SAPHO syndrome: Difference between revisions

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{{Infobox_Disease |
  Name          = {{PAGENAME}} |
  Image          = |
  Caption        = |
  DiseasesDB    = 30718 |
  ICD10          = |
  ICD9          = |
  ICDO          = |
  OMIM          = |
  MedlinePlus    = |
  MeshID        = |
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{{SI}}
{{SI}}
{{CMG}}
* {{CMG}}
 
{{SK}} Acquired hyperostosis syndrome
{{SK}} Acquired hyperostosis syndrome
==Overview==
==Overview==
Line 27: Line 14:


== Etiology ==
== Etiology ==
* The etiology is still unknown [2]. The pathogenesis involves a combination of genetic and immunological components.  
* The etiology is still unknown. The pathogenesis involves a combination of genetic and immunological components.<ref>{{Cite journal
 
| author = [[G. Assmann]] & [[P. Simon]]
| title = The SAPHO syndrome--are microbes involved?
| journal = [[Best practice & research. Clinical rheumatology]]
| volume = 25
| issue = 3
| pages = 423–434
| year = 2011
| month = June
| doi = 10.1016/j.berh.2011.01.017
| pmid = 22100290
}}</ref>
* HLA-B27 is more frequent in SAPHO.
* 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].
* 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.<ref>{{Cite journal
* 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]
| author = [[L. T. Burgemeister]], [[D. L. P. Baeten]] & [[S. W. Tas]]
| title = Biologics for rare inflammatory diseases: TNF blockade in the SA PHO syndrome
| journal = [[The Netherlands journal of medicine]]
| volume = 70
| issue = 10
| pages = 444–449
| year = 2012
| month = December
| pmid = 23230013
}}</ref>
* Different types of pathogens were isolated from different bone sites and pustules in the skin, including Staphylococcus aureus, 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.<ref>{{Cite journal


* 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.  
| author = [[A. P. Rozin]] & [[A. M. Nahir]]
* 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].
| title = Is SAPHO syndrome a target for antibiotic therapy?
* 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.
| journal = [[Clinical rheumatology]]
| volume = 26
| issue = 5
| pages = 817–820
| year = 2007
| month = May
| doi = 10.1007/s10067-006-0274-6
| pmid = 16601916
}}</ref>


== Clinical presentation ==
* 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.<ref>{{Cite journal
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).
| author = [[M. Malmstrom]], [[F. Fyhrquist]], [[T. U. Kosunen]] & [[A. Tasanen]]
| title = Immunological features of patients with chronic sclerosing osteomyelitis of the mandible
| journal = [[International journal of oral surgery]]
| volume = 12
| issue = 1
| pages = 6–13
| year = 1983
| month = February
| pmid = 6406380
}}</ref>


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 axial skeleton is involved in 91 % and the peripheral joints in 36 % of cases.
* 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.<ref>{{Cite journal


Besides sternocostal and sternoclavicular joints, which are the most
| author = [[M. Hurtado-Nedelec]], [[S. Chollet-Martin]], [[P. Nicaise-Roland]], [[S. Grootenboer-Mignot]], [[R. Ruimy]], [[O. Meyer]] & [[G. Hayem]]
| title = Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome
| journal = [[Rheumatology (Oxford, England)]]
| volume = 47
| issue = 8
| pages = 1160–1167
| year = 2008
| month = August
| doi = 10.1093/rheumatology/ken185
| pmid = 18559374
}}</ref>
* 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.


commonly affected, it mainly affects the sacroiliac or hip
== 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. <ref>{{Cite journal


joints, knees, and ankles. For anterior chest wall disease,
| author = [[Polly J. Ferguson]] & [[Monica Sandu]]
| title = Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis
| journal = [[Current rheumatology reports]]
| volume = 14
| issue = 2
| pages = 130–141
| year = 2012
| month = April
| doi = 10.1007/s11926-012-0239-5
| pmid = 22359228
}}</ref>
* 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.<ref>{{Cite journal


three stages have been described (Table 1). The costoclavicular
| author = [[W. Dihlmann]] & [[S. W. Dihlmann]]
| title = Acquired hyperostosis syndrome: spectrum of manifestations at the sternocostoclavicular region. Radiologic evaluation of 34 cases
| journal = [[Clinical rheumatology]]
| volume = 10
| issue = 3
| pages = 250–263
| year = 1991
| month = September
| pmid = 1790633
}}</ref>
* 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.<ref>{{Cite journal


ligament is involved in 48 % of cases, and it is
| author = [[P. A. J. Monsour]] & [[J. B. Dalton]]
| title = Chronic recurrent multifocal osteomyelitis involving the mandible: case reports and review of the literature
| journal = [[Dento maxillo facial radiology]]
| volume = 39
| issue = 3
| pages = 184–190
| year = 2010
| month = March
| doi = 10.1259/dmfr/23060413
| pmid = 20203282
}}</ref>
* 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 Sweet’s syndrome and Sneddon–Wilkinson disease.<ref>{{Cite journal


considered a decisive early finding in SAPHO [7, 32, 33].
| author = [[Marcello Govoni]], [[Matteo Colina]], [[Alfonso Massara]] & [[Francesco Trotta]]
| title = "SAPHO syndrome and infections"
| journal = [[Autoimmunity reviews]]
| volume = 8
| issue = 3
| pages = 256–259
| year = 2009
| month = January
| doi = 10.1016/j.autrev.2008.07.030
| pmid = 18721907
}}</ref>
* 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.<ref>{{Cite journal


The smallest number of cases in the literature are based
| author = [[Julia Fruehauf]], [[Brigitte Cierny-Modre]], [[Laila El-Shabrawi Caelen]], [[Thomas Schwarz]], [[Roland Weinke]] & [[Elisabeth Aberer]]
| title = Response to infliximab in SAPHO syndrome
| journal = [[BMJ case reports]]
| volume = 2009
| year = 2009
| month =
| doi = 10.1136/bcr.10.2008.1145
| pmid = 21686446
}}</ref>
* Sonozaki et al. [45] 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.<ref>{{Cite journal


on temporomandibular joint involvement [11, 13, 34, 35].
| author = [[G. K. Eyrich]], [[T. Langenegger]], [[E. Bruder]], [[H. F. Sailer]] & [[B. A. Michel]]
| title = Diffuse chronic sclerosing osteomyelitis and the synovitis, acne, pustolosis, hyperostosis, osteitis (SAPHO) syndrome in two sisters
| journal = [[International journal of oral and maxillofacial surgery]]
| volume = 29
| issue = 1
| pages = 49–53
| year = 2000
| month = February
| pmid = 10691145
}}</ref>


The percentage distribution of arthritis in various parts of
==Differential diagnosis==
 
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
SAPHO must be differentiated from other diseases that cause [[bone pain]], [[edema]], and [[erythema]].<ref>{{Cite journal
 
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]].
| author = [[Polly J. Ferguson]] & [[Monica Sandu]]
| title = Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis
| journal = [[Current rheumatology reports]]
| volume = 14
| issue = 2
| pages = 130–141
| year = 2012
| month = April
| doi = 10.1007/s11926-012-0239-5
| pmid = 22359228
}}</ref>


{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
Line 154: Line 214:


==Radiologic Findings==
==Radiologic Findings==
* Radiographs may show expanded bone, sclerosis and osteolysis, periosteal reaction, or enthesopathic new bone formation.  
* Radiographs may show expanded bone, sclerosis and osteolysis, periosteal reaction, or enthesopathic new bone formation.<ref>{{Cite journal
* Bone scintigraphy delineates increased uptake in affected bone. Bone scintigraphy in the SAPHO syndrome shows ‘‘bull‘s head’’ appearance.[46].
* Magnetic resonance imaging (MRI) will also detect occult lesions, may show findings not seen on plain radiographs, and provide information about soft tissues.
* In the early stages, the disease usually manifests as an osteolytic process.
* Arthritis shows joint space narrowing and, sometimes, erosions.
* The term ‘‘corner lesion’’ describes focal cortical erosion at one of the vertebral body corners, which is usually seen in adults.
* This can be seen in up to 32 % of cases, and single and multiple levels may be found [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].
* 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
| author = [[R. Depasquale]], [[N. Kumar]], [[R. K. Lalam]], [[B. J. Tins]], [[P. N. M. Tyrrell]], [[J. Singh]] & [[V. N. Cassar-Pullicino]]
 
| title = SAPHO: What radiologists should know
and laboratory parameters.
| journal = [[Clinical radiology]]
| volume = 67
| issue = 3
| pages = 195–206
| year = 2012
| month = March
| doi = 10.1016/j.crad.2011.08.014
| pmid = 21939963
}}</ref>
* Bone scintigraphy shows increased uptake in affected bone, so called ‘‘bull‘s 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.<ref>{{Cite journal


| author = [[Matteo Colina]], [[Marcello Govoni]], [[Carlo Orzincolo]] & [[Francesco Trotta]]
| title = Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects
| journal = [[Arthritis and rheumatism]]
| volume = 61
| issue = 6
| pages = 813–821
| year = 2009
| month = June
| doi = 10.1002/art.24540
| pmid = 19479702
}}</ref>
* 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 ==
== Laboratory tests ==
There are no laboratory tests that are diagnostic of SAPHO.
* elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and elevated levels of components of complements C3 and C4.
* Anemia and leukocytosis


They can be normal or may show elevated inflammatory
== Histology ==
 
* In the early stages, there is acute inflammation with a predominantly neutrophilic infiltrate, and both bone resorption and prominent periosteal bone formation.<ref>{{Cite journal
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-
| author = [[Ch Matzaroglou]], [[D. Velissaris]], [[A. Karageorgos]], [[M. Marangos]], [[E. Panagiotopoulos]] & [[M. Karanikolas]]
| title = SAPHO Syndrome Diagnosis and Treatment: Report of Five Cases and Review of the Literature
| journal = [[The open orthopaedics journal]]
| volume = 3
| pages = 100–106
| year = 2009
| month = November
| doi = 10.2174/1874325000903010100
| pmid = 19997538
}}</ref>
* multinucleated giant cells, granulomatous foci, and necrotic bone fragments.
* he infiltrate consists of scattered lymphocytes, plasma cells, histiocytes, and only a few polymorphonuclear cells.<ref>{{Cite journal


Nedelec et al. [30] showed significantly increased levels of
| author = [[M. Hurtado-Nedelec]], [[S. Chollet-Martin]], [[P. Nicaise-Roland]], [[S. Grootenboer-Mignot]], [[R. Ruimy]], [[O. Meyer]] & [[G. Hayem]]
 
| title = Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome
IgA in their cohort of 29 SAPHO patients, while the levels
| journal = [[Rheumatology (Oxford, England)]]
 
| volume = 47
of IgM and IgG were normal. This information can possibly
| issue = 8
 
| pages = 1160–1167
be used as an additional tool in making the diagnosis,
| year = 2008
 
| month = August
but further investigations need to be done. Also,
| doi = 10.1093/rheumatology/ken185
 
| pmid = 18559374
== Histology ==
}}</ref>
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]).
* 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==
==Treatment==
* nonsteroidal anti-inflammatory drugs (NSAIDs) are generally considered as the first-line treatment option.<ref>{{Cite journal


Because to the variety of clinical presentations, the treatment
| author = [[P. A. J. Monsour]] & [[J. B. Dalton]]
| title = Chronic recurrent multifocal osteomyelitis involving the mandible: case reports and review of the literature
| journal = [[Dento maxillo facial radiology]]
| volume = 39
| issue = 3
| pages = 184–190
| year = 2010
| month = March
| doi = 10.1259/dmfr/23060413
| pmid = 20203282
}}</ref>
* 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


of SAPHO syndrome remains a challenge and outcomes
agents are only indicated when symptoms persist for at


are known to be disappointing, especially with the
least 4 weeks, despite adequate NSAID therapy.
 
* There is
skin component of the disease. There have been no randomized
increasing evidence of anti-TNFa usage in the treatment of
 
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
such patients.<ref>{{Cite journal


least 4 weeks, despite adequate NSAID therapy. There is
| author = [[Salvador Arias-Santiago]], [[Daniel Sanchez-Cano]], [[Jose Luis Callejas-Rubio]], [[Maria Antonia Fernandez-Pugnaire]] & [[Norberto Ortego-Centeno]]
| title = Adalimumab treatment for SAPHO syndrome
| journal = [[Acta dermato-venereologica]]
| volume = 90
| issue = 3
| pages = 301–302
| year = 2010
| month = May
| doi = 10.2340/00015555-0822
| pmid = 20526553
}}</ref>


increasing evidence of anti-TNFa usage in the treatment of
Case reports and case series on TNFa
 
such patients. Case reports and case series on TNFa


blockade often demonstrate a marked improvement in the
blockade often demonstrate a marked improvement in the
Line 364: Line 341:
spondyloarthropathies and lower dosages cannot maintain
spondyloarthropathies and lower dosages cannot maintain


the remission of disease [58]. Both skeletal and cutaneous
the remission of disease.<ref>{{Cite journal


lesions responded well in most of the described cases, with
| author = [[H. G. Taylor]] & [[P. T. Dawes]]
| title = Sterno-costo-clavicular hyperostosis
| journal = [[The British journal of clinical practice]]
| volume = 46
| issue = 4
| pages = 276–278
| year = 1992
| month = Winter
| pmid = 1290744
}}</ref>


exception of PPP, which sometimes failed to respond. In
Both skeletal and cutaneous


some cases, infliximab induced exacerbation of skin manifestation.
lesions responded well in most of the described cases, with


Arias-Santiago et al. [59] suggested adalimumab
exception of PPP, which sometimes failed to respond.<ref>{{Cite journal


as a possible alternative therapy in such cases, and there are
| author = [[H. G. Taylor]] & [[P. T. Dawes]]
| title = Sterno-costo-clavicular hyperostosis
| journal = [[The British journal of clinical practice]]
| volume = 46
| issue = 4
| pages = 276–278
| year = 1992
| month = Winter
| pmid = 1290744 


also reports on the successful treatment of SAPHO with
}}</ref>


etanercept and the IL-1 receptor antagonist anakinra.
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.<ref>{{Cite journal


Anakinra appeared to be helpful in five out of six SAPHO
| author = [[A. P. Rozin]] & [[A. M. Nahir]]
 
| title = Is SAPHO syndrome a target for antibiotic therapy?
patients, two of which previously failed to respond to TNF
| journal = [[Clinical rheumatology]]
 
| volume = 26
blockers [60]. Autologous bone transplantation using
| issue = 5
 
| pages = 817–820
microvascular flaps is applied as an experimental treatment
| year = 2007
 
| month = May
procedure [15].
| doi = 10.1007/s10067-006-0274-6
 
| pmid = 16601916
Physiotherapy can always be used as an additional
}}</ref>
 
* Autologous bone transplantation using microvascular flaps is applied as an experimental treatment procedure.
treatment for osteoarticular manifestations. Surgery is
* Surgery is considered for patients who failed to respond to medical therapy.
 
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==
==References==
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Revision as of 00:45, 6 April 2018

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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

Etiology

  • The etiology is still unknown. The pathogenesis involves a combination of genetic and immunological components.[1]
  • 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.[2]
  • Different types of pathogens were isolated from different bone sites and pustules in the skin, including Staphylococcus aureus, 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.[3]
  • 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.[4]
  • 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.[5]
  • 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. [6]
  • 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.[7]
  • 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.[8]
  • 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 Sweet’s syndrome and Sneddon–Wilkinson disease.[9]
  • 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.[10]
  • Sonozaki et al. [45] 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.[11]

Differential diagnosis

SAPHO must be differentiated from other diseases that cause bone pain, edema, and erythema.[12]

Disease Findings
Soft tissue infection
(Commonly cellulitis) 		History of skin warmness, swelling and erythema. Bone probing is the definite way to differentiate them.[13][14]
Osteonecrosis
(Avascular necrosis of bone) 		Previous history of trauma, radiation, use of steroids or biphosphonates are suggestive to differentiate osteonecrosis from ostemyelitis.[15][16]
MRI is diagnostic.[17][18]
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.[19]
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.[20]
Gout Gout presents with joint pain and swelling. Joint aspiration and crystals in synovial fluid is diagnostic for gout.[21]
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.[22]

Radiologic Findings

  • Radiographs may show expanded bone, sclerosis and osteolysis, periosteal reaction, or enthesopathic new bone formation.[23]
  • Bone scintigraphy shows increased uptake in affected bone, so called ‘‘bull‘s 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.[24]
  • 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.[25]
  • multinucleated giant cells, granulomatous foci, and necrotic bone fragments.
  • he infiltrate consists of scattered lymphocytes, plasma cells, histiocytes, and only a few polymorphonuclear cells.[26]
  • 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.[27]
  • 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.[28]

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.[29]

Both skeletal and cutaneous

lesions responded well in most of the described cases, with

exception of PPP, which sometimes failed to respond.[30]

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.[31]
  • 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.

References

  1. ↑ G. Assmann & P. Simon (2011). "The SAPHO syndrome--are microbes involved?". Best practice & research. Clinical rheumatology. 25 (3): 423–434. doi:10.1016/j.berh.2011.01.017. PMID 22100290. Unknown parameter |month= ignored (help)
  2. ↑ L. T. Burgemeister, D. L. P. Baeten & S. W. Tas (2012). "Biologics for rare inflammatory diseases: TNF blockade in the SA PHO syndrome". The Netherlands journal of medicine. 70 (10): 444–449. PMID 23230013. Unknown parameter |month= ignored (help)
  3. ↑ A. P. Rozin & A. M. Nahir (2007). "Is SAPHO syndrome a target for antibiotic therapy?". Clinical rheumatology. 26 (5): 817–820. doi:10.1007/s10067-006-0274-6. PMID 16601916. Unknown parameter |month= ignored (help)
  4. ↑ M. Malmstrom, F. Fyhrquist, T. U. Kosunen & A. Tasanen (1983). "Immunological features of patients with chronic sclerosing osteomyelitis of the mandible". International journal of oral surgery. 12 (1): 6–13. PMID 6406380. Unknown parameter |month= ignored (help)
  5. ↑ M. Hurtado-Nedelec, S. Chollet-Martin, P. Nicaise-Roland, S. Grootenboer-Mignot, R. Ruimy, O. Meyer & G. Hayem (2008). "Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome". Rheumatology (Oxford, England). 47 (8): 1160–1167. doi:10.1093/rheumatology/ken185. PMID 18559374. Unknown parameter |month= ignored (help)
  6. ↑ Polly J. Ferguson & Monica Sandu (2012). "Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis". Current rheumatology reports. 14 (2): 130–141. doi:10.1007/s11926-012-0239-5. PMID 22359228. Unknown parameter |month= ignored (help)
  7. ↑ W. Dihlmann & S. W. Dihlmann (1991). "Acquired hyperostosis syndrome: spectrum of manifestations at the sternocostoclavicular region. Radiologic evaluation of 34 cases". Clinical rheumatology. 10 (3): 250–263. PMID 1790633. Unknown parameter |month= ignored (help)
  8. ↑ P. A. J. Monsour & J. B. Dalton (2010). "Chronic recurrent multifocal osteomyelitis involving the mandible: case reports and review of the literature". Dento maxillo facial radiology. 39 (3): 184–190. doi:10.1259/dmfr/23060413. PMID 20203282. Unknown parameter |month= ignored (help)
  9. ↑ Marcello Govoni, Matteo Colina, Alfonso Massara & Francesco Trotta (2009). ""SAPHO syndrome and infections"". Autoimmunity reviews. 8 (3): 256–259. doi:10.1016/j.autrev.2008.07.030. PMID 18721907. Unknown parameter |month= ignored (help)
  10. ↑ Julia Fruehauf, Brigitte Cierny-Modre, Laila El-Shabrawi Caelen, Thomas Schwarz, Roland Weinke & Elisabeth Aberer (2009). "Response to infliximab in SAPHO syndrome". BMJ case reports. 2009. doi:10.1136/bcr.10.2008.1145. PMID 21686446.
  11. ↑ G. K. Eyrich, T. Langenegger, E. Bruder, H. F. Sailer & B. A. Michel (2000). "Diffuse chronic sclerosing osteomyelitis and the synovitis, acne, pustolosis, hyperostosis, osteitis (SAPHO) syndrome in two sisters". International journal of oral and maxillofacial surgery. 29 (1): 49–53. PMID 10691145. Unknown parameter |month= ignored (help)
  12. ↑ Polly J. Ferguson & Monica Sandu (2012). "Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis". Current rheumatology reports. 14 (2): 130–141. doi:10.1007/s11926-012-0239-5. PMID 22359228. Unknown parameter |month= ignored (help)
  13. ↑ Bisno AL, Stevens DL (1996). "Streptococcal infections of skin and soft tissues". N. Engl. J. Med. 334 (4): 240–5. doi:10.1056/NEJM199601253340407. PMID 8532002.
  14. ↑ Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC (2014). "Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America". Clin. Infect. Dis. 59 (2): 147–59. doi:10.1093/cid/ciu296. PMID 24947530.
  15. ↑ Shigemura T, Nakamura J, Kishida S, Harada Y, Ohtori S, Kamikawa K, Ochiai N, Takahashi K (2011). "Incidence of osteonecrosis associated with corticosteroid therapy among different underlying diseases: prospective MRI study". Rheumatology (Oxford). 50 (11): 2023–8. doi:10.1093/rheumatology/ker277. PMID 21865285.
  16. ↑ Slobogean GP, Sprague SA, Scott T, Bhandari M (2015). "Complications following young femoral neck fractures". Injury. 46 (3): 484–91. doi:10.1016/j.injury.2014.10.010. PMID 25480307.
  17. ↑ Amanatullah DF, Strauss EJ, Di Cesare PE (2011). "Current management options for osteonecrosis of the femoral head: part 1, diagnosis and nonoperative management". Am J. Orthop. 40 (9): E186–92. PMID 22022684.
  18. ↑ Etienne G, Mont MA, Ragland PS (2004). "The diagnosis and treatment of nontraumatic osteonecrosis of the femoral head". Instr Course Lect. 53: 67–85. PMID 15116601.
  19. ↑ Ahmadi ME, Morrison WB, Carrino JA, Schweitzer ME, Raikin SM, Ledermann HP (2006). "Neuropathic arthropathy of the foot with and without superimposed osteomyelitis: MR imaging characteristics". Radiology. 238 (2): 622–31. doi:10.1148/radiol.2382041393. PMID 16436821.
  20. ↑ Lovell, Wood (2014). Lovell and Winter's pediatric orthopaedics. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 978-1605478142.
  21. ↑ Joosten LA, Netea MG, Mylona E, Koenders MI, Malireddi RK, Oosting M, Stienstra R, van de Veerdonk FL, Stalenhoef AF, Giamarellos-Bourboulis EJ, Kanneganti TD, van der Meer JW (2010). "Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1β production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis". Arthritis Rheum. 62 (11): 3237–48. doi:10.1002/art.27667. PMC 2970687. PMID 20662061.
  22. ↑ Picarsic J, Jaffe R (2015). "Nosology and Pathology of Langerhans Cell Histiocytosis". Hematol. Oncol. Clin. North Am. 29 (5): 799–823. doi:10.1016/j.hoc.2015.06.001. PMID 26461144.
  23. ↑ R. Depasquale, N. Kumar, R. K. Lalam, B. J. Tins, P. N. M. Tyrrell, J. Singh & V. N. Cassar-Pullicino (2012). "SAPHO: What radiologists should know". Clinical radiology. 67 (3): 195–206. doi:10.1016/j.crad.2011.08.014. PMID 21939963. Unknown parameter |month= ignored (help)
  24. ↑ Matteo Colina, Marcello Govoni, Carlo Orzincolo & Francesco Trotta (2009). "Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects". Arthritis and rheumatism. 61 (6): 813–821. doi:10.1002/art.24540. PMID 19479702. Unknown parameter |month= ignored (help)
  25. ↑ Ch Matzaroglou, D. Velissaris, A. Karageorgos, M. Marangos, E. Panagiotopoulos & M. Karanikolas (2009). "SAPHO Syndrome Diagnosis and Treatment: Report of Five Cases and Review of the Literature". The open orthopaedics journal. 3: 100–106. doi:10.2174/1874325000903010100. PMID 19997538. Unknown parameter |month= ignored (help)
  26. ↑ M. Hurtado-Nedelec, S. Chollet-Martin, P. Nicaise-Roland, S. Grootenboer-Mignot, R. Ruimy, O. Meyer & G. Hayem (2008). "Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome". Rheumatology (Oxford, England). 47 (8): 1160–1167. doi:10.1093/rheumatology/ken185. PMID 18559374. Unknown parameter |month= ignored (help)
  27. ↑ P. A. J. Monsour & J. B. Dalton (2010). "Chronic recurrent multifocal osteomyelitis involving the mandible: case reports and review of the literature". Dento maxillo facial radiology. 39 (3): 184–190. doi:10.1259/dmfr/23060413. PMID 20203282. Unknown parameter |month= ignored (help)
  28. ↑ Salvador Arias-Santiago, Daniel Sanchez-Cano, Jose Luis Callejas-Rubio, Maria Antonia Fernandez-Pugnaire & Norberto Ortego-Centeno (2010). "Adalimumab treatment for SAPHO syndrome". Acta dermato-venereologica. 90 (3): 301–302. doi:10.2340/00015555-0822. PMID 20526553. Unknown parameter |month= ignored (help)
  29. ↑ H. G. Taylor & P. T. Dawes (1992). "Sterno-costo-clavicular hyperostosis". The British journal of clinical practice. 46 (4): 276–278. PMID 1290744. Unknown parameter |month= ignored (help)
  30. ↑ H. G. Taylor & P. T. Dawes (1992). "Sterno-costo-clavicular hyperostosis". The British journal of clinical practice. 46 (4): 276–278. PMID 1290744  Check |pmid= value (help). Unknown parameter |month= ignored (help)
  31. ↑ A. P. Rozin & A. M. Nahir (2007). "Is SAPHO syndrome a target for antibiotic therapy?". Clinical rheumatology. 26 (5): 817–820. doi:10.1007/s10067-006-0274-6. PMID 16601916. Unknown parameter |month= ignored (help)
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