Dear Sir,

Chronic recurrent multifocal osteomyelitis (CRMO) is a form of non-bacterial osteitis. It has first been described in 1972 [1], and an association with pustolosis palmoplantaris [2, 3] and other autoimmune disorders, such as chronic inflammatory bowel disease (IBD), Wegener’s disease, psoriasis, and Takayasu arteriitis has been discussed [3–7]. Little is known about the pathophysiology of CRMO. Several authors suggested slow-growing infectious pathogens [3], Staphylococcus epidermidis or Propionibacterium acnes [5, 8] as a potential cause. Since antibiotic agents do not influence disease progression and modern molecular techniques fail to detect infectious pathogens, these causes seem rather unlikely. Secondary to its association with other autoimmune diseases, various groups discussed an autoimmunological or pyogenic autoinflammatory cause of CRMO, and autoimmune inflammatory reactions as a response to infectious diseases [3, 9].

IL-10 is an immuno-regulatory cytokine that controls inflammation by limiting inflammatory cytokine expression. Dysregulation in IL-10 expression and single-nucleotide polymorphisms (SNPs) in the IL10 promoter are associated with autoimmune and infectious diseases [10–14]. Most available studies were focused on a series of three SNPs in the 5′ proximal promoter. The IL10 promoter polymorphisms −1082G > A (rs1800896), −819C > T (rs1800871), and −592C > A (rs1800872) are in tight linkage disequilibrium and result in three predominant or “classical” haplotypes: ATA, ACC, and GCC. ATA and ACC have been shown to be associated with relatively low IL-10 expression, whereas GCC is associated with high IL-10 expression [10, 14]. Various studies demonstrated a correlation between IL10 promoter SNPs and differential risk for infectious and autoimmune diseases [10].

Genomic DNA samples from 14 CRMO patients from the Pediatric Rheumatology and Immunology section, University Children’s Hospital Dresden, Germany and 249 healthy controls were analyzed for three well-defined IL10 promoter SNPs (−1082G > A, −819C > T, and −592C > A). We found an association of IL10 promoter polymorphisms with CRMO and demonstrate an increased frequency of high IL-10 expressing −1082G/G alleles (12/14 [0.86] vs. 27/249 [0.27]), and resulting GCC haplotypes (12/14 [0.86] vs. 56/249 [0.23]) (Fig. 1 a, b). GCC haplotypes are considered to be associated with high IL-10 expression. This is interesting, since IL-10 predominantly has immune-modulating functions. Secondary to its immuno-regulatory effects, dysregulation in IL-10 expression is associated with susceptibility to infectious and autoimmune diseases in humans and mice [10]. The association with GCC haplotypes might support the hypothesis that slow-growing pathogens, Probionibacterium acnes, Staphylococcus epidermidis or post-infectious autoimmune-autoinflammatory reactions might play a role in the pathophysiology of CRMO. Next to the anti-inflammatory aspects of IL-10 expression, IL-10 mediates the proliferation of various lymphocytic tissues, including B cells, and enhances antibody production [10]. Since predominantly lymphocytes, but also plasma cells can be found in biopsies, taken from CRMO lesions, an association with GCC haplotypes could partly explain the lymphocyte expansion in affected tissues [3]. Individual IL10 promoter SNPs could also be part of extended haplotypes that may span several hundred kilobases over the entire IL10 gene cluster [10, 12–15]. In agreement with this, a recent study failed to find a link between IL10 promoter SNPs and IBD, but showed an association between a SNP 3′ to the IL10 gene and ulcerative colitis [16].

Fig. 1
figure 1

IL10 promoter polymorphisms in CRMO. a Results of a single-marker analysis of the IL10 promoter polymorphisms −1082G > A are given. In CRMO patients, homozygous −1082G/G alleles are significantly more frequent, compared to healthy controls. b The paired allele frequency based on promoter haplotypes is given. In CRMO patients, homozygous GCC haplotypes are more frequent compared with normal controls

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To our knowledge, this is the first study that shows a possible association of IL10 promoter polymorphisms with CRMO. Secondary to the low number of individuals, further studies are warranted in order to investigate an association of IL10 promoter polymorphisms with CRMO. We would be pleased to collect samples from CRMO patients from Rheumatological centers, and to perform genotyping in order to get further insight into the association of CRMO with IL10 SNPs and extended IL10 haplotypes.