Extracutaneous/osteoarticular manifestations in patients with SAPHO syndrome

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a rare clinical entity. It may occur at any age but children and young to middle-aged adults are the susceptible populations.1 The estimated prevalence of SAPHO syndrome is less than 1/10 000. In the 1960s, SAPHO-related manifestations, such as palmoplantar pustulosis and peripheral synovitis, were reported in several studies.1 Then, French researchers performed a national survey of such cases. Bone lesions, including hyperostosis and osteitis, with or without dermatological manifestations were the main disorders.2 The acronym of SAPHO (Syndrome Acne Pustulosis Hyperostosis Osteitis) was initially defined in 1987 and then “S” was replaced by “Synovitis” later. The clinical and imaging features of SAPHO have high variability. Pain, soft-tissue swelling, and morning stiffness are the common clinical symptoms.1 Its main features include cutaneous and osteoarticular manifestations. Several studies with large sample size summarized the prevalence of bone, skin, and joint manifestations. Chamot et al2 showed 13 severe acne, 44 particular palmoplantar pustulosis (PPP) and 28 hyperostosis in 85 SAPHO patients. The prevalence of skin lesions in European populations ranged from 63% to 84%.3 Gao et al4 showed that osteoarticular disorders were observed in all (46/46; 100%) and dermatological manifestations (PPP or severe acne) were observed in 63.9% of SAPHO patients. A recent study reported similar results for osteoarticular disorders but higher prevalence of dermatological manifestation (94.6%) in a Chinese population (n = 354).5 Osteoarticular manifestations, namely inflammatory osteitis with hyperostosis, are mainly localized in the anterior chest wall, but any skeletal segment could be involved, such as spine and long bones.1 The pathogenesis of SAPHO syndrome has not been well recognized. Innate immunity-linked autoinflammation may play a critical role. Proinflammatory cytokines, such as interleukin-17 (IL-17), IL-8, and tumor necrosis factor α (TNF-α), were elevated in SAPHO patients.6 Autoinflammation may cause systemic lesions. Besides skin and bone manifestations, other lesions were also reported in SAPHO patients. It is necessary to summarize those manifestations for the management of SAPHO. However, to the best of our knowledge, such lesions have not been summarized in literature. In this short report, we showed several extracutaneous/osteoarticular manifestations in patients with SAPHO syndrome. A literature search was conducted for Pubmed and Web of Science using “SAPHO” or “Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis” and “thrombosis” or “osteoporosis” or “muscle” or “brain” or “pulmonary manifestation” as keywords. Then we summarized the findings reported in the literature. Inflammation and coagulation show crosstalk at numerous levels and inflammation can induce or enhance coagulation by inducing endothelial injury and endothelial cell dysfunction.7 Proinflammatory cytokines, such as TNF-α, IL-6, and IL-1, are also associated with thrombotic cascade.8 Interestingly, venous thrombosis is also found in SAPHO patients. A recent report showed 18 cases of venous thrombosis.9 The subclavian vein is the most commonly involved vessel (83.3%, 15/18) and bilateral lesions were also observed in seven cases.9 The associated factors for thrombosis were not fully understood. One important factor was mechanical change due to hyperostosis or due to the stenosis of the subclavian vein, which was also common in SAPHO patients.10 Another factor is the hypercoagulable syndrome caused by systemic inflammation.11 Osteoporosis is usually reported in patients with inflammatory disease, rheumatic diseases, or autoimmune diseases, such as inflammatory bowel disease12 and systemic lupus erythematosus.13 State of inflammation or disease-related medications both contributed to the bone loss. SAPHO shares similar recurrent/chronic inflammatory nature with rheumatic autoimmune systemic diseases. Theoretically, osteoporosis should be common in SAPHO patients. However, only two types of bone lesions—hyperostosis and osteitis—were reported. A recent case-control study compared the bone mass and prevalence of osteoporosis between healthy persons and SAPHO patients.14 Twenty-seven SAPHO patients and 70 healthy persons were included. The bone mass was evaluated by computed tomography (CT). Osteoporosis was defined as a CT value (in Hounsfield units [HU]) less than 135 HU. The results showed that the CT values of the vertebral body in SAPHO patients were significantly lower than in control individuals. Moreover, the prevalence of osteoporosis in SAPHO patients was also higher than in control individuals (40.7% vs. 8.6%). How SAPHO affects bone metabolism is still unknown. Inflammation-related excessive bone resorption may play a critical role. TNF-α, IL-7, and IL-18, which are elevated in SAPHO patients, are all osteoclastogenic cytokines that could promote osteoclast differentiation.15 Receptor activator of nuclear factor-κB (RANKL) is the critical cytokine during osteoclast differentiation. RANKL binds with its receptor RANK and initiates the progress of osteoclast differentiation.16 Interestingly, a recent study showed that the RANKL level in patients with active SAPHO was significantly higher than that in patients with stable disease and a control group. A similar result was observed for the RANKL/osteoprotegerin ratio. Moreover, Cai et al17 showed that osteoclast differentiation pathways are involved in the pathogenesis of SAPHO syndrome. Those data support that bone loss in SAPHO patients is caused by osteoclast-mediated excessive bone resorption. Sarcopenia characterized by loss of muscle mass and function (strength or performance)18 has raised concerns in recent years. Increased cytokines are one of the factors involved in the pathogenesis of primary (age-related) sarcopenia.19 Sarcopenia has been reported in patients with autoimmune and rheumatic diseases,20 such as rheumatoid arthritis, spondyloarthritis, and inflammatory bowel disease. The prevalence of sarcopenia was 10.1%–45.1% for rheumatoid arthritis and was 22.7%–34.3% for spondyloarthritis. Proinflammatory cytokines, such as TNF-α and IL-8, which are thought to be pathogenic in SAPHO, are also associated with sarcopenia.21 The reduced physical activity caused by pain also induced low muscle mass or quality. In addition, disease-related medications may affect the muscle quality. However, few data were reported for muscle manifestations in SAPHO patients. A recent study performed a primary analysis on muscle quality in 23 SAPHO patients (18–60 years old) and 46 healthy control individuals.22 Erector spinae was selected for muscle quality assessment. Fatty infiltration of muscle was assessed based on CT values (HU) at the intermediate level of thoracic spine 8, 10, and 12 (T8, T10, and T12). The muscle densities were divided into three groups based on CT values: normal density (pure muscle), 30–90 HU; fatty infiltration, less than 30 HU; severe fatty infiltration, less than 0 HU. Muscle areas were smaller in SAPHO patients than in controls, especially for muscle area at T10 level. Moreover, prevalence of muscle fatty infiltration in SAPHO patients was significantly higher than that in control individuals (30.4% vs. 2.2%, p < .01). Interestingly, a recent study also showed the masseter muscle involvement in SAPHO patients.23 The possible pathogenesis of muscle manifestation or fatty infiltration in SAPHO is not clarified. Proinflammatory cytokines, such as TNF-α and IL-8 which are thought to be pathogenic in SAPHO, are also associated with sarcopenia.22 Another important reason may be the reduced physical activity caused by pain, which also induced low muscle mass or quality. In addition, disease-related medications may also affect the muscle status. Few case reports also showed brain lesions in SAPHO patients. Shiraishi et al24 reported a case of hypertrophic pachymeningitis in a patient with SAPHO syndrome. Recently, Yazawa and Itabashi25 reported another case of hypertrophic pachymeningitis in a 50 year old woman with SAPHO syndrome. Moreover, multiple brain infarctions were observed. Artery stenosis was found in the cavernous segment of the right internal carotid artery due to the hypertrophic pachymeningitis. Extensive thickening of the right frontal dura or meningeal thickening was also reported in some cases.26 Brain CT or magnetic resonance angiography examinations may be needed for SAPHO patients considering the severe outcome of stroke. Interestingly, stenosis was observed not only in brain arteries, but also in segmental pulmonary artery.27 The hypertrophic dura or arterial stenosis in SAPHO patients may be underestimated because there are no specific symptoms or through the lack of radiological examinations. A recent study showed that SAPHO syndrome may cause pulmonary vasculitis,28 which may be a reason for pulmonary artery stenosis. Moreover, other pulmonary manifestations, such as patchy shadows (32.8%), ground-glass opacity (16.4%), and pleural thickening (13.4%), were not uncommon in SAPHO patients.29 The etiology of brain and pulmonary manifestation within SAPHO syndrome is not understood. Systematic inflammation is a possible underlying mechanism. A recent study reported that the risk of malignancy in SAPHO patients was higher than that in patients with psoriatic arthritis (hazard ratio 6.70; 95% confidence interval 2.227–20.13).30 The etiology is not completely understood, but the chronic inflammation caused by SAPHO syndrome may play a critical role.30 In conclusion, a wide range of manifestations are associated with SAPHO syndrome besides synovitis, acne, pustulosis, hyperostosis, and osteitis. Whether this combination was coincidental or was causal is still unclear because SAPHO syndrome is rare and it is usually under-recognized. Moreover, those additional manifestations may be underestimated because of the lack of imaging examinations and no-specific clinical symptoms. Additional evaluations or examinations for extracutaneous/osteoarticular manifestations may be required in SAPHO patients. Further exploration is also needed to find other manifestations besides those summarized here. Similar to the skin and bone lesions, the pathogenesis of additional manifestations is not fully understood. Inflammation-related pathways may be involved in the pathogenesis of all lesions in SAPHO syndrome. Knowledge or understanding of those extracutaneous/osteoarticular manifestations is helpful for the clinical decision-making or management of patients with SAPHO syndrome. XC participated in the design of the study. NH, JL, and XC wrote the manuscript. NH, JL, WC, and XC searched the literature. JL, NH, WC, JW, ZW, and XC contributed to interpretation of data and preparation of the manuscript. All authors read and approved the final manuscript. Not applicable. Medical development and Medical Assistance Foundation of Jiangsu Province Hospital of Chinese Medicine and National Natural Science Foundation of China (No. 81773460). The authors have no conflicts of interest. This study was approved by the Ethics Board of the Affiliated Hospital of Nanjing University of Chinese Medicine. Informed consent was waived by the Ethics Board of the Affiliated Hospital of Nanjing University of Chinese Medicine. The Helsinki Declaration guidelines were followed during the study. All data generated or analyzed during this study are included in this published article.