SAPHO Syndrome

SAPHO is an acronym coined by Chamot and colleagues (1987) grouping Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis into a single autoinflammatory entity. It is best understood as an innate-immune (autoinflammatory) sterile osteitis, not an autoimmune or infective disease.

One spectrum with CRMO. SAPHO and chronic non-bacterial osteomyelitis (CNO) / chronic recurrent multifocal osteomyelitis (CRMO) sit on one disease spectrum. CRMO is the paediatric multifocal phenotype; SAPHO is the adult phenotype, with the skin association and the chest wall predilection. Many units now use "CNO/CRMO spectrum including SAPHO", and whether the names should merge is still debated: many paediatric rheumatologists advocate a single "chronic non-bacterial osteomyelitis" umbrella, while adult rheumatology retains SAPHO for the skin-associated chest wall phenotype.

A neighbour of the spondyloarthritides. SAPHO overlaps the spondyloarthritis family (sacroiliitis, enthesitis, psoriasiform skin disease, response to TNF blockade), but HLA-B27 positivity is only modestly increased and it is not a classical seronegative spondyloarthropathy. Whether it is a distinct disease or a variant is unsettled. The overlapping features and treatment response argue for spectrum membership; the modest HLA-B27 association and the prominent hyperostosis argue for distinctness.

What the monogenic phenocopies teach. DIRA (IL-1 receptor antagonist deficiency), Majeed syndrome (LPIN2) and PAPA syndrome (PSTPIP1) all produce sterile osteitis, which implicates IL-1 driven neutrophilic inflammation.

The proposed mechanism has two parts:

1. A genetic predisposition to dysregulated innate immunity: the IL-1beta, IL-17, IL-23 and TNF axes, and neutrophil hyperactivity.
2. A hypothesised microbial trigger. Low-virulence Cutibacterium (Propionibacterium) acnes is cultured from a minority of bone biopsies. Whether this is causative antigenic drive or contamination remains unresolved; the prevailing view is a possible antigenic trigger in a genetically primed innate immune system rather than a true infection.

Why the bone becomes big, not lytic. The result is a sterile neutrophilic osteitis followed by an exuberant osteoblastic reparative response, and it is the osteoblastic response that dominates, producing the hallmark hyperostosis and enthesial new bone. Early lesions are oedematous and partly lytic; chronic lesions are sclerotic, with thickened cortex, enthesial ossification and, at the chest wall, ossification of the costoclavicular ligament. This is why the clinical sign is a hard, enlarging, tender lump rather than a discharging sinus.

No universally validated criteria exist, and two working sets are quoted in vivas.

Kahn and Khan inclusion criteria. Any one is sufficient:

1. Osteoarticular disease associated with acne conglobata, acne fulminans or hidradenitis suppurativa
2. Osteoarticular disease associated with palmoplantar pustulosis
3. Hyperostosis (axial or appendicular) with or without skin disease
4. Chronic recurrent multifocal osteomyelitis involving the axial or appendicular skeleton, with or without skin disease

Exclusions. Septic osteomyelitis, infectious chest wall arthritis, infectious palmoplantar pustulosis, palmoplantar keratoderma, diffuse idiopathic skeletal hyperostosis (DISH), retinoid-induced osteitis and bone neoplasm.

Their limits. Kahn's criteria are unvalidated and predate modern imaging; consensus criteria incorporating whole-body MRI are awaited.

In children, the Bristol and Jansson criteria for CNO emphasise typical radiological lesions plus either multifocality, a raised CRP or a compatible biopsy, with malignancy and infection excluded.

The order of exclusion. SAPHO is accepted only once the alternatives have been excluded. Work through them in this order:

1. History and skin. Ask about psoriasis, palmoplantar pustulosis, acne fulminans or conglobata and inflammatory bowel disease, and examine the skin, nails and soles. A skin lesion together with a typical skeletal site raises SAPHO high in the differential but does not confirm it.
2. Exclude sepsis first. Aspirate, culture and image for an abscess or sequestrum (table below), adding extended, mycobacterial and fungal cultures if the course is indolent or tuberculosis risk is endemic. A positive culture means pyogenic or tuberculous osteomyelitis, and it is treated as infection.
3. Map the skeleton. Whole-body MRI or bone scintigraphy decides whether the disease is multifocal or solitary. Look for bilateral symmetrical clavicular and sternocostal uptake, the 'bullhead' pattern. Multifocal symmetrical anterior chest wall disease with typical skin lesions supports sterile osteitis.
4. A solitary lesion in a young patient is treated as a sarcoma until proven otherwise, never with an unplanned local excision.
5. Bloods and marrow. In a child with night sweats, weight loss, cytopenias or blasts on the film: blood film, LDH and marrow biopsy. In an older adult with a known primary: alkaline phosphatase, PSA, tumour markers and staging CT. These exclude lymphoma, leukaemia, Langerhans cell histiocytosis (eosinophilic granuloma, with lytic, punched-out lesions of the skull and spine) and sclerotic metastasis.
6. Benign sclerotic mimics. Recognising Paget disease and condensing osteitis of the clavicle avoids unnecessary immunosuppression and over-treatment of self-limiting disease.
7. Biopsy if doubt persists: a solitary lesion, an atypical site, no skin disease, or failure to settle.
8. Accept sterile osteitis when the distribution is multifocal and typical, the dermatosis characteristic, the cultures negative and neither biopsy nor imaging shows malignancy, and label it SAPHO or chronic recurrent multifocal osteomyelitis. A new solitary aggressive lesion reopens the question: the diagnosis remains one of exclusion.

The orthopaedic role is diagnosis, exclusion of mimics, safe biopsy where indicated, and referral, not resection. There are no large randomised trials; the ladder below reflects consensus practice and observational cohorts.

Operating on it as osteomyelitis is the commonest harm. Serial debridements, sequestrectomy and long-term antibiotics are given for a sterile disease; the bone gets more hyperostotic, the wound fails, and the diagnosis is still missed. Negative cultures from an adequate sample in a hyperostotic clavicle should trigger the SAPHO question, not another washout. Treat it as SAPHO unless microbiology is positive, stop operating, and escalate medical therapy with rheumatology.

Resecting hyperostosis for pain or cosmesis brings scar pain and shoulder girdle instability as well as recurrence. Escalate medical therapy instead: resection is reserved for genuine mechanical or neurovascular compromise, or for salvage after failed maximal medical therapy, and consent must explicitly cover recurrence of the hyperostosis.

Accepted indications.

Medial clavicle or sternoclavicular resection (salvage, rarely required):

• Position: supine, a bump between the scapulae, head turned away, arm free-draped; head-up tilt to reduce venous pressure
• Imaging and equipment: contrast CT venogram preoperatively; image intensifier; oscillating saw; vascular clamps, with a cardiothoracic or vascular surgeon on standby
• Preparation: group and save; consent for vascular injury, pneumothorax, recurrence of hyperostosis, shoulder girdle instability and cosmetic deformity
• Approach: transverse incision over the medial clavicle extending onto the manubrium; subplatysmal flaps; split the pectoralis and sternocleidomastoid attachments
• Dissection: stay subperiosteal on the posterior clavicle; the retroclavicular plane is the danger zone
• Resection and reconstruction: resect no more than the medial 1 to 2 cm; preserve or reconstruct the costoclavicular (rhomboid) ligament to prevent superior migration; consider tendon graft stabilisation
• At-risk structures: subclavian and brachiocephalic veins, subclavian artery, brachial plexus, pleural apex, internal thoracic vessels
• Fixation and closure: no internal fixation is normally used; meticulous haemostasis, drain, layered closure
• Aftercare: sling for 3 to 4 weeks, then progressive range of motion; continue medical therapy, because surgery does not treat the underlying autoinflammation
• Pitfalls: recurrent hyperostosis in the resection bed is the commonest failure; wound dehiscence in immunosuppressed patients; venous injury demands immediate vascular control

Prognosis. The disease is chronic and relapsing but generally non-destructive, and most patients maintain function. Substantial spontaneous remission occurs, particularly in paediatric CNO, though a proportion of children have persistent or relapsing disease into adulthood. A poorer outcome is associated with spinal involvement, multifocal disease at onset and delayed diagnosis.

Global epidemiology

• Rare, with prevalence estimated well under 1 in 10,000 in white European populations; likely substantially under-diagnosed globally.
• Female predominance in most adult series; typical adult onset in the third to fifth decades. Paediatric CNO peaks around ages 9 to 12 with a female predominance.
• Regional phenotype differences are important for exams: large East Asian cohorts (notably from China and Japan) report a very high frequency of palmoplantar pustulosis and anterior chest wall disease, whereas European and North American series report proportionally more severe acne and axial disease. The same disease, different skin expression.

Society and consensus guidance

Note there is no arthroplasty or implant registry evidence base for SAPHO — joint replacement is not part of its management, and quoting registry data here would be inappropriate.

Practice variation by resource setting

• Where advanced imaging is limited, bone scintigraphy remains the practical whole-body screening tool; where MRI is available, whole-body STIR is preferred, particularly in children, to avoid radiation.
• In tuberculosis-endemic regions, mycobacterial and fungal disease must be excluded rigorously — empirical antituberculous therapy for a sterile osteitis is a recognised diagnostic pitfall.
• Access to biologic therapy varies widely; where unavailable, bisphosphonate infusion is the highest-value escalation because it is inexpensive, widely available and effective for osteitis pain.

Beyond the questions of nomenclature, Cutibacterium acnes and diagnostic criteria discussed above, three practical questions remain open:

1. First-line escalation: bisphosphonate or TNF inhibitor? Bisphosphonates are cheaper, safer and excellent for osteitis pain and vertebral lesions; TNF inhibitors are better for axial inflammation and coexisting skin and joint disease. Practice varies by unit and access.
2. Paradoxical pustulosis with TNF blockade. How often it forces a switch to IL-17 or IL-23 directed therapy is not well quantified.
3. Whole-body MRI as a routine staging and monitoring tool. It is increasingly standard in children and less established in adults, with no validated activity score in wide use.

Related pages. The same disease under its paediatric name: Chronic Recurrent Multifocal Osteomyelitis — SAPHO and CRMO are increasingly regarded as one autoinflammatory bone disease across two age groups. The infection it is mistaken for, repeatedly: Osteomyelitis Pathophysiology, Septic Arthritis Pathophysiology and Tuberculosis of the Spine (Pott's) — sterile osteitis debrided as chronic infection is the commonest harm on this page. The rheumatological family it belongs to: Seronegative Spondyloarthropathy, Ankylosing Spondylitis — whose thin marginal syndesmophytes contrast with SAPHO's bulky non-marginal bridges — plus Psoriatic Arthritis of the Hand, Reactive Arthritis (Reiter's), Sacroiliac Joint Dysfunction and Tendon-Bone Interface and Enthesis. The tumours a solitary lesion could be: Ewing Sarcoma, Osteosarcoma, Langerhans Cell Histiocytosis, Osteoid Osteoma, Metastatic Bone Disease and Multiple Myeloma — with Biopsy Principles and Techniques for the tract that must be planned before the needle. Reading the films: Periosteal Reaction Patterns, Polyostotic Bone Lesions, Predicting Bone Tumour by Age, Regional (Local) Osteopenia and Paget's Disease of Bone, the other cause of a dense expanded clavicle. The anterior chest wall itself: Sternoclavicular Joint Injuries, Sternoclavicular Joint Dislocation, Clavicle Fractures and Thoracic Outlet Syndrome — hyperostosis compressing the subclavian vein is the one genuine surgical emergency here.