Our approach in our SSRP Clinical practice is to better understand the mechanisms of disease and then implement plan. Here are some of our thoughts, please note we have taken a different approach than current recommendations of NSAIDS, steroids, bisphosphonates, methotrexate, sulfasalazine, and newer immunotherapies.
Our treatment recommendations are for an adult as referenced in this question. Pediatric dosing would vary.
CRMO Pathophysiology:
- Defect in the TLR4/MAPK/inflammasome signaling cascade leads to an imbalance in cytokine expression in monocytes, specifically inflammatory monocytes.
- Toll-like receptors (TLRs) and NOD-like receptors (NLRs) sense danger signals
- Danger signals activate inflammasomes and IL-1B is secreted
- IL-10 and IL-19 expression is reduced
- JNK and p38 MAPK are not affected therefore pro-inflammatory cytokines (TNFa, IL-6, IL-1B, IL-20) are still expressed
- TNFa, IL-6, IL-20 and IL-1B increase interaction of RANK and RANKL receptors.
CRMO Overview:
- Autoinflammatory bone disorder. It is NON-BACTERIAL (though some studies show Cutibacterium (formerly Propionibacterium) acnes plays a role in the pathogenesis )
- Believed to have defects on the TLR4/MAPK/inflammasome signaling cascade (leads to imbalance in cytokine expression in monocytes)
- Studies have shown the disbalance between cytokine and chemokine expression is a potential disease marker for diagnosis of CNO/CRMO
- Affects mostly children and adolescents
- Affects all ethnicities
- Genetics may play a role. Has been associated with other inflammatory conditions i.e. inflammatory bowel disease, acne, ankylosing spondylitis and psoriasis (but no specific gene mutation identified)
- Most frequently involves:
- Metaphysis of long bones
- Pelvic bones
- Vertebral column ( 50 percent adults)
- Shoulder girdle/clavicle
- Inflammasome activation of IL-1B secretion by monocytes from CRMO is reversible by co-culture with recombinant IL-10 or IL-19 suggesting immunomodulatory function of IL-10 and IL-19 on inflammasome activation
- One compound heterozygous mutation in the filamin-binding domain of the FBLIM1 gene (FBLIM1 is believed to act as anti-inflammatory molecule that controls bone remodeling through regulation of RANKL activation via ERK1/2 phosphorylation
- Transcriptional level-FBLIM1 expression regulated by transcription factor STAT3. IL-10 induces STAT3 activation therefore the inhibition of IL10 promoter can be involved
- Host interactions with skin and gut microbiota have significant effects on immune homeostasis. Alterations to microbiomes can result in inflammation and autoimmune/inflammatory conditions. All CRMO-associated disorders are characterized by significant alterations to microbiomes
Treatment Recommendation:
- Right track with TA1 because of the influence it has on IL-10. Ta1 will enhance IL10 ,IL-2 Il-12 .Acts as Agonist of TLR-2 . Reduces production of reactive oxygen Species preventing oxidative Damage improving function of Superoxide Dismutase and catalase and glutathione peroxidase.
- Start TA1 50 IU daily 2 weeks should see pain and swelling improvements then switch to 20 IUs daily for 3 months , then reevaluation.
- Adding TB4 as another immune peptide can add at 2 weeks if no improvement. downregulates inflammation. Tβ4 directly targets the NF‐κB RelA/p65 subunit suppressing TNF‐α‐mediated NF‐κB activation and reducing the levels of a large number of downstream key proinflammatory cytokines like IL-1B and IL‐8.
- Start at TB4 30 IU BID 2 weeks then review and if improving symptoms go to 15 IU’s BID 3 months with TA1 above.
- Pentosan Polysulfate 54 works through some of the inflammatory mechanisms that CRMO affects. Interesting option for further discussion.
- Recommend doing a genetic gut microbiome test called NirvanaBiome . You will more than likely see dysbiosis that needs to be addressed. Short chain fatty acid production and B vitamin production will be deficient. Our belief is microbiome is involved and the NSAID treatment contributed to further dysbiosis. Consider both prebiotics and Butyrate to start.
- Utilizing TA1 improving IL10 and TB4 suppression of TNF‐α‐mediated NF‐κB activation IL1b will promotes deactivation of the IL1 Rankl ligand on the osteoclast inhibiting resorption.
- Always remember diagnostic image of choice whole body MRI, looking for asymptomatic lesions, specifically vertebral body! These lead to fracture.
- With the controversy over bacterial infection., LL-37 is reserved for recalcitrant repose to treatment above. If open biopsy positive would implement LL-37 – 100mcg bid 6 weeks with above treatment plan.
Here is a great review of CRMO. Discussing the Presentation, Pathogenesis and Treatment. Hofmann, Sigrun R., Franz Kapplusch, Hermann J. Girschick, Henner Morbach, Jessica Pablik, Polly J. Ferguson, and Christian M. Hedrich. “Chronic Recurrent Multifocal Osteomyelitis (CRMO): Presentation, Pathogenesis, and Treatment.” Current Osteoporosis Reports 15, no. 6 (2017): 542–54. https://doi.org/10.1007/s11914-017-0405-9.
Other references
Skrabl-Baumgartner, Andrea, Peter Singer, Theresa Greimel, Gregor Gorkiewicz, and Josef Hermann. “Chronic Non-Bacterial Osteomyelitis: A Comparative Study between Children and Adults.” Pediatric Rheumatology Online Journal 17 (July 23, 2019): 49. https://doi.org/10.1186/s12969-019-0353-2.
Schaal, Matthias C., Liya Gendler, Bettina Ammann, Nina Eberhardt, Aleš Janda, Henner Morbach, Kassa Darge, Hermann Girschick, and Meinrad Beer. “Imaging in Non-Bacterial Osteomyelitis in Children and Adolescents: Diagnosis, Differential Diagnosis and Follow-up—an Educational Review Based on a Literature Survey and Own Clinical Experiences.” Insights into Imaging 12 (August 9, 2021): 113. https://doi.org/10.1186/s13244-021-01059-6.
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