Chronic Recurrent Multifocal Osteomyelitis (CRMO): Presentation, Pathogenesis, and Treatment

Abstract

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.

Recent findings: 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 In this context, we present previously unpublished data on cytokine and chemokine expression in monocytes and tissues.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.

Keywords: Biomarkers; Bone; CNO; CRMO; Chronic non-bacterial osteomyelitis; Chronic recurrent multifocal osteomyelitis; Cytokine; Inflammation; Treatment.

Fig. 1

Inflammatory organ involvement in CNO/CRMO. Psoriasis and palmoplantar pustulosis (~ 8%), inflammatory bowel disease (~ 10%), severe acne (~ 10%), and ankylosing spondylitis (~ 25%) have been demonstrated associated with CNO/CRMO [7, 8]. (Figure modified after [8])

Fig. 2

Magnetic resonance imaging in CNO/CRMO. Magnetic resonance imaging in a 15-year-old male patient with swelling and warmth over right mandible. a Transversal TIRM sequences unveiled bone swelling and edema of the right mandible (arrow). b Native and c contrast-enhanced transversal T1 sequences with fat saturation unveiled new bone formation (arrows), resulting swelling, and in c enhancement in the right mandible (asterisk). d Coronary T1 sequences with fat saturation in the same patient. e Whole body MRI (coronary TIRM sequences) unveiled additional sites of bone inflammation at both proximal humeri and the right upper iliac spine (circles) (MRI images with friendly permission from Gabriele Hahn, Pediatric Radiology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany)

Fig. 3

Molecular pathophysiology of CNO/CRMO. Inflammation is a potent and undirected defense mechanism against exogenous pathogens or endogenous danger signals (such as infections, tissue damage). The sensing of danger signals occurs by pattern recognition receptors (PRRs), such as the membrane-associated Toll-like receptors (TLRs) and the predominantly cytoplasmic localized NOD-like receptors (NLRs). After recognition of danger signals by monocytes/macrophages, multiprotein complexes, referred to as inflammasomes are activated. The NLRP3 inflammasome comprises NLRP3, ASC, and procaspase-1. After inflammasome activation, caspase-1 cleaves pro-IL-1β and leads to the secretion of active IL-1β. In monocytes from CRMO patients, MAP kinase Erk1 and 2 signaling is impaired, resulting in reduced expression of the immune regulatory cytokines IL-10 and IL-19. JNK and p38 MAPK are unaffected, leading to the expression of pro-inflammatory cytokines (TNFα, IL-6, IL-1β, IL-20). Reduced expression of IL-10 and IL-19 contributes to increased inflammasome activation and subsequent IL-1β release. Pro-inflammatory cytokines TNFα, IL-6, IL-20, and IL-1β increase the interaction of membrane RANK receptors with their soluble ligand RANKL on osteoclast precursor cells and induce osteoclast differentiation and activation.MAPK: mitogen-activated protein kinase; CRMO: chronic recurrent multifocal osteomyelitis; Erk1: extracellular signal-regulated kinase-1; TLR: Toll-like receptor; IL: interleukin; JNK: Jun kinase; TNF: tumor necrosis factor; NF-κB: nuclear factor-κB; Casp1: caspase-1; PAMP: pathogen-associated molecular pattern; DAMP: danger-associated molecular pattern; RANK: receptor activator of nuclear factor-κB; RANKL: RANK ligand

Fig. 4

Inflammation marker expression in monocytes from CRMO patients. Monocytes from treatment-naive CRMO patients (N = 17) and age and gender matched healthy controls (N = 17) were isolated by negative selection of CD14⁺ cells using standard procedures (Miltenyi). Monocytes were cultured at 1 × 10⁶ per milliliter media (RPMI, gentamycine, penicillin) with 5% CO2 at 37 °C. Some cells were stimulated with 100 ng/mL LPS over night as indicated. Protein levels were measured from cell culture supernatants on the LUMINEX2000 platform, using multiplex gene expression arrays (Millipore). a Monocytes from CRMO patients fail to express immune regulatory proteins GM-CSF (under resting conditions), IL-10 (under resting conditions and after stimulation with LPS), and IL-1RA (in response to stimulation with LPS). b Monocytes from CRMO express increased levels of pro-inflammatory IL-1b, IL-6, and TNFα (under resting conditions and in response to stimulation with LPS). c and d Monocytes from CRMO patients express increased amounts of pro-inflammatory chemokines IL-8, MCP-1, MIP-1a, and MIP-1b under resting conditions, MIG in response to stimulation with LPS, and IP-10 under resting conditions and in response to stimulation with LPS. These observations further indicate a significant imbalance in the expression of pro- and anti-inflammatory proteins, suggesting a pro-inflammatory phenotype of monocytes in CRMO which show signs of “spontaneous” activation

Fig. 5

Histomorphological appearance of bone inflammation in CNO/CRMO, bacterial osteomyelitis (BOM), and Langerhans cell histiocytosis (LCH). Formalin-fixed, decalcified, and paraffin-embedded bone biopsy specimens were immune-stained with antibodies directed against CD14 (monocyte marker), NLRP3, IL-1β, and IL-10 using standard techniques (as indicated). Displayed magnification is ×100. In the top panel, HE stains are displayed. Control: trabecular bone with fatty marrow and hematopoietic tissue from a bone healthy patient undergoing osteotomy. CRMO: moderately dense infiltrate of inflammatory cells, predominantly neutrophils and monocytes, some marrow fibrosis. BOM: dense infiltrate of inflammatory cells with predominant neutrophils, cellular bone remodeling and bone necrosis. LCH: Ovoid Langerhans cells, some with linear grooves of nuclei, admixed with inflammatory cells, including a large number of eosinophils, lymphocytes, neutrophils, and plasma cells. Infiltrates of CD14-positive monocytes are a central component of inflammation in acute BOM, early phase CRMO, and LCH. Expression of the inflammasome component NLRP3 is increased in inflammatory infiltrates of BOM > CRMO > LOM, translating into IL-1 β protein expression in BOM and CRMO. As suggested by studies in ex vivo isolated monocytes, IL-10 expression in inflammatory bone lesions from CRMO patients is reduced as compared to lesions from BOM and LCH patients

Fig. 6

Treatment of CNO/CRMO. NSAIDs (e.g., naproxen) are usually applied as first-line therapy in CNO/CRMO patients. Monitoring includes clinical investigations and MRI scans after 3 to 6 months. Treatment goals are clinical and, in the case of vertebral involvement, radiological remission. In NSAID-refractory cases, treatment can be escalated with corticosteroids. The authors usually apply 2 mg/kg oral prednisone per day plus NSAIDs over 5 to 10 days. In cases who first respond to corticosteroid treatment but then flare, high-dose steroids (2 mg/kg/day) can be repeated and supplemented by low-dose corticosteroids (0.1–0.2 mg/kg/day) over a longer period, e.g., to “bridge” until DMARDs are working. In individuals who fail to reach clinical and (if vertebrae are involved) radiological remission or relapse again, bisphosphonates, TNFα inhibitors, sulfasalazine, or methotrexate (MTX) should be considered. In patients with vertebral body involvement and structural damage, aggressive treatment should be discussed initially, e.g., with bisphosphonates