Case 1: Multifocal bone lesions in a teenager

A 15-year-old healthy female of East Indian decent presented with a two-day history of nontraumatic left ankle pain, swelling, erythema and fever, with a temperature up to 40°C. There was no other joint involvement, rashes, lethargy, weight or appetite loss, or night sweats. There was no history of recent travel, sick contacts or sexual activity. She took acetaminophen and ibuprofen for both pain and fever, but was on no other medications. Family history was negative for autoimmune conditions, inflammatory bowel disease and malignancy. Two years before she had presented with a one-week history of bilateral ankle pain followed by a four-day history of right ankle pain, swelling and erythema and a two-week history of daily fever, reduced energy and a 2.3 kg weight loss. At that time, her erythrocyte sedimentation rate (ESR) was 76 mm/h (normal 1 mm/h to 10 mm/h). Serology was negative for Epstein-Barr virus, varicella, Bartonella, Coxiella burnetii and toxoplasmosis. A malaria screen, and blood and urine cultures were negative. The joint was not aspirated at this time. Antinuclear antibody (ANA)/antineutrophil cytoplasmic antibody (ANCA) were negative and both complement component 3 and 4 were in the normal range. A bone scan (Figure 1A) showed multi-focal areas of increased activity in the right radius, right femur, and left and right tibia. She was treated with naproxen with complete resolution of her symptoms. Although there were no known tuberculosis (TB) contacts, she had a TB-positive skin test and a recent travel history to India so was treated with isoniazid for nine months for latent TB. Her ESR normalized after six months. Bone scans at initial presentation (A) and at admission, approximately two years later (B). X-rays of her tibia and fibula approximately one month later showed no abnormalities, other than generalized osteopenia. On current admission, she had a heart rate of 120 beats/min with a respiratory rate of 20 breaths/min and a temperature of 39.2°C. Physical examination revealed left ankle swelling and erythema, with an overall limited range of passive and active movement. Examination of her other joints was normal. The remainder of her examination was unremarkable. Twenty-four hours after presentation, despite complete resolution of her symptoms, she continued to spike fevers with temperatures >39°C. Her C-reactive protein was 20.5 mg/L (range 0 mg/L to 8 mg/L), ESR was 31 mm/h, white blood cell count was 2.9×109/L (normal 4×109/L to 10×109/L), neutrophils were 1.26×109/L (normal 2×109/L to 7.5×109/L), haemoglobin was 115 g/L (normal 120 g/L to 153 g/L) and her platelet count was were 173×109/L (normal 150×109/L to 400×109/L). Blood cultures were negative. Bone biopsy showed chronic inflammation with focal clusters of plasma cells. No malignant cells were noted. To rule out malignancy, given the low white blood cell count and boney lesions, a bone marrow aspirate was performed; it showed no increased blasts or malignant cells. Bone biopsy and bone marrow cultures were both negative for TB, bacteria and fungi. A bone scan (Figure 1B) showed intense tracer uptake in the distal left tibial metaphysis, right and left femoral meta-physis, symphysis pubis and both superior rami. X-rays of her clavicles appeared normal. She also underwent magnetic resonance imaging (MRI) of her lower extremities, which showed increased signal intensity in the left tibia and minimal joint effusion. A differential diagnosis of septic arthritis, acute osteomyelitis, trauma, malignancy, TB-related chronic osteomyelitis, Poncet’s disease and reactive arthritis were all considered in the described case. However, given the patient’s previous presentation, the rapid resolution of symptoms in the absence of antibiotics, and the findings from imaging and biopsy, a diagnosis of chronic recurrent multifocal osteomyelitis (CRMO) was made. Treatment was started with indomethacin; within 72 h her fever and ankle symptoms had resolved. She was discharged home with instructions to continue the indomethacin until follow-up in the rheumatology clinic after three months. In all cases of bone or joint pain, potentially damaging and treatable causes, such as septic arthritis and acute osteomyelitis, must be ruled out first. In this case, given the clinical picture of boney lesions and low white blood cell count, investigation for malignancies such as multifocal osseous lymphoma or leukemia was especially important. CRMO is an inflammatory condition characterized by multi-focal nonpyogenic inflammatory bone lesions, which can occur at any site in the skeleton, but is more commonly found to affect the metaphyses of the long bones and the clavicles (1). CRMO often takes a relapsing and remitting course with an insidious onset (2). It is often accompanied by systemic symptoms (as seen in our case) such as fever, night sweats and weight loss. Autoinflammatory diseases, autoimmunity, errors of metabolism and postinfectious reactive inflammation have all been discussed as potential theories to explain the pathogenesis of CRMO (3). Although early reports considered propionibacterium acnes to be a relevant pathogen in CRMO, later studies have not confirmed this (3). Trials of long-term antibiotic treatment have failed to demonstrate long-term effectiveness, and cultures do not seem to yield a consistent infectious agent (3). CRMO is primarily a disease of childhood and adolescence (1). The disease is rare, accounting for 2% to 5% of all osteomyelitis cases, and primarily affects young girls, with a female/male ratio of 5:19. However, the true prevalence of CRMO is unknown (1). A diagnosis of CRMO is essentially a diagnosis of exclusion (2). It may be considered when boney lesions cannot be attributed to malignancy (eg, Ewing’s sarcoma, lymphoma or metastases) or autoimmune conditions such as juvenile idiopathic arthritis or infection. Eosinophilic granuloma (boney presentation of histiocytosis X) may lead to lytic bone lesions and pathological fractures, and when numerous may be related to the onset of a more systemic disease (2). There is no definitive diagnostic tool for diagnosing CRMO (4). Diagnosis is reached through the clinical picture, findings on imaging and bone scan, exclusion of other diagnoses through biopsy and culture and progression of disease. Imaging should start with radiographic evaluation of the symptomatic sites, with progression to magentic resonance imaging (MRI) (1). Subclinical lesions may be detected by full body imaging, and they may often follow a symmetrical pattern (1). Traditionally Tc 99m bone scintigraphy is used, although whole body MRI is also now being utilized (1). If a diagnosis of CRMO is made, other associated pathologies should be considered; associations have been made to Sweet’s syndrome, and to synovitis, acne pustulosis, hyperostosis, and osteitis (SAPHO) (5). There is an increased prevalence of human leukocyte antigen B27, inflammatory bowel disease and psoriasis in patients with SAPHO (2). Diffuse sclerosing osteomyelitis of the mandible is a condition thought to be a localized form of CRMO (6). The main treatment modality used at present is nonsteroidal anti-inflammatory medication. Medications such as sulfasalazine have also been used. Tumour necrosis factor α and interleukin-1 blockers have also been used, particularly in more resistant cases; however, further studies are needed to establish their role in the treatment of CRMO (7). Immune modulating agents may be useful when coexisting autoinflammatory disease, such as inflammatory bowel disease, is diagnosed (3). Recently, bisphosphonate therapy, such as pamidronate, has been proposed as a treatment for patients with both CRMO and diffuse sclerosing osteomyelitis of the mandible who do not improve with nonsteroidal anti-inflammatory drug treatment (8). Long-term prognosis is generally good, with most children studied having no evidence of disease sequelae (9). However, a small portion of children do develop persistent disease and are therefore at risk for long-term physical and psychological complications (9). CRMO should be considered in patients with multiple boney lesions that cannot be explained by other diagnoses. In all cases of joint or bone pain, potentially damaging and treatable causes such as septic arthritis and acute osteomyelitis must be ruled out first. CRMO is essentially a diagnosis of exclusion. Treatment is with nonsteroidal anti-inflammatory medications, but relapses are common. Although the prognosis appears to be largely favourable, long-term follow-up is still necessary in these patients.

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