SAPHO syndrome

SAPHO syndrome is a rare, chronic autoinflammatory disorder defined by the constellation of synovitis, acne, pustulosis, hyperostosis, and osteitis.[1][2] It is characterized by sterile inflammatory bone lesions and associated neutrophilic dermatoses, most commonly palmoplantar pustulosis and severe acne.[1][3] The anterior chest wall (sternum, clavicles, sternocostoclavicular joints) is the hallmark skeletal site, but the axial skeleton, sacroiliac joints, peripheral bones, and the mandible may all be involved.[3][4] Pathogenesis is incompletely understood; a multifactorial model implicates genetic susceptibility, dysregulated innate immunity with interleukin-1 and other pro-inflammatory cytokine overproduction, and a possible triggering role of Cutibacterium (formerly Propionibacterium) acnes.[5][6] In the jaws, SAPHO manifests as diffuse sclerosing osteomyelitis (DSO), predominantly of the mandible.[4][7] Imaging characteristically shows a mixed osteolytic-osteosclerotic pattern with solid periosteal reaction and bone enlargement.[8] No validated diagnostic criteria exist; diagnosis rests on the combination of clinical and radiological findings after exclusion of infection and malignancy.[2][9] Management is conservative, centered on bisphosphonates, NSAIDs, DMARDs, and biologic agents; surgical intervention in the jaws is associated with high relapse rates.[6][10]

The acronym SAPHO was coined in 1987 by Chamot and colleagues to unify a group of inflammatory osteo-cutaneous disorders that had previously been described under separate names.[2][11] Accepted synonyms and related terms include:

• SAPHO syndrome — the current standard designation
• Diffuse sclerosing osteomyelitis (DSO) of the mandible — the term used in oral and maxillofacial surgery when jaw involvement is the presenting feature[4][12]
• Chronic recurrent multifocal osteomyelitis (CRMO) — widely considered the pediatric counterpart or a disease on the same spectrum[13][14]
• Sternocostoclavicular hyperostosis — an older term emphasizing the most common skeletal site
• Sasaki syndrome — proposed to replace SAPHO specifically for palmoplantar pustulosis with sternocostoclavicular arthropathy without other skin manifestations[11]

The Benhamou criteria are the most commonly applied inclusion criteria in published cohorts, requiring one of four inclusion categories (bone/joint disease with characteristic skin lesion, sterile multifocal osteitis, sterile hyperostosis, or CRMO).[15][16] No formally validated diagnostic criteria exist.[2]

• Age: In systemic cohorts the mean age at diagnosis is approximately 40 years. Mandibular involvement tends to present younger, with a median onset age of 13 years for isolated DSO and 25 years for syndrome-type DSO.[3][4]
• Sex: Overall female predominance (approximately 2:1). Isolated mandibular DSO shows an even stronger female predilection; syndrome-type DSO with systemic features has a more balanced sex ratio.[3][4]
• Frequency: SAPHO is rare, with no reliable population-based incidence data. Mandibular involvement is reported in a minority of SAPHO patients; in one 41-patient series, only 2 had mandibular osteitis.[15]
• Anatomic distribution: The anterior chest wall is involved in the vast majority of patients, followed by the spine (thoracic > lumbosacral > cervical) and sacroiliac joints. In the jaws, the mandible is affected almost exclusively; maxillary involvement is exceptional.[3][4][7][17]

Presentation and symptoms

Mandibular SAPHO typically presents with progressive jaw pain, facial swelling, and trismus.[7] The clinical course is episodic, with symptom-free intervals punctuated by painful flares.[12] Additional orofacial findings reported in case series include temporomandibular joint arthritis and, occasionally, dysphagia from extensive mandibular enlargement.[7] Gingival pustules representing neutrophilic mucositis have been described as a rare oral soft-tissue manifestation.[18]

Systemic features

Cutaneous manifestations accompany the osteoarticular disease in the majority of patients but may precede or follow bone symptoms by years, complicating recognition:[2][3]

• Palmoplantar pustulosis — the most common skin finding
• Severe acne (acne conglobata or acne fulminans)
• Psoriasis vulgaris — occasionally coexists with pustulosis
• A minority of patients lack any dermatologic involvement[15]

Anterior chest wall pain is the most frequent systemic skeletal complaint; spinal and sacroiliac pain are also common.[3] Peripheral arthritis may affect the knees and wrists.[15]

Laboratory findings

Elevated high-sensitivity C-reactive protein (hs-CRP) is found in the majority of patients.[3] Erythrocyte sedimentation rate may be mildly elevated. HLA-B27 positivity is uncommon.[3][15] Bone turnover markers (osteocalcin, β-CTX) may be elevated, particularly in isolated mandibular DSO.[4]

Red flags

• Dental procedures may trigger or exacerbate mandibular disease; nearly 40% of mandibular SAPHO patients in one cohort had undergone an oral procedure within one month before symptom onset.[10]
• Delayed diagnosis is common because the various clinical features may appear years apart and not all manifestations develop in every patient.[2]

Location and distribution

The mandible is the near-exclusive jaw site; maxillary involvement is exceptional.[4][7] The body and ramus are most commonly affected, and the process may extend to include the condyle.[12] Unilateral involvement predominates in isolated DSO, whereas bilateral mandibular disease is more frequent when systemic SAPHO features are present.[4]

Periphery and shape

Lesion margins are characteristically poorly defined, blending imperceptibly into adjacent normal bone.[19] There is no corticated border. The overall shape is irregular and expansile, conforming to the anatomy of the affected mandibular segment rather than forming a discrete mass.

Internal architecture

The hallmark internal pattern is a mixed osteolytic-osteosclerotic appearance, distinguishing SAPHO-related mandibular osteomyelitis from suppurative osteomyelitis, which tends to be predominantly osteolytic.[8] Key features include:

• Extensive medullary and cortical sclerosis — the dominant finding, often diffuse throughout the affected segment[20]
• Osteolytic foci — interspersed areas of radiolucency representing active inflammatory osteolysis; these may be the earliest radiographic change[9][10]
• Absence of sequestra — a critical distinguishing feature from chronic suppurative osteomyelitis and osteoradionecrosis, in which sequestra are characteristic[20]

Periosteal reaction and cortical involvement

• Solid (homogeneous) periosteal new bone formation is characteristic, producing subperiosteal bone deposition along the outer cortex. This contrasts with the lamellated ("onion-skin") periosteal reaction typical of suppurative osteomyelitis.[8][20]
• Cortical thickening is common, contributing to overall bone enlargement.[20][21]
• Cortical disruption without sequestration may be seen in active disease, with poorly demarcated cortical margins.[19]
• No pathological fractures — unlike suppurative osteomyelitis and osteoradionecrosis.[20]

Bone enlargement and growth pattern

Progressive enlargement of the mandible is characteristic, resulting from a combination of periosteal new bone formation and endosteal sclerosis.[8][20] The expansion is fusiform and may produce clinically visible facial asymmetry. Condylar process deformation has been described in advanced cases.[20]

Effects on adjacent structures

• Inferior alveolar nerve canal: The canal may become obscured or blurred by surrounding sclerosis.[12]
• Masticatory muscles: Hypertrophy and edema of the masseter muscle are commonly associated with mandibular DSO on cross-sectional imaging.[20][21]
• Teeth: Teeth within the affected segment generally remain vital. Displacement or resorption of teeth is not a prominent feature, helping to distinguish DSO from neoplastic processes. Widening of the periodontal ligament space may occasionally be observed.
• Temporomandibular joint: Arthritis of the TMJ has been reported in association with mandibular SAPHO.[7]

Recognized variants and temporal evolution

• Early (active) phase: Predominantly osteolytic foci with mild periosteal reaction; may mimic aggressive pathology.[9]
• Late (chronic) phase: Progressive osteosclerosis with dense bone formation and bone enlargement; the osteoproliferative pattern dominates.[9][20]
• Bilateral mandibular involvement is more common in syndrome-type DSO than in isolated DSO.[4]

Bone scintigraphy

Whole-body bone scintigraphy (WBBS) with 99mTc-MDP is a key diagnostic tool for confirming multifocal skeletal involvement and supporting the diagnosis of SAPHO.[3][9] The characteristic "bull's head" (bullhead) sign — symmetric tracer uptake in the sternum and bilateral sternoclavicular joints — is considered a hallmark finding.[3][17] Three patterns of osteoarticular involvement have been identified by cluster analysis: sternoclavicular, costal, and spinal types.[17] Mandibular uptake, when present, confirms active osteitis in the jaw and helps distinguish SAPHO from isolated mandibular pathology.[4] SPECT/CT improves lesion localization and characterization of atypical presentations.[22]

MRI

MRI is superior to CT for detecting bone marrow edema, the earliest sign of active mandibular osteitis, and for monitoring treatment response.[10][21] In the mandible, MRI demonstrates:

• Bone marrow edema on fluid-sensitive sequences during active disease
• Contrast enhancement within the mandibular bone and adjacent masticatory muscles[21]
• Perineural edema along the inferior alveolar nerve, which correlates with pain during relapse[21]
• Pathologically enlarged cervical lymph nodes[21]

Following bisphosphonate treatment, resolution of bone marrow edema on MRI correlates with clinical remission.[10]

Medical CT

CT of the anterior chest wall and spine demonstrates osteolysis, sclerosis, and hyperostosis at the sternocostoclavicular region and vertebral bodies.[3][23] Characteristic vertebral CT signs include the "bright corner sign," "half-circle sign," and "round sign".[23] CT is superior to MRI for detecting osteosclerosis, while MRI is superior for bone marrow edema.[23]

PET/CT

PET/CT can identify metabolically active chronic lesions and may assist in differentiating SAPHO from malignancy, though its role remains supplementary.[9]

The differential diagnosis of mandibular SAPHO centers on distinguishing sterile inflammatory osteitis from infectious osteomyelitis, neoplasia, and other fibro-osseous conditions. The combination of mixed sclerotic-lytic bone changes, solid periosteal reaction, absence of sequestra, and episodic clinical course in a young female patient should raise suspicion for SAPHO, particularly when extracranial skeletal or cutaneous findings coexist.

The highest-risk diagnostic pitfall is misinterpreting early osteolytic SAPHO lesions as malignancy or infectious osteomyelitis, leading to unnecessary aggressive surgery or prolonged antibiotic therapy. When clinical and imaging findings are suggestive, bone biopsy with culture is warranted to exclude infection and neoplasia, and whole-body bone scintigraphy should be obtained to identify multifocal disease.[2][9]

Bone biopsy findings in SAPHO are variable and nonspecific, depending on disease duration.[24]

Temporal histologic spectrum

• Early lesions: Acute neutrophilic inflammation, edema, and prominent periosteal new bone formation — histologically indistinguishable from bacterial osteomyelitis[24]
• Intermediate lesions: Predominantly chronic lymphocytic inflammation[24]
• Late lesions: Markedly sclerotic bone trabeculae with prominent marrow fibrosis and only mild chronic inflammation; advanced cases may closely resemble Paget disease histologically[24]

Key features

• Cultures and special stains for microorganisms are characteristically negative, though Cutibacterium acnes has been isolated from bone biopsies in a substantial proportion of patients, more frequently from open biopsies and from patients with concurrent skin manifestations.[5]
• Multinucleated giant cells, noncaseating granulomas, and areas of new bone formation have been described in the related entity CRMO.[14]
• No pathognomonic histologic criteria exist; diagnosis requires clinicopathologic correlation.[24]

Radiologic-pathologic correlation

The mixed osteolytic-osteosclerotic radiographic pattern corresponds to the coexistence of active inflammatory osteolysis (neutrophilic or lymphocytic infiltrate with bone resorption) and reparative osteosclerosis (reactive new bone formation and marrow fibrosis).[8][24] The solid periosteal reaction seen radiographically reflects the prominent periosteal new bone formation observed histologically.[8][24] The histologic resemblance to fibrous dysplasia in the mandible has been noted as a diagnostic challenge for pathologists.[12]

Workup and referral

When mandibular DSO is identified, referral to rheumatology is essential to evaluate for systemic SAPHO features.[4][7] The recommended workup includes:

• Dermatologic examination for palmoplantar pustulosis, severe acne, or psoriasis
• Whole-body bone scintigraphy to identify multifocal skeletal involvement[3][17]
• Laboratory studies: CRP/ESR, bone turnover markers, HLA-B27
• Bone biopsy with culture to exclude infection and malignancy when the diagnosis is uncertain[9][24]

Conservative treatment

Conservative management is the mainstay and achieves improvement in the large majority of patients with mandibular involvement:[10]

• NSAIDs — first-line symptomatic therapy[2][3]
• Bisphosphonates (particularly intravenous pamidronate) — effective for bone involvement; resolution of bone marrow edema and osteolysis has been documented on follow-up imaging. Pamidronate produced at least partial response in the majority of evaluable patients in one cohort.[10][15]
• DMARDs (methotrexate, sulfasalazine) — used for disease modification with variable results[3][6]
• Corticosteroids — used for flare management[3]
• Biologic agents — anti-TNF-α agents (infliximab, adalimumab), IL-1 receptor antagonists (anakinra), and JAK inhibitors (tofacitinib, upadacitinib, abrocitinib) have shown efficacy in refractory cases[26][27][28]
• Antibiotics (azithromycin, doxycycline) — used based on the Cutibacterium acnes hypothesis; efficacy is inconsistent[6][15]

Surgical considerations

Surgical intervention in the mandible (decorticalization, sequestrectomy, curettage) is associated with high relapse rates; all 14 surgically treated patients in one cohort relapsed within a median of 2 months.[10] Surgery should be reserved for cases refractory to medical therapy, and preventive dental care is encouraged to minimize the need for invasive oral procedures.[7][10]

Prognosis

The long-term prognosis of SAPHO is generally favorable despite a prolonged and relapsing course.[2] Mandibular disease may cause significant morbidity from pain, trismus, and facial asymmetry, but life-threatening complications are rare. Dental procedures represent a possible trigger for mandibular flares and should be undertaken with caution.[10]

Relationship to CRMO

CRMO is widely considered the pediatric counterpart of SAPHO, and the two conditions likely represent a disease spectrum.[13][14] The mandible is a recognized site of involvement in CRMO, and children presenting with mandibular osteomyelitis and multifocal bone lesions should be evaluated for both entities.[14] Isolated mandibular DSO in children and adolescents may represent an early or limited form of the same disease process.[4]

Dental procedure risk

Dental procedures appear to be a risk factor for triggering or exacerbating mandibular SAPHO.[10] Elective oral surgery should be approached cautiously in known SAPHO patients, with emphasis on preventive dental care to reduce the need for invasive interventions.[7][10]