SAPHO syndrome

SAPHO syndrome
DiseasesDB	30718

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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 [2]. 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. [19].
• Different types of pathogens were isolated from different bone sites and pustules in the skin, including Staphylococcus aureus [20], Haemophilus parainfluenzae, 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. [28]

• 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 [30].
• Assman and Simon [2] 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

Osteoarticular manifestations involve osteitis, hyperostosis,

synovitis, arthropathy, and enthesopathy that present

with pain, tenderness, and sometimes swelling over the

affected areas and fever.

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 (Fig. 1).

Synovitis mostly manifests as nonerosive

oligoarthritis of larger joints. Joint involvement can be

primary arthritis or an extension of the osteitis adjacent to

the articular structures. Arthritis has been reported in up to

92.5 % of SAPHO cases. The axial skeleton is involved in

91 % and the peripheral joints in 36 % of cases.

Besides

sternocostal and sternoclavicular joints, which are the most

commonly affected, it mainly affects the sacroiliac or hip

joints, knees, and ankles. For anterior chest wall disease,

three stages have been described (Table 1). The costoclavicular

ligament is involved in 48 % of cases, and it is

considered a decisive early finding in SAPHO [7, 32, 33].

The smallest number of cases in the literature are based

on temporomandibular joint involvement [11, 13, 34, 35].

The percentage distribution of arthritis in various parts of

the body is demonstrated schematically in Fig. 2.

Soft tissue surrounding joints and bones can be affected

as well. It may be misinterpreted as a neoplastic or lymphatic

mass [7, 36], and, although rare, the soft tissue

swelling can lead to serious complications, such as thoracic

outlet syndrome [11, 36–38].

Enthesopathy can lead to ligament ossification, which

can result in the development of bony bridging across

joints.

CRMO is an aseptic inflammatory disorder clinically

characterized with insidious onset of bone lesions with pain

and swelling that is often worse at night, with or without

fever. 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. Some other

sites, such as the clavicules, vertebral bodies, mandible,

pelvis, and small bones of the hands and feet, have been

shown to be affected as well. Involvement is multifocal,

usually unilateral, and it can be accompanied by skin

lesions (most often, palmoplantar pustulosis and psoriasis

have been described) [32, 39]. As stated earlier, some

investigators believe that CRMO is the pediatric presentation

of SAPHO, but it seems that the differentiating

clinical feature is mainly in the localization of inflammation:

in pediatric CRMO patients, the extremities are more

often affected and in SAPHO patients, the axial skeleton

with costosternoclavicular region is the focus [5].

Differential diagnosis

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

Disease	Findings
Soft tissue infection (Commonly cellulitis)	History of skin warmness, swelling and erythema. Bone probing is the definite way to differentiate them.
Osteonecrosis (Avascular necrosis of bone)	Previous history of trauma, radiation, use of steroids or biphosphonates are suggestive to differentiate osteonecrosis from ostemyelitis. MRI is diagnostic.
Charcot joint	Patients with Charcot joint commonly develop skin ulcerations that can in turn lead to secondary osteomyelitis. Contrast-enhanced MRI may be diagnostically useful if it shows a sinus tract, replacement of soft tissue fat, a fluid collection, or extensive marrow abnormalities. Bone biopsy is the definitive diagnostic modality.
Bone tumors	May present with local pain and radiographic changes consistent with osteomyelitis. Tumors most likely to mimic osteomyelitis are osteoid osteomas and chondroblastomas that produce small, round, radiolucent lesions on radiographs.
Gout	Gout presents with joint pain and swelling. Joint aspiration and crystals in synovial fluid is diagnostic for gout.
SAPHO syndrome (Synovitis, acne, pustulosis, hyperostosis, and osteitis)	SAPHO syndrome consists of a wide spectrum of neutrophilic dermatosis associated with aseptic osteoarticular lesions. It can mimic osteomyelitis in patients who lack the characteristic findings of pustulosis and synovitis. The diagnosis is established via clinical manifestations; bone culture is sterile in the setting of osteitis.
Sarcoidosis	It involves most frequently the pulmonary parenchyma and mediastinal lymph nodes, but any organ system can be affected. Bone involvement is often bilateral and bones commonly affected include the middle and distal phalanges (producing “sausage finger”), wrist, skull, vertebral column, and long bones.
Langerhans' cell histiocytosis	The disease usually manifests in the skeleton and solitary bone lesions are encountered twice as often as multiple bone lesions. The tumours can develop in any bone, but most commonly originate in the skull and jaw, followed by vertebral bodies, ribs, pelvis, and long bones.

Radiologic Findings

Radiographs may show expanded bone, sclerosis and

osteolysis, periosteal reaction, or enthesopathic new bone

formation. Bone scintigraphy delineates increased uptake

in affected bone and may reveal asymptomatic disease or

abnormalities not apparent on radiographs. The advantage

of scintigraphy is the demonstration of multiple sites of

involvement, so it is helpful for the elimination of malignancy

or infection. Symmetric uptake in the sternoclavicular

region with a typical ‘‘bull‘s head’’ appearance shown

in bone scintigraphy is characteristic of the SAPHO syndrome

(Fig. 3) [46]. It was first described by Freyschmidt

and Sternberg [47] but, even though it is considered to be

pathognomonic, it is not a very sensitive indicator of

SAPHO.

Magnetic resonance imaging (MRI) will also detect

occult lesions, may show findings not seen on plain

radiographs, and provide information about soft tissues.

Characteristic radiographic findings are hyperostosis and

osteitis. Hyperostosis is radiographically seen as diffuse

thickening of the periosteum, cortex, and endosteum, with

narrowing of the medullary canal [47]. Both are characterized

by increased bone sclerosis [35, 39].

In the early stages, the disease usually manifests as an

osteolytic process. As healing progresses, the lytic/sclerotic

picture is produced. Characteristic features of osteitis and

hyperostosis become more apparent with time [35].

Joint involvement is characterized by arthritis, with joint

space narrowing and, sometimes, erosions. There might be

periarticular osteopenia. Ligamentous ossifications can be

observed as well [32, 37].

Several spine lesions have been described regarding this

syndrome, and they include vertebral body corner lesions,

nonspecific spondylodiscitis and osteodestructive lesions

seen in adults and children, and osteosclerotic vertebral

lesions, paravertebral ossification, and sacroiliitis seen in

adults.

The term ‘‘corner lesion’’ describes focal cortical erosion

at one of the vertebral body corners, which is usually

seen in adults. Nonspecific spondylodiscitis is seen as focal

erosive changes with sclerosing remodeling of the vertebral

end plates, usually anteriorly located at the discovertebral

junction. This can be seen in up to 32 % of cases, and

single and multiple levels may be found [35]. Takigawa

et al. [14] observed nonconsecutive and consecutive multilevel

lesions, both at a proportion of 38 %. It may be

painful for many weeks but, usually, with time, it becomes

asymptomatic. Rarely it is a cause of neurological complications

or deformity [35].

Osteodestructive lesions include osteolytic vertebral

lesions, usually limited to one vertebrae, with a variable

degree of collapse. Collapse may induce kyphosis, spinal

canal stenosis, and spinal cord injury. If it is quite marked,

it can present as a vertebra plana in children, which is not

characteristic of an adult population [14]. Sacroiliitis can

be seen and it is usually unilateral. Ankylosis may be

present as well, and it is usually connected with the relief

of pain [7, 38, 48].

Affection of the long bones is commonly seen among

children. Predominantly, the metadiaphyses are affected,

especially the distal femur, and proximal and distal tibia.

Radiographically, it may manifest as lytic lesions, sclerotic

or mixed lesions, and periosteal reaction may eventually

develop. MRI is the technique of choice in young patients

suspected of SAPHO/CRMO, particularly due to the lack

of radiation requirements and its sensitivity in detecting

early subclinical lesions. It is seen as bone marrow edema,

which shows up as hypointense on T1 and hyperintense on

T2 signals in the affected metaphysis. As the disease progresses,

hypointense T1 and T2 signals in the medullary

space and cortex represent medullary sclerosis and cortical

thickening [17]. Lesions are usually multiple and often

symmetrical. Involvement of the adjacent epiphysis and

altered bone growth are rare [17, 35].

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

[38]. Similar findings were shown by Fritz et al. [49]. They

found that the sensitivity of conventional radiography in

the early stages of the disease is 13 % and, compared to

MRI, it shows only 16 % of the lesions seen on MRI. For

identifying subclinical foci, whole-body scintigraphy or

whole-body MRI is very useful. Actually, if initial radiographs

are negative and disease is suspected, bone scintigraphy

is used as the next step to detect occult

inflammatory lesions and clinically suspected localizations.

Because of increased cost, the use of whole-body MRI is

recommended for indeterminate cases, monitoring of disease

activity, and for better delineation of soft tissue

changes. Intravenous contrast will highlight abscesses and

other soft tissue changes that may be associated with more

aggressive conditions [17]. It should be kept in mind that

imaging procedures cannot accurately distinguish among

SAPHO/CRMO, malignancy, and osteomyelitis, and such

findings should always be interpreted within other clinical

and laboratory parameters.

Laboratory tests

There are no laboratory tests that are diagnostic of SAPHO.

They can be normal or may show elevated inflammatory

markers, such as erythrocyte sedimentation rate (ESR),

C-reactive protein (CRP), and elevated levels of components

of complements C3 and C4. Mild leukocytosis and

mild anemia were observed as well. Compared to healthy

controls, these patients have elevated levels of immunoglobulin

A [2, 50]. A study searching for some specific

antibody profiles for those patients has been conducted

recently, but, unfortunately, without any success. Hurtado-

Nedelec et al. [30] showed significantly increased levels of

IgA in their cohort of 29 SAPHO patients, while the levels

of IgM and IgG were normal. This information can possibly

be used as an additional tool in making the diagnosis,

but further investigations need to be done. Also,

Histology

The histologic characteristics of the bone lesions change over the course of the disease. In the early stages, there is acute inflammation with a predominantly neutrophilic infiltrate, and both bone resorption and prominent periosteal bone formation have been described ([null 5], [null 42], [null 43]). In biopsy specimens from children with CRMO, multinucleated giant cells, granulomatous foci, and necrotic bone fragments have been observed ([null 5], [null 44]). Subsequently, the infiltrate consists of scattered lymphocytes, plasma cells, histiocytes, and only a few polymorphonuclear cells ([null 5], [null 42], [null 43]). Memory T lymphocytes of the CD8+ subset constitute the major cell type ([null 45]). 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 ([null 5], [null 42], [null 43]).

Treatment

Because to the variety of clinical presentations, the treatment

of SAPHO syndrome remains a challenge and outcomes

are known to be disappointing, especially with the

skin component of the disease. There have been no randomized

controlled trials on the effectiveness of various

therapies, but nonsteroidal anti-inflammatory drugs

(NSAIDs) are generally considered as the first-line treatment

option [4]. Antimicrobial therapy is useful in patients

with positive biopsy cultures, but it has little or no effect in

others. Successful treatment has been reported for doxycycline,

azithromycin, sulfamethoxazole/trimethoprim, and

clindamycin [20, 55]. Azithromycin acts not only as an

antimicrobial, but also as an anti-inflammatory and

immunomodulatory drug, and Schilling and Wagner suggest

the simultaneous usage of azithromycin together with

calcitonin (osteotropic drug) [56]. Other treatment options

include colchicine, corticosteroids, bisphosphonates, and

disease-modifying agents, such as methotrexate, sulfasalazine,

and anti-TNFa therapy. Bisphosphonates act by

inhibiting bone resorption and turnover, and by possible

anti-inflammatory activity that suppresses the production

of IL-1, IL-6, and TNFa [57]. They have no effect on skin

lesions. Local corticosteroid injections have also been

tried, but this treatment modality has a significant effect

only on osteitis lesions [53]. Some authors used corticosteroids

orally and, in that case, they will act on both

skeletal and skin manifestations. Dermatologists use topical

corticosteroids, psoralen plus ultraviolet A (PUVA)

photochemotherapy, and retinoids [58]. 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 6–8-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 [58]. 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.

Arias-Santiago et al. [59] suggested 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 [60]. Autologous bone transplantation using

microvascular flaps is applied as an experimental treatment

procedure [15].

Physiotherapy can always be used as an additional

treatment for osteoarticular manifestations. Surgery is

considered for patients whose condition has failed to

respond to all other therapeutic interventions [61]. Wide

resections are reserved to treat complications when patients

develop deformity or loss of function with pain [15]. There

are several reports in the literature about the surgical

treatment of such patients; for example, resection of the

medial clavicle or the sternoclavicular joint, which seemed

to provide variable improvement in pain, although some

authors report no improvement with this intervention [54].

Furthermore, mandibular involvement has been treated

with minor surgical procedures, such as decortications and

curettage, but extensive

References

• Skeletal Radiology. 2003 Jun;32(6):311-27.

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