Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)

Abstract

Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear.Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.

Figure 1

The imbalance between pro- and anti-inflammatory cytokines is a hallmark of auto-inflammatory bone disorders. A) The prolonged interaction between pyrin and PSTPIP1 in PAPA syndrome results in impaired inhibition of the NRLP3 inflammasome, resulting in enhanced IL-1β and IL-18 release after cleavage from pro-IL-1β/pro-IL-18 by activated caspase-1 (Casp.-1). B) In DIRA, a lack of functional IL-1 receptor antagonist (IL-1RA) results in impaired peripheral control of IL-1 signaling. C) In Majeed syndrome, Lipin2 deficiency may result in increased levels of fatty acids that may be recognized by TLR-2 and -4, resulting in Jun kinase (JNK) activation and subsequent pro-inflammatory signaling. D) In CRMO monocytes, impaired ERK1/2 activation results in reduced Sp-1 recruitment and decreased histone H3 phosphorylation (H3S10P) of the IL10 promoter. This molecular defect results in a failure to express IL-10 and an imbalance between pro- and anti-inflammatory cytokines.

Figure 2

Histological appearance of early and late stages of CRMO. A) Hematoxylin and eosin (HE) stained bone biopsy in the early phase of CRMO. Neutrophils and monocytes (arrows) are the predominant cell types. B) HE stained bone biopsy showing chronic inflammation in CRMO with monocytes, lymphocytes and plasma cell infiltration. C) HE stained biopsy of the late chronic fibrosing stage in CRMO.

Figure 3

Treatment of CNO/CRMO. NSAIDs, preferentially naproxen, should be applied as first-line therapy for most patients. When disease activity is high or complications, such as vertebral involvement or fractures, are present at the time of diagnosis, corticosteroids or biological treatment may be considered. Treatment effects should be monitored after three months, using MRI. If patients fail to respond within three months, treatment can be escalated. The authors apply 2 mg/kg oral prednisone per day over two weeks, followed by clinical assessment and MRI imaging after three months. Our treatment goal is clinical, and, in the case of vertebral involvement, complete radiological remission. In the case of a relapse after initial improvement, we repeat high-dose steroids (2 mg/kg/day) for seven days or apply low-dose corticosteroids (0.1-0.2 mg/kg/day) over a longer period. In individuals who relapse again or fail to reach clinical and (if vertebrae are involved) radiological remission, TNF-α inhibitors or bisphosphonates should be considered. Though, reports on the use of sulfasalazine and particularly methotrexate are limited, we made favorable experience using sulfasalazine in the treatment of concomitant inflammatory bowel disease, skin involvement, or HLA-B27 positivity.