Current Understanding of the Pathogenesis and Management of Chronic Recurrent Multifocal Osteomyelitis

Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder that primarily affects children. Its hallmark is recurring episodes of sterile osteomyelitis. The clinical presentation is insidious onset of bone pain with or without fever. Laboratory studies typically reveal nonspecific evidence of inflammation. Radiologic imaging and histologic appearance resemble those of infectious osteomyelitis. There is a strong association with inflammatory disorders of the skin and intestinal tract in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic component to disease susceptibility. Two genetic syndromes have CRMO as a prominent phenotype—Majeed syndrome and deficiency of the interleukin-1 receptor antagonist—and suggest that interleukin-1 may be a key cytokine in disease pathogenesis. This review briefly summarizes the main clinical and radiologic aspects of the disease and then focuses on genetics and pathophysiology and provides an update on treatment.     

Chronic non-bacterial osteomyelitis in children

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) in children is a chronic non-suppurative inflammation involving multiple sites. Some children affected by chronic non-bacterial osteomyelitis (CNO) do not have multiple lesions or a recurrent course. OBJECTIVE: To characterise the long term outcome of children with the full spectrum of CNO. METHODS: 30 children diagnosed with CNO were followed up for a mean of 5.6 years and their disease assessed using a clinical score, multiple imaging, and a diagnostic biopsy, including extensive microbial analysis. RESULTS: 9 patients had unifocal non-relapsing disease, 3 unifocal lesions with relapses, 9 multifocal lesions without relapses, and 9 multifocal lesions with relapses (CRMO). Granulocytes were present significantly more often in CRMO than in unifocal and non-recurrent lesions. Pustulosis was more common in multifocal cases regardless of recurrence. Mean duration of treatment in 15 children with a single occurrence was 9.2 months. Naproxen treatment was generally effective. Naproxen treatment in 12 patients with relapses lasted 25 months. However, 7 of these were not effectively treated with naproxen alone. Five were treated with oral glucocorticoids for 27 days in addition to naproxen, which induced remission in four, lasting for at least 1.5 years. Longitudinal growth of affected bones was not altered, except for the development of hyperostosis. CONCLUSION: CNO is a spectrum of inflammatory conditions, with CRMO being the most severe. Most children with CNO have a favourable outcome of the disease. Oral glucocorticoids may be necessary in severe recurrent cases.     

Sternocostal involvement in chronic recurrent multifocal osteomyelitis associated with ulcerative colitis

Chronic recurrent multifocal osteomyelitis (CRMO) is a chronic, relapsing, inflammatory, non-infectious disorder of the skeletal system and is of unknown origin. Early diagnosis of the disease is essential to exact treatment. The relationship between inflammatory bowel disease and CRMO is understood as extraintestinal rheumatic manifestations. CRMO associated with ulcerative colitis (UC) is very rarely reported. This case is first report of sternocostal involvement in CRMO associated with UC.     

Chronic recurrent multifocal osteomyelitis: a case report

Chronic recurrent multifocal osteomyelitis (CRMO) is a recognized condition that usually affects children and adolescents. It's characterized by insidious onset of local swelling and pain in affected bones. Clinical, biological and especially radiological abnormalities are suggestive of septic osteomyelitis, so the diagnosis is delayed. Bone biopsy with culture is certainly necessary to rule out bacterial osteomyelitis and bone tumor. Authors report the case of a 27-years old man in whom the diagnosis of CRMO was done after 14 years course.     

Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO)

Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn’s disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal–Wallis and Mann–Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn’s disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn’s disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn’s disease patients with “bone pain” and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.     

Association of chronic non-bacterial osteomyelitis with Crohn’s disease but not with CARD15 gene variants

Chronic non-bacterial osteomyelitis (CNO) is an inflammatory, non-infectious disorder of the skeletal system with unknown etiology. Besides bone-inflammation, patients may present with inflammatory involvement of other tissues. Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of CNO. We describe the occurrence of Crohn’s disease (CD) in four patients, previously diagnosed with CRMO. Mutations in CARD15, encoding the NOD2 protein, have recently been found in patients with CD. Based on the occurence of CNO and CD in these four and several reported patients, we hypothesized that CD and CRMO might share a common autoinflammatory process. Thus, we searched for CD associated CARD15 gene variants R702W, G908R and 1007fs in 29 CNO patients, 4 of them additionally diagnosed with CD. In the latter one out of the four showed compound heterozygosity for the gene variants R702W and 1007fs. The allele frequency in the 25 patients diagnosed with CNO but not CD was not different from that already reported in healthy people (R702W 4.0%, G908R 2.0%, 1007fs 2.0%). The occurrence of non-bacterial bone inflammation and granulomatous intestinal inflammation seems to represent an extended phenotype of CD, which partly might be explained by potential disease causing mutations in CARD15. However, CNO without intestinal inflammation is not associated with common CARD15 gene variants. Therefore, other variants of genes coding for proteins involved in innate immunity and inflammation might predispose for the occurrence of CNO.     

Die chronische rekurrierende multifokale Osteomyelitis in Assoziation mit chronisch entzündlichen Darmerkrankungen: Die enteropathische CRMO

The enterogenic reactive arthritides and entheropathic spondyloarthropathies are well-known entities. The so-called gut iteropathy concept offers an interesting working hypothesis to link the gut inflammation and the lymphocytic infiltration of the synovium. However, the association of rheumatic diseases belonging to the entity of the SAPHO syndrome with inflammatory bowel diseases (IBD) has only been rarely described in the literature. Among 138 cases of our (heterogenic) SAPHO cohort, we detected 5 patients (1 male, 4 females) with a proven association of SAPHO syndrome with IBD (in 4 cases Crohn's disease, in 1 case ulcerative colitis). Two patients belonged to the juvenileadolescent form and 3 to the adult form of SAPHO syndrome. In all cases the underlying osteoarticluar disease was classified as chronic recurrent multifocal osteomyelitis (CRMO), 2 of them presenting as inflammatory anterior chest wall syndrome. There was a strong association with psoriatic pustular dermatitis. Thus, we present 5 cases of "enteropathic CRMO" demonstrating several analogies to the enteropathic spondyloarthropathies. Both disease entities have in common i) metachronic development with osteoarticluar manifestations often preceding the gastrointestinal disease; ii) Crohn's like lesions that may develop from the stomach to the colon; iii) concomittent or intermittent skin pustulosis which mostly resolves; iiii) the gastrointestinal disease that often dominates the whole syndrome namely in the longterm follow-up. We suggest to transfer the hypothesis of the gut-synovium axis of enteropathic spondyloarthropathies to the entity of CRMO. This concept offers an opportunity to link the target organs gut mucosa, bone marrow and the skin via homing of antigen specific lymphocytes. This concept may help to better understand the pathogenesis of the "Skibo" (i. e., skin-bone) disease CRMO.     

The Dilemma of Chronic Recurrent Multifocal Osteomyelitis

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare idiopathic inflammatory disease that affects mainly children and young adults, resulting in significant morbidity especially if not diagnosed early. The clinical signs and symptoms are nonspecific, with a consequential delay in diagnosis. Radiological and histopathological criteria are important for its definition. Two cases of CRMO are reported, highlighting the diagnostic challenge and demonstrating the importance of timely investigations.     

Gut, inflammation and osteoporosis: basic and clinical concepts

Chronic inflammatory disorders such as inflammatory bowel diseases (IBD) affect bone metabolism and are frequently associated with the presence of osteoporosis. Bone loss is regulated by various mediators of the immune system such as the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, or interferon-gamma. TNF-alpha, a master cytokine in human IBD, causes bone erosions in experimental models and these effects are exerted by osteoclasts. Other TNF-related cytokines such as receptor activator of nuclear factor kappa B (RANK), its ligand, RANKL, and osteoprotegerin are important mediators in inflammatory processes in the gut and are critically involved in the pathophysiology of bone loss. The awareness and early diagnosis of osteoporosis in states of chronic inflammation, together with applied therapies such as bisphosphonates, may be beneficial in inflammation-associated osteoporosis. Although several mechanisms may contribute to osteoporosis in patients with IBD and coeliac disease, inflammation as an important factor has so far been neglected. As key inflammatory mediators in IBD such as TNF-alpha are involved in the disease process both in gut and bone, we hypothesise that neutralisation of TNF-alpha could prove an efficient strategy in the treatment of inflammation-related osteoporosis in the future.     

Chronic urticaria: what is new, where are we headed

Chronic urticaria can be defined as the occurrence of widespread daily or nearly daily wheals for at least 6 weeks, which may be accompanied by angioedema. It is a disease with a considerable impact on patients' quality of life. Furthermore, these patients may undergo extensive laboratory evaluations seeking a cause only to be frustrated when none is found. There is no curative treatment for this disorder and we do not understand the mechanisms that lead to the onset of disease. However, in recent years there have been significant advances in the understanding of some of the molecular mechanisms that cause cutaneous inflammation that is manifest as urticaria and angioedema. In this review we will summarize our recent contributions to this field and try to offer insights regarding future directions for research.     

Chronic inflammation,cardiometabolic diseases and effects of treatment: Psoriasis as a human model

Chronic inflammation in humans is associated with accelerated development of cardiometabolic diseases such as myocardial infarction, stroke, and diabetes. Strong evidence from animal models and human interventional trials including CANTOS (The Canakinumab Anti-inflammatory Thrombosis Outcome Study) suggests that targeting residual systemic inflammation in humans may impart a benefit in reducing cardiometabolic diseases. Diseases associated with heightened immune-activation and systemic inflammation including psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and human immunodeficiency virus infection are associated with upwards of two to seven-fold risk of future adverse cardiac events even when adjusted for traditional risk factors. Over the past decade, psoriasis has been utilized as a human model to study inflammatory-induced cardiometabolic dysfunction and to better understand residual risk due to inflammation. The high prevalence and early onset of cardiovascular disease in psoriasis enhances the likelihood of discovering novel pathways in vascular disease progression when followed over time. Furthermore, the United States Food and Drug Administration approved treatments for psoriasis include cytokine inhibitors (anti-tumor necrosis factor, anti-interleukin 17, anti-interleukin 12/23) which while treating the skin disease provide a unique opportunity to characterize how treating the inflammatory pathways may impact atherosclerosis. Herein, we provide a review of chronic inflammation, cardiometabolic disease associations, and treatment effects with a focus on psoriasis as a human model of study.     

Chronic pancreatitis: Do serum biomarkers provide an association with an inflammageing phenotype?

BackgroundChronic pancreatitis is an inflammatory disorder of the pancreas that is associated with accelerated mortality for patients suffering from this disease. The association between chronic inflammation and accelerated biological ageing has been well described and is often referred to as “inflammageing”. In this review we seek to determine how systemic inflammation in chronic pancreatitis may contribute to an accelerated ageing phenotype.MethodsA systematic literature search with a predefined search protocol was performed on Medline, Embase and Cochrane libraries according to the PRISMA guidelines.ResultsThe initial search identified 499 studies. After title, abstract and full text screen of the search results, 20 were included for further evaluation. In the 20 remaining articles 41 inflammatory mediators were identified – mainly involved in chronic inflammation, fibrosis and particularly cardinal features of inflammageing such as sarcopenia and osteoporosis.ConclusionChronic pancreatitis is associated with elevated levels of inflammatory mediators many of which are associated with an accelerated ageing phenotype and may explain some of the clinical sequelae of this disease.     

Vertebral deformities and inflammatory bowel disease

Loss of bone mass and an increased risk of fractures is an issue of major concern for physicians treating inflammatory bowel disease patients. Multiple causes for decreased bone mass have been identified in the past, but the role of inflammation may be of pivotal importance. We here discuss the latest insights into the pathogenesis of inflammatory bowel disease-related bone loss and the implications for treatment.     

Chronic kidney disease in postmenopausal women

Menopause is derived from the Greek words men (month) and pauses (cessation) and means permanent cessation of menstruation after the loss of ovarian activity. Chronic kidney disease (CKD) has recently been associated with cardiovascular events in several studies. CKD patients have a heavy burden of traditional cardiovascular risk factors in addition to a range of nontraditional risk factors such as inflammation and abnormal metabolism of calcium and phosphate. In this review, the association of CKD and cardiovascular disease (CVD), as well as of osteoporosis in postmenopausal women is discussed. CKD mineral and bone disorder, characterized by disturbances of calcium/phosphate/parathyroid hormone, bone abnormalities and vascular and soft tissue calcification, is highly prevalent in CKD and is a strong, independent predictor of bone fracture, CVD and death. Estrogen has been shown to: (a) decrease the expression of angiotensin type 1 receptors in vasculature and kidneys; (b) reduce the expression and activity of angiotensin-converting enzyme, and (c) cause the release of angiotensinogen substrate from the liver. However, the degree of activation or suppression of the renin-angiotensin-aldosterone system by estrogen has not been clearly established. Clinical data on the effects of estrogen therapy on bone mineral densities are extremely limited in the ESRD population. CVD is the most common cause of death in postmenopausal women with CKD and many contributing factors have been explored. Future research for prevention of CVD in postmenopausal women with CKD would focus on the biology of vascular calcification as well as bone loss.     

Bowman-Birk Inhibitor Concentrate Reduces Colon Inflammation in Mice with Dextran Sulfate Sodium-Induced Ulcerative Colitis

Bowman-Birk inhibitor concentrate (BBIC) is asoybean extract enriched in the BowmanBirk inhibitor, aprotein protease inhibitor. The Bowman-Birk inhibitorcan inhibit proteases released from inflammation mediating cells and suppress superoxide anionradical secretion from immunocytes. This studyinvestigates the ability of Bowman-Birk inhibitorconcentrate to inhibit colon inflammation in the dextransulfate sodium model of ulcerative colitis, aninflammatory bowel disease. When compared to mice on astandard diet, mice given food supplemented with 0.5%BBIC during and after dextran sulfate sodium treatment showed suppression of three of four scoredhistopathological inflammation criteria (P < 0.01),total histopathological score (P < 0.01), a 15% lowermortality rate (P < 0.01), and a delayed onset of mortality. We conclude that dietaryBowman-Birk inhibitor concentrate can beneficiallyaffect dextran sulfate sodium-treated mice and may beuseful in the treatment of human inflammatory boweldiseases, particularly ulcerative colitis.     

Chronic inflammation, colorectal cancer and gene polymorphisms

Chronic inflammation is commonly present in gastrointestinal mucosal sites at increased risk for cancer, such as in inflammatory bowel disease (IBD) or chronic gastritis caused by Helicobacter pylori infection. Why some patients have more mucosal inflammation than others, and why certain individuals with chronic inflammation develop cancer, are problems that have not been solved. Unlike the case for the syndromic forms of familial colorectal cancer (CRC), the risks for IBD and other forms of chronic inflammation have not been linked to highly penetrant single gene mutations. Single nucleotide polymorphisms (SNP) are variations in DNA sequence that can be linked to any phenotype (cancer, chronic inflammation, etc.) in genome-wide association studies (GWAS). CRC has been linked to several highly penetrant single gene loci, as well as multiple SNP. The propensity to develop IBD has not been linked to single gene mutations in most instances, but has been linked to SNP in the NOD2 locus (which appear to create hypomorphic alleles for this bacterial response gene), the IL23R locus, the autophagy gene ATG16L1 and a wide range of other loci including the Toll-like receptors, JAK2 and STAT3, and perhaps 70 more. At present, the problem in predicting risk for chronic inflammation is that there are many genetic polymorphisms with relatively modest individual effects. Our challenge is to understand how the SNPs that are linked to variations in the inflammatory response interact with one another (i.e. to understand the 'epistasis' involved), and to integrate this with the variety of individual environmental exposures. This represents an opportunity for informatics science to help personalize our approach to chronic inflammatory diseases of the gut and identify those at greatest risk for cancer.     

Childhood chronic recurrent multifocal osteomyelitis: pamidronate therapy decreases pain and improves vertebral shape

OBJECTIVE: Chronic relapsing multifocal osteomyelitis (CRMO) results in significant morbidity, especially in those with vertebral collapse. Symptomatic benefit with intravenous pamidronate (PAM) has been shown; however, few studies have demonstrated radiological benefit. We describe clinical and radiological data on 7 pediatric cases of CRMO treated with PAM. METHODS: Retrospective chart review on all children with CRMO treated with PAM. Response to PAM was measured by subjective reports and radiology including vertebral morphometry. RESULTS: Seven patients (1 male) presented with bone pain at a median age of 8 years (range 5-14). Symptoms had been present for a median of 18 months (range 11-51) before PAM therapy. All patients had involvement of multiple nonspinal sites, 5 children had spinal involvement with vertebral fractures, and 5 had joint involvement. Six cases had symptomatic improvement within 6 months of starting PAM, which was sustained during PAM therapy (median 26 mo, range 6-41) and persisted in the 4 cases who had ceased treatment for the duration of followup (27 mo, range 18-51). The least benefit was seen in the 3 cases with synovial joint involvement. The 3 cases with spinal radiological followup showed modeling of vertebral fractures and in one patient improvement in kyphosis. No radiological improvement in nonspinal lesions was seen. CONCLUSION: PAM therapy was associated with symptomatic improvement and vertebral modeling in children with CRMO. We suggest that children with bone pain and/or spinal involvement be considered for PAM therapy early after diagnosis.     

ACPA and Bone Loss in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by bone loss. Degree of inflammation and autoantibody positivity have both been identified as important initiators of skeletal damage in RA. Whereas it is well appreciated that inflammation initiates bone loss via the action of cytokines, the effect of autoantibodies in initiating bone destruction has long been underestimated. It has, nonetheless, been known for years that antibodies against citrullinated proteins (ACPA) and rheumatoid factor are associated with a more destructive disease course. It was recently shown that ACPA bind osteoclast precursor cells and directly promote their differentiation into bone-resorbing osteoclasts. Other results have shown that in ACPA-positive individuals bone loss starts even before the onset of clinical disease; this is indicative of the independent effect of these antibodies in initiating skeletal damage. The observation that the mere presence of ACPA is associated with pathological changes suggests that these antibodies have functional properties and initiate the onset of disease long before patients consult the rheumatologist because of symptomatic joint disease. These findings also indicate that “RA” is a syndrome rather than a single disease, suggesting that autoantibody-positive patients are both genetically and clinically distinct phenotypes.     

Chronic recurrent multifocal osteomyelitis and psoriasis—A report of a new association and review of related disorders

In summary, we have described two patients with CRMO and psoriasis, and have reviewed the musculoskeletal manifestations associated with pustular eruptions of the palms and soles. In view of the frequent occurrence of PPP in patients with CRMO, we suggest that the occurrence of psoriasis in our two patients is more than coincidence, and that noninfectious, inflammatory lesions of bone may be another musculoskeletal manifestation of psoriasis. This rare association, as well as the association of PPP with disorders associated with new bone formation, may shed new insights on the relatively common finding of periosteal elevation associated with psoriatic arthritis and the occasional severe juxta-articular osteolytic destructive bone lesions seen in psoriatic arthritis.     

Experimental Colitis Induced by Trinitrobenzenesulfonic Acid (An Ultrastructural and Histochemical Study)

Inflammatory bowel disease (IBD) of humans is achronic and devastating disease of unknown etiology.Models of acute colitis in animals have been achieved byintrarectal administration of agents such as 2,4,6-trinitrobenzenesulfonic acid (TNBS) intorat colon. This agent induces focal inflammation andalterations in the colon with features similar to thosefound in chronic inflammatory diseases in humans. The aim of this study was to assess the effectof TNBS administration on histological andultrastructural features of the rat colon, especially inareas not affected by transmural inflammation. Also in areas without transmural inflammation, weobserved a significant increase in crypt diameter and inthe number and area of the goblet cells, as well asalterations in the contents of mucin in goblet cells. We conclude that TNBS treatment in rats led tosevere changes in normal architecture of the colon andalso in damaged areas where no direct inflammation wasproduced.