Clinical heterogeneity of SAPHO syndrome: Challenge of diagnosis

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is spectrum of highly heterogeneous diseases firstly proposed by Chamot et al. [1]. Characterized by the coexisting of dermatological and osteoarticular manifestations, the disease entity has been delineated by nearly 50 terminologies [2]. Osteitis is considered the core pathophysiological change of SAPHO syndrome – the anterior chest wall is most frequently affected, followed by the axial skeleton including spine and sacroiliac joints, as well as peripheral joints, long bones, and flat bones [3]. Palmoplantar pustulosis (PPP) and severe acne (SA) are the two major dermatological manifestations, with psoriasis vulgaris as a concomitant condition. In rare cases, follicular occlusion triad (FOT) may occur as a severe form of SA [4]. Early diagnosis remains a great challenge for rheumatologists for this highly heterogeneous disorder.

The diagnostic criteria have undergone several revisions over the past three decades (Table 1). The criteria proposed by Kahn in 1994 [5] rely heavily on biopsy – pathologically confirmed osteitis or osteomyelitis with or without characteristic skin lesions was important for establishing the diagnosis. In 1999, Hayem et al. [6] reported a long-term follow-up study of 120 cases showing a good prognosis which gave rise to the idea of obviating unnecessary invasive procedures in diagnosis. In 2003, modified criteria [7] were proposed highlighting that clinical evidence of osteoarticular involvement combined with typical skin lesions (palmoplantar pustulosis, or severe acne) was sufficient to make the diagnosis. For patients without typical skin manifestations, biopsy was still indicated. Chronic recurrent multifocal osteomyelitis (CRMO) in children was also included in the syndrome. In 2012, the review by Nguyen et al. [3] re-emphasized the criteria firstly proposed by Benhamou in 1988 [8], again stressing the role of imaging approaches – hyperostosis of the characteristic sites (the anterior chest wall, limbs, or spine) is sufficient for diagnosis. CRMO is also not limited to children. In place of invasive biopsy, the evolution of diagnostic criteria highlights the importance of clinical and imaging evidence of osteoarticular involvement with typical dermatological manifestations.

Table 1. Evolving diagnostic criteria for SAPHO syndrome.

Kahn et al. (1994) [5]

1. Chronic recurrent multifocal sterile and axial osteomyelitis, with or without dermatosis  2. Acute, subacute, or chronic arthritis associated with palmoplantar pustulosis, pustulous psoriasis, or severe acne  3. Any sterile osteitis associated with palmoplantar pustulosis, pustulous psoriasis, or severe acne

Kahn et al., modified in 2003 [7]

Inclusion criteria:  Bone–joint involvement associated with palmoplantar pustulosis and psoriasis vulgaris  Bone–joint involvement associated with severe acne  Isolated sterile hyperostosis/osteitis (adults) (exception: growth of P. acnes)  Chronic recurrent multifocal osteomyelitis (children)  Bone–joint involvement associated with chronic bowel diseases Exclusion criteria:  Infectious osteitis  Tumoral conditions of the bone  Non-inflammatory condensing lesions of the bone

Benhamou et al., 1988 [8]

1. Osteo-articular manifestations of acne conglobata, acne fulminans, or hidradenitis suppurativa  2. Osteo-articular manifestations of palmoplantar pustulosis  3. Hyperostosis (of the anterior chest wall, limbs or spine) with or without dermatosis  4. Chronic recurrent multifocal osteomyelitis involving the axial or peripheral skeleton with or without dermatosis

At present, it is not difficult to diagnose SAPHO syndrome for most patients with characteristic skin manifestations and osteoarticular lesions in typical sites. Yet, in patients without skin lesions, and those with long bones or flat bones involvement, the diagnosis remains challenging. Misdiagnosis as bone neoplasms was common in patients with lesions in the tibia, fibula, or humerus [9]. Involvement of the mandibles is known as sterile mandibular osteomyelitis, with which patients often undergo surgery repeatedly and hard to be early diagnosed [10].

We have established a large dynamic cohort of patients with SAPHO syndrome, and reported the clinical characteristics of 164 cases in 2016 [11]. In our experience, whole body bone scintigraphy has unique advantages in revealing systemic lesions, long bone lesions, and characteristic changes [12–14] – increased tracer uptake in the anterior chest wall (especially the “bull’s head” sign [15]) in combination with typical history and skin manifestations helps establish the diagnosis. Moreover, bone scintigraphy is capable to reveal subclinical lesions, i.e. those without symptoms currently yet having pathological changes related to SAPHO syndrome [15–19]. However, given its low specificity, these findings must be interpreted carefully in correlation with history (e.g. previous symptoms) and results from other imaging techniques (e.g. MRI or CT). CT scan enables clear visualization of bone sclerosis and destruction, especially vertebral body collapse and bony bridging in the spine, but is weak in distinguishing active lesions from quiescent ones [2,12,20–22]. In addition, we discovered that vertebral corner lesions and the “kissing” involvement pattern shown on CT may be new diagnostic signs for SAPHO syndrome [21]. Magnetic resonance imaging (MRI) is capable of differentiating SAPHO syndrome from other diseases such as spinal infection and metastasis [20,23–25]. Active and quiescent lesions can also be well discriminated on MRI – bone marrow edema shown on MRI with fat-suppressed sequences typically indicates active lesions, while fat deposition chronic ones [2,12,22,23]. Such findings may provide important clues to treatment modification. In our open-labeled single arm study on long-term efficacy of intravenous bisphosphonates in SAPHO patients (Clinical Trials Identifier NCT02544659), whole-spine MRI was used to evaluate bone marrow edema in the vertebrae as one of the outcomes. At present, 1-year follow-up has been finished and the results were promising. Recently, we summarized our second cohort of 354 patients with SAPHO syndrome highlighting the axial skeletal involvement (under review), and discovered that patients with axial lesions had greater disease activity despite of more aggressive treatments. We believe further subtyping is in urgent need to facilitate recognition, management, and future researches of this highly heterogeneous disease.

The report by Okuno et al. [26] and our cohort [11] are both large population studies in Asian patients with SAPHO syndrome. In contrast with Caucasian population, Asian patients presented more frequently with PPP (51.5–66.7% [6,27–29] versus 70.7–92.3% [11,26]), and, less frequently with SA (14.3–40% [6,27–29] versus 9.8–16.1% [11,26]). Moreover, spinal lesions were more common in Asian patients than Caucasians (41.8–45.2% [11,26] versus 2.3–33.3% [6,27,28]). Given the importance of axial skeletal involvement and types of skin lesion in characterizing the disease, we hypothesized that Asian patients may exhibit a distinct clinical phenotype compared with Caucasian patients. Also, such heterogeneity may suggest different genetic basis of SAPHO syndrome in various races.

The pathogenesis of SAPHO syndrome remains a mystery. Inflammation in crosstalk with bone destruction may play a central role. Anić et al. [30] proposed two patterns of the disease – the inflammatory pattern, suggesting the use of tumor necrosis factor-α (TNF-α) inhibitors, and the bone remodeling pattern, for which bisphosphonates seems to be effective. On one hand, in the study by Okuno [26], a series of inflammatory markers (e.g. CRP, ESR, CH50 and MMP-3) were determined to help quantify the status of inflammation. Our study also found that CRP may be a good parameter to monitor disease activity [11]. On the other hand, it is also of high interest to investigate into markers of bone metabolism to help determine the status of bone disease, including bone formation markers [e.g. bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type I procollagen (PINP), and osteocalcin] and bone resorption markers [e.g. N-terminal telopeptide crosslink (NTX), and C-telopeptide crosslink (CTX)]. Further translational study is urgent need to improve stratified management. As the authors stated in the article by Okuno [26], we call on better awareness of this under-recognized disease to facilitate patient recruitment and further characterizing of this highly heterogeneous syndrome.

Conflict of interest

None.

Additional information

Funding

This work was supported by the CAMS Initiative for Innovative Medicine [grant number 2017-I2M-3-001], the Capital Medical Research and Development Fund [grant number 2016-4-40112], and the National Key Research and Development Program of China [grant number 2016YFC0901500].