SAPHO syndrome

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Template:SAPHO Syndrome Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2] 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

  • 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.
  • The 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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