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Chronic Recurrent Multifocal Osteomyelitis a Concise Review and Genetic Update

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Chronic Recurrent Multifocal Osteomyelitis a Concise Review and Genetic Update CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Number 000, pp. 000–000 © 2007 Lippincott Williams & Wilkins Chronic Recurrent Multifocal Osteomyelitis A Concise Review and Genetic Update Hatem I. El-Shanti, MD; and Polly J. Ferguson, MD Chronic recurrent multifocal osteomyelitis is an autoinflam- tifocal osteomyelitis (CRMO) is an autoinflammatory matory disorder characterized by bone pain and fever, a bone disease characterized by bone pain and fever with an course of exacerbations and remissions, and a frequent as- unpredictable course of exacerbations and spontaneous re- sociation with other inflammatory conditions. Because its missions. It is one type of nonbacterial osteitis and is fre- etiology is largely unknown, the diagnosis is still based on quently associated with other inflammatory conditions clinical criteria; treatment is empiric and not always success- 11,51,79 ful. The diagnosis is supported by the presence of osteolytic such as pustulosis palmoplantaris (PPP), Sweet syn- 4,29,78 65,82,98 lesions with surrounding sclerosis apparent on radiographs, drome, and psoriasis. Most of the originally 23 and silent asymptomatic lesions frequently appear on reported patients are from Scandinavian countries ; how- nuclear scans. The histologic findings in bone biopsies are ever, patients of other ethnicities were later reported.75 nonspecific, showing inflammatory changes with granulo- Chronic recurrent multifocal osteomyelitis became rec- cytic infiltration. Several observations suggest the contribu- ognized as a separate clinical entity under the name sym- tion of genetic factors to the etiology of chronic recurrent metric osteomyelitis in 1972.35 Because symmetry was not multifocal osteomyelitis. Indeed, mutations in LPIN2 cause a always present, the name chronic recurrent multifocal os- syndromic form of chronic recurrent multifocal osteomyeli- 13 tis known as Majeed syndrome, while mutations in pstpip2 teomyelitis was suggested and then adopted by the medi- cause a murine form of the disorder. The roles played by cal community. Different terms are used to describe dis- LPIN2 and the human homolog of pstpip2, PSTPIP2, in the orders with nonbacterial osteitis, including SAPHO (syno- etiology of chronic recurrent multifocal osteomyelitis are un- vitis, acne, pustulosis, hyperostosis, and osteitis) certain but are currently being investigated. We emphasize syndrome,9,28,58 pustulotic arthroosteitis,44–46,48 and the need to validate diagnostic clinical criteria and develop chronic sclerosing osteomyelitis,59 all probably represent- new pathogenesis-based targeted therapy. ing the same pathogenetic mechanism.5 Osteitis is a com- Level of Evidence: Level IV, therapeutic and prognostic mon feature in both SAPHO syndrome and CRMO and study. See the Guidelines for Authors for a complete descrip- the latter is believed the pediatric presentation of the tion of levels of evidence. former.2,58 However, children with SAPHO syn- drome10,62,96 and adults with CRMO are described.86 The etiology of CRMO is unknown, but is unlikely due Autoinflammatory diseases are a group of disorders char- to infection, immune deficiency, or autoimmunity. Several acterized by seemingly unprovoked inflammation in the observations, such as affected siblings,8,32,79 concordant absence of high-titer autoantibodies or antigen-specific T monozygotic twins,39 and a recent association study,39 cells.92 They include the hereditary periodic fever syn- suggest contribution of genetic factors to the etiology of dromes and are believed caused by disturbances in the CRMO. The presence of an autosomal recessive syn- regulation of innate immunity.61,74 Chronic recurrent mul- dromic form of CRMO31,68–70 called Majeed syndrome further supports this suggestion. Another observation is From the Department of Pediatrics, University of Iowa Carver College of the presence of a spontaneously occurring mouse model 17,30,43 Medicine, Iowa City, IA. with clear autosomal recessive inheritance (cmo). The authors have received funding from NIH/NIAMS: 1 R21 AR053924-01 Recently, two genes have been identified to play a role in (HIE); NIH/NIAMS: 1 R03 AR051130-01 (PJF); and Carver Medical Re- search Initiative Grant, University of Iowa (HIE, PJF). the etiology of CRMO, LPIN2 being responsible for 31 Correspondence to: Hatem I. El-Shanti, MD, Department of Pediatrics, Uni- Majeed syndrome, and pstpip2 being responsible for the versity of Iowa Carver College of Medicine, 200 Hawkins Drive, W125 GH, cmo mouse.30 Iowa City, IA 52242. Phone: 319-356-2674; Fax: 319-356-3347; E-mail: [email protected]. In this review, we provide an overview of the clinical DOI: 10.1097/BLO.0b013e3180986d73 and management aspects of CRMO and discuss the iden- 1 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Clinical Orthopaedics 2 El-Shanti and Ferguson and Related Research tified genes that play a role in its etiology. Although a proposed in a recent study that included a sizable cohort genetic contribution to the etiology of CRMO has been with sterile osteomyelitis.50 Patients were grouped as: (1) suggested, we here present an overview of the two recently acute nonbacterial osteomyelitis (symptoms for less than 6 identified genes that are responsible for a syndromic hu- months with one or more bone lesions); (2) chronic non- man form of CRMO and for a murine form. We also bacterial osteomyelitis (symptoms for more than 6 months discuss and speculate on the role of these two genes in without remissions with one or more bone lesions); or (3) bone inflammation. CRMO (multiple bone lesions or one bone lesion with PPP and recurrence). Search Strategy The most consistent laboratory abnormality is the el- evation of the erythrocyte sedimentation rate.12,88,97 The We performed a PubMed search of the MEDLINE bio- white blood cell count may or may not be elevated.88 medical literature, using the terms chronic recurrent mul- TNF-␣ was elevated (> 25 pg/mL) in 66% of patients with tifocal osteomyelitis (141 references), LPIN2 (10 refer- 50 ences), PSTPIP1 or PSTPIP2 (30 references), SAPHO CRMO. All cultures of blood, bone biopsies, and pus- syndrome (29 references), chronic sclerosing osteomyeli- tules were negative for fungal and bacterial growth, in- cluding mycobacterium, mycoplasma, and anaerobes.88 tis (94 references), and pustulotic arthroosteitis (15 refer- 91 ences). Our searches of articles published in the English There have been suggestions of a viral etiology which is supported by the response to interferon treatment in a few language revealed considerable overlap in articles identi- 3,33 fied under the different search terms, and we reviewed the patients. However, there is otherwise little or no data articles for pertinence to our review article. We also supporting a role of viruses in the disease process or the searched articles in French or German languages. We re- successful treatment with interferon. viewed the abstracts of the articles published in these lan- Radiographs usually show irregular osteolytic le- guages and obtained and utilized the articles that added sions (radiolucency) with surrounding sclerosis 11–13,25,29,34,35,37,41,42,63,64,77,79,84,89,90,100 any information to this review.8 Due to the rarity of these (Fig 1). There conditions, we elected to include all studies in our analy- is increased uptake on nuclear scans using Tc-99, and sis, however, when information overlapped we referenced silent asymptomatic lesions may appear as well (Fig the most recent articles built on conclusions or reports of 2).25,29,34,37,42,64,77,79,84,89,90,100 A computed tomography previous articles. We also extracted information and views scan or an MRI scan may be required to confirm the di- from the abstract book, presentations, posters, and discus- agnosis.37,42,54,63,67,85,89 MRI can be helpful in determin- sions from the fourth international meeting on autoinflam- ing disease activity and extent of disease, and can be used matory disorders, “FMF and Beyond,” held in Bethesda, to help guide the bone biopsy procedure.53 MD, USA, on November 6–10, 2005. A bone biopsy taken from an active lesion usually shows nonspecific inflammatory changes Clinical Picture with granulocytic infiltration (Fig 13,24,25,29,34,35,37,41,42,63,64,79,84,89,90,100 The classic clinical picture of chronic recurrent multifocal 3). Examination of osteomyelitis is dominated by periodic bone pain and fe- biopsies at different stages showed CRMO begins as an ver. There is a slight female predominance. The age at acute inflammatory process with a predominance of poly- onset of symptoms ranges from infancy to 55 years with a morphonuclear (PMN) leukocytes plus evidence of osteo- median age of 10 years.12 The onset is almost always clastic bone resorption with or without multinucleated gi- 12 insidious with pain and tenderness, whereas the swelling ant cells. At a later stage, the inflammatory infiltrate and fever are not always present.20,23 At any one time, the shows predominance of lymphocytes, plasma cells, histio- 12 number of osteomyelitis lesions is variable, ranging from cytes, and PMN leukocytes. New bone formation is evi- two to 18.71,97 The course of disease is characterized by denced by fibrosis around foci of inflammation, irregular periodic waxing and waning of symptoms over a duration bone marrow space, and increased osteoblast activity.63 of 1 to 20 years.20,23,25,27 The inflammatory lesions are Progressive sclerosis and hyperostosis occur mostly in the localized in a distribution that is similar to the hematog- clavicle and occasionally in the tibia, femur, metatarsal, enous osteomyelitis of childhood usually in the metaphy- jaw, and ischiopubic bones.55,63 Sometimes biopsies show ses of long bones and the clavicle.12 The involvement of acute, subacute, and chronic nonspecific osteomyelitis other bone sites, such as the vertebrae,6,23 the mandible,23 mixed in the same lesion.22,76,89 Histologic changes cor- and the frontal and sphenoid bones99 is less frequently related poorly with clinical features but relatively well reported.
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