Conference Coverage

Are CRMO and SAPHO syndrome one and the same?



– Chronic recurrent multifocal osteomyelitis (CRMO) in children and SAPHO syndrome in adults may well be a single clinical syndrome.

Dr. Anne M. Stevens, pediatric rheumatologist at University of Washington, Seattle, and Janssen Pharmaceuticals Bruce Jancin/MDedge News

Dr. Anne M. Stevens

That contention, recently put forth by Austrian investigators, resonates with Anne M. Stevens, MD, PhD, a pediatric rheumatologist at the University of Washington, Seattle, and senior director for the adaptive immunity research program at Janssen Pharmaceuticals.

“Is CRMO just for kids? No,” she asserted at the 2020 Rheumatology Winter Clinical Symposium.

First off, she noted that the nomenclature is shifting: The more familiar acronym CRMO is giving way to CNO (chronic nonbacterial osteomyelitis) in light of evidence that roughly 30% of patients with CRMO start out with a single characteristic bone lesion, with the disease turning multifocal in the subsequent 4 years in the great majority of cases.

SAPHO syndrome – an acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis – a formerly obscure disease entity first described in 1987 in France, has suddenly become a trendy research topic, with three small studies presented at the 2019 annual meeting of the American College of Rheumatology.

CNO is a pediatric autoinflammatory bone disease characterized by sterile bone lesions, most often on the clavicle, spine, mandible, and lower extremities. It is marked by prominent focal bone and/or joint pain, worse at night, with or without swelling. With no agreed-upon diagnostic criteria or biomarkers, CNO is a diagnosis of exclusion. Two-thirds of the time the condition is initially misdiagnosed as bacterial osteomyelitis or a malignant tumor.

Austrian investigators at the University of Graz recently conducted a retrospective comparison of 24 pediatric patients diagnosed with CNO and 10 adults with SAPHO syndrome. The median age at diagnosis of CNO was 12.3 years versus 32.5 years for SAPHO syndrome. The two groups shared compelling similarities in mean number of bone lesions, prevalence of skin involvement, and other aspects of initial clinical presentation, as well as laboratory and histopathologic findings on bone biopsy.

There were, however, several notable clinical differences in this small dataset: CNO bone lesions affected mainly the lower extremities, clavicle, spine, and mandible, while SAPHO syndrome more commonly involved the sternum (50% vs. 8%) and vertebrae (50% vs. 21%). Also, the most frequent cutaneous manifestation was palmoplantar pustulosis in adults with SAPHO syndrome, while severe acne predominated in children with CNO. In both children and adults, the skin lesions most often arose after the bone symptoms, making early diagnosis a challenge.

Another similarity: Although there have been no randomized treatment trials in either CNO or SAPHO syndrome, case series suggest the same treatments are effective for both, with NSAIDs as first line, followed by nonbiologic disease-modifying antirheumatic drugs, tumor necrosis factor (TNF) inhibitors, or bisphosphonates.

CNO diagnosis, treatment, and follow-up

Various investigators have pegged the sensitivity of physical examination for diagnosis of CNO at 31%, radiographs at a lowly 13%, and bone scintigraphy at 74%, all in comparison with MRI.

“Our go-to now is MRI with STIR [short tau inversion recovery],” according to Dr. Stevens. “There’s no contrast – so no IV – no radiation, and it’s fast, 20 minutes for a whole body MRI in a little kid, 45 minutes in a big one.”

Insurers are reluctant to pay for serial whole-body MRIs for patient follow-up, so it’s often necessary to order a series of images covering different body parts.

Her University of Washington colleague Dan Zhao, MD, PhD, is developing infrared thermal imaging as an inexpensive, convenient alternative to MRI which could theoretically be done at home. In a pilot study in 30 children with CNO and 31 controls, inflamed leg segments showed significantly higher temperatures. Larger studies are planned.

Dr. Stevens advised leaning towards a diagnosis of CNO with avoidance of bone biopsy in a patient with multifocal osteomyelitis at the typical sites, a normal CBC, the typical extraosseous manifestations, and normal or only mildly elevated erythrocyte sedimentation rate and C-reactive protein in an otherwise well-appearing child. In contrast, strongly consider a bone biopsy to rule out malignancy or infection if the child has unexplained highly elevated C-reactive protein and erythrocyte sedimentation rate, cytopenia, high fever, excessive pain, lymphadenopathy, hepatosplenomegaly, or suspicious imaging findings.

German rheumatologists have developed a clinical score for diagnosis of CNO. A normal blood cell count gets 13 points; symmetric bone lesions 10; lesions with marginal sclerosis 10; a normal body temperature 9; two or more radiologically proven lesions 7; a C-reactive protein of 1 mg/dL or greater 6; and vertebral, clavicular, or sternal lesions 8. A score of 39 points or more out of a possible 63 had a 97% positive predictive value for CNO in a retrospective study of 224 children with CNO, proven bacterial osteomyelitis, or malignant bone tumors. A score of 28 points or less had a 97% negative predictive value for CNO. An indeterminate score of 29-38 warrants close monitoring.

The scoring system hasn’t been validated, but most pediatric rheumatologists agree that it’s useful, according to Dr. Stevens.

The Childhood Arthritis and Rheumatology Research Alliance (CARRA) is in the process of developing standardized diagnostic and classification criteria and treatment plans for CNO. Dr. Zhao was first author of a CARRA consensus treatment plan for CNO refractory to NSAID monotherapy. The plan for the first 12 months includes three options: methotrexate or sulfasalazine, TNF inhibitors with or without methotrexate, and bisphosphonates.

“The main point of this is you try a medicine and then wait 3 months. If they’re not responding then, switch medicines or add another drug. Monitor every 3 months based upon pain,” she said.

Dr. Stevens reported research collaborations with Kineta and Seattle Genetics in addition to her employment at Janssen Pharmaceuticals.

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