Most commonly, people with CRMO experience bone pain, which is described as deeper and sharper than muscle pain, longer-lasting and less affected by movement. Bone pain can occur anywhere but is more commonly focussed on joints, particularly knees and ankles, but vertebrae (back), mandible (jaw), clavicle (collar bones) and pelvis are considered ‘classic sites’ in CRMO. The pain episodes generally  come and go are and may last for several days.

Sometimes skin symptoms are present, such as acne and blisters, and co-morbidities such as inflammatory bowel disease and psoriasis are not uncommon.

Other symptoms of CRMO can include fever, nausea, excessive sweating, night sweats, and fatigue. These symptoms can greatly affect quality of life but the non-specific nature of them adds to the difficulty in making a diagnosis.

Evidence is emerging that CRMO is associated with disease-causing variants in genes associated with the interleukin-1 receptor.

Specifically, CRMO2 is the name given to CRMO with disease-causing variants in the IL1RN gene and CRMO3 likewise for IL1R1. Genes code for proteins and the protein in this case is the interleukin-1 receptor. The changes to the gene code that cause CRMO types 2 and 3 mean that the interleukin-1 receptor can’t bind properly to another protein that normally holds it in an ‘off’ position. This means that the interleukin-1 receptor is stuck in an ‘on’ position and the result is an overactive interleukin-1 pathway.

Interleukin-1 is a potent pro-inflammatory cytokine. A cytokine is a type of protein that directs cell movement (cyto is derived from Greek for ‘cell’ and kine as in kinetics). When the interleukin-1 receptor is activated, the local area gets the direction to up the inflammatory processes and then you have inflammation in that area. Because CRMO is caused by a body-wide variant, this can be happening in multiple places at once.

Not everyone with CRMO will have a known disease-causing variant in IL-1R or related genes. This doesn’t mean it’s not CRMO and a clinical diagnosis can be made without identifying a disease-causing variant. The genetics behind CRMO is an active area of research and new information is being discovered all the time.

So, is CRMO autoinflammatory or autoimmune?

CRMO is autoinflammatory. For the cases where the causative genes have been identified, the effect is that the IL-1 receptor is hyperactive. The IL-1 receptor is a key part of a pro-inflammatory pathway. This malfunction of the receptor results in chronic inflammation in affected areas. It’s not a case of misrecognition, as in autoimmune diseases, which involve the specific (adaptive) immune system, this is a non-specific (innate) immune system hyperactivation and that makes it clearly autoinflammatory.

There is no definitive test to diagnose CRMO. Doctors rely on symptoms and clinical exams to make the diagnosis, which usually involves a process of ruling out other conditions. This can be a drawn out and frustrating process, involving blood tests, X-rays, bone scans, CT and MRI scans and bone biopsies.

The European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) have recently developed diagnostic criteria for paediatric CNO, published in September 2025, as follows

Step 1, Verify entry criteria (ALL should be present):

• Bone pain and/or musculoskeletal functional limitation ≥6 wk
• Age of onset <18 y
• Abnormal findings from radiograph and/or advanced imaging including MRI, CT, bone scintigraphy at nonarthritic bone sites

Step 2, Verify exclusion criteria (NONE should be present):

• Confirmatory evidence of mutually exclusive mimicker diseases (eg infections, malignancies, refer to full paper for more details)
• Platelet <100,000/mm³
• Pathological LDH concerning for malignancy
• Complete and sustained clinical and laboratory response to antimicrobial treatment alone

Step 3, Add the scores: Add the highest value from each of 9 domains (refer to full paper for these details). A score of ≥55 is required to classify a patient as having CNO.

The first point of Step 2 in the EULAR/ACR criteria describes the process of ruling out other conditions which they have termed ‘mimickers’. In addition to ruling out an infectious or malignant cause, some of the rare autoinflammatory conditions similar to CRMO that may be considered in the diagnostic process include, but are not limited to:

• ankylosing spondylitis (AS), an inflammatory type of arthritis primarily affecting the spine;
• Majeed syndrome, considered to be a recessively inherited type of CRMO that involves disease-causing variants in the LPIN2 gene;
• synovitis, acne, pustulosis, hyperostosis and osteomyelitis (SAPHO), particularly when skin symptoms are present, such as acne and blisters;
• pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) usually involves a disease-causing variant in the PSTPIP1 gene; and
• deficiency of interleukin-1 receptor antagonist (DIRA) which, like CRMO2, involves the IL1RN gene.

There is no cure for CRMO. Treatments focus on managing symptoms by reducing pain and inflammation. For pain management, non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen are most commonly used. Short courses of corticosteroids may be needed for severe flare ups.

Bisphosphonates such as pamidronate disodium or zoledronic acid may be prescribed, which inhibit bone resorption. The thing about bones is that they aren’t just part of a static, skeletal structure. Bones are highly dynamic and are constantly breaking down and being rebuilt, according to the conditions and needs of the body. This is the normal process of bone resorption. The reasoning behind the use of bisphosphonates, is to slow down the resorption process a little bit, as excessive inflammation can get the levels out of whack.

If these treatment strategies aren’t working, then biologic drugs that target pro-inflammatory cytokines may be considered.

CRMO can be a painful and debilitating condition, but there will also be periods when there are few or no symptoms at all. These periods of remission can make the recurring and relapsing nature of the condition confusing and disheartening, as they can deeply impact on quality of life and completely ruin life plans. These ups and downs can also be difficult for friends and family to understand and accept, which can create a negative social impact on the person with CRMO.

If you know someone with CRMO, be kind and trust that they are doing their best. Supportive friends and family can make a difficult life a little bit easier. People with CRMO often have to see many different specialists to deal with the various parts of their bodies affected by CRMO. It is common for someone with CRMO to be under the care of a rheumatologist, orthopaedic doctor, immunologist, dermatologist and more, in addition to their GP who is responsible for coordinating their care.