Association of polymorphic variants in serotonin re-uptake transporter gene with Crohn's disease: a retrospective case-control study.

AIM: To analyze the distribution of SLC6A4 gene polymorphisms in Crohn's disease (CD) patients and their association with the disease. METHODS: We evaluated the presence/absence of promoter (5-HTTLPR, rs25531) and intron 2 (STin2 VNTR) polymorphic variants of SLC6A4 gene in a retrospective case-control study including 192 CD patients and 157 healthy controls (HC). Genotyping was performed by polymerase chain reaction. The association of polymorphisms with CD and its clinical subtypes was analyzed using χ2 and Fisher exact test, binary logistic regression, and haplotype analysis. RESULTS: CD patients and healthy controls had similar sex (88 [45.8%] vs 84 [53.5%] women, respectively; P=0.154) and age (41.3±12.8 years vs 41.7±8.8 years, respectively, P=0.091) distribution. Significant differences were observed in the STin2 genotype and allele distribution between CD patients and healthy controls (P=0.003 and P=0.002, respectively) and between the corresponding female subgroups (P=0.004 and P=0.007, respectively), with a significant negative association of biallelic ss (STin2.9 and Stin2.10) STin2 genotype with CD (P=0.013, age- and sex-adjusted odds ratio [OR] 0.5, 95% confidence interval [CI] 0.29-0.86; women: P=0.006, age-adjusted OR 0.32, 95% CI 0.14-0.72) and a significantly higher S-STin2.12 (5-HTTLPR/rs25531: S-STin2: STin2.12) haplotype distribution in CD patients (P=0.004, OR 1.62, 95% CI 1.16-2.26). There was no significant association between 5-HTTLRP and rs25531 genotype or allele frequencies and CD and between any SLC6A4 polymorphic loci with clinical CD subtypes. CONCLUSION: STin2 VNTR polymorphism of SLC6A4 gene may contribute to CD pathogenesis.

3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 2: Surgical Management and Special Situations.

This paper is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease [CD] and concerns the surgical management of CD as well as special situations including management of perianal CD and extraintestinal manifestations. Diagnostic approaches and medical management of CD of this ECCO Consensus are covered in the first paper [Gomollon et al JCC 2016].

AN EPIDEMIOLOGICAL STUDY OF THIOPURINE-METHYLTRANSFERASE VARIANTS IN A CROATIAN INFLAMMATORY BOWEL DISEASE PATIENT COHORT.

Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. Over 20 variant TPMT-encoding alleles, which cause reduced enzymatic activity, have been discovered so far. Our aim was to investigate the frequencies of variant alleles, i.e. genotypes in inflammatory bowel disease (IBD) patients and healthy individuals and to compare these frequencies with selected world populations. The most common variant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C were analyzed with polymerase chain reaction-based assays and allele-specific polymerase chain reaction-based assays in 685 participants including 459 IBD patients and 226 healthy volunteers. Study results revealed 434/459 (94.55%) IBD patients and 213/226 (94.25%) healthy subjects to be homozygous for the wild-type allele (TPMT*1/*1). TPMT*1/*2 and TPMT *1/*3C genotypes were found in 4/459 (0.87%) and 7/459 (1.53%) IBD patients, respectively; in healthy volunteers they were not found. TPMT*1/*3A genotype was found in 14/459 (3.05%) IBD patients and 13/226 (5.75%) healthy subjects. Variant genotypes were statistically significantly more common in Crohn's disease subgroup than in ulcerative colitis subgroup. The prevalence of variant genotypes was 23/338 (6.80%) in Crohn's disease subgroup as compared with 2/121 (1.65%) in ulcerative colitis subgroup (χ2 = 4.59; p = 0.032). In conclusion, the most frequently occurring nonfunctional TPMT allele in Croatian population is TPMT*3A. The overall frequency of mutant alleles in our population is statistically nonsignificantly lower when compared with other populations of Caucasian origin. The Crohn's disease group had more mutant alleles than the ulcerative colitis group.

ATP7B Gene Mutations in Croatian Patients with Wilson Disease.

AIMS: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism, characterized by its accumulation in tissues which results in hepatic, neurological, and/or psychiatric symptoms. The aim of this study was to investigate the genetics of WD in Croatian patients. METHODS: Correlation of the clinical presentation subtype and the age at onset of the diagnosis of WD with the ATP7B genotype was investigated in a group of Croatian WD patients. DNA from peripheral blood samples was tested for the p.His1069Gln by direct mutational analysis and other polymorphisms were identified by sequence analysis of coding and flanking intronic regions of ATP7B gene. RESULTS: In the group of 75 WD patients of Croatian origin, 18 different mutations in ATP7B gene were detected, three of which were novel. The p.His1069Gln mutation was most frequent, being detected in 44 Croatian WD patients (58.7%). Most ATP7B mutations (90.4%) were located in exons 5, 8, 13, 14, and 15. CONCLUSIONS: Clinical diagnosis of WD was confirmed in 59 patients by detecting mutations on both ATP7B alleles. The age at onset of WD and the type of WD clinical presentation showed no significant correlation with the ATP7B genotype.

[Croatian guidelines for gastric cancer prevention by eradication of Helicobacter pylori infection]. / Hrvatski postupnik za prevenciju zelucanog raka eradikacijom infekcije Helicobacterom pylori.

Gastric cancer is the fourth most common type of cancer and the second leading cause of cancer-related death in the world. Although gastric cancer has a multifactorial etiology, infection with Helicobacter pylori is highly associated with gastric carcinogenesis. Carcinogenesis is also influenced by some environmental factors and host genetic diversity, which engenders differential host inflammatory responses that can influence clinical outcome. Chronic gastritis induced by H. pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, but the effects of bacterial eradication on carcinogenesis have remained unclear up to now. Although eradication of H. pylori infection appears to reduce the risk of gastric cancer, several recent controlled interventional trials by H. pylori eradication to prevent gastric cancer have yielded disappointing results. To clarify this problem in a high-risk population, the investigators conducted a prospective, randomized, double-blind, placebo-controlled, population-based studies. The results of previous studies highlight the importance of longer and careful follow-up after eradication therapy. It seems that eradication treatment is effective in preventing gastric cancer if it is given before preneoplastic conditions/lesions, gastric atrophy, metaplasia, and dysplasia, have had time to develop. Furthermore, the significant efficacy of treatment observed in younger patients suggests the need to eradicate H. pylori as early as possible. This consensus aimed to propose guidelines for the diagnosis, management and control of individuals with chronic gastritis, atrophy, intestinal metaplasia, or dysplasia.

MDR1 polymorphisms are associated with inflammatory bowel disease in a cohort of Croatian IBD patients.

BACKGROUND: Inflammatory bowel diseases (IBD) are chronic diseases of unknown etiology and pathogenesis in which genetic factors contribute to development of disease. MDR1/ABCB1 is an interesting candidate gene for IBD. The role of two single nucleotide polymorphisms, C3435T and G2677T remains unclear due to contradictory results of current studies. Thus, the aims of this research were to investigate the association of MDR1 polymorphisms, C3435T and G2677T, and IBD. METHODS: A total of 310 IBD patients, 199 Crohn's disease (CD) patients and 109 ulcerative colitis (UC) patients, and 120 healthy controls were included in the study. All subjects were genotyped for G2677T/A and C3435T polymorphism using RT-PCR. In IBD patients, review of medical records was performed and patients were phenotyped according to the Montreal classification. RESULTS: Significantly higher frequency of 2677T allele (p=0.05; OR 1.46, 95% CI (1.0-2.14)) and of the 3435TT genotype was observed among UC patients compared to controls (p=0.02; OR 2.12; 95% CI (1.11-4.03). Heterozygous carriers for C3435T were significantly less likely to have CD (p=0.02; OR 0.58, 95% CI (0.36-0.91)). Haplotype analysis revealed that carriers of 3435T/2677T haplotype had a significantly higher risk of having UC (p=0.02; OR 1.55; 95% CI (1.06-2.28)). CONCLUSION: MDR1 polymorphisms are associated with both CD and UC with a stronger association with UC.

[The role of anti-TNF therapy in ulcerative colitis]. / Mjesto anti-TNF terapije u lijecenju ulceroznog kolitisa.

Anti-TNF-alfa molecules are currently being used to treat ulcerative colitis regarding to the fact that TNF-alpha has an important role in the pathogenesis of IBD. Although these drugs improved the therapy of patients, immunogenicity limits their potential for clinical use. Infliximab and adalimumab are effective for induction and maintenance of remission in outpatients with moderate to severe steroid-refractory ulcerative colitis. Biologics can be a drug of choice for patients with refractory proctitis and refractory pouchitis. In hospitalized patients with steroid-resistant severe ulcerative colitis who are candidates for colectomy, infliximab may be second-line option. Adequate long-term maintenance therapy with anti-TNF is required after rescue therapy for a sustained benefit. Regarding to the known risk for side-effects of anti-TNF drugs especially in patients concomitantly treated with thiopurines it is urgent future research.

[Inflammatory bowel disease]. / Upalne bolesti crijeva.

Inflammatory bowel disease (IBD) is heterogenous group of inflammatory disorders characterized by chronic immune activation and inflammation of the gastrointestinal tract, associated with numerous extraintestinal manifestations. Two most important forms are Crohn's disease and ulcerative colitis with several phenotypes. Etiopathogenesis of IBD is still unknown. Diagnostic and therapeutic approach of IBD is very complex and requires excellent knowledge of the clinical course and complications of the disease itself and therapy. The paper provides present therapeutic strategy with emphasis on the importance of mucosal healing and analysis of present knowledge of the role of biologics in the therapy of IBD.

[Assessment of liver disease severity in patients with chronic viral hepatitis]. / Procjena tezine ostecenja jetre u bolesnika s kronicnim virusnim hepatitisom.

The best indicator of the severity of liver damage and prognosis in chronic viral hepatitis is extension of liver fibrosis. Extension of liver fibrosis can be assessed by liver biopsy and non-invasive physical or biological methods. Biopsy is used to define ethiology, severity (stage of fibrosis) and prognosis of liver disease. These informations are also usefull when estimating the risk-benefit and deciding on the modalities of antiviral therapy. Serological tests and elastography may distinguish significant fibrosis (F > or = 2) from baseline fibrosis (AUROC 0.77-0.83 for serology and 0.84 for elastography) and cirrhosis from noncirrhotic stages (AUROC 0.77-0.86 for serology and 0.9-0.94 for elastography). Individual method of choice with best performance to distinguish cirrhosis from noncirrhotic stages of liver is elastography. Combination of serological tests and transient elastography has 93-95% accuracy to predict liver cirrhosis, and in case of concordant values of both tests biopsy could be avoided in 77-80% of patients. In case of discordant values or those in favour of intermediate stages of fibrosis liver biopsy should be performed because in these situations non-invasive tests are less reliable. According to several studies liver stiffness as assessed by transient elastography has high predictive value for the development of decompensated cirrhosis and portal hypertensive complications and may also discriminate the patients with respect to the predicted 5-year survival.

[Intraductal papillary mucinous neoplasm of the pancreas: case report and review of the literature]. / Intraduktalna papilarna mucinozna novotvorina gusterace: prikaz slucaja i pregled literature.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a relatively rare clinical entity with a main characteristic being mucus production. Extension of IPMN along pancretic ducts and mucus production lead to ductal obstruction and dilatation, resulting in recurrent episodes of acute pancreatitis. Molecular background of IPMN-a comprises several aberrations, with the K-ras gene mutation being the likely trigger that initiates further genetic changes. Due to its indolent nature, IPMN is most commonly diagnosed in the 7th decade of life. Depending on the histology type, IPMN has a malignant potential. Therefore, surgical therapy remains a "gold standard" of treatment. Insidious, slow progression of the disease and absence of symptoms in a certain number of patients makes diagnostic approach to this entity difficult. In this paper we present a patient with IPMN of the pancreas, in whom the episodes of acute pancreatitis had been present for 22 years.

[Endoscopic mucosal resection of sessile polypoid colorectal lesions: a two-year retrospective study, technique description, indications and complications]. / Endoskopska mukozna resekcija sesilnih polipoidnih lezija debelog crijeva: dvogodisnja retrospektivna analiza, prikaz tehnike, indikacija i komplikacija.

INTRODUCTION: Endoscopic mucosal resection (EMR) is a therapeutic method for removal of sesile premalignant lesions and intramucosal carcinoma of the gastrointestinal tract. No reports on EMR data in Croatia have been published yet. MATERIALS AND METHODS: All patients included in the study were managed at the University Hospital Centre Zagreb between December 2006 and December 2008. EMR was performed using strip technique with submucosal injection of epinephrine (dilution with saline 1:5000-10000). RESULTS: EMR of sessile polypoid colorectal lesions was performed in 95 patients. The most common localisation of the disease was rectum (52 pts - 54.7%). In most patient size of the lesion was between 16-25 mm (43 pts - 45%). En-bloc resection was performed in 75 patients and piecemeal resection in the rest. Bleeding occurred immediately during the EMR in 5 pts (5.3%). Patohistological diagnosis revealed tubulovillous adenoma in 67 pts (70%). Invasive carcinoma was observed in 6 pts (6.3%) and intramucosal carcinoma in 20 pts (21%). On follow up, 73 pts (77%) did not show and sign of disease recurrence. Surgery was needed in 6 pts (6.3%) due to the diagnosis of invasive carcinoma. CONCLUSION: EMR is safe and reliable method with low risk of serious complications and acceptable recurrence rate.

A pilot study of transrectal endoscopic ultrasound elastography in inflammatory bowel disease.

BACKGROUND: Using standard diagnostic algorithms it is not always possible to establish the correct phenotype of inflammatory bowel disease which is essential for therapeutical decisions. Endoscopic ultrasound elastography is a new endoscopic procedure which can differentiate the stiffness of normal and pathological tissue by ultrasound. Therefore, we aimed to investigate the role of transrectal ultrasound elastography in distiction between Crohn's disease and ulcerative colitis. METHODS: A total 30 Crohn's disease, 25 ulcerative colitis, and 28 non-inflammatory bowel disease controls were included. Transrectal ultrasound elastography was performed in all patients and controls. In all ulcerative coltis patients and 80% of Crohn's disease patients endoscopy was performed to assess disease activity in the rectum. RESULTS: Significant difference in rectal wall thickness and strain ratio was detected between patients with Crohn's disease and controls (p = 0.0001). CD patients with active disease had higher strain ratio than patients in remission (p = 0.02). In ulcerative colitis group a significant difference in rectal wall thickness was found between controls and patients with active disease (p = 0.03). A significant difference in rectal wall thickness (p = 0.02) and strain ratio (p = 0.0001) was detected between Crohn's disease and ulcerative colitis patient group. Crohn's disease patients with active disease had a significantly higher strain ratio compared to ulcerative colitis patients with active disease (p = 0.0001). CONCLUSION: Transrectal ultrasound elastography seems to be a promising new diagnostic tool in the field of inflammatory bowel disease. Further study on a larger cohort of patients is needed to definitely assess the role of transrectal ultrasound elastography in inflammatory bowel disease.

[Croatian guidelines for use of enteral nutrition in Crohn's disease]. / Hrvatske smjernice za primjenu enteralne prehrane u Crohnovoj bolesti.

Nutrition has an important role in the management of inflammatory bowel disease (IBD), especially in patients with Crohn's disease (CD). This role includes the prevention and correction of malnutrition, the prevention of osteoporosis and the promotion of optimal growth and development in children. In active Crohn's disease, nutritional therapy (in the form of enteral feeding) is an effective primary therapy for pediatric patients. Studies have shown that there is no difference in the efficacy of elemental, oligomeric and polymeric enteral formulas. Therefore, the use of polymeric formula is recommended because of higher palatability, better acceptance by patients, lower rate of complications and lower cost when compared with other enteral formulas. Today we have knowledge that some nutrients which are added to modified special enteral formulas have almost pharmacological terapeutic potential in the management of inflammatory bowel disease. Novel nutritional therapeutic strategies for inflammatory bowel disease, such as transforming growth factor-beta-enriched (TGF-beta2) enteral feeding, showed beneficial effects in several clinical studies. Croatian guidelines for enteral nutrition in Crohn's disease have been developed by interdisciplinary expert group of Croatian clinicians involved with inflammatory bowel disease. The guidelines are based on evidence from relevant medical literature and clinical experience of working group.

Chronic Budd-Chiari syndrome as a rare complication of Crohn's disease: a case report.

The Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction involving the hepatic veins, inferior vena cava, or both. BCS has occasionally been reported in the literature as a very rare complication of ulcerative colitis. However, association of Crohn's disease (CD) and BCS is extremely rare with only a single case reported in the world literature to date. We report a case of a young woman with chronically active, therapy-resistant CD who developed massive ascites, elevation of liver enzymes, and coagulopathy in the course of her disease. She was subsequently diagnosed with BCS for which a successful liver transplantation was performed. Chronically active therapy resistant CD and methylenetetrahydrofolate reductase gene mutation have been identified as possible risk factors for development of BCS in this patient.

Inflammatory bowel diseases: controversies in the use of diagnostic procedures.

The term inflammatory bowel disease (IBD) denotes a genetically, immunologically and histopathologically heterogeneous group of inflammatory bowel disorders classified at present time as ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC). Diagnosis of IBD is based on a non-strictly defined combination of clinical and diagnostic parameters. In order to guide the treatment, patients must be assessed by determining IBD phenotype, disease extension and distribution, extraintestinal manifestations, disease behavior, disease severity and drug responsiveness. Each element of the diagnostic process cannot be looked at alone, but has to be incorporated into general clinical assessment, bearing in mind that different phenotypes and age groups require specific diagnostic solutions. Advances in technology provided the possibility for the assessment of the entire digestive system with endoscopy leading the way. Sophisticated imaging methods made the analysis of the bowel wall with its vascularity and adjacent mesentery possible. The challenge is still the small bowel, where a combination of endoscopy and imaging methods is used. The use of imaging methods should be, among other things, guided by level of irradiation which is especially important in young patients and in patients requiring repeated investigations. Using abdominal ultrasound as a low-cost, noninvasive procedure, one has to take into account that it is very operator-dependent method. In UC, endoscopy is used for the evaluation of the extent and activity of the disease and to assess complications like stricture, dysplasia and cancer. UC is classified by the disease extent into proctitis, left-sided colitis and extensive colitis beyond the splenic flexure. Pediatric patients with UC have more extensive disease than adults with rectal sparing in up to 30% of patients. The severity of mucosal changes are reported as Baron endoscopic score. Endoscopic findings correlate well with clinical activity and are commonly incorporated into Mayo index, combination of clinical Truelove Witts index and Baron score. Complications like strictures require imaging methods as supplement to endoscopy. The incidence of CD, particularly in children and adolescents, has risen during the past decade, with children often having extensive and severe disease The nature of CD requires the use of wide array of endoscopic and imaging methods, placed properly in the diagnostic algorithms for specific disease phenotypes and complications and adapted for specific age groups. Endoscopic features of CD are very variable and can be quantified as Crohn's Disease Endoscopic Index of Severity (CDEIS) or Simple Endoscopic Score for CD (SES-CD). Disease activity is most commonly assessed by CDAI. Perianal disease activity should be measured by PDAI due to low CDAI scores in these patients. The activity of CD in children should be assessed by the Pediatric Activity Index. IC is part of the IBD spectrum where chronic colitis cannot be defined as either UC or CD after sequential colonoscopies and colonic biopsies or at colectomy.

[Assessment of hepatic injury in patients with chronic viral hepatitis]. / Procjena ostecenja jetrenog parenhima u bolesnika s kronicnim virusnim hepatitisom.

The management and prognosis of chronic viral hepatitis greatly depend on the extent and progression of liver fibrosis. Although liver biopsy is still considered as the gold standard to evaluate hepatic fibrosis, it is an invasive procedure with rare but potentially severe complications. It is also prone to sampling errors. These limitations have stimulated the search for new noninvasive approaches. A number of noninvasive techniques such as indirect or direct markers and measurement of liver stiffness using transient elastography have been proposed for the assessment of hepatic fibrosis. The performance of simple tests derived from routine laboratory parameters appears to be similar to that of more complex and expensive fibrosis panels. Transient elastography seems to be more accurate than blood tests for diagnosing cirrhosis. The goal of disease specific, accurate and sensitive markers of fibrosis is worth the effort. The true success in such an attempt can be characterized as hopeful; however, these noninvasive methods can be anticipated to become an important tool in clinical practice.

Appropriate therapy for fistulizing and fibrostenotic Crohn's disease: Results of a multidisciplinary expert panel - EPACT II.

INTRODUCTION: Many therapeutic decisions in the management of fistulizing and fibrostenotic Crohn's disease (CD) have to be taken without the benefit of strong scientific evidence. For this reason, explicit appropriateness criteria for CD fistula and stenosis treatment were developed by a multidisciplinary European expert panel in 2004 with the aim of making them easily available on the Internet and thus allowing individual case scenario evaluation; these criteria were updated in 2007. METHODS: Twelve international experts convened in Geneva, Switzerland in December 2007. Explicit clinical scenarios, corresponding to real daily practice, were rated on a 9-point scale based on evidence from the published literature and panelists' own expertise. Median ratings were stratified into three categories: appropriate (7-9), uncertain (4-6) and inappropriate (1-3). RESULTS: Overall, panelists rated 60 indications pertaining to fistulas. Antibiotics, azathioprine/6-mercaptopurine and conservative surgery are the mainstay of therapy for simple and complex fistulas. In the event of previous failure of azathioprine/6-mercaptopurine therapy, methotrexate and infliximab were considered appropriate for complex fistulas. The panel also rated 72 indications related to the management of fibrostenotic CD. The experts considered balloon dilation, if the stricture was endoscopically accessible, stricturoplasty and bowel resection to be appropriate for small bowel fibrostenotic Crohn's disease, and balloon dilation and bowel resection appropriate for fibrostenotic colonic disease. In the presence of an ileocolonic or ileorectal anastomotic stricture of <7 cm, endoscopic balloon dilation, and bowel resection were considered appropriate. CONCLUSION: Antibiotics, azathioprine/6-mercaptopurine, and conservative surgery are the mainstay of therapy for fistulizing Crohn's disease. Infliximab is a therapeutic option in patients without prior response to immunosuppressant therapy. In fibrostenotic Crohn's disease, endoscopic balloon dilation, if feasible, or surgical therapy should be considered. These expert recommendations are available online (www.epact.ch). Prospective evaluation is now needed to test the validity of these appropriateness criteria in clinical practice.

Proinflammatory cytokines and receptor activator of nuclear factor kappaB-ligand/osteoprotegerin associated with bone deterioration in patients with Crohn's disease.

OBJECTIVES: The high incidence of bone disease and the increasing evidence of Crohn's disease (CD) bone decline in corticosteroid users and nonusers suggest that bone metabolism is affected by inflammatory process. The aim of the study was to compare serum levels of proinflammatory cytokines, markers of bone turnover and regulatory molecules of osteoclast biogenesis, receptor activator of nuclear factor kappaB-ligand (RANKL) and osteoprotegerin (OPG), between naïve and long-standing CD patients. METHODS: The study included 95 CD patients, 15 of them with newly diagnosed and previously untreated CD. The spine and hip bone mineral density was measured by dual-energy X-ray absorptiometry. Biochemical markers were determined by immunoassay. RESULTS: Osteopenia was recorded at diagnosis in 53% of naïve patients and osteoporosis was found in 26% of long-standing CD patients. The newly diagnosed patients showed correlation between TNF-alpha and soluble RANKL (sRANKL) (r=0.5; P=0.04), and this positive relationship characterized the study population as a whole (r=0.3; P=0.003). Analysis of the OPG and sRANKL relationship showed absence of correlation in patients with healthy skeleton, whereas an inverse correlation was found in those with osteopenia (r=-0.31; P=0.033) and osteoporosis (r=-0.48; P=0.028). In naïve patients with reduced T score, the correlation between sRANKL and OPG was highly inverse (r=-0.8; P=0.02) and these patients were characterized by lower BMI, significantly higher level of proinflammatory cytokines, elevated C-reactive protein, and increased activity of free sRANKL and OPG. CONCLUSION: Bone disease that accompanies CD at diagnosis suggests that bone metabolism is affected by the underlying inflammatory process per se, as probably confirmed by our finding of the central proinflammatory cytokine TNF-alpha being strongly associated with the osteoclastogenic mediator RANKL, and inversely with bone density.