Tag Archives: chronic recurrent multifocal osteomyelitis

Chronic Nonbacterial Osteomyelitis (CNO): What a GI Doctor Should Know

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L Lim et al. The Journal of Pediatrics, Volume 283, 114636. Open Access! Chronic Nonbacterial Osteomyelitis: A Noninfectious Autoinflammatory Disorder of Bone

Prior to this review, I was familiar with the term chronic recurrent multifocal osteomyelitis (CRMO) but not CNO. CRMO is a severe form of CNO, usually characterized by symmetrical inflammatory bone lesions (DY Zhao et al. J Transl Autoimmun 2021; 4:100095. Chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO)).

In this useful review, it is noted that IBD was associated with ~9% of cases of chronic nonbacterial osteomyelitis (CNO).

    Key points:

    • “IBD identified before, during, or after CNO diagnosis, has been well-reported as an associated condition.34-37 A review of cases of CNO with IBD showed that the diagnosis of CNO preceded the diagnosis of IBD in over half of the reported cases.38“
    • “Children with CNO frequently experience a high burden of pain and impaired physical function. CNO can cause permanent deformities in any bone, but especially if there is spinal involvement and diagnosis and treatment are delayed”
    • “Bone biopsies should be performed if there is clinical suspicion of infection or malignancy, although tissue usually is not needed for diagnosis unless the clinical presentation is atypical”
    • “MRI is now the standard imaging test that usually starts with targeted examination of the affected area…A whole-body MRI (WB-MRI) should be considered for all patients with CNO at diagnosis when possible, as it may help support a diagnosis of CNO by detecting additional sites of bone inflammation that may be clinically inapparent, particularly vertebral lesions”
    • “Non-steroidal anti-inflammatory drugs (NSAIDs) are usually first-line treatment for children with CNO, except for those with vertebral lesions, who require systemic treatment… over half of children treated with NSAIDs experience a disease flare within the first 2 years,14 requiring either retreatment with NSAIDs or another systemic medication”
    • “In the presence of vertebral CNO lesions, or after failing NSAID monotherapy, three categories of systemic treatments are recommended by the Childhood Arthritis and Rheumatology Research Alliance (CARRA)56: 1) synthetic DMARDs, 2) bisphosphonates, or 3) tumor necrosis factor-inhibitor (TNFi) biologic agents with or without methotrexate (to prevent the development of antibodies to the drug)”
    • “In practice, TNFi tends to be used more if children also have comorbid conditions for which TNFi already is indicated such as inflammatory arthritis and sacroiliitis,7 IBD,4,72 and psoriasis.4,14,24 “

    My take: Being familiar with CNO is important for GI physicians as it can occur (rarely) in our patients with IBD. Another important caveat, which is not discussed in this review, is that CNO can occur paradoxically due to the use of TNFi treatment.

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    IBD and Chronic Recurrent Multifocal Osteomyelitis: Paradoxical Association with anti-TNF Therapy in Some Cases

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    MJ Dushnicky et al. JPGN 2021; 73: 626-629. Pediatric Patients with a Dual Diagnosis of Inflammatory Bowel Disease and Chronic Recurrent Multifocal Osteomyelitis

    This article describes a retrospective review of seven patients with a dual diagnosis of inflammatory bowel disease (IBD) and chronic recurrent multifocal osteomyelitis (CRMO). In their cohort 4 of 6 were receiving anti-TNF therapy at the time of CRMO diagnosis. Misleading statements from this article:

    1. The triad of IBD, CRMO and psoriasis has not been reported previously to their knowledge
    2. “It seems unlikely that anti-TNF-alpha therapy would promote its [CRMO] development”

    In JPGN Reports (not available on pubmed), Cordesse et al (JPGN Reports; November 2020 – Volume 1 – Issue 2 – p e007) identified the association of IBD, CRMO and psoriasis; in addition, they identified a paradoxical reaction to anti-TNF-alpha therapy; in this case series of three patients, anti-TNF-alpha therapy triggered CRMO and stopping anti-TNF-alpha therapy led to resolution of CRMO in two of the cases.

    In a response to a letter to the editor (Hochman JA. JPGN 2022; DOI: 10.1097/MPG.0000000000003407. Faulty Information Regarding CRMO and IBD), Dushnicky et al (DOI: 10.1097/MPG.0000000000003433) note that JPGN Reports is not available on Pubmed; however, the articles that have described this association are near the top of a google search if one looks for “IBD, CRMO and Psoriasis.” Interestingly, in their response to the letter to the editor, the authors did not amend their claim that anti-TNF therapy is unlikely to promote CRMO despite being furnished with information showing that it can. In my view, the situation with CRMO is similar to psoriasis which can be treated with anti-TNF therapy and can paradoxically be caused by anti-TNF agents as well.

    My take:

    1. CRMO is important to recognize due to its association with IBD and to realize that antibiotics are not an effective treatment.
    2. Anti-TNF-alpha agents can cause CRMO in some patients.
    3. In 2022, a web browser search (eg Google), in addition to Pubmed, is probably worthwhile when claiming that this is the first case of xyz ‘to our knowledge.’
    Bahamas (from a friend)

    Paradoxical Chronic Recurrent Multifocal Osteomyelitis (CRMO)

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    A recent case series (A Cordesse et al. JPGN Reports; 2020. November 2020 – Volume 1 – Issue 2 – p e007doi: 10.1097/PG9.0000000000000007. Chronic Recurrent Multifocal Osteomyelitis in Pediatric Crohn Disease, A Paradoxical Effect to Antitumor Necrosis Factor Alpha) reported on paradoxical Chronic Recurrent Multifocal Osteomyelitis (CRMO) which I have seen in one of my patients as well.

    Key points:

    • In patients receiving anti-TNF agents which are usually effective for CRMO, CRMO may develop paradoxically and may be associated with a psoriaform reaction.
    • At the time of diagnosis of paradoxical reaction, all patients were in remission due to anti-TNFα efficiency. Trough levels of anti-TNFα were in the expected range, and there were no anti–anti-TNFα antibodies.
    • All patients recovered after discontinuation of infliximab (n = 2) or adalimumab (n = 1). 

    My take: This study describes a rare adverse effect of anti-TNFα agents. If CRMO develops while on one of these agents, an alternative treatment is needed.

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    Why ImproveCareNow is Needed

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    A few recent articles make a strong argument for collaborative networks, like ImproveCareNow, to improve data collection to determine the most effective therapies.

    1. Kierkus J, et al. JPGN 2015; 60: 580-85.
    2. Audu GK, et al. JPGN 2015; 60: 586-91
    3. Dotson JL, et al. Inflamm Bowel Dis 2015; 21: 1109-14
    4. Saps M, et al. JPGN 2015; 60: 645-53.

    A brief description of each study.

    1. This study presented a multi-center randomized open-label trial of 99 pediatric patients with Crohn’s disease (CD) who were administered infliximab (IFX) along with an immunomodulator (azathioprine or methotrexate).  After a 10 week induction, 84 were randomized to either monotherapy for 54 weeks or dual therapy for 26 weeks. The authors did not find significant differences in response between the groups.  However, they reached a conclusion: “Twenty-six weeks likely represent (sic) the safe duration of combined IFX/immunomodulator therapy in our sample of pediatric patients with CD.”

    2. The second study described three cases of chronic recurrent multifocal ostesomyelitis (CRMO) associated with inflammatory bowel disease.  They tried to identify all pediatric cases in UK in the last 10 years. (As an aside, I have treated one teenager with CRMO and ulcerative colitis.)

    3. The third study is a retrospective single center of 30 patients with pediatric Crohn’s disease (CD) who developed intra-abdominal abscesses (IAA) over a 12-year period.  The authors note that this is “the largest single-center review of children and adolescents with CD and IAA to date.” Yet due to the small sample size, the study provides little guidance on this important medical problem; there were no predictors of successful medical or percutaneous drainage therapy.  In addition, with the increasing use of biologics, the authors note that “the issue of which patients will eventually require surgery is even less clear.” Changes in imaging (eg. MRE) and changes in medical management (eg. more enteral nutrition and less corticosteroids) are not discussed.

    4. The fourth study is a comprehensive review of randomized placebo-controlled pharmacological clinical trials in children with functional abdominal pain disorders.  They found “no evidence to support the use of most commonly used drugs in children. Only 7 pharmacological RCTs on AP-FGIDs in children were found. Most studies were single center based and had a small sample size.  The methods and outcomes were heterogeneous…We found a considerable risk of bias in most studies…There is an urgent need for well-designed randomized clinical trials using age-appropriate validated outcome measures.”

    Each of these studies makes a compelling argument for collaborative research networks.  The first study had a relatively small number of patients, short follow-up period, lack of blinding, and numerous methodological limitations.  How did the authors determine that 26 weeks was the time to stop dual therapy? Among adults with CD, a well-designed SONIC study (NEJM 2010; 362: 1383) showed the superiority of dual therapy during the study period.  In children, because of concerns about thiopurine safety, the best approach is still unclear. The second study identified only three patients despite examining a large population.  Similarly, the third study describes 30 patients with a common complication of CD but provides little insight.

    The fourth study is a cautionary tale illustrating the lack of progress due to the absence of collaborative research.  Reports indicate a high prevalence of functional abdominal pain; one study indicated that abdominal pain affects “38% of school children weekly” (J Pediatr 2009; 154: 322-6).  In fact, studies on the high prevalence of this disorder dates back for 60 years (Apley, 1975; Apley & Hale, 1973; Apley & Naish, 1958). Despite the prevalence of this problem, the data for all of the treatments is poor.  The lack of progress in defining treatments for functional abdominal pain is multifactorial, including the following:

    • Cost: For many of the available treatments, there is not a financial incentive to conduct research.
    • Biomarker: lack of objective markers for improvement
    • Disease Stigma: many people attribute functional disorders as being due solely to psychological factors
    • Physician Champions: in pediatric gastroenterology, it took concerted physician efforts over many years to develop ImproveCareNow.  Similar physician champions would be needed to improve the outcomes for children with functional disorders

    Bottomline: While ImproveCareNow has a lot of work ahead including improving data reliability and ascertaining accurate outcome measures, I think the effort is forward-thinking and will make a difference in understanding and treating children with IBD.  ImproveCareNow has more than 600 participating pediatric gastroenterologists and more than 20,000 patients. What I would like to see is a sister network to address the morbidity from functional disorders so that in 60 years (or sooner), we will be better equipped to treat children with abdominal pain that is not due to IBD.

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