SAPHO syndrome
Synonyms and keywords: Acquired hyperostosis syndrome

# Overview
SAPHO syndrome is thought to comprise a spectrum of disorders that share some clinical, radiologic and pathologic characteristics. An entity known as chronic recurrent multifocal osteomyelitis (CRMO) was first described in 1972. Subsequently in 1978 several cases of CRMO were associated with clinical findings of palmoplantar pustulosis. Since then, a number of associations between skin conditions and osteoarticular disorders have been reported with a variety of different names including sternocostoclavicular hyperostosis, pustulotic arthro-osteitis, and acne-associated spondyloarthropathy. SAPHO was coined in 1987 and basically represents a spectrum of inflammatory osteitis which may or may not be associated with dermatologic pathology.

# Definition
- Synovitis
- Acne -- commonly involving the face and upper back.
- Pustulosis -- usually involving the palms of the hands and/or soles of the feet (palmo-plantar pustulosis).
- Hyperostosis
- Osteitis

# Etiology
- The etiology is still unknown. The pathogenesis involves a combination of genetic and immunological components.
- HLA-B27 is more frequent in SAPHO.
- Chromosome 18 plays a role in the SAPHO syndrome. Lipin 2 is involved in modulating apoptosis of polymorphonuclear cells, and mutations of the NOD2 gene may lead to an abnormal immune response to bacterial peptidoglycans via activation of the proinflammatory transcription factor nuclear factor kappa B.
- Different types of pathogens were isolated from different bone sites and pustules in the skin, including Staphylococcus aureus, Haemophilus, and Actinomyces, as well as Treponema.
- The most important is Propionibacterium acnes, which is identified more often, but positive cultures can only be seen in a small number of total bone biopsy specimens.
- According to some of them, humoral immune response is hyperactive and in others, it is hypoactive. This is similar to the cell-mediated immune response that has been reported as normal or hyperactive; total immune system impairment has been reported as well.
- SAPHO is characterized by elevated IL-8 and IL-18 levels. They had not detect any autoantibodies among their SAPHO patients, including rheumatoid factor, anti-CCP2, or antinuclear antibodies. IL-8 and TNFa production by purified polymorphonuclear leukocytes (PMN) were elevated in these patients compared to the controls, but the oxidative burst and IL-18 production were normal.
- They also showed that, after 28 days of etanercept therapy, PMN, IL-8, and TNFa production was downregulated and TNFa plasma levels were increased.
- Assman and Simon have shown that the proinflammatory response observed in SAPHO is mediated by the ability of P. acnes to trigger interleukin IL-1, IL-8, and IL-18 and TNFa release by monocytes, keratinocytes, sebocytes, and dendritic cells.

# Clinical presentation
- It involve osteitis, hyperostosis, synovitis, arthropathy, and enthesopathy.
- Osteitis is the inflammation of bone, which may involve the cortex and the medullary cavity. 
- Hyperostosis reflects excessive bone growth and may result in enthesopathic new bone formation and joint fusion.
- Synovitis mostly manifests as nonerosive oligoarthritis of larger joints. Joint involvement can be primary arthritis or an extension of the osteitis adjacent tonthe articular structures.
- Arthritis has been reported in up to 92.5 % of SAPHO cases.
- The costoclavicular ligament is involved in 48 % of cases, and it is considered a decisive early finding in SAPHO.
- Swelling and warmth can occur over the affected areas. It is most commonly found in the metaphyseal regions of long bones of the lower extremities.
- Typical skin lesions seen in SAPHO patients include palmoplantar pustulosis (PPP) and severe acne.
- Acne can manifest as acne conglobata, acne fulminans, or hidradenitis suppurativa. Women more often develop PPP and men show severe forms of acne. Pyoderma gangrenosum is the other less frequent manifestation and different forms of psoriasis have also been described, as well as Sweets syndrome and SneddonWilkinson disease.
- Skin lesions may vary in severity and may precede (in 50 % of the cases), follow, or occur simultaneously with the onset of arthritis. Usually, the time interval between the onset of skin and osteoarticular manifestations is <2 years, but an interval of 38 years has been recorded in the literature.
- Sonozaki et al.  showed that skin lesions precede or follow the onset of osteoarticular lesions showed that the skin manifestations anteceded or presented at the same time as the skeletal
- manifestations in 68 % of their cohort. Dermatological manifestations are known to be resistant to therapy and quite often have a chronic, protracted course.

# Differential diagnosis
SAPHO must be differentiated from other diseases that cause bone pain, edema, and erythema.

# Radiologic Findings
- Radiographs may show expanded bone, sclerosis and osteolysis, periosteal reaction, or enthesopathic new bone formation.
- Bone scintigraphy shows increased uptake in affected bone, so called bulls head appearance.
- In the early stages, the disease usually manifests as arthritis and shows joint space narrowing and erosions.
- Bone deformities may induce kyphosis, spinal canal stenosis, and spinal cord injury.
- MRI is the investigation of choice in young patients suspected of SAPHO syndrome. It shows hypointense T1 and T2 signals in the medullary space and cortex represent medullary sclerosis and cortical thickening.
- Lesions are usually multiple and often symmetrical. Involvement of the adjacent epiphysis and altered bone growth are rare.
- Many of the radiological manifestations of the disease can be seen on plain radiographs. It is important to emphasize that radiographs made during the first 3 months of the disease course are normal in 80 % of cases and all patients had abnormal radiographs at the end of follow-up.
- Whole-body scintigraphy or whole-body MRI is very useful for identifying subclinical foci.

# Laboratory tests
- elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and elevated levels of components of complements C3 and C4.
- Anemia and leukocytosis

# Histology
- In the early stages, there is acute inflammation with a predominantly neutrophilic infiltrate, and both bone resorption and prominent periosteal bone formation.
- Multinucleated giant cells, granulomatous foci, and necrotic bone fragments.
- The infiltrate consists of scattered lymphocytes, plasma cells, histiocytes, and only a few polymorphonuclear cells.
- Memory T lymphocytes of the CD8+ subset constitute the major cell type.
- In the late stages, the infiltrate is sparse or absent and enlarged sclerotic trabeculae as well as marrow fibrosis are observed.
- There are increased numbers of osteoblasts and occasionally osteoclasts as well.

# Treatment
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally considered as the first-line treatment option.
- Antimicrobial therapy is useful in patients with positive biopsy cultures, but it has little or no effect in others.  Doxycycline, azithromycin, sulfamethoxazole/trimethoprim, and clindamycin.
- Bisphosphonates act by inhibiting bone resorption and turnover.
- Disease-modifying agents are only indicated when symptoms persist for at least 4 weeks, despite adequate NSAID therapy.
- There is increasing evidence of anti-TNFa usage in the treatment of such patients.
- Case reports and case series on TNFa blockade often demonstrate a marked improvement in the clinical picture, regardless of whether or not this treatment is permanently effective. The most often published cases in the literature are about the use of infliximab in these patients. Usually, 5 mg/kg at weeks 0, 2, and 6 followed by a 68-week interval has been used, just like that used in spondyloarthropathies. Lower doses of infliximab and reduction in the duration of intervals have been tested, but it has been noted that decreased infusion intervals like in spondyloarthropathies and lower dosages cannot maintain the remission of disease.
- Both skeletal and cutaneous lesions responded well in most of the described cases, with exception of PPP, which sometimes failed to respond.
- In some cases, infliximab induced exacerbation of skin manifestation.
- Adalimumab as a possible alternative therapy in such cases, and there are also reports on the successful treatment of SAPHO with etanercept and the IL-1 receptor antagonist anakinra.
- Anakinra appeared to be helpful in five out of six SAPHO patients, two of which previously failed to respond to TNF blockers.
- Autologous bone transplantation using microvascular flaps is applied as an experimental treatment procedure.
- Surgery is considered for patients who failed to respond to medical therapy.