms of SAPHO and the consultation at the Department of JOE — Volume -, Number -, - 2015
Case Report/Clinical Technique Endodontics. At the same time that the endodontic retreatment was completed on tooth #19, the diagnosis of SAPHO was confirmed, and administration of the systemic therapy (anti–TNF-a biologic medication in association with methotrexate) was started. Biologic medications are a class of drugs created by genetic engineering. They act against specific targets including TNF-a, IL-1, IL-6, T cells, or B cells, reducing or blocking their activity. The use of these drugs has been associated with several chronic inflammatory diseases such as rheumatoid arthritis, Crohn disease, and many other rheumatic and autoimmune disorders (43). Biologics are now being prescribed for the treatment of osteoporosis (44), and the use of an anti–IL-b for the secondary prevention of cardiovascular disease, based on the inflammatory hypothesis of atherothrombosis, is currently being evaluated in an ongoing clinical trial (45). Adalimumab, a recombinant human immunoglobulin G monoclonal antibody, binds the TNF-a and prevents its interaction with the cell-surface TNF receptors (43). All biologic drugs could increase the risk of infection or set the ground for the reactivation of previous infections; the interferences of biologics on the treatment of chronic dental diseases like AP is still not completely known (43, 46). Methotrexate is a DMARD and acts as a competitive inhibitor of dihydrofolate reductase, with a spectrum of action that varies from antimalignant therapy to anti-inflammatory (43, 47). After pharmacologic treatment of the syndrome and endodontic retreatment, the patient experienced a marked decrease in both systemic and mandibular pain symptoms. Apical periodontitis showed fast radiographic healing as well. This clinical case raises the question of whether the endodontic infection that happened some years ago may have acted as a trigger for the syndrome (in a likely genetically predisposed subject) by stimulating an immune response and creating a shift toward an autoimmune disease. On the other hand, the healing of apical periodontitis (refractory to the first endodontic treatment and retreatment) after the pharmacologic treatment of a major systemic syndrome may suggest that the overall medical treatment may have influenced the results of the endodontic retreatment.
Conclusions The existence and features of the SAPHO syndrome need to be brought to the attention of endodontists. The understanding and ability to diagnose this syndrome, especially in cases in which the oral region is the only or the first affected area, may allow an early diagnosis of the syndrome and the differential diagnosis with other diseases. The administration of methotrexate and anti–TNF-a biologic medication may have influenced the healing of the persistent apical periodontitis, and this potential role needs to be further investigated. Furthermore, the possible association of the disease with an endodontic infection can raise awareness about the possible association between endodontic infection and systemic diseases.
Acknowledgments The authors deny any conflicts of interest related to this study.
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41. Assmann G, Kueck O, Kirchhoff T, et al. Efficacy of antibiotic therapy for SAPHO syndrome is lost after its discontinuation: Interventional study. Arthritis Res Ther 2009; 11:R140. 42. Niazi SA, Clarke D, Do T, et al. Propionibacterium acnes and Staphylococcus epidermidis isolated from refractory endodontic lesions are opportunistic pathogens. J Clin Microbiol 2010;48:3859–69. 43. Cotti E, Schirru E, Acquas E, et al. An overview on biologic medications and their possible role in apical periodontitis. J Endod 2014;40:1902–11. 44. Cummings SR, San Martin J, McClung MR, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2009;362:756–65. 45. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1b inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab antiinflammatory thrombosis outcomes study (CANTOS). Am Heart J 2011;162:597–605. 46. Guivarc’h M, Ordioni U, Jean-Hugues C, et al. Implications of endodontic-related sinus aspergillosis in a patient treated by infliximab: a case report. J Endod 2015;41:125–9. 47. Chan ES, Cronstein BN. Methotrexate—how does it really work? Nat Rev Rheumatol 2010;6:175–8.
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A Case of SAPHO Syndrome with Endodontic Implications and Treatment with Biologic Drugs Elisabetta Cotti, DDS, MS,* Roberto Careddu, DDS,* Elia Schirru, DDS,† Silvia Marongiu, MD,‡ Maria Pina Barca, MD,‡ Paolo Emilio Manconi, MD,‡ and Giuseppe Mercuro, MD‡ Abstract Introduction: SAPHO syndrome (SS) is an autoinflammatory disease characterized by synovitis, acne, pustulosis, hyperostosis, and osteitis. Among the sites affected by the osteoarticular manifestations of SS are the anterior chest wall and the mandible. The etiology of SS is still unknown; theories advocate a genetic predisposition and an infectious cause in association with disorders of the immune system. Methods: We report a case of SS in which there was the involvement of the mandible with a lesion of endodontic origin. A 44-year-old white woman diagnosed with SS at the university hospital was referred to the Department of Conservative Dentistry and Endodontics for a consultation. She reported spontaneous pain localized to the periapical area of tooth #19 with a history of multiple restorative and endodontic treatments. It was diagnosed as a previously treated tooth with symptomatic apical periodontitis (AP) at the time of the endodontic evaluation. A second retreatment was then performed in 1 appointment under local anesthesia. During retreatment, a separated instrument and a ledge were found in the mesiobuccal canal, and attempts to bypass it were not successful; the canal was then obturated to the reachable length. Within the same month, the patient was also administered an anti–tumor necrosis factor alpha biologic medication in association with a disease-modifying antirheumatic drugs for the treatment of SS. Within 3 months, the overall therapy had led to a marked improvement of the systemic and mandibular symptoms, and a periapical radiograph showed almost complete healing of the lesion. Medical examinations have shown a total remission of signs and symptoms starting 6 months after the initiation of treatment. After 5 years, the disease is under control, and tooth #19 is symptom free and shows absence of AP. Conclusions: The endodontists need to be aware of
the existence of SS and the possible effects of the use of disease-modifying antirheumatic drugs and biologic medications on the treatment of persistent AP. (J Endod 2015;-:1–6)
Key Words Apical periodontitis, biologic medications, SAPHO syndrome
S
APHO is the acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis and is used to define a rare syndrome characterized by chronic inflammatory cutaneous and musculoskeletal disorders (1). There are not sufficient data to assess the prevalence of SAPHO syndrome (SS) and its distribution in different countries, but some authors estimate it to be approximately 1 in 10,000 in whites (2, 3); it predominantly occurs in young females (4, 5). The current classification for SS is primitive inflammatory osteitides in the spectrum of autoinflammatory diseases (6), and its etiology is still relatively unknown; current theories include a genetic predisposition (6–8) and an infectious (9, 10) or postinfectious cause in possible association with disorders of the immune system (11, 12). Microorganisms isolated from the lesions include Propionibacterium acnes and Staphylococcus aureus; however, P. acnes is the most prevalent (13, 14). The typical onset of SS is accompanied by the gradual and episodic appearance of skeletal pain, which is usually localized in the anterior chest wall and is sometimes associated with unilateral or bilateral swelling of the sternoclavicular area (1, 15–17). The characteristic lesions of SS can be divided into osteoarticular manifestations, skin manifestations, and ‘‘other’’ manifestations (Table 1). Osteoarticular manifestations are represented by synovitis, hyperostosis, and osteitis. The sites more often affected are the anterior chest wall (70%–90%), the rachis (30%–60%), the sacroiliac joints (30%–40%), the peripheral joints (30%) (18), and the mandible (10%) (19, 20). The clinical features of mandibular involvement of SS include ankylosis of the temporomandibular joint and, more frequently, chronic osteitis (20). The lesions, which are often quite extensive and can affect the entire jaw, may present with pain and swelling of the bone but without suppurative events (21–23). Bone lesions of SAPHO do not belong to any specific class of osteomyelitis (24); therefore, it is difficult to make a differential diagnosis with other types of bone lesions (25). Cutaneous manifestations characteristic of SS are palmoplantar pustulosis and acne in different variants such as acne fulminans or acne conglobata; other cutaneous
From the Departments of *Conservative Dentistry and Endodontics and ‡Department of Medical Sciences, University of Cagliari, Cagliari, Italy; and †Department of Endodontology, King’s College Dental Institute, London, United Kingdom. Address requests for reprints to Dr Elisabetta Cotti, Department of Conservative Dentistry and Endodontics, University of Cagliari, Via Roma 149, 09124 Cagliari, Italy. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2015 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2015.04.005
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TABLE 1. Manifestations of the SAPHO Syndrome Body systems Osteoarticular
Skin
Other manifestations
Manifestations Hyperostosis Osteitis Limitation of motion Swelling Palmoplantar pustulosis Acne fulminans Acne conglobate Hydradenitis suppurativa Pyoderma gangrenosum Pustular psoriasis Crohn disease Ulcerative colitis
lesions are represented by Hidradenitis suppurativa and Pyoderma gangrenosum (15, 26). The radiographic patterns of mandibular lesions in SS have been classified as an ‘‘osteolytic pattern’’ characterized by bone resorption and a ‘‘mixed pattern’’ characterized by areas of both osteolysis and osteosclerosis and often accompanied by important resorptive defects (27). The diagnosis of SS is based on a correct medical history report with a careful examination of clinical signs and symptoms. Radiographic examinations are a fundamental complement to finalize the diagnosis. Regular radiographs can reveal the presence of bone lesions in more advanced stages of the syndrome (18). Bone scintigraphy with technetium-99m (m99Tc) is useful to disclose bone lesions (including in the mandible) and to evaluate, through the uptake of the radioactive tracer, the areas of most intense bone activity (26). 18F-Fluoro-deoxyglucose positron emission tomographic/computed tomographic (CT) imaging or magnetic resonance imaging can be alternatively used to monitor the activity of the lesions. CT imaging is often used for guided bone biopsies, which are important for making a differential diagnosis with neoplastic lesions and to verify the presence of bacteria within the lesion (18, 26, 28–30). A classification of the criteria used to differentially diagnose SS is represented in Table 2 (9, 31). To date, the therapy for SS is based on the use of nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs), corticosteroids, antibiotics, bisphosphonates, and biologic drugs. In some cases, a surgical approach may be necessary (32). We report a case of SAPHO syndrome in which there was involvement of the mandible with a concomitant lesion of endodontic origin.
In October 2009, a 44-year-old white woman was brought to the Department of Internal Medicine, University of Cagliari Hospital, Cagliari, Italy. She had marked asthenia and reported recent weight loss; a daily low-grade fever, and the progressive appearance of a hard, painful swelling in the left clavicle in the last month. She also reported pain in the left mandible (in the molar area), which irradiated to the neck and left shoulder. The clinical examination of the patient confirmed the chief complaints. Routine blood examination showed the presence of mild anemia (hemoglobin = 10.5 g/dL) and human leukocyte antigen B, increased erythrocyte sedimentation rate, and C-reactive protein. CT examination of the left clavicle revealed a complex bone pattern with ‘‘areas of hyperostosis and erosion of the cortical plate, sclerosis with obliteration of the medullary canal, presence of irregularly shaped bone lesions alternated with areas of newly formed bone tissue of variable density’’ as reported by the radiologist. CT imaging of the chest showed large and bilateral areas of erosion in the sternoclavicular joints. Whole-body bone scintigraphy showed areas of hypercaptation in the sternum, left clavicle, and left mandible (Fig. 1). After cardiovascular assessment, the patient underwent CT-guided biopsy in the left clavicle, which revealed the presence of reactive tissue of non-neoplastic origin with bone thickening and remodeling; no bacteria were isolated. The tentative diagnosis was SAPHO syndrome. While the patient was undergoing further examinations, she was referred to the Department of Conservative Dentistry and Endodontics at the university hospital for a consultation.
TABLE 2. Classification Criteria for SAPHO Syndrome Inclusion
Exclusion
Bone and/or joint involvement + PPP and PV Bone and/or joint involvement + severe acnes Chronic multifocal osteomyelitis in children Sterile hyperostosis in adults Bone and/or joint involvement + chronic bowel diseases
Bone tumors Noninflammatory condensing lesions of bone Osteitis
PPP, Palmoplantar pustulosis; PV, Pyoderma vegetans. Data from Govoni M, Colina M, Massara A, et al. Sapho syndrome and infections. AutoimmunRev 2009;8:256–9 (9) and Benhamou CL, Chamot AM, Kahn MF. Synovitis-acne-pustulosis hyperostosisosteomyelitis syndrome (SAPHO). A new syndrome among the spondyloarthropathies? Clin Exp Rheumatol 1988;6:109–12 (31). Based on a presentation by Kahn MF, ACR 67th Annual Scientific Meeting, 2003.
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Figure 1. Bone scintigraphy performed in 2009 shows areas of ipercaptation in the sternum, left clavicle, and left mandible (arrows).
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Case Report/Clinical Technique The patient reported the presence of moderate pain in the left mandible localized in the buccal periapical area corresponding to tooth #19. She also mentioned that tooth #19 had a history of multiple treatments over the past years. According to the patient’s records, in the last 10 years, tooth #19 had been restored twice because of recurrent caries, and, subsequently, after strong pain, the tooth received a root canal treatment. Six months after the first endodontic treatment, the symptoms had worsened, and retreatment had been performed. One year after retreatment, symptoms had not subsided, and at the same time, the patient had started to present the other systemic symptoms described previously. Because the patient had kept some dental records over the years, it was possible to verify most of the reported history of tooth #19. A panoramic radiograph dated 1998 showed an extensive restoration in tooth #19 (Fig. 2A), which was also visible in a second radiograph dated 2001 (Fig. 2B). At the time of the endodontic consultation (2009), the oral examination showed a hard swelling sensitive to palpation in the buccal mucosa around tooth #19 that was also tender to percussion. The panoramic radiograph revealed a periapical lesion corresponding to tooth #19 that appeared endodontically treated and restored (Fig. 2C). Ecographic examination showed an ‘‘echogenic,’’ solid, and vascularized lesion indicative of a possible granuloma (33) (Fig. 2D). The endodontic diagnosis was a previously treated tooth with symptomatic apical periodontitis. Together with the patient, it was decided to attempt a second retreatment after discussing the alternative options (surgery or extraction). The retreatment was performed in 1 appointment. A mandibular nerve block anesthesia using 1 carpule of lidocaine with adrenaline 1:100,000 was administered; the rubber dam was placed, and the access cavity was made using high speed with a round diamond bur and continuous water cooling. Upon opening the access cavity, the
internal part of a composite core was removed, and 3 canal orifices were localized. Gutta-percha was removed from the canals using a solvent (Endosolv E; Septodont, Saint Maur des Fosses, France), Gates Glidden burs #1 to #4, and hand instrumentation with K files #10 to #25 in a crown-down mode. During the removal of the gutta-percha and sealer from the canals, a ledge was localized in the apical third of the mesiobuccal canal, and a separated instrument was found (Fig. 3A). Attempts to bypass the instrument and the ledge were not successful; it was then decided to complete the retreatment and consider the future possibility of a surgery. The preparation of the root canals was completed with hand instrumentation using K files (K Flex Files; SybronEndo, Orange, CA), copious irrigation with 5% sodium hypochlorite, and a final rinse of 15% EDTA. The canals were dried and obturated using gutta-percha cones, sealer (Pulp Canal Sealer, SybronEndo), and a warm vertical compaction technique. The mesiobuccal canal was obturated to the length that was possible to reach; the access cavity was restored with dentinal adhesive and composite resin (Estelite; Tokuyama, Tokyo, Japan) (Fig. 3B). Because of the presence of symptoms and hard swelling, the patient was medicated with ibuprofen 600 mg every 6 hours for 48 hours and amoxicillin 500 mg every 6 hours for 7 days. The patient was contacted every day, and she explained that she had felt an exacerbation of the pain (even under the medications) the day after the treatment was completed and that she gradually felt better. Within the next month, based on further clinical findings and laboratory tests, the diagnosis of SAPHO syndrome was confirmed, and the treatment was based on the administration of an anti–tumor necrosis factor alpha (TNF-a) biologic medication in association with a DMARD (adalimumab [Humira, AbbVie, North Chicago, IL], 40 mg fortnightly; methotrexate [Rheumatrex, Dava, Fort Lee, NJ], 10 mg weekly). At the
Figure 2. (A) Detail from a panoramic radiograph dated 1998; it shows the presence of an extensive mesio-occlusal-distal restoration on tooth #19 (arrow). (B) Detail from a panoramic radiograph dated 2001; the restoration on tooth #19 is still visible, and there are no signs of AP. (C) October 2009: detail from a panoramic radiograph (at the time of our first evaluation). It discloses the presence of a new restoration on tooth# 19; the tooth has been treated endodontically, and there are signs of apical periodontitis (arrow). (D) October 2009: the echographic examination performed in the periapical area of tooth #19 (circled) displays an echogenic, solid, and vascularized lesion indicative of a possible granuloma.
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Figure 3. (A) October 2009: the intraoperative radiograph shows a separated instrument in the mesiobuccal canal (arrow) and confirms the presence of AP. (B) October 2009: a radiograph showing the retreatment completed in tooth #19. (C) February 2010: an intraoral radiograph of tooth #19 at the 3-month followup showing healing of apical periodontitis. (D) April 2014: an intraoral radiograph of tooth #19 at the 4-year follow-up showing a healthy periapical bone.
1-month follow-up, she was experiencing a diminished tenderness to palpation and percussion, and the hard swelling in the mandible was reduced. Within 3 months, the overall therapy had led to a marked improvement of the systemic symptoms with attenuation of the osteoarticular pain, disappearance of the skin lesions, and normalization of the inflammatory markers. The mandibular swelling had disappeared, and the patient was symptom free. An intraoral radiograph showed almost complete healing of the lesion at the 3-month recall (Fig. 3C). Six months after initiation of the therapy, the patient reported a subjective state of well-being, and clinical examinations showed a total remission of signs and symptoms. All instrumental investigations performed in the medical follow-up showed that conditions had considerably improved compared with the initial state. The investigations performed both clinically and radiographically in tooth #19 showed an absence of symptoms, which was associated with radiographic healing of the lesion in the mandible despite the impossibility to complete successful retreatment (Fig. 3D). The patient has been kept under treatment for SS for the last 5 years; although she has experienced times of new exacerbation of general symptoms, her state is considered stabilized. The latest recall on tooth #19 showed an absence of symptoms and healing of the apical periodontitis.
Discussion SAPHO syndrome is a disease that associates osteoarticular manifestations with other clinical signs, mainly skin lesions. Its etiology is still unknown although the most likely hypothesis is that SS is an autoinflammatory disease triggered in genetically predisposed subjects by an infectious event caused by a low virulence pathogen (1–12, 15–27). 4
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The close interaction between infection and rheumatic diseases has extensively been studied; infectious agents may be the basis of a phenomenon called molecular mimicry that leads to the creation of a crossreactive immune response that affects self-structures (11, 34). To date, P. acnes is the microorganism most strongly related to SS; it has been isolated in cutaneous lesions and 42%–67% of bone biopsies of patients with the syndrome (9, 10, 26, 34, 35). It was stipulated that P. acnes could be the cause of the immune stimulation against the self-structures in this syndrome (36–38). Studies on P. acnes have shown its ability to stimulate the production of interleukin (IL)-1, IL-8, and TNF-a by PMNs, which in patients with SS are less concentrated (because of a desensitization probably linked to the chronic infection by P. acnes) (12, 39). In addition, components of P. acnes have immune modulatory activity modulated by Toll-like receptor 9 (34, 38). It has also been shown that P. acnes can trigger a nonspecific activation of cell-mediated immunity; the immune response that follows may be an attempt to remove the bacterium, potentially promoting continuation of the inflammation (9). Because P. acnes has not been consistently isolated from all biopsies from SAPHO patients, it can be speculated that this microorganism can survive in forms that are noncultivable in common culture media or that the body is actually able to remove it (9, 39). P. acnes has been associated with other bacteria with the persistence of endodontic infections that are resistant to treatment (40–42). In the present case report, the patient was able to provide us with most of her dental records, which made it possible to follow the history of tooth #19 from early restoration to development of an apical periodontitis that was refractory to the first endodontic treatment. When it was decided to perform a second retreatment because of the persistence of symptoms, the timing coincided with the appearance of systemic symptoms of SAPHO and the consultation at the Department of JOE — Volume -, Number -, - 2015
Case Report/Clinical Technique Endodontics. At the same time that the endodontic retreatment was completed on tooth #19, the diagnosis of SAPHO was confirmed, and administration of the systemic therapy (anti–TNF-a biologic medication in association with methotrexate) was started. Biologic medications are a class of drugs created by genetic engineering. They act against specific targets including TNF-a, IL-1, IL-6, T cells, or B cells, reducing or blocking their activity. The use of these drugs has been associated with several chronic inflammatory diseases such as rheumatoid arthritis, Crohn disease, and many other rheumatic and autoimmune disorders (43). Biologics are now being prescribed for the treatment of osteoporosis (44), and the use of an anti–IL-b for the secondary prevention of cardiovascular disease, based on the inflammatory hypothesis of atherothrombosis, is currently being evaluated in an ongoing clinical trial (45). Adalimumab, a recombinant human immunoglobulin G monoclonal antibody, binds the TNF-a and prevents its interaction with the cell-surface TNF receptors (43). All biologic drugs could increase the risk of infection or set the ground for the reactivation of previous infections; the interferences of biologics on the treatment of chronic dental diseases like AP is still not completely known (43, 46). Methotrexate is a DMARD and acts as a competitive inhibitor of dihydrofolate reductase, with a spectrum of action that varies from antimalignant therapy to anti-inflammatory (43, 47). After pharmacologic treatment of the syndrome and endodontic retreatment, the patient experienced a marked decrease in both systemic and mandibular pain symptoms. Apical periodontitis showed fast radiographic healing as well. This clinical case raises the question of whether the endodontic infection that happened some years ago may have acted as a trigger for the syndrome (in a likely genetically predisposed subject) by stimulating an immune response and creating a shift toward an autoimmune disease. On the other hand, the healing of apical periodontitis (refractory to the first endodontic treatment and retreatment) after the pharmacologic treatment of a major systemic syndrome may suggest that the overall medical treatment may have influenced the results of the endodontic retreatment.
Conclusions The existence and features of the SAPHO syndrome need to be brought to the attention of endodontists. The understanding and ability to diagnose this syndrome, especially in cases in which the oral region is the only or the first affected area, may allow an early diagnosis of the syndrome and the differential diagnosis with other diseases. The administration of methotrexate and anti–TNF-a biologic medication may have influenced the healing of the persistent apical periodontitis, and this potential role needs to be further investigated. Furthermore, the possible association of the disease with an endodontic infection can raise awareness about the possible association between endodontic infection and systemic diseases.
Acknowledgments The authors deny any conflicts of interest related to this study.
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