Phase 2 Trial of Iberdomide in Systemic Lupus Erythematosus.

BACKGROUND: Iberdomide, a cereblon modulator promoting degradation of the transcription factors Ikaros and Aiolos, which affect leukocyte development and autoimmunity, is being evaluated for the treatment of systemic lupus erythematosus (SLE). METHODS: In this phase 2 trial, we randomly assigned patients in a 2:2:1:2 ratio to receive oral iberdomide (at a dose of 0.45, 0.30, or 0.15 mg) or placebo once daily for 24 weeks, in addition to standard medications. The primary end point at week 24 was a response on the SLE Responder Index (SRI-4), which was defined as a reduction of at least 4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 score (a 24-item weighted score of lupus activity that ranges from 0 to 105, with higher scores indicating greater disease activity), no new disease activity as measured on the British Isles Lupus Assessment Group 2004 index, and no increase of 0.3 points or more in the Physician's Global Assessment score (on a visual-analogue scale ranging from 0 [no disease activity] to 3 [maximal disease]). RESULTS: A total of 288 patients received the assigned intervention: 81 received iberdomide at a dose of 0.45 mg, 82 received iberdomide at a dose of 0.30 mg, 42 received iberdomide at a dose of 0.15 mg, and 83 received placebo. At week 24, the percentages of patients with an SRI-4 response were 54% in the iberdomide 0.45-mg group, 40% in the iberdomide 0.30-mg group, 48% in the iberdomide 0.15-mg group, and 35% in the placebo group (adjusted difference between the iberdomide 0.45-mg group and the placebo group, 19.4 percentage points; 95% confidence interval, 4.1 to 33.4; P = 0.01), with no significant differences between the groups that received the lower doses of iberdomide and the group that received placebo. Iberdomide-associated adverse events included urinary tract and upper respiratory tract infections and neutropenia. CONCLUSIONS: In this 24-week, phase 2 trial involving patients with SLE, iberdomide at a dose of 0.45 mg resulted in a higher percentage of patients with an SRI-4 response than did placebo. Data from larger, longer trials are needed to determine the efficacy and safety of iberdomide in SLE. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03161483; EudraCT number, 2016-004574-17.).

Assessment and Prediction of Adherence to Methotrexate Using Three Self-Report Questionnaires in Patients with Rheumatoid Arthritis.

Introduction: Methotrexate (MTX) reduces rheumatoid arthritis activity and ameliorates the long-term functional status in these patients. To achieve this aim, patients need to take their medication regularly. Nevertheless, non-adherence to MTX still remains a considerable issue in the management of rheumatoid arthritis. Objective: This study aimed to estimate the adherence to methotrexate in patients with rheumatoid arthritis and to identify specific non-adherence risk factors. Methods: A cross-sectional study included 111 patients (mean age 56.2 ± 10.6 years, 78.4% female, and mean disease duration 6 years (3-13)). Three adherence self-assessment questionnaires were used: the Compliance-Questionnaire-Rheumatology (CQR19), the Medication Adherence Reports Scale (MARS-5), and the Visual Analogue Scale (VAS). We also collected demographic data, disease and treatment characteristics, and anxiety/depression estimation results (Hospital Anxiety and Depression Scale, HADS). Results: Adherence was identified in 48.6% of patients (COR19), 70.3% of patients (MARS-5), and 82.9% of patients (VAS questionnaire). All three questionnaires displayed a significant positive mutual correlation: CQR19 with MARS-5 and VAS (r = 0.364, r = 0.329, respectively, p < 0.001 for both) and between the VAS and MARS-5 scores (r = 0.496, p < 0.001). A significant positive prediction was shown for urban residence (0.347 (0.134-0.901), p = 0.030) using the MARS-5, female sex (0.264 (0.095-0.730), p = 0.010) according to the CQR19, and for a dose of methotrexate (0.881 (0.783-0.992), p = 0.036) using the VAS, while negative predictions were shown for comorbidity number (3.062 (1.057-8.874), p = 0.039) and depression (1.142 (1.010-1.293), p = 0.035) using the MARS-5 and for older age (1.041 (1.003-1.081), p = 0.034) according to the CQR19. The use of steroids was a significant positive predictor in all three questionnaires and remained an independent predictor for methotrexate adherence in the multivariate logistic regression. Conclusions: We showed non-adherence to methotrexate in a significant number of patients using all three questionnaires. Concomitant steroid therapy emerged as an independent positive predictor for adherence.

Biological impact of iberdomide in patients with active systemic lupus erythematosus.

OBJECTIVES: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). METHODS: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling. RESULTS: Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (-58.3%), and plasmacytoid dendritic cells (-73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (-81.5%; p<0.001) but decreased other gene signatures in all patients. CONCLUSION: Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature. TRIAL REGISTRATION NUMBER: NCT03161483.

Effects of Sideritis scardica Extract on Glucose Tolerance, Triglyceride Levels and Markers of Oxidative Stress in Ovariectomized Rats.

Menopause is characterized by deep metabolic disturbances, including decreased insulin sensitivity, adiposity, and changes in lipid profiles. Estrogen replacement therapy can partially reverse these changes, and while it is safe in most healthy postmenopausal women, there are still existing concerns regarding an increased risk for breast and endometrial cancer as well as a risk for cardiovascular and thromboembolic disease. Therefore, certain natural compounds with positive metabolic effects may be considered as a possible alternative or adjunctive treatment in patients not willing to take estrogens or patients with contraindications for estrogens. The aim of this study was to investigate the influence of Sideritis scardica (mountain tea) extract on metabolic disturbances induced by ovariectomy in rats. The study included 24 rats divided into three groups: ovariectomized rats treated with 200 mg/kg S. scardica extract for 24 weeks (n = 8), ovariectomized non-treated (n = 8), and Sham-operated (n = 8) rats. Food intake, weight gain, body composition, fasting glucose levels, response to oral glucose challenge, liver glycogen content, catalase activity, thiol groups, and malondialdehyde concentrations as well as AMP-activated protein kinase activity in liver cells were studied. Ovariectomized rats treated with S. scardica extract had lower blood triglycerides, reduced fasting glucose levels, as well lower glucose peaks after oral glucose challenge, increased liver glycogen content, and significantly higher catalase activity and thiol group concentration than non-treated ovariectomized rats. The ability of S. scardica extract to attenuate metabolic disturbances associated with ovariectomy was associated with the activation of AMP-activated protein kinase in liver cells.

Correction to: Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

In the Original Publication, the e-mail address of the author Milan Petronijevic is incorrect. The correct e-mail address is milanpetronijevic@yahoo.com.

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

Osteoarthritis (OA) is characterized by deterioration of the joints and associated with considerable pain and disability. OA is a chronic disease that requires intervention with both non-pharmacological and pharmacological treatment modalities and, inevitably, disease progression may necessitate successive treatments throughout the course of the disease. There is increasing data on the shortfalls of current pharmacological treatment of OA, and safety concerns associated with analgesic therapy use in OA arising from increasing evidence of gastrointestinal, cardiovascular, hepatic and renal adverse events with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). Consequently, symptomatic slow-acting drugs for OA (SYSADOAs) may now be considered as a first-line treatment for knee OA, with a particular emphasis placed on the outstanding benefit: risk ratio of pharmaceutical-grade glucosamine and chondroitin sulfate formulations. In this short communication we review recent publications concerned with the safety of paracetamol, NSAIDs and SYSADOAs. Greater understanding of the benefits and limitations of current medications will lead to better disease management in OA. Furthermore, adherence to guideline recommendations across Europe and internationally, such as those from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), will promote evidence-based medicine and patient-centric care, ultimately leading to greater physician and patient satisfaction.

Self-Preferred Initial Position Could Be a Viable Alternative to the Standard Squat Jump Testing Procedure.

Petronijevic, MS, Garcia Ramos, A, Mirkov, DM, Jaric, S, Valdevit, Z, and Knezevic, OM. Self-preferred initial position could be a viable alternative to the standard squat jump testing procedure. J Strength Cond Res 32(11): 3267-3275, 2018-The purpose of this study was to compare both the magnitude and reliability of different variables (knee angle, squat depth, jump height [Hmax], maximum force [Fmax], and maximum power [Pmax]) between the standardized squat jump (SJ) and the SJ performed from the self-preferred position. Eleven team handball players (age: 19.5 ± 1.1 years; height: 1.88 ± 0.06 m; and body mass: 82.1 ± 8.7 kg) and 13 physically active students (age: 20.5 ± 0.9 years; height: 1.81 ± 0.06 m; and body mass: 76.6 ± 6.6 kg) were evaluated on 2 sessions during the standardized SJ (knee angle fixed at 90°) and the self-preferred SJ (self-selected knee angle to maximize Hmax). Two blocks of both 3 standardized SJ and 3 self-preferred SJ were performed on the first session, whereas only 1 block was performed in the second session. The squat depth was smaller for the self-preferred SJ, whereas the knee angle, Fmax, and Pmax were higher for the self-preferred SJ (p < 0.025). The magnitude of Hmax did not significantly differ between both jump types. Most importantly, the reliability of the mechanical outputs (Hmax, Fmax, and Pmax) was generally higher for the self-preferred SJ (9 of 12 comparisons), whereas only in 2 of 12 comparisons the reliability was meaningfully higher for the standardized SJ. No differences were observed between presumably more (handball players) and less skilled individuals (physically active subjects). These results suggest that the self-preferred SJ should be recommended over the standardized SJ (90° knee angle) because it is not only quicker and more ecologically valid, but could also provide the performance variables with higher reliability.

Impact of disease activity on impaired glucose metabolism in patients with rheumatoid arthritis.

OBJECTIVE: To explore glucose metabolism in rheumatoid arthritis (RA) and its association with insulin resistance (IR) risk factors and disease activity indicators, including matrix metalloproteinase-3 (MMP3). METHODS: This single-center study included 127 non-diabetic subjects: 90 RA patients and 37 matched controls. IR-related risk factors, disease activity (DAS28-ESR/CRP), concentrations of inflammation markers, MMP3, glucose, specific insulin, and C-peptide (a marker of ß-cell secretion) were determined. Homeostasis Model Assessment was used to establish insulin resistance (HOMA2-IR) and sensitivity (HOMA2-%S). Associations of HOMA2 indices with IR-related risk factors, inflammation markers, and RA activity were tested using multiple regression analyses. RESULTS: RA patients had significantly increased HOMA2-IR index than controls. In the RA group, multivariate analysis revealed DAS28-ESR, DAS28-CRP, tender joint counts, patient's global assessment, and MMP3 level as significant positive predictors for HOMA2-IR (ß = 0.206, P = 0.014; ß = 0.192, P = 0.009; ß = 0.121, P = 0.005; ß = 0.148, P = 0.007; ß = 0.075, P = 0.025, respectively), and reciprocal negative for HOMA2-%S index. According to the value of the coefficient of determination (R2), DAS28-ESR ≥ 5.1 has the largest proportion of variation in both HOMA2-IR indices. DAS28-ESR ≥ 5.1 and ESR were independent predictors for increased C-peptide concentration (ß = 0.090, P = 0.022; ß = 0.133, P = 0.022). Despite comparability regarding all IR-related risk factors, patients with DAS28-ESR ≥ 5.1 had higher HOMA2-IR than controls [1.7 (1.2-2.5) vs. 1.2 (0.8-1.4), P = 0.000]. There was no difference between patients with DAS28-ESR < 5.1 and controls [1.3 (0.9-1.9) vs. 1.2 (0.8-1.4), P = 0.375]. CONCLUSIONS: RA activity is an independent risk factor for impaired glucose metabolism. DAS28-ESR ≥ 5.1 was the main contributor to this metabolic disturbance, followed by MMP3 concentration, outweighing the impact of classic IR-related risk factors.

Rheumatoid arthritis is an independent risk factor for increased carotid intima-media thickness: impact of anti-inflammatory treatment.

OBJECTIVES: To evaluate the extent of subclinical atherosclerosis in patients with RA and low cardiovascular risk by measuring intima-media thickness (IMT) of the carotid arteries and to determine factors associated with increased IMT. METHODS: IMT was measured by ultrasonography in 42 non-diabetic, normotensive, female RA patients and 32 matched healthy controls [age 45.3 (10.0) vs 45.2 (9.8) years] at common carotid arteries (CCAs), carotid bifurcation (BF) and internal carotid arteries (ICAs), bilaterally. Mean and maximal (max) IMTs were calculated from three measurements at each site. Clinical work-up included laboratory analyses, determination of the disease activity and evaluation of treatment. RESULTS: RA patients had increased IMT (mm) in comparison with controls [CCA(max): 0.764 (0.148) vs 0.703 (0.100); CCA(mean): 0.671 (0.119) vs 0.621 (0.085); BF(max): 1.055 (0.184) vs 0.941 (0.161); BF(mean): 0.889 (0.168) vs 0.804 (0.124); ICA(max): 0.683 (0.108) vs 0.613 (0.093); ICA(mean): 0.577 (0.101) vs 0.535 (0.076)]. Parameters associated with IMT in RA patients were (correlation at x/6 measurement sites): age (6/6), BMI (2/6), smoking (2/6), RF concentration (2/6), sedimentation rate (1/6) and duration of MTX + chloroquine therapy (4/6; inverse correlation). Multivariate regression analysis revealed that RA is an independent risk factor for increased IMT. Factors correlating with IMT in the controls were: age (6/6), BMI (3/6), total cholesterol (5/6), low-density lipoprotein cholesterol (3/6), total/high-density lipoprotein cholesterol (2/6), triglycerides (1/6) and glycaemia (4/6). CONCLUSION: Despite a favourable risk profile, our female RA patients had significantly enlarged carotid IMT than controls. RA itself was an independent risk factor for increased IMT. Impact of chronic inflammation on atherosclerosis was confirmed by negative correlation of IMT and duration of anti-inflammatory treatment.

Low bone mineral density and high bone metabolism turnover in premenopausal women with unipolar depression.

INTRODUCTION AND HYPOTHESIS: The majority of studies reporting decreased bone mineral density (BMD) in patients with unipolar depression neglected sex and age differences and menopause as the most important risk factor for osteoporosis. We presumed that physically healthy premenopausal women with unipolar depression have decreased BMD and altered bone cell metabolism. METHODS: BMD at lumbar spine and femoral neck by dual X-ray absorptiometry, bone alkaline phosphatase sera activity, 5b-tartarate resistant acid phosphatase sera activity and urine N-terminal telopeptide were measured in 73 premenopausal women with unipolar depression and compared with 47 healthy, age- and osteoporosis risk factors-matched premenopausal women. The duration and severity of depression, hormonal status (cortisol, prolactin, parathormone, oestradiol), antidepressive treatment, and physical activity through whole and modified QUALEFFO-41 questionnaire were evaluated. The results were statistically elaborated by the chi-square test, Student's t-test for independent samples, one-way analysis of variance - ANOVA, one-sample Kolmogorov-Smirnov test. Correlations were assessed by means of Pearson's coefficient. RESULTS: Patients with unipolar depression had significantly lower BMD, the decrease of which correlated only with the duration of depression. High bone metabolism turnover was found with a predomination of osteoresorption which, but not osteosynthesis, correlated with the severity of depression, estimated through Hamilton depression scores. Despite higher but not significant levels of cortisol in women with unipolar depression, the BMD decrease and high bone turnover seem not to be the consequence of hormonal changes or medical treatment. The significant correlations between physical activity and osteoresorption markers were found indicating possible underlying mechanism. CONCLUSIONS: Premenopausal women with unipolar depression have significantly lower BMD because of stimulated bone cell metabolism with predomination of osteoresorption process, mostly due to decreased physical activity in depression. These women should be investigated for osteoporosis and the multidisciplinary team approach is advocated.

B-type Natriuretic Peptide as a Marker of Different Forms of Systemic Sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune connective tissue disease which affects various tissues and organs, including skin, lungs, kidneys, gastrointestinal tract and cardiovascular system. Cardiac involvement is the most commonly recognized problem and a significant cause of morbidity. The brain natriuretic peptide (BNP) is a previously known marker of elevated cardiovascular risk in SSc, but the levels of BNP in various forms of SSc have not been investigated so far. AIM: The aim of our study was to evaluate the influence of SSc on the function of the right ventricle and the right atrium using the echocardiographic parameters. Moreover, we examined the levels of BNP in different forms of SSc as well as the association of disease severity with the plasma concentrations of BNP. METHODS: We included 42 patients with newly diagnosed SSc and patients whose disease had been diagnosed earlier. SSc patients and non-SSc control patients were examined by using echocardiography and the concentrations of BNP were determined. RESULTS: We analyzed differences in the parameters of right ventricle (RV) function and right atrium (RA) function between SSc patients and healthy controls. The two groups had similar distribution of gender, but SSc patients were significantly older than controls. RV wall thickness was increased in SSc patients (p<0.001), while right ventricular end-systolic area (RVESA; p=0.408) and right ventricular end-diastolic area (RVEDA; p=0.368) did not differ among the examinees. In contrast, RA minor-axis dimension (p=0.001) and the tricuspid annular plane systolic excursion (TAPSE) (p=0.001) were significantly higher in SSc patients. Also, we analyzed differences in brain natriuretic peptide (BNP) concentrations between diffuse cutaneous systemic sclerosis (DSSc) and limited cutaneous systemic sclerosis (LSSc) patients. DSSc patients had significantly higher concentrations of BNP. We found that levels of BNP were in significant positive correlations with age (p=0.007), disease duration (p=0.023), C reactive protein (CRP) (p=0.032), right ventricle fractional area change (FAC) (p=0.022), pulmonary vascular resistance (PVR) and Rodnan score (p=0.019). CONCLUSIONS: Given the obtained results, the laboratory determination of BNP could be useful in differentiating different forms of systemic sclerosis as well as in predicting the severity of the disease and future cardiovascular complications.

Haloperidol affects bones while clozapine alters metabolic parameters - sex specific effects in rats perinatally treated with phencyclidine.

BACKGROUND: The presentation of schizophrenia (SCH) symptoms differs between the sexes. Long-term treatment with antipsychotics is frequently associated with decreased bone mineral density, increased fracture risk and metabolic side effects. Perinatal phencyclidine (PCP) administration to rodents represents an animal model of SCH. The aim of this study was to assess the effects of chronic haloperidol and clozapine treatment on bone mass, body composition, corticosterone, IL-6 and TNF-α concentrations and metabolic parameters in male and female rats perinatally treated with PCP. METHODS: Six groups of male and six groups of female rats (n = 6-12 per group) were subcutaneously treated on 2nd, 6th, 9th and 12th postnatal day (PN), with either PCP (10 mg/kg) or saline. At PN35, one NaCl and PCP group (NaCl-H and PCP-H) started receiving haloperidol (1 mg/kg/day) and one NaCl and PCP group (NaCl-C and PCP-C) started receiving clozapine (20 mg/kg/day) dissolved in drinking water. The remaining NaCl and PCP groups received water. Dual X-ray absorptiometry measurements were performed on PN60 and PN98. Animals were sacrificed on PN100. Femur was analysed by light microscopy. Concentrations of corticosterone, TNF-α and IL-6 were measured in serum samples using enzyme-linked immunosorbent assay (ELISA) commercially available kits. Glucose, cholesterol and triacylglycerol concentrations were measured in serum spectrophotometrically. RESULTS: Our results showed that perinatal PCP administration causes a significant decrease in bone mass and deterioration in bone quality in male and female rats. Haloperidol had deleterious, while clozapine had protective effect on bones. The effects of haloperidol on bones were more pronounced in male rats. It seems that the observed changes are not the consequence of the alterations of corticosterone, IL-6 and TNF-α concentration since no change of these factors was observed. Clozapine induced increase of body weight and retroperitoneal fat in male rats regardless of perinatal treatment. Furthermore, clozapine treatment caused sex specific increase in pro-inflammatory cytokines. CONCLUSION: Taken together our findings confirm that antipsychotics have complex influence on bone and metabolism. Evaluation of potential markers for individual risk of antipsychotics induced adverse effects could be valuable for improvement of therapy of this life-long lasting disease.

Relapse of Takayasu arteritis as a cause of suicidal poisoning and subsequent major ischemic stroke successfully treated with thrombolytic therapy.

Introduction: Takayasu arteritis (TA) is a rare large vessel arteritis, affecting primarily aorta and its major branches. Its clinical manifestations can vary significantly - from asymptomatic to serious vascular events. Acute neurological complications are frequent at the onset of the disease and in relapses. Anxiety and depression are more frequent in TA patients than in general population as well as during relapses. Prevalence of transient ischemic attack or ischemic stroke in TA patients is approximately 10-20%. Case report: We presented a patient with TA that began with a depressive episode resulting in attempted suicide by bromazepame poisoning. This was subsequently followed by major ischemic stroke caused by thrombosis of the left middle cerebral artery (probably due to aortic arch embolism) successfully treated with intravenous thrombolysis. Conclusion: Intravenous thrombolysis appears to be safe and effective in patients with TA and stroke.

Parameters of Calcium Metabolism Fluctuated during Initiation or Changing of Antipsychotic Drugs.

OBJECTIVE: Serum parameters of calcium homeostasis were measured based on previously published evidence linking osteoporotic fractures and/or bone/mineral loss with antipsychotics. METHODS: Prospective, four-week, time-series trial was conducted and study population consisted of patients of both genders, aged 35-85 years, admitted within the routine practice, with acute psychotic symptoms, to whom an antipsychotic drug was either introduced or substituted. Serial measurements of serum calcium, phosphorous, magnesium, 25(OH)D, parathyroid hormone, calcitonin, osteocalcin and C-telopeptide were made from patient venous blood samples. RESULTS: Calcium serum concentrations significantly decreased from baseline to the fourth week (2.42±0.12 vs. 2.33±0.16 mmol/L, p=0.022, n=25). The mean of all calcemia changes from the baseline was -2.6±5.7% (-24.1 to 7.7) with more decreases than increases (78 vs. 49, p=0.010) and more patents having negative sum of calcemia changes from baseline (n=28) than positive ones (n=10) (p=0.004). There were simultaneous falls of calcium and magnesium from baseline (63/15 vs. 23/26, p<0.001; OR=4.75, 95% CI 2.14-10.51), phosphorous (45/33 vs. 9/40, p<0.001; 6.06, 2.59-14.20) and 25(OH)D concentrations (57/21 vs. 13/35, p<0.001; 7.31, 3.25-16.42), respectively. Calcemia positively correlated with magnesemia, phosphatemia and 25(OH)D values. Parathyroid hormone and C-telopeptide showed only subtle oscillations of their absolute concentrations or changes from baseline; calcitonin and osteocalcin did not change. Adjustment of final calcemia trend (depletion/accumulation) for relevant risk factors, generally, did not change the results. CONCLUSION: In patients with psychotic disorders and several risks for bone metabolism disturbances antipsychotic treatment was associated with the decrease of calcemia and changes in levels of the associated ions.

Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis and Low Cardiovascular Risk: The Role of von Willebrand Factor Activity.

BACKGROUND: To evaluate association between von Willebrand factor (vWF) activity, inflammation markers, disease activity, and subclinical atherosclerosis in patients with rheumatoid arthritis (RA) and low cardiovascular risk. METHODS: Above mentioned parameters were determined in blood samples of 74 non-diabetic, normotensive, female subjects, with no dyslipidemia(42 patients, 32 matched healthy controls, age 45.3±10.0 vs. 45.2±9.8 years). Intima-media thickness (IMT) was measured bilaterally, at common carotid, bifurcation, and internal carotid arteries. Subclinical atherosclerosis was defined as IMT>IMTmean+2SD in controlsat each carotid level and atherosclerotic plaque as IMT>1.5 mm. Majority of RA patients were on methotrexate (83.3%), none on steroids >10 mg/day or biologic drugs. All findings were analysed in the entire study population and in RA group separately. RESULTS: RA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5±69.3% vs. 95.3±36.8%, p<0.05). Predictive value of vWF activity for subclinical atherosclerosis was confirmed by logistic regression. vWF activity correlated significantly with erythrocyte sedimentation rate, fibrinogen, modified disease activity scores (mDAS28-ESR, mDAS28-CRP), modified Health Assessment Questionnaire (p<0.01 for all), duration of smoking, number of cigarettes/day, rheumatoid factor concentration (p<0.05 for all), and anti-CCP antibodies (p<0.01). In the entire study population, vWF activity was higher in participants with subclinical atherosclerosis (130±68% vs. 97±38%, p<0.05) or atherosclerotic plaques (123±57% vs. 99±45%, p<0.05) than in those without. Duration of smoking was significantly associated with vWF activity (ß 0.026, p = 0.039). CONCLUSIONS: We demonstrated association of vWF activity and subclinical atherosclerosis in low-risk RA patients as well as its correlation with inflammation markers, all parameters of disease activity, and seropositivity. Therefore, vWF might be a valuable marker of early atherosclerosis in RA patients.

Chronic risperidone exposure does not show any evidence of bone mass deterioration in animal model of schizophrenia.

BACKGROUND: It has been shown that bone mass is centrally regulated. Thus schizophrenia being a disease of the central nervous system is an interesting model for studying bone. Most second generation antipsychotic drugs including risperidone are used in the treatment of schizophrenia. Weight gain and metabolic disturbances are common side effects. OBJECTIVE: The aims of this study were to investigate bone mass, body composition and light microscopic pathology examinations of femur in an animal model of schizophrenia (pharmacologically induced by postnatally administered phencyclidine-PCP) and to further examine the effects of chronic treatment with risperidone on these parameters in rats. METHODS: Four groups of male rats were studied:1) control group-NaCl postnatally administered, n=9; 2) PCP group-postnatal PCP administration to rat pups (on day 2,6,9 and 12), n=6; 3) risperidone group-rats treated with risperidone alone for 9weeks from day 35 (NaCl-RSP group, n=7); 4) PCP rats treated with risperidone for 9weeks from day 35 (PCP-RSP group, n=7). Bone mass and body composition were measured in vivo by dual X ray absorptiometry (areal DXA and fat mass). Light microscopic analysis of the femoral metaphysis was performed in all groups after sacrificing the animals. RESULTS: Postnatal phencyclidine (PCP) administration to rat pups caused a long lasting reduction of total bone mass versus control animals (aDXA 128±2mg/cm(2) vs 139±5mg/cm(2), p<0.05). Examination of the femoral bone revealed a decrease in the number and thickness of the metaphyseal trabecule and cortical thinning. There was a decrease in total and retroperitoneal fat. Nine weeks of administration of risperidone alone to rats, resulted in significant weight gain and had no effect on bone mass versus control animals (aDXA was 136±7mg/cm(2) vs 139±5mg/cm(2), p>0.05). Furthermore, there were no changes in the light microscopic analysis of femoral metaphysis in comparison with controls. When PCP rats were treated with risperidone, they did not change their body weight nor bone mass versus PCP alone (aDXA 126±2mg/cm(2) vs 128±2mg/cm(2), p>0.05) but intriguingly on examination of the femoral bone an increase in the number and thickness of the metaphyseal trabecule was found (trabecular thickness 0.6±0.1µm vs 0.35±0.1µm, p<0.01). CONCLUSION: This study shows that in the PCP rat model of schizophrenia bone mass is reduced. When PCP rats were treated with risperidone bone mass remained unchanged but intriguingly and unexpectedly light microscopic examination of femoral metaphysis showed an increase in thickness of metaphyseal trabeculae. The mechanism of risperidone's action on bone remains to be clarified.

[Colonic perforation as an unusual manifestation of Behcet's disease].

INTRODUCTION: Behcet's disease is multisystemic vasculitis which affects vein and artery blood vessels. Intestinal perforation rarely occurs as clinic manifestation in as little as 1% of patients. The transverse colon is the most infrequent site of perforation. We presented a patient diagnosed with Behcet's disease who underwent both surgical and conversative treatment due to perforation of the colon. CASE REPORT: A 34-year-old patient was admitted to the hospital with fever, aphthous ulcerations on oral mucosa and genitals and bilateral uveitis. On the basis of clinical symptoms and the International Criteria developed in 1990 Behcet's disease was diagnosed. During the next few days the patient developed erythema nodosum, diarrheic syndrome and acute abdominal symptoms due to perforation of the transverse colon. An emergent laparotomy was undertaken involving resection of a perforated segment of the colon, and bipolar colostomy on the left side of abdomen. Following the surgery the patient was treated except for antibiotics with three successive pulse doses of methylprednisolone (500 mg/daily) and cyclophosphamide (15 mg/kg). The treatment was continued by gradual decrease in the close of the corticosteroid (perorally) and by cyclophosphamide first with monthly doses (5 monthly pulse doses of 15 mg/kg cyclophosphoamide), and then with 3-month doses (totally 6 doses) up to totally 12 g. CONCLUSION: The therapy with pulse doses of methylprednisolone combined with pulse doses of cyclophosphamide was very effective in the reported case with the complex clinical manifestations leading to resolution of gastrointenstinal, ocular and orogenital lesions.

[Systemic lupus erythematosus and dermatomyositis--case report].

The association of systemic lupus erythematosus (SLE) with idiopathic polymyositis or dermatomyositis is reported to occur in the range of 4-16%. Myositis can occur before or after SLE, or sporadically both diseases can be present simultaneously. This case report concerns a 36-year-old female patient suffering from Raynaud's phenomenon, polyarthralgia in the small joints of the hands, and skin changes compatible with Gotron's indications. Symmetric proximal muscle weakness of the extremities, fever of up to 40 degrees C, heliotrope rashes with erythematous changes in the face, upper arms, and posterior shoulders occurred subsequently. Laboratory analyses revealed increased acute phase reactants, hypochromic anaemia, lymphopenia, and increased levels of all muscle enzymes. Immunoserology demonstrated positive ANA, anti-Sm, and anticardiolipin antibodies (aCL), while anti dsDNA, anti Ro, anti La, and anti Jo-1 antibodies proved negative. Hypocomplementaemia and elevated levels of immune complexes were also detected. Pathologic sediment and proteinuria were revealed via urine analyses, while a kidney biopsy confirmed lupus nephritis (type IVa according to the World Health Organisation classification). Biopsy of erythematous changes of the posterior shoulder demonstrated leukocytoclastic vasculitis. Electromyography of the lower extremities established myopathic changes. Inflammation of the muscles was confirmed via magnetic resonance imaging. The patient was categorised as having two separate coexistent diseases--SLE and dermatomyositis. Both the classification criteria of the American College of Rheumatology for SLE and the diagnostic criteria for dermatomyositis, proposed by Bohon and Peter, were fulfilled simultaneously. Treatment commenced with pulses of methylprednisolone and continued with oral therapy, including Resochin. Pulses of intravenous cyclophosphamide were also administered. After six weeks of therapy, biohumoral remission of both diseases was achieved, while complete recovery from muscle weakness was accomplished after four months.