The SAPHO syndrome: a clinical and imaging study

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1 DOI /s x BRIEF REPORT The SAPHO syndrome: a clinical and imaging study Meritxell Sallés & Alejandro Olivé & Ricard Perez-Andres & Susana Holgado & Lourdes Mateo & Elena Riera & Xavier Tena Received: 30 May 2010 /Revised: 25 August 2010 /Accepted: 30 August 2010 # Clinical Rheumatology 2010 Abstract The purpose of this study is to describe the clinical and radiological manifestations of patients with the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Retrospective study ( ) was performed in a single center. All patients with the SAPHO syndrome were included. Fifty-two patients were included: 26 male, mean age at diagnosis is 42 ± 12 years. Ostearticular involvement was present before cutaneous involvement in 59.6% of patients and concomitantly in 23.5%. Anterior chest pain was the commonest clinical manifestation, it was present in 38 patients (73%), followed by peripheral arthritis in 17 patients (32%), and sacroliliac pain in 14 patients (26.9%). Cutaneous involvement was present in 33 patients (63.5%). HLA B27 antigen was present in eight patients (17.7%). Bone scintigraphy M. Sallés (*) Rheumatology Section, Althaia, Avg. Bases de Manresa 6-8, Manresa 08242, Spain msl@comb.cat A. Olivé (*) : S. Holgado : L. Mateo : X. Tena Rheumatology Section, Hospital Universitari Germans Trias i Pujol, Crta Canyet sn, Badalona 08916, Spain aolive.germanstrias@gencat.cat R. Perez-Andres Radiology Service, Hospital Universitari Germans Trias i Pujol, Crta Canyet sn, Badalona 08916, Spain E. Riera Rheumatology Section, Mutua Terrassa, Mutua Terrassa, Spain showed an increased uptake in 42 patients (93.3%). The location of the uptake was mainly in sternoclavicular and manubriosternal joints. CT scan was performed in all hot joints showing sclerosis, erosions, hyperostosis, and soft tissue involvement. Refractory patients were treated mainly with pamidronate. Although SAPHO syndrome is an entity that share features that fit into a variety of established disease categories, the present study has a homogenous clinical and radiological pattern that gives support to believe that the SAPHO syndrome is an isolated clinical entity. Keywords Psoriatic arthritis. SAPHO syndrome. Spondyloarthropathy Introduction The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome was first proposed in 1987 by Chamot et al. [1] as a unifiying concept to describe the association between ostearticular disorders and skin manifestations. The many different names more than 50 in all given to this syndrome of bone and skin abnormalities reflect the confusing statements that have been made in the medical literature. This descriptive designation represents the spectrum of clinical and radiological manifestations. The commonest denominations are: pustulotic arthroosteitis, acne-associated arthropathy, sternoclavicular hyperostosis, and chronic recurrent multifocal osteomyelitis [2 4]. Chamot and Kahn coined the acronym SAPHO in order to gather a group of diseases that share clinical and radiological characteristics. The hallmark of the syndrome is hyperostosis and osteitis in the upper thoracic wall. Extra thoracic sites of synovitis may be observed as well,

2 especially involving the sacroiliac joint in a bilateral or unilateral pattern. Dermatological conditions associated with the SAPHO syndrome are palmoplantar pustulosis (PPP) and acne. Acne is usually severe and can present as acne conglobata, acne fulminans, and hidradenitis suppurativa. Psoriasis vulgaris has also been seen in association with the SAPHO syndrome [1, 2, 4]. The diagnosis of the SAPHO syndrome is clinical, however the contribution of imaging studies are of great importance. Laboratory analyses are of limited value. Human leukocyte antigen (HLA) B27 antigen has been reported to be positive in 13 30% of SAPHO patients [2, 4, 5]. The etiology and prevalence of the syndrome is unknown. The majority of reported cases come from Japan and northern and western Europe [1 13]. The purpose of this study is to present a series of 52 cases of the SAPHO syndrome recruited in a single center from 1984 to 2007 and describe the clinical and radiological manifestations. Patients and methods Setting We conducted a retrospective study ( ), recruiting all eligible patients with the SAPHO syndrome included in the database registry (a modified version of the ACR code system) of the Rheumatology Section of Hospital Universitari Germans Trias i Pujol. A tertiary hospital with a referral area of 800,000 inhabitants. The registry included all patients reviewed at the unit since its onset in The database contains demographic data on patients and diagnosis. The final diagnosis was confirmed by a senior rheumatologist. Study population Fifty-two patients who fulfilled the criteria of Benhamou et al. [1] were included. The criteria were: (a) Osteoarticular manifestations of palmoplantar pustulosis or severe acne; (b) Hyperostosis with or without dermatosis; (c) Chronic recurrent multifocal osteomyelitis involving axial or peripheral skeleton, with or without dermatosis. Exclusion features were septic osteomyelitis, infectious chest wall arthritis, infectious palmoplantar pustulosis, palmoplantar keratodermia, diffuse idiopathic skeletal hyperostosis, and ostearticular manifestations of retinoid therapy. Medical records were reviewed. The following data were collected: age, gender, age at symptom onset, age at SAPHO syndrome diagnosis, sites of ostearticular involvement, prior or current skin disease, evolution and previous and current treatment response. All available imaging studies were reviewed, namely plain radiographs, bone scintigraphy with Tecnetium 99, and computed tomography (CT) scans. CT (scans Picker PQ 5000) was performed on axial hot locations determined by scintigraphy. CT protocol: slice thickness of 2 mm with an index of 1 mm FOV 90 mm, soft tissue and bone windows were performed in all cases. Erythrocyte sedimentation rate (ESR; Westergreen), haemogram (Coulter), plasma biochemistry, C-reactive protein (Nephelometry), and HLA B27 antigen (Flow cytometry) were reviewed. Results Altogether, 52 patients with the SAPHO syndrome were included. The demographics characteristics could be seen in Table 1. All patients were Caucasics. Ostearticular involvement was present before cutaneous involvement in 59.6% of patients, and concomitantly in 23.5%. Ostearticular manifestations could be seen in Table 1. Cutaneous involvement was present in 33 cases (63.5%). Psoriasis was isolated in three patients, in the rest of them there was a concomitant PPP. Mean ESR was 30±30 mm/h (range 2 99 mm/h) and C- reactive protein 12.6±26.7 mg/dl (0 161 mg/dl). HLA B27 antigen was determined in 45 patients and was positive in eight cases (17.7%). Bone scintigraphy was performed in 45 patients showing an increased uptake in 42 cases (93.3%). The uptake was Table 1 Clinical and demographic characteristics N 52 Gender 26 Male, 26 female Mean age (years) 42±12 (range15 73) Mean age 1º symptom (years) 37±13 (range 10 71) Diagnostic delay (years) 4.5±5.6 (range 0 26) Osteoarticular manifestations Anterior chest pain 38 (73%) Peripheral arthritis 17 (32.7%) Sacroiliac syndrome 14 (26.9%) Shoulder girdle 12 (23.1%) Back pain 7 (13.5%) Dorsal pain 3 (5.7%) Talalgia 1 (1.2%) Asymptomatic 2 (3.8%) Cutaneous involvement 33 (63.5%) Palmoplantar pustulosis 17 (51.5%) Acne 13 (39.4%) Psoriasis 11 (33.3%)

3 localized in: sternoclavicular joints in 30 patients (71.4%), manubriosternal joint in 15 (35.7%), sacroiliac joints in 7 (16.6%), isolated sternocostal joint in 3 (7.1%), and spine, mandible, tibiae, and skull one in each patient. A CT scan was performed in all joints which showed an uptake of the tracer that is in 44 patients (84.6%). The location of the involvement in the anterior chest wall and the radiological characteristics could be seen in Table 2. Inflammatory bowel disease was found in two patients (3.8%), both were women and had Crohn's disease. There was not extrarticular involvement. Treatment of patients with the SAPHO syndrome consisted in: NSAIDs in 50 patients (96.1%), corticosteroids in 2 patients (3.6%), intravenous pamidronate in 10 patients (19.2%), methotrexate in 7 patients (13.5%), sulphasalazine in 4 patients (7.7%), azathioprine in 1 patient (1.9%) and infliximab in 1 patient (1.9%), this later patient having also Crohn s disease. The evolution of the disease showed two patterns: auto limited flares in 37 patients (71%) and a chronic inflammatory pattern; this later group of patients were those that required other treatments than NSAIDs. Discussion The present work describes the clinical and radiological manifestations of the SAPHO syndrome in the setting of a continental Euro-Mediterranean country. As other authors suggested, the SAPHO syndrome usually present in adults in the middle age of life, women are more commonly affected than men; in the present work, gender distribution is equitative [1]. Table 2 CT scan location and characteristics of the lesions Location Sternoclavicular joint 32 (72.7%) Manubriosternal joint 15 (34.1%) Sacroiliac joint 9 (20.5%) Costosternal joint 3 (16%) Vertebral 1 (2.3%) Mandible 1 (2.3%) Chronic recurrent multifocal osteomyelitis 1 (2.3%) Radiological features: CT Sclerosis 77.3% Erosions 44% Hyperostosis 41% Soft tissue 13.6% Joint-space narrowing 9% Bony ankylosis 7.5% Osteolysis 1.5% Anterior chest wall pain is the hallmark of the SAPHO syndrome. Seventy three percent of our patients had this symptom, a percentage which is similar to the work presented by Goupille [8] (66%) and Sonozaki [6] (94%). Interestingly enough, peripheral arthritis was commoner than sacroiliitis. Previous studies have shown that sacroiliitis is more frequent than arthritis [7 9]. Involvement of the skin is another prominent symptom; however the absence of the dermopathy might be possible. In the present paper, 63.5% of the patients had cutaneous involvement. French authors suggest a slightly superior percentage 84 93% [7 9]. PPP is the prototype of cutaneous involvement however other conditions are also described: pustular psoriasis, severe acne, and psoriasis vulgaris (PV) [1, 2, 5, 7, 13]. This pattern of cutaneous involvement is described mainly by continental European and Japanese authors. The inclusion of PV within the spectrum of the cutaneous involvement in the SAPHO syndrome has been controversial. Some authors consider that these patients should be included in the group of psoriatic arthritis [14]. In the present paper, 33.3% of the cutaneous involvement corresponded to PV; it was usually associated to PPP, or to a typical ostearticular involvement. This result was similar to Hayem et al. [9]. Other authors do not include PV as a part of the SAPHO syndrome [1, 6, 8]. The absence of cutaneous involvement at the onset of clinical manifestations or the appearance of skin manifestations years later was present in 59.6% of patients; this fact obviously delayed the diagnosis of the disease. The predominance of ostearticular involvement as the main symptom of the disease is different from previous work [6, 9]. The diagnosis of the SAPHO syndrome is clinical and radiological. Imaging studies such as X-ray, bone scintigraphy (99 Tc), and CT scan are very useful. Plain X-ray is limited to locations other than the upper chest: sacroiliac joints, spine, and peripheral joints. Bone scintigraphy (99 Tc) is very useful for an early diagnosis; it is sensitive and with an excellent CT scan correlation. It allows localizing ostearticular involvement even in sub clinical areas [9]. In the present work, 93.3% of patients had an uptake of the tracer in any location, a percentage similar to other series [1, 9, 11]. The uptake of the sternocostoclavicular and manubriosternal joints is characteristic and denominated in bullhorn [5] (Fig.1). CT scan is the best technique to evaluate the upper chest wall and particularly the sternocostoclavicular joints [5, 15, 16]. After reviewing the radiological characteristics, we found a common denominator: bony sclerosis (77.3%), followed by erosions (44%) and hyperostosis (41%); (Fig. 2a).

Fig. 1 Bone Scintigraphy (99Tc): bull-horn These radiological features are common and have been previously described; giving to the SAPHO syndrome a characteristic pattern that helps to differentiate

Interestingly enough, Jurik [17] compared the radiological findings of the upper chest wall of patients with ankylosing spondylitis (AS), reactive artritis (ReA), psoriatics arthritis, and arthritis

4 Fig. 1 Bone Scintigraphy (99Tc): bull-horn These radiological features are common and have been previously described; giving to the SAPHO syndrome a characteristic pattern that helps to differentiate from other diseases [17 20]. Interestingly enough, Jurik [17] compared the radiological findings of the upper chest wall of patients with ankylosing spondylitis (AS), reactive artritis (ReA), psoriatics arthritis, and arthritis associated with PPP. Arthritis of the sternoclavicular and manubriosternal joints was present in all; furthermore, erosions, sclerosis, ankylosis and hyperostosis were also found in all. However patients with arthritis associated with PPP had more bony sclerosis and hyperostosis, and the ossification of the costoclavicular ligament was found only in this group. Furthermore, the primary bone lesion was only present in patients with PPP or acne, but not in AS or ReA. The involvement of sacroiliac joints is usually unilateral, with predominant sclerosis and hyperostosis in the ilium, this pattern helps to differentiate it from other spondyloarthropathies (Fig. 2b). The spine is often involved, namely, thoracic, lumbar, and cervical vertebra could be affected. Diskitis, bony slerosis, and paravertebral osifications similar to syndesmophytes are described. Peripheral arthritis is often not erosive. Long bones are occasionally involved; sclerosis and an increase in trabecular and cortical width is common [5, 17 20]. There is no specific marker for the SAPHO syndrome. ESR and C-reactive protein are moderately elevated, as reported in the present paper. The seminal works on SAPHO syndrome suggested that HLA B27 antigen was present in 15 33% of patients [1, 2], recently the percentage decreased to 4 14% [8, 9, 13]. In the present study, the positivity was of 17.8%. The presence of HLA B27 antigen, sacroiliitis, the association with Crohn's disease and uveitis are data that make us think to include the SAPHO syndrome in the group of the spondyloarthropathies as an isolated entity. Other authors are prone to include it within the group of psoriatic arthritis. There are no randomized and controlled studies in the treatment of the SAPHO syndrome. NSAIDs have been the most frequently used drug, however their efficacy is not complete. Other drugs such as corticosteroids, methotrexate, colchicine, tetracyclines, and sulfasalazine have been used with variable results [2]. Intravenous biphosphonates have been used with fairly good results in several open studies [21 24]. In the present study, we used pamidronate for refractory patients. All the patients improved clinically but there were not changes in C-reactive protein, furthermore the scintigraphy performed after treatment did not showed a decreased in the uptake of the tracer [23]. Just recently TNFα antagonist have been used successfully in the treatment of the SAPHO syndrome, however the studies were open and non-randomized [25 27]. The course of the SAPHO syndrome varied greatly from patient to patient, it appears to be a chronic disorder with intermittent exacerbations and remissions but with an overall improvement with time, radiological progression is slow. In the present paper, 29% of patients had a chronic disease; similar data were presented by Maugars [7], Hayem [9], and Colina [13]. The present study has several limitations, namely: a retrospective design performed in a single center and last Fig. 2 a CT Scan of manubriosternal joints: erosions, sclerosis, and hyperostosis. b: CT Scan of sacroiliac joints: bilateral sacroiliitis with a predominant sclerosis of the iliac side of the joint

5 but not least the number of patients included is limited. However the homogeneity of the clinical and radiological studies presented in this paper and the similarity with previous work gives support to believe that the SAPHO syndrome is a well-defined clinical entity. Disclosures References None. 1. Chamot AM, Benhamou L, Kahn MF, Beraneck L, Kaplan G, Prost A (1987) Le syndrome acné pustulose hyperostose ostéite (SAPHO). Rev Rhum Mal Osteoartic 54: Kahn MF, Khan MA (1994) The SAPHO syndrome. In: Wright V, Helliwell P. Psoriatic arthritis. Baillieres's Clin Rheumatol 8: Kahn MF (1993) Psoriatic arthritis and synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome. Curr Opin Rheumatol 5: Resnick D, Niwayama G (1995) Enostosis, hyperostosis and periostitis. In: Resnick D, Niwayama G (eds) Diagnosis of bone and joint disorders, 3rd edn. Saunders, Philadelphia, pp Boutin RD, Resnick D (1998) The SAPHO syndrome: an evolving concept for unifying several idiopathic disorders of bone and skin. AJR 170: Sonozaki H, Mitsui H, Miyanaga Y, Okitsu K, Igarashi M et al (1981) Clinical features of 53 cases with pustulotic arthro-osteitis. Ann Rheum Dis 40: Maugars Y, Berthelot JM, Ducloux JM, Prost A (1995) SAPHO syndrome: a followup study of 19 cases with special emphasis on enthesis involvement. J Rheumatol 22: Goupille P, Valat JP (1996) SAPHO syndrome and spondyloarthropathy. J Rheumatol 23: Hayem G, Bouchaud-Chabot A, Benali K, Roux S, Palazzo E, Silbermann-Hoffman O et al (1999) SAPHO syndrome: a long-term follow-up study of 120 cases. Semin Arthritis Rheum 29: Schilling F, Kessler S (2000) SAPHO syndrome: clinicorheumatologic and radiologic differentia and classification of a patient sample of 86 cases. Z Rheumatol 59: Kalke S, Perera SD, Patel ND, Gordon TE, Dasgupta B (2001) The sternoclavicular syndrome: experience from a district general hospital and results of a national postal survey. Rheumatology 40: Olive A, Perez-Andres R, Rivas A, Holgado S, Casado E, Guma M et al (1999) Síndrome SAPHO: estudio de 16 casos. Med Clin (Barc) 112: Colina M, Govoni M, Orzincolo C, Trotta F (2009) Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects. Arthritis Rheum 61: Heliwell P, Marchesoni A, Peters M, Barcker M, Wright V (1991) A re-evaluation of the ostearticular manifestations of psoriasis. Br J Rheumatol 30: Destouet JM, Gilula LA, Murphy WA, Sagel SS (1981) Computed tomography of the sternoclavicular joint and sternum. Radiology 138: Dihlmann W, Dihlmann SW (1991) Acquired hyperostosis syndrome: spectrum of manifestations at the sternocostoclavicular region-radiologic evaluation of 34 cases. Clin Rheumatol 10: Jurik AG (1991) Seronegative arthritides of the anterior chest wall: a follow-up study. Skeletal Radiol 20: Jurik AG (1990) Anterior chest wall involvement in patients with pustulosis palmoplantaris. Skeletal Radiol 19: Earwaker JWS, Cotten A (2003) SAPHO: syndrome or concept? Imaging findings. Skeletal Radiol 32: Sugimoto H, Tamura K, Fujii T (1998) The SAPHO syndrome: defining the radiologic spectrum of diseases comprising the syndrome. Eur Radiol 8: Courtney PA, Hosking DJ, Fairbairn KJ, Deighton CM (2002) Treatment of SAPHO with pamidronate. Rheumatology 41: Amital H, Applbaum YH, Aamar S, Daniel N, Rubinow A (2004) SAPHO syndrome treated with pamidronate: an open label study of 10 patients. Rheumatology 43: Valls-Roc M, Sanmarti M, Salles M, Holgado S, Olive A (2005) SAPHO syndrome and pamidronate revisited. Rheumatology 44: Colina M, La Corte R, Trotta F (2009) Sustained remission of SAPHO syndrome with pamidronate: a follow-up of fourteen cases and a review of the literatura. Clin Exp Rheumatol 27: Olivieri I, Padula A, Ciancio G, Salvarani C, Niccoli L, Cantini F (2002) Successful treatment of SAPHO syndrome with infliximab: report of two cases. Ann Rheum Dis 62: Wagner AD, Andresen J, Jendro MC, Hülsemann JL, Zeidler H (2002) Sustained response to tumor necrosis factor a-blocking agents in two patients with SAPHO syndrome. Arthritis Rheum 46: Moll C, Hernandez MV, Cañete JD, Gomez-Puerta J, Soriano- Collado A et al (2008) Ilium osteitis as the main manifestation of the SAPHO syndrome: response to infliximab therapy and review of the literature. Semin Arthritis Rheum 37:

Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients

RHEUMATOLOGY Rheumatology 2016;55:1023 1030 doi:10.1093/rheumatology/kew015 Advance Access publication 25 February 2016 Original article Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: