http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(6): 1015–1018 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.874744
CASE REPORT
Severe inflammation associated with synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome was markedly ameliorated by single use of minocycline Yasunobu Takizawa1, Atsuko Murota1, Keigo Setoguchi1, and Yoshihisa Suzuki2 1Department of Allergy and Immunological Diseases, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan and 2Department of Orthopedics, Kyosai Tachikawa Hospital, Tokyo, Japan
Abstract
Keywords
We describe the case of a 63-year-old female who presented with severe inflammatory spondylitis, refractory to various antibiotics. Mycobacterial and fungal osteomyelitis were unlikely. Although asymptomatic, she also had osteomyelitis in the sternocostoclavicular region, and was suspected of having synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, against which minocycline showed marked efficacy. The presence of severe inflammatory SAPHO, albeit rare, together with the marked efficacy of tetracycline, should be noted.
SAPHO, Tetracycline, Propionibacterium acnes
Introduction SAPHO syndrome, an acronym for the combination of synovitis, acne, pustulosis, hyperostosis, and osteitis, has been established by Chamot and Kahn [1, 2] to describe a unique clinical entity affecting the bones, joints, and skin. SAPHO comprises such a wide spectrum of disorders that a number of clinicians include it in the group of immunological seronegative spondyloarthropathies [3–5], while others consider it a reactive osteitis against a specific infectious pathogen, such as Propionibacterium acnes (P. acnes) [5–7]; accordingly, the treatment strategy varies widely from immunosuppressive therapy to antibiotics [5, 7, 8]. Here, we describe a case of SAPHO syndrome with fever and severe low-back pain, which was resistant to various antibiotics on suspicion of infectious spondylitis and was finally improved with minocycline.
Case report A 63-year-old woman had been suffering from low-back pain for a prolonged period, but the pain became intense and she began to have a continuous fever above 38 °C in late April 2009. She visited the orthopedic department of another hospital on May 28, 2009. Physical examination revealed high body temperature of 40.2 °C. Her body weight decreased by 5 kg over 3 months. She complained of severe pain of the lower back, strongest around the thoracic–lumbar junction. Regardless of this, the musculoskeletal system was wholly intact. No abnormal finding was observed on examination of the head and neck, cardiopulmonary system, abdomen, nervous system, and skin. Laboratory data were as follows: white blood cell (WBC) count: 7,900/μL, red blood cell (RBC) count: 331 × 104/μL, hemoglobin: 84 g/L, platelets: 684 × 103/μL, erythrocyte sedimentation rate (ESR): 140 mm/h, and C-reactive protein (CRP): 198 mg/L. Correspondence to: Yasunobu Takizawa, Department of Allergy and Immunological Diseases, Tokyo, Japan. Metropolitan Komagome Hospital, Tokyo. E-mail: [email protected]
History Received 3 October 2012 Accepted 24 January 2013 Published online 11 February 2013
Other data of note were alkaline phosphatase: 615 (normal range: 115–359) IU/L, calcium: 2.0 mmol/L, phosphorus: 1.16 mmol/L, pyridinoline cross-linked carboxy terminal telopeptide of type collagen: 27.2 (−4.5) ng/mL, parathyroid hormone intact: 24 (10–65) pg/mL, total protein: 83 g/L, albumin: 25 g/L, lactate dehydrogenase: 211 (111–245) IU/L, immunoglobulin G (IgG): 28.65 (8.5–17) g/L, IgA: 8.6 (1.1–4.1) g/L, IgM: 0.66 (0.46–2.6) g/L, and no M-protein. Rheumatoid factor, antinuclear antibody, and anti-cyclic citrullinated peptide (CCP) antibody were negative. Her human leukocyte antigen (HLA) was A2, A31, B51, B52. Urianalysis was normal. X-ray showed sclerosis and mild compression of the vertebral bodies and ossified paraspinal ligaments, between the levels of Th10 and L2. On short inversion time inversion recovery (STIR) magnetic resonance imaging (MRI), high intensity was observed in the vertebrae and anterior longitudinal ligament between the levels of Th10 and L2. In addition, gadolinium enhancement was observed in most of the same part, being strongest in the anterior parts of the vertebral bodies and ligament. In contrast, no abnormal finding was observed in the discs (Figure 1a). Although no microbes were detected from blood culture and MRI findings were atypical in that the discs were spared from inflammation, the high fever, severe localized pain of the back, and marked increase of inflammatory markers strongly suggested septic spondylitis. Tuberculous spondylitis was considered as a relevant differential diagnosis, but vertebral biopsy was not attempted because the severest inflammation was seen adjacent to the aorta. Tuberculous skin test, as well as gastric lavage smear and culture for mycobacterium, were negative. Computed tomography (CT) of the neck, chest, and abdomen revealed no evidence of tuberculous infection. Cefazolin (1 week) was started, but it did not show any effect. Then, meropenem (1 week), vancomycin (1 month), and ceftazidime (1 month) were used as shown in Figure 2, but the high fever and severe back pain continued and ESR and CRP levels remained high as a whole. The combination of vancomycin and ceftazidime at first seemed to show some efficacy, but fever and CRP rose
1016
Y. Takizawa et al.
Mod Rheumatol, 2014; 24(6): 1015–1018
Figure 1. Radiological findings before introduction of minocycline. a Contrast enhancement on fat-suppressed MRI was observed in the vertebral bodies, especially in the anterior parts, as well as the longitudinal ligament between the levels of Th10 and L2, while the intervertebral discs were spared from inflammation. b, c Bone scintigraphy with lowered sensitivity (b) clearly revealed increased uptake in the right sternocostoclavicular region and vertebral bodies as well as the longitudinal ligament between Th10 and L2. In the one with normal sensitivity (c), mild uptake was observed as well in the os pubis and os ischii
again and remained high after about 1 month of use. Repeated blood cultures were negative for multidrug-resistant organisms such as multidrug-resistant Pseudomonas or vancomycin-resistant enterococci; moreover, the inflammation began to show gradual, spontaneous improvement again despite there being no use of antibiotics; thus, it was finally concluded that the patient’s fever
and inflammatory response were fluctuating irrespective of the antibiotic treatment. The resistance to antibiotics led us to suspect the possibility of tuberculous spondylitis again, and the patient was referred to our hospital. In addition to the severe back pain, close musculoskeletal examination revealed marked swelling around the right clavicle,
Figure 2. Clinical course with the transition of CRP levels, which the fever and degree of low-back pain mostly paralleled. The marked inflammatory response, which continued with fluctuation regardless of sufficient use of antibiotics, began to improve after initiation of minocycline
DOI 10.3109/14397595.2013.874744
Figure 3. Pathological findings of the right clavicle (hematoxylin and eosin, ×200). Inflammatory cells, mainly consisting of lymphocytes, histiocytes, and plasma cells, infiltrated the bone marrow with increased fibrosis. No malignancy such as lymphoma or granulomatous inflammation was observed
although she did not feel any pain. In addition, X-ray and CT showed destruction of the right sternoclavicular joint, sclerosis and thickening of the right clavicle and right first rib, and inflammation of the surrounding soft tissue. No bacterium was cultured from the biopsied bone specimen. The QuantiFERON test was negative for tuberculosis, and culture from the biopsy specimens of the clavicle revealed no presence of Mycobacterium. Fungal infection was also ruled out through a laboratory test and bone culture. Histopathological examination of the right clavicle revealed infiltration of histiocytes, lymphocytes, and plasmacytes, suggesting chronic inflammation (Figure 3), and no granulomatous inflammation or malignancy was observed. In addition, hot spots were observed diffusely in the right clavicle, the right first and second ribs, and the manubrium of the sternum on bone scintigraphy (Figure 1b, c). At this time, the doctors suspected that the patient’s diagnosis was SAPHO syndrome, considering the characteristic radiographic findings including unilateral sternocostoclavicular hyperostosis. Although she lacked eruptions, she actually fulfilled the currently accepted diagnostic criteria for SAPHO syndrome, determined by Kahn et al. [2]. Nonsteroidal anti-inflammatory drugs (NSAIDs), used continuously for the patient to reduce her pain and fever, did not show any therapeutic efficacy, although they have been reported to be frequently effective [4, 7]. As tetracycline has been shown to be one of the efficacious drugs [4, 9], minocycline was subsequently chosen prior to glucocorticoid and immunosuppressive agents. After administering minocycline, her symptoms started to improve with a decline of the level of CRP within 2 weeks. Three months later, she showed a favorable condition and was discharged on foot.
Discussion General symptoms of SAPHO syndrome are usually mild, and it is very difficult to differentiate SAPHO from bone infectious diseases when a patient is afflicted by severe inflammation [1, 2, 4, 10]. Indeed, long-term use of various antibiotics and repeated laboratory and radiological evaluations were required in our case before reaching the diagnosis. However, it is necessary for us to bear in mind that there have been few but sporadic case reports of SAPHO syndrome with severe inflammatory responses like our case [9, 10]. Classically, SAPHO among adults was thought to be accompanied by eruptions, but chronic recurrent multifocal osteomyelitis (CRMO) among adults has recently been recognized [2, 4].
Case report 1017 SAPHO without eruption is gaining more attention, due to the proposal of a clinical concept of nonbacterial osteitis (NBO) by Jansson et al. [11], which includes not only CRMO but also sterile osteitis of various clinical courses as well, as a disease closely related to SAPHO. However, while juvenile CRMO has been well studied and known as a relatively benign, self-limiting disease often controlled by NSAIDs [12], the clinical features of adult NBO or CRMO have yet to be clarified due to the very small number of case reports. Our case, which could be classified into CRMO, had a very severe clinical course, contrasting with the benign juvenile type; in addition, Takigawa et al. [13] reported a severe, destructive adult case lacking eruptions. Both were refractory to NSAID therapy. Thus, adult CRMO or NBO patients might have a severer clinical course than juvenile cases, but more case reports have to be collected to clarify its exact features, including the appropriate treatment. In addition, care has to be taken concerning eruptions in these patients, because they sometimes appear after osteitis in SAPHO [11]. The etiology of SAPHO is still unknown, but an association with infection by semipathogenic bacteria, especially Propionibacterium acnes (P. acnes), has been suggested [6, 7, 9, 14]. Colina [9] systematically reviewed the literature, and reported that P. acnes was detected in 46 out of 90 cultures of bone biopsy. Lowvirulence chronic bone infection by P. acnes, persisting intracellularly in the cell-wall-deficient form [16], is believed to initiate or stimulate a chronic inflammatory response with accompanying symptoms. Antibiotics have been tried in several studies based on this infectious theory [4, 7–9, 15, 16]. Although there has been no literature on minocycline, doxycycline, another member of the tetracyclines, has been relatively well studied, with contradictory results. Some insisted that it was therapeutically ineffective; for instance, Colina et al. [17] reported that only 2 of 9 patients benefited from doxycycline. Two cases reported by Takigawa et al. [13] suffered from vertebral destruction despite its use. On the contrary, doxycycline showed mild efficacy in 20 patients in a study by Hayem [4]; marked efficacy in two cases was reported by Ballara [15]. Colina [9] reported a febrile case with positive bone culture for P. acnes, who was resistant to NSAIDs and glucocorticoids but markedly responded to doxycycline monotherapy; intriguingly, our patient showed a clinical course similar to this case. Besides tetracyclines, macrolides [8] and trimethoprim [7] were also reported to show some efficacy. This might be because only these could permeate cell membranes and kill intracellular parasitic organisms such as cell-wall-deficient P. acnes, but it should be noted that these agents also have anti-inflammatory and immunomodulatory effects. As for tetracycline, many interesting properties unrelated to the antibiotic activity have led to their widely divergent clinical use [18]. Expected underlying mechanisms include antiprotease activities, inhibition of matrix metalloproteinases, and suppression of proinflammatory functions of monocytes and macrophages through regulation of the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K)/Akt pathway [19]. Although the efficacy of antibiotics was reported as above, and we consider that minocycline might be one of the efficacious treatment choices for SAPHO, treatment of SAPHO syndrome has yet to be well established and comprises various medications including NSAIDs, glucocorticoid, immunosuppressants, biologics, bisphosphonates, and antibiotics [20]. Under these conditions, an appropriate treatment period with antibiotics has yet to be determined, but long-term use may be recommended, since some reported treatment success with long-term use (over half a year) of antibiotics [7, 15], while others reported a high frequency of relapse after their cessation [8]. As SAPHO contains a very wide variety of disorders, it is still essential to collect as many cases as possible to clarify the nature
1018
Y. Takizawa et al.
of the syndrome, including atypical ones that are difficult to differentiate from infectious osteomyelitis, like our case.
Conflict of interest The authors declare that there is no conflict of interest.
References 1. Chamot AM, Benhamou CL, Kahn MF, Beraneck L, Kaplan G, Prost A. Acne-pustulosis-hyperostosis-osteitis syndrome. Results of a national survey. 85 cases. Rev Rhum Mal Osteoartic. 1987;54:187–96. 2. Kahn MF, Khan MA. The SAPHO syndrome. Baillieres Clin Rheumatol. 1994;8:333–62. 3. Vittecoq O, Said LA, Michot C, Mejjad O, Thomine JM, Mitrofanoff P, et al. Evolution of chronic multifocal osteitis toward spondyloarthropathy over the long term. Arthritis Rheum. 2000;43:109–19. 4. Hayem G, Bouchaud-Chabot A, Benali K, Roux S, Palazzo E, Silbermann-Hoffman O, et al. SAPHO syndrome: a long-term followup of 120 cases. Semin Arthritis Rheum. 1999;29:159–71. 5. Rohekar G, Inman RD. Conundrums in nosology: synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome and spondylarthritis. Arthritis Rheum. 2006;55:665–9. 6. Hurtado-Nedelec M, Cholett-Martin S, Nicaise-Roland P, GrootenboerMignot S, Ruimy R, Meyer O, et al. Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology (Oxford). 2008;47:1160–7. 7. Rozin AP. SAPHO syndrome: is a range of pathogen-associated rheumatic diseases extended?. Arthritis Res Ther. 2009;11:131. 8. Assmann G, Kueck O, Kirchhoff T, Rosenthal H, Voswinkel J, Pfreundschuh M, et al. Efficacy of antibiotic therapy for SAPHO syndrome is lost after its discontinuation: an interventional study. Arthitis Res Ther. 2009;11:R140. 9. Colina M, Lo Monaco A, Khodeir M, Trotta F. Propionibacterium acnes and SAPHO syndrome: a case report and literature review. Clin Exp Rheumatol. 2007;25:457–60.
Mod Rheumatol, 2014; 24(6): 1015–1018
10. Kalke S, Perera SD, Patel ND, Gordon TE, Dasgupta B. The sternoclavicular syndrome: experience from a district general hospital and results of a national postal survey. Rheumatology. 2001;40:170–7. 11. Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, et al. Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford). 2007;46:154–60. 12. Ferguson PJ, Sandu M. Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis. Curr Rheumatol Rep. 2012;14:130–41. 13. Takigawa T, Tanaka M, Nakanishi K, Misawa H, Sugimoto Y, Takahata T, et al. SAPHO syndrome associated spondylitis. Eur Spine J. 2008;17:1391–7. 14. Schaeverbeke T, Lequen L, Barbeyrac B, Labbé L, Bébéar CM, Morrier Y, et al. Propionibacterium acnes isolated from synovial tissue and fluid in a patient with oligoarthritis associated with acne and pustulosis. Arthritis Rheum. 1998;41:1889–93. 15. Ballara SC, Siraj QH, Maini RN, Venables PJ. Sustained response to doxycycline therapy in two patients with SAPHO syndrome. Arthritis Rheum. 1999;42:819–21. 16. Perry A, Lambert P. Propionibacterium acnes: infection beyond the skin. Expert Rev Anti Infect Ther. 2011;9:1149–56. 17. Colina M, Govoni M, Orzincolo C, Trotta F. Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects. Arthritis Rheum. 2009;61:813–21. 18. Griffin MO, Ceballos G, Villarreal FJ. Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action. Pharm Res. 2011;63:102–7. 19. Pang T, Wang J, Benicky J, Saavedra JM. Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition. Biochim Biophys Acta. 2012;1820:503–10. 20. Zhao Z, Li Y, Li Y, Zhao H, Li H. Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome with review of the relevant published work. J Dermatol. 2011;38:155–9.
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CASE REPORT
Severe inflammation associated with synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome was markedly ameliorated by single use of minocycline Yasunobu Takizawa1, Atsuko Murota1, Keigo Setoguchi1, and Yoshihisa Suzuki2 1Department of Allergy and Immunological Diseases, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan and 2Department of Orthopedics, Kyosai Tachikawa Hospital, Tokyo, Japan
Abstract
Keywords
We describe the case of a 63-year-old female who presented with severe inflammatory spondylitis, refractory to various antibiotics. Mycobacterial and fungal osteomyelitis were unlikely. Although asymptomatic, she also had osteomyelitis in the sternocostoclavicular region, and was suspected of having synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, against which minocycline showed marked efficacy. The presence of severe inflammatory SAPHO, albeit rare, together with the marked efficacy of tetracycline, should be noted.
SAPHO, Tetracycline, Propionibacterium acnes
Introduction SAPHO syndrome, an acronym for the combination of synovitis, acne, pustulosis, hyperostosis, and osteitis, has been established by Chamot and Kahn [1, 2] to describe a unique clinical entity affecting the bones, joints, and skin. SAPHO comprises such a wide spectrum of disorders that a number of clinicians include it in the group of immunological seronegative spondyloarthropathies [3–5], while others consider it a reactive osteitis against a specific infectious pathogen, such as Propionibacterium acnes (P. acnes) [5–7]; accordingly, the treatment strategy varies widely from immunosuppressive therapy to antibiotics [5, 7, 8]. Here, we describe a case of SAPHO syndrome with fever and severe low-back pain, which was resistant to various antibiotics on suspicion of infectious spondylitis and was finally improved with minocycline.
Case report A 63-year-old woman had been suffering from low-back pain for a prolonged period, but the pain became intense and she began to have a continuous fever above 38 °C in late April 2009. She visited the orthopedic department of another hospital on May 28, 2009. Physical examination revealed high body temperature of 40.2 °C. Her body weight decreased by 5 kg over 3 months. She complained of severe pain of the lower back, strongest around the thoracic–lumbar junction. Regardless of this, the musculoskeletal system was wholly intact. No abnormal finding was observed on examination of the head and neck, cardiopulmonary system, abdomen, nervous system, and skin. Laboratory data were as follows: white blood cell (WBC) count: 7,900/μL, red blood cell (RBC) count: 331 × 104/μL, hemoglobin: 84 g/L, platelets: 684 × 103/μL, erythrocyte sedimentation rate (ESR): 140 mm/h, and C-reactive protein (CRP): 198 mg/L. Correspondence to: Yasunobu Takizawa, Department of Allergy and Immunological Diseases, Tokyo, Japan. Metropolitan Komagome Hospital, Tokyo. E-mail: [email protected]
History Received 3 October 2012 Accepted 24 January 2013 Published online 11 February 2013
Other data of note were alkaline phosphatase: 615 (normal range: 115–359) IU/L, calcium: 2.0 mmol/L, phosphorus: 1.16 mmol/L, pyridinoline cross-linked carboxy terminal telopeptide of type collagen: 27.2 (−4.5) ng/mL, parathyroid hormone intact: 24 (10–65) pg/mL, total protein: 83 g/L, albumin: 25 g/L, lactate dehydrogenase: 211 (111–245) IU/L, immunoglobulin G (IgG): 28.65 (8.5–17) g/L, IgA: 8.6 (1.1–4.1) g/L, IgM: 0.66 (0.46–2.6) g/L, and no M-protein. Rheumatoid factor, antinuclear antibody, and anti-cyclic citrullinated peptide (CCP) antibody were negative. Her human leukocyte antigen (HLA) was A2, A31, B51, B52. Urianalysis was normal. X-ray showed sclerosis and mild compression of the vertebral bodies and ossified paraspinal ligaments, between the levels of Th10 and L2. On short inversion time inversion recovery (STIR) magnetic resonance imaging (MRI), high intensity was observed in the vertebrae and anterior longitudinal ligament between the levels of Th10 and L2. In addition, gadolinium enhancement was observed in most of the same part, being strongest in the anterior parts of the vertebral bodies and ligament. In contrast, no abnormal finding was observed in the discs (Figure 1a). Although no microbes were detected from blood culture and MRI findings were atypical in that the discs were spared from inflammation, the high fever, severe localized pain of the back, and marked increase of inflammatory markers strongly suggested septic spondylitis. Tuberculous spondylitis was considered as a relevant differential diagnosis, but vertebral biopsy was not attempted because the severest inflammation was seen adjacent to the aorta. Tuberculous skin test, as well as gastric lavage smear and culture for mycobacterium, were negative. Computed tomography (CT) of the neck, chest, and abdomen revealed no evidence of tuberculous infection. Cefazolin (1 week) was started, but it did not show any effect. Then, meropenem (1 week), vancomycin (1 month), and ceftazidime (1 month) were used as shown in Figure 2, but the high fever and severe back pain continued and ESR and CRP levels remained high as a whole. The combination of vancomycin and ceftazidime at first seemed to show some efficacy, but fever and CRP rose
1016
Y. Takizawa et al.
Mod Rheumatol, 2014; 24(6): 1015–1018
Figure 1. Radiological findings before introduction of minocycline. a Contrast enhancement on fat-suppressed MRI was observed in the vertebral bodies, especially in the anterior parts, as well as the longitudinal ligament between the levels of Th10 and L2, while the intervertebral discs were spared from inflammation. b, c Bone scintigraphy with lowered sensitivity (b) clearly revealed increased uptake in the right sternocostoclavicular region and vertebral bodies as well as the longitudinal ligament between Th10 and L2. In the one with normal sensitivity (c), mild uptake was observed as well in the os pubis and os ischii
again and remained high after about 1 month of use. Repeated blood cultures were negative for multidrug-resistant organisms such as multidrug-resistant Pseudomonas or vancomycin-resistant enterococci; moreover, the inflammation began to show gradual, spontaneous improvement again despite there being no use of antibiotics; thus, it was finally concluded that the patient’s fever
and inflammatory response were fluctuating irrespective of the antibiotic treatment. The resistance to antibiotics led us to suspect the possibility of tuberculous spondylitis again, and the patient was referred to our hospital. In addition to the severe back pain, close musculoskeletal examination revealed marked swelling around the right clavicle,
Figure 2. Clinical course with the transition of CRP levels, which the fever and degree of low-back pain mostly paralleled. The marked inflammatory response, which continued with fluctuation regardless of sufficient use of antibiotics, began to improve after initiation of minocycline
DOI 10.3109/14397595.2013.874744
Figure 3. Pathological findings of the right clavicle (hematoxylin and eosin, ×200). Inflammatory cells, mainly consisting of lymphocytes, histiocytes, and plasma cells, infiltrated the bone marrow with increased fibrosis. No malignancy such as lymphoma or granulomatous inflammation was observed
although she did not feel any pain. In addition, X-ray and CT showed destruction of the right sternoclavicular joint, sclerosis and thickening of the right clavicle and right first rib, and inflammation of the surrounding soft tissue. No bacterium was cultured from the biopsied bone specimen. The QuantiFERON test was negative for tuberculosis, and culture from the biopsy specimens of the clavicle revealed no presence of Mycobacterium. Fungal infection was also ruled out through a laboratory test and bone culture. Histopathological examination of the right clavicle revealed infiltration of histiocytes, lymphocytes, and plasmacytes, suggesting chronic inflammation (Figure 3), and no granulomatous inflammation or malignancy was observed. In addition, hot spots were observed diffusely in the right clavicle, the right first and second ribs, and the manubrium of the sternum on bone scintigraphy (Figure 1b, c). At this time, the doctors suspected that the patient’s diagnosis was SAPHO syndrome, considering the characteristic radiographic findings including unilateral sternocostoclavicular hyperostosis. Although she lacked eruptions, she actually fulfilled the currently accepted diagnostic criteria for SAPHO syndrome, determined by Kahn et al. [2]. Nonsteroidal anti-inflammatory drugs (NSAIDs), used continuously for the patient to reduce her pain and fever, did not show any therapeutic efficacy, although they have been reported to be frequently effective [4, 7]. As tetracycline has been shown to be one of the efficacious drugs [4, 9], minocycline was subsequently chosen prior to glucocorticoid and immunosuppressive agents. After administering minocycline, her symptoms started to improve with a decline of the level of CRP within 2 weeks. Three months later, she showed a favorable condition and was discharged on foot.
Discussion General symptoms of SAPHO syndrome are usually mild, and it is very difficult to differentiate SAPHO from bone infectious diseases when a patient is afflicted by severe inflammation [1, 2, 4, 10]. Indeed, long-term use of various antibiotics and repeated laboratory and radiological evaluations were required in our case before reaching the diagnosis. However, it is necessary for us to bear in mind that there have been few but sporadic case reports of SAPHO syndrome with severe inflammatory responses like our case [9, 10]. Classically, SAPHO among adults was thought to be accompanied by eruptions, but chronic recurrent multifocal osteomyelitis (CRMO) among adults has recently been recognized [2, 4].
Case report 1017 SAPHO without eruption is gaining more attention, due to the proposal of a clinical concept of nonbacterial osteitis (NBO) by Jansson et al. [11], which includes not only CRMO but also sterile osteitis of various clinical courses as well, as a disease closely related to SAPHO. However, while juvenile CRMO has been well studied and known as a relatively benign, self-limiting disease often controlled by NSAIDs [12], the clinical features of adult NBO or CRMO have yet to be clarified due to the very small number of case reports. Our case, which could be classified into CRMO, had a very severe clinical course, contrasting with the benign juvenile type; in addition, Takigawa et al. [13] reported a severe, destructive adult case lacking eruptions. Both were refractory to NSAID therapy. Thus, adult CRMO or NBO patients might have a severer clinical course than juvenile cases, but more case reports have to be collected to clarify its exact features, including the appropriate treatment. In addition, care has to be taken concerning eruptions in these patients, because they sometimes appear after osteitis in SAPHO [11]. The etiology of SAPHO is still unknown, but an association with infection by semipathogenic bacteria, especially Propionibacterium acnes (P. acnes), has been suggested [6, 7, 9, 14]. Colina [9] systematically reviewed the literature, and reported that P. acnes was detected in 46 out of 90 cultures of bone biopsy. Lowvirulence chronic bone infection by P. acnes, persisting intracellularly in the cell-wall-deficient form [16], is believed to initiate or stimulate a chronic inflammatory response with accompanying symptoms. Antibiotics have been tried in several studies based on this infectious theory [4, 7–9, 15, 16]. Although there has been no literature on minocycline, doxycycline, another member of the tetracyclines, has been relatively well studied, with contradictory results. Some insisted that it was therapeutically ineffective; for instance, Colina et al. [17] reported that only 2 of 9 patients benefited from doxycycline. Two cases reported by Takigawa et al. [13] suffered from vertebral destruction despite its use. On the contrary, doxycycline showed mild efficacy in 20 patients in a study by Hayem [4]; marked efficacy in two cases was reported by Ballara [15]. Colina [9] reported a febrile case with positive bone culture for P. acnes, who was resistant to NSAIDs and glucocorticoids but markedly responded to doxycycline monotherapy; intriguingly, our patient showed a clinical course similar to this case. Besides tetracyclines, macrolides [8] and trimethoprim [7] were also reported to show some efficacy. This might be because only these could permeate cell membranes and kill intracellular parasitic organisms such as cell-wall-deficient P. acnes, but it should be noted that these agents also have anti-inflammatory and immunomodulatory effects. As for tetracycline, many interesting properties unrelated to the antibiotic activity have led to their widely divergent clinical use [18]. Expected underlying mechanisms include antiprotease activities, inhibition of matrix metalloproteinases, and suppression of proinflammatory functions of monocytes and macrophages through regulation of the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K)/Akt pathway [19]. Although the efficacy of antibiotics was reported as above, and we consider that minocycline might be one of the efficacious treatment choices for SAPHO, treatment of SAPHO syndrome has yet to be well established and comprises various medications including NSAIDs, glucocorticoid, immunosuppressants, biologics, bisphosphonates, and antibiotics [20]. Under these conditions, an appropriate treatment period with antibiotics has yet to be determined, but long-term use may be recommended, since some reported treatment success with long-term use (over half a year) of antibiotics [7, 15], while others reported a high frequency of relapse after their cessation [8]. As SAPHO contains a very wide variety of disorders, it is still essential to collect as many cases as possible to clarify the nature
1018
Y. Takizawa et al.
of the syndrome, including atypical ones that are difficult to differentiate from infectious osteomyelitis, like our case.
Conflict of interest The authors declare that there is no conflict of interest.
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