Serum levels of interleukin 17 and 22 in patients with systemic sclerosis: a single-center cross-sectional study.

Systemic sclerosis (SSc) is a chronic, autoimmune disease characterized by inflammation, vasculopathy, and fibrosis of the skin and internal organs. Immunological response in SSc is still poorly understood. Cytokines play a significant role in this process leading to vasculopathy and fibrosis. In this cross-sectional study, we aimed to investigate serum levels of Th-17-related cytokines, IL-17 and IL-22, and to determine their correlation to the clinical association in SSc patients. Serum IL-17 and IL-22 levels were examined in 42 SSc patients and 29 healthy individuals. Associations between serum IL-17 and IL-22 levels and the duration of the disease, the extent of skin fibrosis, capillaroscopic findings, and involvement of the internal organs were explored. Serum IL-17 levels were not different in SSc and the control group. Serum IL-22 levels were significantly elevated in SSc patients compared to healthy individuals (p = 0.04). A positive correlation was found between the IL-22 sera levels and interstitial lung disease (p = 0.007). These results suggest IL-22 as a potential biomarker in SSc-related interstitial lung disease.

Off-label use of mycophenolate mofetil in the treatment of rare and complex rheumatic connective tissue diseases.

OBJECTIVES: We aimed to investigate the clinical off-label use of mycophenolate mofetil (MMF), including its safety and efficacy in patients with rare and complex rheumatic connective tissue diseases (rCTDs). METHODS: A survey was distributed across experts from ERN-ReCONNET reference centres in order to assess the experience with MMF off-label use. Patient-level data of patients with rCTDs under treatment with MMF was also collected for analysis of safety and efficacy. RESULTS: Twelve experts from eleven centres distributed throughout Europe (7 countries) answered the survey. The experience was concordant in that, despite of its off-label use, experts reported opting frequently for this therapeutic alternative with robust confidence on its efficacy and safety. The analysis of 108 patients with rCTDs under MMF revealed a good safety profile, as well as good clinical outcomes, especially for systemic lupus erythematosus and idiopathic inflammatory myopathies. The presence of interstitial lung disease was, as expected, associated with a worse clinical outcome despite use of MMF. CONCLUSIONS: MMF is widely used in reference centres for rCTDs. Its safety profile and efficacy seem to be recognised by experts and demonstrated with patient-level analysis. While selected rCTDs will likely remain an off-label indication for MMF, robust data seem to support this therapy as an appropriate alternative for safely and effectively treating many manifestations of rCTDs.

The added value of a European Reference Network on rare and complex connective tissue and musculoskeletal diseases: insights after the first 5 years of the ERN ReCONNET.

In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients.It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.

Effects of 8-week increment aerobic exercise program on bone metabolism and body composition in young non-athletes.

PURPOSE: The effects of aerobic exercise on bone metabolism are still unclear. Thus, the main goal of this study was to explore if there was an effect of the short-term aerobic exercise program on the bone remodeling process and if there were sex differences in the effect of the training program on bone metabolism. METHODS: Twenty-one participants (men and women) aged 20-23 performed an 8-week aerobic exercise program three times per week in 1-h sessions with increases in the exercise load every 2 weeks. Bone density, bone mineral content and concentration of markers of bone metabolism: osteocalcin, C-terminal procollagen type I peptide, pyridinoline, parathyroid hormone, osteoprotegerin, and the receptor activator of nuclear kappa B ligand by ELISA were measured at the start and at the end of the study, while changes in body composition were assessed by a bioelectric impedance analysis method 6 times during the study. RESULTS: The aerobic exercise program increased the concentration of osteocalcin (11.34 vs 14.24 ng/ml), pyridinoline (67.51 vs 73.99 nmol/l), and the receptor activator of nuclear kappa B ligand (95.122 vs 158.15 pg/ml). A statistically significant increase in bone density at neck mean (1.122 vs 1.176 g/cm3) and in bone mineral content at dual femur (33.485 vs 33.700 g) was found in women, while there was no statistically significant change at any site in men. CONCLUSION: 8 weeks of the aerobic exercise program with increment in intensity increased some of bone remodeling biomarkers and showed different effects for men and women.

Optic neuritis as a presenting feature of Behçet's disease: case-based review.

Behçet's disease (BD) is vasculitis affecting vessels of variable sizes characterized with recurrent oral and/or genital aphthous ulcers accompanied by cutaneous, ocular, articular, gastrointestinal, and/or central nervous system inflammatory lesions. The disease is characterized by recurrent attacks and remissions of different durations, which is one of the reasons why the diagnosis is, in most cases, made several years after the onset of first symptoms. We present a 24-year old male, with South Eastern European heritage, with relapsing bilateral optic neuritis as a first symptom of the disease, followed by aseptic meningitis 2 years, and vascular manifestation 3 years after onset, which finally led to the diagnosis of Behçet's disease. Vascular symptoms were thromboembolism of the right leg and aneurism of the right popliteal artery that due to the size required surgical treatment. The patient was treated with glucocorticoids, azathioprine and anti-tumor necrosis factor-alpha therapy, that proved to be the best treatment options for all manifestations of the disease. Based on our literature review, optic neuritis is a known and rare clinical feature of BD. To our knowledge, there are only several literature reports in which optic neuritis is the initial symptom of BD. Our case report and literature review emphasize the importance of recognizing optic neuritis without inflammatory eye disease as a possible presenting symptom of BD and accentuate detailed medical history review at each patient's visit.

LIFESTYLE RISK FACTORS AND BONE MASS IN RECURRENT STONE-FORMING PATIENTS: A CROSS-SECTIONAL STUDY IN 144 SUBJECTS.

Patients with urolithiasis, particularly hypercalciuria, may have reduced bone mineral density (BMD). There are numerous risk factors contributing to reduction of BMD such as advanced age, sedentary lifestyle, smoking, low calcium intake, etc. The aim of our study was to investigate the association of lifestyle risk factors and daily intake of milk and dairy products with determinants of BMD in a group of recurrent calcium stone formers (RSF) compared with healthy subjects (HS). The study was carried out at the Department of Mineral Research, Faculty of Medicine in Osijek, Croatia. The study included 144 subjects, i.e. 56 RSF and 78 HS. BMD was assessed by dual-energy x-ray absorptiometry. A standard self-reported questionnaire was used to collect data on lifestyle risk factors. Current dietary intake was assessed by personal interview that included questions about milk and dairy product intake. Low BMD was observed in 44.64% of RSF and 35.90% of HS. RSF consumed significantly less milk and dairy products than HS. Calcium restriction in dietary recommendations might be unnecessary due to the impact on bone mineral loss in RSF and dual-energy x-ray absorptiometry should be included in the routine evaluation of RSF.

Differences in the prevalence and characteristics of metabolic syndrome in rheumatoid arthritis and osteoarthritis: a multicentric study.

The purpose of the study was to examine whether rheumatoid arthritis (RA) patients have higher prevalence of metabolic syndrome (MetS) than osteoarthritis (OA) patients in association with a higher level of chronic systemic inflammation in rheumatoid arthritis. A total of 583 RA and 344 OA outpatients were analyzed in this multicentric study. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. A 1.6-fold higher prevalence of MetS was found in patients with OA compared with the RA patients. Among the parameters of MetS, patients with OA had significantly higher levels of waist circumference, systolic blood pressure, fasting blood glucose and triglycerides, whereas HDL cholesterol and diastolic blood pressure values were similar in both groups of patients. Higher values of inflammatory markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] in MetS than in non-MetS patients and higher prevalence of MetS in patients with CRP level ≥5 mg/L in both RA and OA patients were found. In multivariate logistic regression analysis, significant predictors of MetS were type of arthritis (OA vs. RA; OR 2.5 [95 % CI 1.82-3.43]), age (OR 1.04 [95 % CI 1.03-1.06]) and ESR (OR 1.01; [95 % CI 1.00-1.01]). The significant association between OA and MetS was maintained in the regression model that controlled for body mass index (OR 1.87 [95 % CI 1.34-2.61]). The present analysis suggests that OA is associated with an increased risk of MetS, which may be due to a common underlying pathogenic mechanism.

Osteoprotegerin and Vascular Calcification: Clinical and Prognostic Relevance.

Osteoprotegerin (OPG) is a key regulator in bone metabolism, that also has effect in vascular system. Studies suggest that osteoprotegerin is a critical arterial calcification inhibitor, and is released by endothelial cells as a protective mechanism for their survival in certain pathological conditions, such as diabetes mellitus, chronic kidney disease, and other metabolic disorders. That has been shown in studies in vitro and in animal models. The discovery that OPG deficient mice (OPG -/- mice) develop severe osteoporosis and arterial calcification, has led to conclusion that osteoprotegerin might be mulecule linking vascular and bone system. Paradoxically however, clinical trials have shown recently that OPG serum levels is increased in coronary artery disease and correlates with its severity, ischemic cardial decompensation, and future cardiovascular events. Therefore it is possible that osteoprotegerin could have a new function as a potential biomarker in early identification and monitoring patients with cardiovascular disease. Amongst that osteoprotegerin is in association with well known atherosclerosis risc factors: undoubtedly it is proven its relationship with age, smoking and diabetes mellitus. There is evidence regarding presence of hyperlipoproteinemia and increased serum levels of osteoprotegerin. Also the researches have been directed in genetic level, linking certain single nucleotid genetic polymorphisms of osteoprotegerin and vascular calcification appearance. This review emphasises multifactorial role of OPG, presenting numerous clinical and experimental studies regarding its role in vascular pathology, suggesting a novel biomarker in cardiovascular diseases, showing latest conclusions about this interesting topic that needs to be further explored.

[CRYOGLOBULINEMICVASCULITIS AS A MANIFESTATION OF PARANEOPLASTIC SYNDROME--A CASE REPORT]. / KRIOGLOBULINEMICNI VASKULITIS KAO MANIFESTACIJA PARANEOPLASTICKOG SINDROMA--PRIKAZ BOLESNIKA.

Cryoglobulinemia refers to the presence of circulating cryoglobulins in the serum which may lead to organ damage and systemic response characterized by fatigue, arthralgias, purpura, glomerulonephritis and neuropathy. The disease mainly affects small and medium-sized blood vessels and causes vasculitis due to cryoglobulin-containing immune complexes. Mixed cryoglobulinemia (type I and II) are most often associated with infections, especially hepatitis C virus (HCV), but may occur as part of lymphoproliferative and autoimmune diseases. We present a 75-year-old male patient with acrocyanosis and digital necrosis of the left hand and purpura of the lower extremities. Since 2001 the patient was treated for Non-Hodgkin's lymphoma of the stomach (MALT) and since 2002 for Sjogren's syndrome. Extensive diagnostic procedures revealed cryoglobulinemia type II, but without evidence of HCV infection or relapse of lymphoproliferative disorder. Furthermore, poorly differentiated prostate adenocarcinoma was diagnosed and antiandrogen treatment was initiated. One year after the onset of symptoms acrocyanosis and digital necrosis, gastric adenocarcinoma was diagnosed, without metastatic disease, and surgical treatment was performed. However, postoperatively recurrence of new digital necrosis of the hands occurred along with clinical deterioration and multiple organ failure leading to lethal outcome. Association of cryoglobulinemia and solid tumors is rarely described in the literature, so it is very important to perform comprehensive diagnostic evaluation and detect potential underlying disease as soon as possible.

[Pathophysiology of osteoporosis]. / Patofiziologija osteoporoze.

The balance of degradation and bone formation is important for the normal process of remodeling and maintenance of bone mass. Genetic, hormonal, immunological and other factors affect bone remodeling throughout life. Disorder of bone turnover plays key role in the pathophysiology of osteoporosis and presents a complex process which involves bone cells, cytokines and their receptors. Nowadays, important role of RANK/RANKL/OPG system in the pathophysiology of osteoporosis is well known, but it is still important to investigate the intracellular signaling pathways in the development of osteoporosis and other metabolic bone diseases.

Is the prevalence of arterial hypertension in rheumatoid arthritis and osteoarthritis associated with disease?

In this study, we compare the prevalence of arterial hypertension (HT) in rheumatoid arthritis (RA) and osteoarthritis (OA) patients, exposed to high- and low-grade chronic inflammation, respectively, to assess the possible association between chronic inflammation and HT. A total of consecutive 627 RA and 352 OA patients were enrolled in this multicentric study. HT was defined as a systolic blood pressure (BP) ≥ 140 and/or diastolic BP ≥ 90 mmHg or current use of any antihypertensive drug. Overweight/obesity was defined as body mass index (BMI) ≥ 25, and patients ≥65 years were considered elderly. The prevalence of HT was higher in the OA group than in the RA group [73.3 % (95 % CI, 68.4, 77.7) and 59.5 % (95 % CI, 55.6, 68.4) P < 0.001, respectively]. When the results were adjusted for age and BMI, the HT prevalence was similar in both groups [RA 59 % (95 % CI, 55.1, 63.8) OA 60 % (95 % CI, 58.4, 65.0)]. In both groups, the prevalence of HT was higher in the elderly and those who were overweight than in the younger patients and those with a BMI < 25. Overweight (BMI ≥ 25) and age ≥65 were independent predictors of HT in multivariate logistic regression model, which showed no association between HT and the disease (RA or OA). The results indicate a robust association of age and BMI with HT prevalence in both RA and OA. The difference in HT prevalence between RA and OA is due rather to age and BMI than to the features of the disease, putting into question specific association of HT with RA.

[Antisynthetase syndrome - a case report]. / Antisintetaza sindrom - prikaz bolesnice.

Twenty-eight year-old woman with predominant signs of polymyositis, pulmonary interstitium involvement and with positive anti-Jo1 antibodies was suspected for antisynthetase syndrome. Over the next three months sores and ulcerations have appeared at the fingertips. In the later course of the disease clinical picture of mixed connective tissue disease associated with interstitial lung disease, with a dominant picture of systemic sclerosis have emerged. She was treated with glucocorticoides and immunosuppressive therapy. Patient condition was mostly stable, without significant progression of lung lesions. Early diagnosis and treatment antisynthetase syndrome significantly contributes to more favorable course and outcome of disease. A prerequisite for that are well-defined diagnostic criteria and an appropriate choice of treatment.

[Pathophysiology of gout]. / Patofiziologija uricnog artritisa.

Hyperuricemia is rather often metabolic disorder in general population. It is multifactorial disorder influenced by purine rich diet, alcohol consumption, diuretics use and renal deterioration. In the presence of local urate superasturation and lower solubility, monosodium crystals are deposited in joints, kidneys and soft tissue leading to clinical manifestations, such as gout, tophaceus deposits, nephrolithiasis and uric nephropathy. Major advances in understanding the pathogenesis of hyperuricemia and gout have been made recently, including genetic studies of urate transporters in kidneys as well as innate immune inflammatory responses and cytokine production which will be discussed thoroughly in this paper.

Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor. CASE PRESENTATION: We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. CONCLUSIONS: In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.

Association of nephrolithiasis and gene for glucose transporter type 9 (SLC2A9): study of 145 patients.

AIM: To investigate the association of nephrolithiasis and solute carrier family 2, facilitated glucose transporter, member 9 (SLC2A9), also known as glucose transporter type 9, Glut9. METHODS: A total of 145 participants were recruited in the period April-October 2008 from the Department of Mineral Research of the Medical School Osijek, Osijek, Croatia; 58 (40%) had confirmed nephrolithiasis and 87 (60%) were asymptomatic. Four single nucleotide polymorphisms (SNP) from the SLC2A9 gene were genotyped in both groups (rs733175, rs6449213, rs1014290, and rs737267). RESULTS: There was a weak but significant association of all 4 SNPs and nephrolithiasis (P=0.029 for rs733175; P=0.006 for rs6449213; P=0.020 for rs1014290, and P=0.011 for rs737267). Logistic regression in an age- and sex-adjusted model suggested that genotype C/T for rs6449213 had odds ratio for nephrolithiasis of 2.89 (95% confidence interval 1.13-7.40). This SNP explained a total of 4.4% of nephrolithiasis variance. CONCLUSION: Development of nephrolithiasis may be associated with SLC2A9 gene. Further studies are needed to clarify the role of SLC2A9 gene as a link between uric acid and nephrolithiasis.

Merkel cell carcinoma: case report.

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine carcinoma of the skin. Although it is 40 times less common than malignant melanoma, its mortality is much higher compared to melanoma. From 1986 to 2001 there was rapidly increasing incidence in reported cases of MCC, with a tripling in the rate over this 15-year period. The vast majority of MCC presents on sun-exposed skin. The head and neck area is the most common site of tumor occurrence. We present 70-year old female patient with painless red-colored nodule, size 2 x 2 x 2 cm on the dorsal side of mid left forearm. The surgical excision with negative margins was performed, and pathohistological analysis confirmed Merkel cell carcinoma. Sentinel lymph node biopsy was negative. In conclusion, as MCC is a very aggressive rare skin carcinoma with lethal outcome, it should be mandatory to perform biopsies of any suspected skin lesion.

Urolithiasis and osteoporosis: clinical relevance and therapeutic implications.

Several clinical and epidemiological studies revealed increased bone turnover and lower bone mass in patients with urolithiasis. Bone mass loss is particularly evident in idiopathic calcium stone formers. However, pathogenetic mechanisms and factors implicated in bone loss in these patients are still unknown. Dietary calcium restriction, increased intake of salt and animal proteins, vitamin D receptor polymorphisms are likely risk factors, while role of inflammatory cytokines, osteopontin and prostaglandin mediated bone resorption is yet to be determined. Regarding treatment and prevention, it has been proven that calcium supplements and high calcium diet with the addition of potassium alkali have an important role in prevention and treatment of both, urolithiasis and osteoporosis. Thiazide diuretics reduce hypercalciuria in renal tubules, and in addition promote osteoblast differentiation. Finally, bisphosphonates, a commonly used drugs in treatment of osteoporosis, show the potential to inhibit calcium stone formation, whereas a possible protective effect of antioxidants in bone loss and renal injurie needs to be investigated further.

Serum Osteoprotegerin in Patients with Calcified Aortic Valve Stenosis in Relation to Heart Failure.

The aim of the study was to assess the role of serum osteoprotegerin (OPG) as a biomarker in patients with aortic valve stenosis (AS) in relation to heart failure and symptomatic status. This was a case control study, which included 51 patients with AS and 39 control subjects. At the time of study enrolment, detailed medical history was obtained and all subjects underwent physical examination, chest x-ray and echocardiography. OPG levels were measured in all subjects, and serum N-terminal of the pro b-type natriuretic peptide (NT pro BNP) levels were determined in patients with AS. Serum OPG levels were elevated in patients with AS compared to control subjects (p=0.001). Patients with heart failure due to AS had elevated serum OPG levels in comparison to patients without heart failure (p=0.001). A significant correlation between OPG and symptomatic status was observed in all patients with AS (p<0.001), however, it was not the case in patients without heart failure (p=0.425). There was a positive correlation between OPG and NT pro BNP concentrations with objective signs of heart failure on chest x-ray (p<0.001). Negative correlation of OPG concentrations with aortic valve area was present (p<0.040), as well as with left ventricular ejection fraction (p<0.001). Serum OPG could be a valuable biomarker in the evaluation of severity of calcified AS and serve as an additional indicator besides clinical presentation and echocardiography in the assessment of surgical treatment or aortic valve replacement.

Preference for weekly and monthly bisphosphonates among patients with postmenopausal osteoporosis: results from the Croatian PROMO Study.

The PROMO (preference for once monthly bisphosphonate) Study, conducted in seven hospital centres in Croatia between June 2007 and June 2008, was designed to analyse patient preference for weekly and monthly bisphosphonates in everyday clinical practice where the significant proportion of patients are not completely satisfied with the current osteoporosis treatment. Eligible participants were women with postmenopausal osteoporosis taking weekly bisphosphonates for the last 6 months. Those who agreed to be enrolled were transferred from weekly to monthly ibandronate for the next 6 months. There was no washout period between the two treatment regimens. At the baseline, patients expressed their satisfaction with the weekly treatment. At the end of the study, all patients were asked to complete the five-question survey specially designed for this study. Study population comprised 258 participants. Among 248 patients who completed the study, 244 (98.4%) declared their preference for one of the regimens or they had no preference. Once-monthly regimen was preferred by 231 patients (94.7%), whereas once-weekly regimen was preferred by five patients (2.0%). Eight patients (3.3%) indicated no preference. Furthermore, 93.0% of patients thought that monthly dosing was more convenient. Compared to weekly regimen, monthly dosing was associated with significantly higher satisfaction with the treatment and with significantly less adverse events. In line with these data, 85.9% of patients stated improved quality of life with monthly ibandronate. In summary, the PROMO Study demonstrated strong patient preference for monthly over weekly dosing which is expected to improve suboptimal adherence to weekly bisphosphonates.