Published online November 1, 2005
PEDIATRICS Vol. 116 No. 5 November 2005, pp. 1231-1233 (doi:10.1542/peds.2004-2206)
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EXPERIENCE AND REASON

Successful Treatment of Chronic Recurrent Multifocal Osteomyelitis With Tumor Necrosis Factor-{alpha} Blockage

Andrea Deutschmann, MD*, Christoph J. Mache, MD*, Koppany Bodo, MD{ddagger}, Doris Zebedin, MD§ and Ekkehard Ring, MD*

* Pediatrics
§ Department of Radiology
{ddagger} Department of Institute of Pathology, Medical University of Graz, Graz, Austria


   ABSTRACT
TOP
 ABSTRACT
CASE REPORT
 DISCUSSION
 REFERENCES
 
We describe the case of an 18-year-old girl with chronic recurrent multifocal osteomyelitis (CRMO) over a period of 10 years. She had suffered predominantly from very painful recurrent swelling of her cheeks. Various therapeutic regimens including nonsteroidal antiinflammatory drugs and steroids had shown only a partial or temporary response.

Because tumor necrosis factor-{alpha}–blocking agents have been successfully applied in Crohn's-associated CRMO and the related SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome, tumor necrosis factor-{alpha}–blocking therapy with infliximab was initiated. Thereafter, apart from 1 mild episode, no additional recurrences were observed during 21 months of follow-up. Infliximab was well tolerated, and steroids were tapered off.

Our observation indicates that infliximab may be an effective therapeutic option in CRMO.

Key Words: chronic recurrent multifocal osteomyelitis • CRMO • tumor necrosis factor-{alpha} blockage • infliximab

Abbreviations: CRMO, chronic recurrent multifocal osteomyelitis • TNF-{alpha}, tumor necrosis factor-{alpha} • NSAID, nonsteroidal antiinflammatory drug • SAPHO, synovitis, acne, pustulosis, hyperostosis and osteitis

Because the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO) is unknown, a causal therapy is not available. We report our experience with tumor necrosis factor-{alpha} (TNF-{alpha}) blockage in a patient with CRMO.


   CASE REPORT
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 ABSTRACT
 CASE REPORT
DISCUSSION
 REFERENCES
 
At the age of 8 years the girl first presented with recurrent painful swellings of her cheeks (unilateral, alternate, or symmetric). The frequency of these episodes was highly variable, with the intervals ranging from 2 weeks to 1 year. Because of the racking pains, the motility of her jaw was intermittently reduced to lockjaw. In the course of 1 episode, painful swelling at her left thigh was described. During the episodes, laboratory findings were normal except for a slightly elevated C-reactive protein level (33 mg/L [normal range: <8 mg/L]) and erythrocyte sedimentation rate (50 mm/hour). Radiography of the mandible showed a slight alteration of the bone structure on the left side and periosteal reactions in both mandibular rami. Magnetic resonance imaging (MRI) showed bone marrow edema in the left mandibular ramus as well as a contrast enhancement in the masseteric muscles (Fig 1).


Figure 1
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  		Fig 1. Coronal MRI of the skull (T1-weighted image): Bone marrow edema of the left ramus of the mandible and inhomogeneous enhancement of the left ramus of the mandible and both masseteric muscles.

 
At 9 years of age a second MRI was performed during an acute episode. MRI changes had progressed to bilateral inhomogeneous enhancement in the spongiosa of the mandible and to localized destruction of the corticalis. A computed tomography scan confirmed the bone destruction and also demonstrated hypertrophic changes with diffuse sclerosis (Fig 2). A Tc99m bone scan revealed increased uptake in the affected areas. Additional regions of enhanced labeling were detected in the left sacroiliac joint and the metaphysis of the left femur. An enoral biopsy of the mandible was performed. All cultures were negative. The histologic findings were consistent with chronic nonspecific osteomyelitis (Fig 3). Thus, the diagnosis of CRMO was established.


Figure 2
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  		Fig 2. Axial computed tomography scan of the skull at 1 year of follow-up: enlargement of both rami of the mandible with sclerotic and lytic lesions.

 

Figure 3
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  		Fig 3. Bone-biopsy specimen of the mandible (hematoxylin/eosin, x400 magnification): there is fibrous tissue between the irregular bone trabeculae with solitary lymphocytes and sparse capillary blood vessels.

 
The patient was treated with multimodal-therapy regimens that included nonsteroidal antiinflammatory drugs (NSAIDs) such as acetylsalicylic acid and diclofenac. Because Propionibacterium acnes has been considered a trigger of the disease, a 3-month course of clindamycin was administered without benefit. During acute episodes she required additional analgesic therapy with piritramid. Furthermore, therapy was modified by baclofen, calcitonin, orthodontic measures, physical therapy, and behavior therapy. Transient improvement was observed during management, but her symptoms recurred at irregular intervals.

At the age of 12 years oral prednisolone was added with good initial response. However, the steroid requirement to achieve comparable response rates gradually increased. At 16 years, therapy with an anti-TNF-{alpha} antibody was initiated. The patient received infliximab (5 mg/kg body weight) every 4 weeks for 12 months and then every 8 weeks thereafter. Apart from 1 mild episode after 3 months, no additional episodes of pain have occurred. Her C-reactive protein level and erythrocyte sedimentation rate returned to normal, and the steroids and NSAIDs were tapered off. A follow-up MRI at the age of 18 years did not show any persistent contrast enhancement in the spongiosa of the mandible or the masseteric muscles. Clinical remission has now been maintained for >21 months without any adverse effects.


   DISCUSSION
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 ABSTRACT
 CASE REPORT
 DISCUSSION
REFERENCES
 
Here we report a pediatric patient with CRMO who was successfully treated with a TNF-{alpha} blocker. CRMO is a systemic, nonpurulent inflammatory disease that involves different osseous sites. At onset it often presents as a monotopic osteomyelitis. The metaphyseal region of long bones is predominantly involved. It is a disease of unknown origin. Some authors suppose P acnes as a trigger in the pathogenesis of the disease.1,2 There is also some evidence for a genetic basis of CRMO.3

An association with pustulous dermatosis (psoriasis, acne, palmoplantar pustulosis) is found in ~25% of children who have CRMO.1 We did not observe any cutaneous involvement in our patient. CRMO primarily affects children and has been considered to be the pediatric variant of SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome or as 1 feature under the "roof" of the SAPHO syndrome.1,4 The SAPHO syndrome includes a group of disorders characterized by bone lesions and is associated with cutaneous manifestations.

In adult patients with SAPHO syndrome, intense expression and production of TNF-{alpha} were observed in bone-biopsy specimens. Recent reports indicate a benefit of TNF-{alpha}–blocking agents in adults with SAPHO syndrome.5,6 Infliximab therapy also led to marked improvement in Crohn's-associated CRMO in an 11-year-old girl.7 TNF-{alpha} has a broad spectrum of biological activities, and chronic, low-level production of TNF-{alpha} may contribute to the inflammatory phenotype in CRMO. Encouraging results have been reported with the use of anti-TNF antibodies in the treatment of rheumatoid arthritis and Crohn's disease.8

In our patient we decided to administer a long-term protocol of infliximab with increasing time intervals. Yet, controversy exists about the duration of therapy and the difference between continuous and intermittent application. Because TNF-{alpha} is an important cytokine involved in containment of infection, it is important to maximize the benefit and minimize the risks of TNF-{alpha}–blocking therapy such as fatal sepsis and reactivation of latent tuberculosis.9

Our observation indicates that infliximab may be an effective therapeutic option in CRMO refractory to NSAIDs or short-term steroids. Controlled studies with larger numbers of patients are now necessary.


   FOOTNOTES
 
Accepted Feb 2, 2005.

Address correspondence to Andrea Deutschmann, MD, Department of Pediatrics, Medical University of Graz, Auenbruggerplatz 30, 8036 Graz, Austria. E-mail: andrea.deutschmann{at}meduni-graz.at

No conflict of interest declared.


   REFERENCES
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
 REFERENCES
 

  1. Schilling F, Kessler S. Chronic recurrent multifocal osteomyelitis—I. Review [in German]. Klin Padiatr. 2001;213 :271 –276[CrossRef][Medline]
  2. Girschick HJ, Huppertz HI, Harmsen D, Krauspe R, Muller-Hermelink HK, Papadopoulos T. Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing. Hum Pathol. 1999;30 :59 –65[CrossRef][Medline]
  3. Golla A, Jansson A, Ramser J, et al. Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3–18q22. Eur J Hum Genet. 2002;10 :217 –221[CrossRef][Medline]
  4. Van Dornuum S, Barraclough D, McColl G, Wicks I. SAPHO: rare or just not recognized? Semin Arthritis Rheum. 2000;30 :70 –77[CrossRef][ISI][Medline]
  5. Olivieri I, Padula A, Ciancio G, Salvarani C, Niccoli L, Cantini F. Successful treatment of SAPHO syndrome with infliximab: report of two cases. Ann Rheum Dis. 2002;61 :375 –376[Free Full Text]
  6. Wagner AD, Andresen J, Jendro MC, Hülsemann JL, Zeidler H. Sustained response to tumor necrosis factor {alpha}-blocking agents in two patients with SAPHO syndrome. Arthritis Rheum. 2002;46 :1965 –1968[CrossRef][ISI][Medline]
  7. Carpenter E, Jackson MA, Friesen CA, Scarbrough M, Roberts CC. Crohn's-associated chronic recurrent multifocal osteomyelitis responsive to infliximab. J Pediatr. 2004;144 :541 –544[CrossRef][ISI][Medline]
  8. Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996;334 :1717 –1725[Free Full Text]
  9. Baghai M, Osmon DR, Wolk DM, Wold LE, Haidukewych GJ, Matteson EL. Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept. Mayo Clin Proc. 2001;76 :653 –656[ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics




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