Chronic Recurrent Multifocal Osteomyelitis (CRMO): Presentation, Pathogenesis, and Treatment
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Purpose of Review
Chronic non-bacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder. We summarize the clinical presentation, diagnostic approaches, most recent advances in understanding the pathophysiology, and available treatment options and outcomes in CNO/CRMO.
Though the exact molecular pathophysiology of CNO/CRMO remains somewhat elusive, it appears likely that variable defects in the TLR4/MAPK/inflammasome signaling cascade result in an imbalance between pro- and anti-inflammatory cytokine expressions in monocytes from CNO/CRMO patients. In this context, we present previously unpublished data on cytokine and chemokine expression in monocytes and tissues.
CNO/CRMO is an autoinflammatory bone disorder resulting from imbalanced cytokine expression from innate immune cells. Though the exact molecular pathophysiology remains unclear, variable molecular defects appear to result in inflammasome activation and pro-inflammatory cytokine expression in monocytes from CNO/CRMO patients. Recent advances suggest signaling pathways and single molecules as biomarkers for CNO/CRMO as well as future treatment targets.
KeywordsChronic non-bacterial osteomyelitis CNO Chronic recurrent multifocal osteomyelitis CRMO Treatment Inflammation Cytokine Bone Biomarkers
Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disorder mostly affecting children and adolescents [1, 2, 3]. Autoinflammatory disorders are characterized by an activation of the innate immune system in the absence of high-titer autoantibodies and (at least initially) no involvement of autoreactive lymphocytes. Several genetically inherited monogenic autoinflammatory conditions include early-onset non-infectious osteomyelitis, namely, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), and pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA). Though sharing clinical and pathophysiological features with sporadic CNO, this manuscript will only briefly discuss monogenic autoinflammatory bone disorders and mainly focus on CNO.
Clinical Presentation and Epidemiology
Clinical presentation and severity of CNO vary significantly between individual patients, covering a wide spectrum with asymptomatic or mild inflammation of single bones at the one end, and chronic recurrent multifocal, and sometimes bone destruction causing osteomyelitis at the other end (then referred to as chronic recurrent multifocal osteomyelitis, CRMO). CNO/CRMO most frequently involves metaphyses of long bones, the pelvic bones, the vertebral column, or the shoulder girdle/clavicle [3, 7, 12].
Clinical signs of bone inflammation include localized skin redness (rare), warmth and/or swelling, and pain. Additional symptoms may be caused by paraosseous inflammation, involving peripheral nerves and/or vessels, skin or bowel inflammation, and synovitis. A subset of CNO patients exhibit inflammatory organ involvement, including psoriasis and palmoplantar pustulosis (~ 8%), inflammatory bowel disease (~ 10%), and severe acne (~ 10%) (Fig. 1) . Some CNO patients develop sacroiliitis, and some patients may progress from childhood CNO to spondylarthropathies in later life stages . In adults, skin inflammation is significantly more common as compared to children. As mentioned above, acne and/or palmoplantar pustulosis frequently occur in the context of synovitis, hyperostosis, and osteitis, which is then referred to as SAPHO syndrome.
Epidemiological data in CNO/CRMO are sparse, and include small case series and regional cohorts. CNO primarily affects children and adolescents, but can generally occur in all age groups. The peak onset of the disease is between 7 and 12 years of age [1, 2, 3, 9]. Chronic non-bacterial osteomyelitis is one of the most common autoinflammatory bone disorders in central Europe. According to several case series, CNO may be almost as common as infectious osteomyelitis [7, 15, 16, 17]. However, secondary to sometimes rather mild and unspecific clinical symptoms, CNO may be missed.
In the absence of widely accepted diagnostic criteria and disease biomarkers, CNO/CRMO remains a diagnosis of exclusion. Clinical signs include bone pain, local swelling, rarely skin redness and heat, associated skin manifestations (including palmoplantar pustulosis, psoriasis, and acne), sometimes mildly elevated temperatures, and pathological fractures (usually of affected vertebral bodies). Non-infectious arthritis can be present in up to 30% of patients [3, 7]. Routine inflammatory parameters (WBC, white blood cell count; CrP, C-reactive protein; ESR, erythrocyte sedimentation rate) are usually normal or mildly elevated.
In unclear cases, bone biopsies are usually performed to exclude chronic infection, malignancies, or other systemic disease. Important differential diagnoses include malignancies (leukemia, lymphoma, primary and secondary bone tumors), infections (bacterial osteomyelitis, tuberculosis, etc.), immunodeficiency (e.g., defects in the IL-12: interferon axis that may be accompanied by mycobacterial infections), Langerhans cell histiocytosis (LCH), and other autoinflammatory disorders (e.g., Majeed syndrome [26, 27, 28, 29, 30], DIRA , or PAPA ). Disease onset before 2 years of age is extremely uncommon and should prompt considering differential diagnoses.
Mechanisms of Chemokine and Cytokine Dysregulation in CNO/CRMO
Despite recent scientific achievements, the exact molecular pathophysiology of CNO is only incompletely understood. Generally, familial (or monogenic) diseases including CNO as a descriptive symptom can be differentiated from the entity of sporadic CNO, by other disease features. Though not the main focus of this manuscript, studies on monogenic/familial forms of “CNO” contributed to the pathophysiological understanding of sporadic CNO/CRMO.
There are at least three human diseases involving chronic multifocal sterile osteomyelitis that are caused by single gene mutations: (i) Majeed syndrome (LPIN2 mutations), (ii) deficiency of interleukin-1 receptor antagonist (DIRA, mutations in IL1RN) [26, 32, 33], and (iii) pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA, mutations in PSTPIP1).
Majeed syndrome is characterized by early-onset multifocal osteomyelitis, dyserythropoietic anemia, and joint contractures. It is caused by loss of function mutations in the LPIN2 gene, encoding for the lipin 2 protein, a phosphatidate phosphatase (PAP) that plays a role in lipid metabolism. Lipin2-deficient monocytes produce high amounts of pro-inflammatory cytokines IL-6 and TNFα when stimulated by saturated fatty acids. Overexpression of LPIN2 on the other hand reduces inflammatory cytokine levels . For Majeed syndrome, there is evidence that it is an IL-1β-mediated disease, since bone inflammation and serum inflammation markers improve in response to IL-1β blockade, while TNFα blockers have almost no effect .
Deficiency of IL-1 receptor antagonist is characterized by early-onset destructive sterile bone lesions (osteitis and periostitis) and sterile pustulosis of the skin. If left untreated, DIRA leads to a severe systemic inflammatory response syndrome and respiratory failure  due to the lack of functional IL-1 receptor antagonist and subsequently uncontrolled IL-1β signaling. Treatment with recombinant IL-1 receptor antagonist results in prompt amelioration and disease control [32, 36].
Pyogenic arthritis, pyoderma gangrenosum, and acne are caused by mutation in the PSTPIP1 gene, involved in regulation of the actin cytoskeleton. PSTPIP1 binds to pyrin, a central negative regulator of the NLRP3 inflammasome. Therapeutic options for PAPA are local and/or systemic steroids, TNFα blockers, and IL-1 blocking agents [9, 37].
Genetic predisposition appears likely to be involved in the pathophysiology of “sporadic” CNO. It was suggested by rare familial clusters of CNO/CRMO and high incidences of comorbid-affiliated inflammatory conditions such as psoriasis and inflammatory bowel disease in CNO patients and first-degree family members (approximately 50%) [7, 13]. Thus, the pathophysiology and inheritance of “sporadic” CNO appears to be complex with, e.g., a combination of associated risk alleles or individually variable (currently unknown) genetic causes resulting in disease resulting in clinically related phenotypes in the absence or presence of environmental factors.
Together with its homologs IL19 and IL20, the IL10 gene is organized in the so-called IL10 cytokine cluster on chromosome 1q32. IL-10 and IL-19 mostly bear immune regulatory functions, while IL-20 exerts pro-inflammatory properties [41••]. Thus, we asked whether the expression of IL-19 and IL-20 are also altered in monocytes from CNO/CRMO patients. In analogy to IL10, IL19 is regulated by Sp-1 and epigenetic remodeling which are altered in monocytes from CRMO patients (H3S10 phosphorylation, DNA methylation), contributing to reduced IL-19 expression in monocytes from CRMO patients [41••].
Recently, inflammatory bone loss and synovial inflammation in IL-10-deficient mice were linked to NLRP3 inflammasome activation [44•]. Furthermore, Scianaro et al.  suggested increased NLRP3 inflammasome activation contributing to the inflammatory phenotype in CRMO, showing increased mRNA expression of inflammasome components (ASC, NLRP3, caspase-1) as well as increased IL-1β transcription and release from peripheral blood mononuclear cells from active CRMO patients compared to patients with inactive disease and controls after stimulation with LPS. We recently linked impaired IL-10 and IL-19 expression with increased IL-1β mRNA expression and IL-1β release in monocytes from CRMO patients [41••]. Enhanced inflammasome activation and IL-1β secretion by monocytes from CRMO patients is reversible by co-culture with recombinant IL-10 or IL-19 [41••], suggesting an immunomodulatory function of IL-10 and IL-19 on inflammasome activation.
These observations resulted in the hypothesis that imbalanced expression of anti- (IL-10 and IL-19) and pro-inflammatory cytokines (IL-1, IL-6, TNFα, IL-20) may result in increased osteoclast differentiation and activation through enhanced interaction between receptor activator of nuclear factor-κB (RANK) and its soluble ligand RANKL on osteoclast precursor cells (Fig. 3) [9, 46, 47].
In addition to the molecular mechanisms mentioned above, IL-10 expression is predetermined by genetic variants within the IL10 proximal promoter region. Three promoter haplotypes rs1800896, rs1800871, and rs1800872, resulting in three haplotype blocks (GCC, ACC, and ATA), influence the capacity of the IL10 promoter to recruit the transcription factor Sp-1. Interestingly, and to our initial surprise, in cohorts of CRMO patients, IL10 promoter haplotype blocks encoding for “high” IL-10 expression (GCC) were significantly more common when compared to such encoding for “low” gene expression (ATA) . Provided the molecular pathologic mechanisms discussed above, we hypothesized that individuals with CRMO-associated molecular disturbances and IL10 promoter haplotype blocks encoding for “low” IL-10 expression may develop more severe disease and may not be diagnosed with CNO/CRMO but other inflammatory conditions. However, this hypothesis remains to be confirmed scientifically.
Recently, a CRMO susceptibility gene has been identified through whole exome sequencing and gene expression microarrays . One homozygous and one compound heterozygous mutation in the filamin-binding domain of the FBLIM1 gene were detected in unrelated CNO patients from South Asia . Filamin-Binding LIM Protein 1 (FBLIM1) has been suggested to act as an anti-inflammatory molecule that controls bone remodeling through the regulation of RANKL activation via ERK1/2 phosphorylation . On the transcriptional level, FBLIM1 expression is regulated by the transcription factor STAT3 . Since the immune regulatory cytokine IL-10 induces STAT3 activation, aforementioned haplotype blocks within the IL10 promoter may be involved in the pathophysiology of CNO. Indeed, Cox et al. demonstrated that both individuals carried such IL10 promoter haplotypes that code for “low” IL-10 expression, which may in turn contribute to reduced STAT3 activation and resulting effects on FBLIM1 expression in the reported individuals [50••].
Biomarkers for the Diagnosis and Monitoring of CRMO
Currently, widely accepted disease biomarkers for the diagnosis of CNO/CRMO are not available. Recently, we reported a preliminary set of serum inflammatory parameters that allow differentiating between newly diagnosed and treatment naïve patients with CRMO, Crohn’s disease, and healthy controls. Biomarkers included the monocyte derived chemokines monocyte chemotactic protein (MCP-)1 and macrophage inflammatory protein (MIP-)1b, the pro-inflammatory cytokines IL-6 and IL-12, the mast cell derived chemokine eotaxin, RANTES, the soluble IL-2 receptor, and the IL-1 receptor antagonist. Increased serum levels of the inflammatory cytokines IL-6 and IL-12, the chemokines MCP-1, MIP-1b, RANTES, and eotaxin, and the soluble IL-2 receptor distinguished among CRMO patients, individuals with Crohn’s disease and healthy controls. However, the proposed set of biomarkers could not distinguish between patients with CRMO or ANA-positive, HLA B27-negative juvenile idiopathic arthritis (JIA). This may be caused by pathophysiological parallels between the two disorders and/or a currently incomplete set of tested parameters . Currently, follow-up studies are under way, including additional parameters and differential diagnoses.
In addition to serum biomarkers, cytokine and chemokine expression from isolated immune cells may be used to diagnose CNO/CRMO. In Fig. 4, cytokine and chemokine expression patterns from ex vivo isolated peripheral blood monocytes from CRMO patients and controls are provided. Indeed, monocytes from CRMO patients fail to express granulocyte monocyte colony-stimulating factor (GM-CSF), and the anti-inflammatory molecules IL-10 and IL-1 receptor antagonist (IL-1RA) under resting conditions and/or in response to TLR4 stimulation with LPS (Fig. 4a). Conversely, monocytes from CRMO patients express increased amounts of pro-inflammatory cytokines (IL-1β, IL-6, TNFα; Fig. 4b) and chemokines (IL-8, Interferon gamma-induced protein 10: IP-10, MCP-1, MIG, MIP-1a, MIP-1b; Fig. 4c, d) in most cases already under resting conditions. These findings support previous reports on dysbalanced cytokine and chemokine expression and promise potential as disease biomarkers for the diagnosis of CNO/CRMO [41••, 42, 43, 51]. However, additional studies are needed to confirm findings, to extend beyond included differential diagnoses, and to generate longitudinal data sets measuring treatment responses.
Murine Models of CRMO
Pstpip2 mutant mice strains as disease models for CRMO. cmo chronic multifocal osteomyelitis, ENU N-ethyl-N-nitrosourea, Pstpip2 proline-serine-threonine phosphatase-interacting protein 2
Lupo mice carry a chemically induced homozygous mutation (c.Y180C; p.I282N) in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene [52, 53]. Chronic multifocal osteomyelitis (cmo) mice carry a spontaneously acquired homozygous mutation (c.T293C, p.L98P) in Pstpip2. To date, the exact molecular contribution of Pstpip2 mutations to sterile bone inflammation remains somewhat unclear . Pstpip2 belongs to the F-BAR (Fes/CIP4 homology-Bin/Amphiphysin/Rvs) domain containing protein superfamily, which couples membrane remodeling with actin dynamics associated to endocytic pathways and filopodium formation . It is a cytosolic, cytoskeleton-associated adapter molecule, which interacts with formin binding protein 17 (FBP17) through its F-BAR domain. In the presence of Pstpip2, an antagonistic recruitment of FBP17 and Pstpip2 to the plasma membrane enables correct activation of actin polymerization at podosomes. In the absence of Pstpip2, actin polymerization is hyperactivated by constitutive membrane recruitment of the FBP17-WASP (Wiskott-Aldrich syndrome protein) complex . Macrophages that express Pstpip2 at reduced levels exhibit abnormal podosome formation, leading to a more invasive phenotype.
Interleukin-1β has been linked with the pathogenesis of osteomyelitis in cmo mice [60, 61••]. Cmo mice lacking the functional IL-1 receptor I (IL-1RI) or IL-1β (but not IL-1α) were completely protected from CNO [60, 61••]. Conversely, cmo mice deficient of the inflammasome components NLRP3, ASC or caspase-1 developed severe CNO, indicating that there must be another kinase or protease other than caspase-1-activating IL-1β. Previously described proteases, performing IL-1β cleavage includes neutrophil serine proteases or caspase-8 [62••], suggesting that neutrophils may play a central role in disease pathogenesis. Thus, Cassel et al. performed experiments to identify immune cell subsets critical for IL-1β release in cmo mice . LPS-primed and ATP-stimulated bone marrow cells but not bone marrow derived macrophages from cmo mice produced high amounts of IL-1β. Increased IL-1β production was reduced by treatment of cmo bone marrow with a serine protease inhibitor (diisopropylfluorophosphate) but not with the pan-caspase-1 inhibitor z-YVAD-fmk , suggesting the involvement of neutrophils in the pathogenesis of cmo. Findings were confirmed by Lukens et al. [61••], who additionally showed that pharmacological depletion of neutrophils with the monoclonal antibody anti-Ly6G protected cmo mice from CNO [63•]. Interestingly, cmo mice either deficient of caspase-1 or -8 developed CNO, whereas cmo mice deficient of both caspases were protected from disease [63•], indicating that both caspases play redundant roles in cmo mice.
Taken together, in agreement with aforementioned findings in monocytes from CRMO patients, recent work in cmo mice suggests a central involvement of IL-1β in disease pathophysiology. Complete deficiency of Pstpip2 results in dysregulated production of IL-1β by neutrophils and enhanced osteoclastogenesis. Of note, myeloid cells determine the phenotype in Pstpip2-deficient animals (at least initially) independent of the adaptive immune system .
Over the recent years, it became increasingly clear that host interactions with skin and gut microbiota have significant effects on immune homeostasis . Particularly in genetically predisposed individuals, alterations to microbiomes can result in uncontrolled inflammation and the expression of autoimmune/inflammatory conditions. Recent data from Lukens et al. [63•] suggest that dietary manipulation of the microbiome in cmo mice can prevent osteomyelitis. The exact molecular mechanisms involved, however, remain unclear. Patients with CRMO exhibit associations with severe acne (10%) and inflammatory bowel disease (10%) , which underscores the therapeutic potential of these observations, since all of these CRMO-associated disorders are characterized by significant alterations to microbiomes .
Treatment and Monitoring
Several retrospective analyses and one prospective observation indicate that NSAIDS are effective in a large subset of patients within the first 1–2 years of treatment. We, however, recently documented that more than 50% of patients flare after 2 years [7, 65•]. Corticosteroids appear to quickly and effectively control inflammatory activity, but rarely induce long-term remission. Though only reported in a small number of patients, treatment with pamidronate or anti-TNF agents has been reported to be highly effective in a significant percentage of CNO/CRMO patients, inducing long-lasting remission in a large subset of patients [3, 9, 66]. However, all reports are limited by retrospective data collection and relatively small patient numbers.
Large prospective clinical trials to determine the best medication and the duration of treatment are lacking. Currently, consensus treatment plan initiatives of the North American Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the German Society of Pediatric Rheumatology (GKJR) are under way and will investigate and compare treatment responses to currently used therapeutic agents and protocols.
In addition to the currently applied treatment options, blockade of other molecules may be beneficial in CNO/CRMO. Since IL-1β is involved in the molecular pathophysiology of CNO/CRMO, recombinant IL-1 receptor antagonist anakinra or anti-IL-1 antibody treatment with canakinumab may be applied. Furthermore, IL-1 blockade proved effective in familial monogenic autoinflammatory disorders involving CNO (namely, Majeed syndrome and DIRA) [32, 35]. However, surprisingly few cases of anti-IL-1 treatment have been reported and showed mixed response with variable outcomes. The potential explanation for the poor response may include low tissue concentrations, pathophysiological heterogeneity in CNO/CRMO, among others.
Blockade of RANKL with the recombinant RANK ligand inhibitor denosumab may reduce osteoclast activation and inflammatory bone loss in CNO/CRMO and promises potential in the treatment of CNO/CRMO. However, at this point, there are no reliable reports on successful application of these treatment options in CNO/CRMO.
Monitoring disease activity is a concern in CNO/CRMO patients, since a significant subset of patients may develop pain amplification syndrome. Thus, clinical scores including pain scores, routine inflammatory parameters, and imaging results have been suggested (PedCNO score) . However, to date, scores are incompletely evaluated and involve time consuming and costly investigations (e.g., MRI). Thus, easily accessible and inexpensive disease biomarkers for the assessment of disease activity are urgently warranted. We recently reported a preliminary set of biomarkers (IL-12, MCP-1, sIL-2R) that may act as markers for treatment response to NSAIDs . Though included as a parameter in PedCNO scores, ESR and CrP correlated less closely with PedCNO scores when compared to the reported serum biomarkers. Thus, after further evaluation in independent cohorts and in response to other treatment options, IL-12, MCP-1, and/or sIL-2R may be used as future biomarkers for disease activity in CNO/CRMO.
Chronic non-bacterial osteomyelitis with its most severe form chronic recurrent multifocal osteomyelitis is an inflammatory bone disorder that can result in damage to bones and other tissues. Due to the lack of widely accepted diagnostic criteria or disease biomarkers, CNO/CRMO remains a diagnosis of exclusion. The molecular pathophysiology of CNO/CRMO remains incompletely understood. However, dysregulated cytokine expression from innate immune cells centrally contributes to the inflammatory phenotype of CNO. Treatment is largely based on small, mostly retrospective case collections and expert opinion, and prospective studies are largely lacking. Currently, consensus treatment protocols are under way and will deliver reliable data on treatment responses and outcomes. The recent identification of several genetic and molecular alterations in CNO/CRMO promise future success in determining exact pathophysiological causes and target-directed treatment options.
Sigrun Hofmann was supported by German Research Foundation (DFG) Grant KFO249, TP2, HO4510/1–2, and Christian Hedrich was supported by the Thyssen Foundation, the intramural MeDDrive program of TU Dresden, the Else Kröner Foundation, and the Foundation for Therapeutic Research.
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Conflict of Interest
Jessica Pablik, Sigrun Hofmann, Herman Girschick, Polly Ferguson, Franz Kapplusch, Henner Morbach, and Christian Hedrich declare no conflict of interest.
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Studies in human tissue samples and primary human cells were approved by the local ethical committees by TU Dresden and University of Wuerzburg. Individuals or their legal guardians gave written informed consent.
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