The estimated prevalence of osteoporosis in Bahrain: a multi-centered-based study.

OBJECTIVES: the primary aim of this study was to examine the prevalence and risk factors of low bone mineral density in Bahrain. METHODS: this was a retrospective study, which targeted a cohort of 4822 Bahraini subjects (mean age 59.36 years: 93% females). Demographic data and results of lumbar and femur DEXA scan for the targeted sample, over the period 2016-2018, were retrieved from four hospitals. RESULTS: The prevalence of low BMD was 62.3% (46.4% had osteopenia and 15.9% had osteoporosis). The highest rate of osteopenia was detected at the age group younger than 44 years. However, with increasing age, the rate of osteopenia declined, whereas osteoporosis increased (P < 0.001). Females were found to be at higher risk of developing both osteopenia (45.8%) and osteoporosis (18.1%) compared to males (39% and 12.4%, respectively) (P < 0.001). Postmenopausal women exhibited higher rates of low BMD (42.4% osteopenia, 22.3% osteoporosis) compared to elderly men (30.9% osteopenia, 9% osteoporosis). CONCLUSIONS: We reported high prevalence of osteopenia and osteoporosis in Bahrain. Low BMD was more common in females, especially in postmenopausal women. Highest prevalence of osteopenia happened at young age. Therefore, we advocate screening at younger age than previously recommended.

The prevalence of pulmonary arterial hypertension in patients with mixed connective tissue disease: a systematic review and meta-analysis.

OBJECTIVES: The prevalence and outcome of mixed connective tissue disease-associated pulmonary arterial hypertension (MCTD-PAH) has not been well understood. Our aim was to review the current knowledge on the prevalence, severity, and mortality of MCTD-PAH. We also aimed to examine the prevalence trend of MCTD-PAH over the years. METHODS: PubMed/Medline, Embase, Scopus and Web of Science electronic databases were searched for the published randomised controlled clinical trials (RCTs) and observational/original studies on PAH in patients with MCTD from January 1972 to December 2020. RESULTS: The results were pooled using random-effects meta-analysis based on DerSimonian and Laird method. A total of 983 patients from eight studies were included in the meta-analysis (K=8, n=983). Pooled prevalence of PAH in MCTD patients was 12.53% [95% CI 8.30-18.48%] with significant level statistical heterogeneity (tau2=0.30, tau=0.55, i2 83.3%, H=2.13 Q(df,7)=31.90, p=0.001). There was no association between PAH and female gender or age. The percentage of deaths in MCTD patients due to PAH varied and reached up to 81.8%. CONCLUSIONS: This is the first systematic review and meta-analysis investigating the prevalence of PAH in patients with MCTD and it revealed an overall prevalence of PAH in patients with MCTD of 12.53%. Our results showed trends of reduced prevalence of MCTD-PAH over last four decade, reconfirmed the lower prevalence rate in recent studies, but revealed an increased mortality rate. We also determined the low impact of the age, gender, and interstitial lung disease on MCTD-PAH.

Adaptations of Clinical Teaching During the COVID-19 Pandemic: Perspectives of Medical Students and Faculty Members.

Background: The COVID-19 pandemic had serious implications on medical schools' programs that necessitated lots of adaptations of teaching, learning, and assessment to guarantee continuity of education in medical schools. Our study aimed to evaluate perspectives of clerkship students and faculty members regarding clinical teaching adaptations implemented during the COVID-19 pandemic. Methods: A descriptive, cross-sectional, survey-based study was conducted and targeted 5th and 6th year clerkship students and full- and part-time clinical faculty. The survey explored (1) perception of the degree of contribution of implemented adaptations to student achievement of expected clinical competencies, (2) degree of confidence regarding students' achievement of expected clinical competencies through such adaptations, and (3) perception of the effect of implemented educational adaptations on students' learning. Descriptive statistics were used, and statistical significance level was set at p < 0.05. Results: The survey exhibited high internal consistency. Both students and faculty members felt that most of the adaptations had moderate to high contribution to student achievement of expected clinical competencies. On a 5-point scale, the highest score was given by faculty members to "Interpretation of investigations" (3.93±0.84) while the lowest scores were given by faculty members (3.10±1.21) and students (2.57±1.36) to "Performing clinical procedures". Students and faculty members agreed that the adaptations had positive effect on students' learning except for the statement "Students were able to easily monitor their academic progress" where students gave less scores than faculty members, with a statistically significance difference (p=0.029). Conclusion: Students and faculty members had similar perspectives regarding the implemented adaptations and their impact and contribution to student learning and achievement of the basic clinical competencies. Both of them agreed on the need for and importance of the implemented adaptations. Our findings recommend such adaptations during the times of crises, which can be conducted through integrating online teaching with face-to-face teaching.

Does four-week consecutive, dawn-to-sunset intermittent fasting during Ramadan affect cardiometabolic risk factors in healthy adults? A systematic review, meta-analysis, and meta-regression.

AIMS: This study aimed to evaluate the effects of Ramadan diurnal intermittent fasting (RDIF; 29-30 days) on cardiometabolic risk factors (CMRF) in healthy adults, and examine the effect of various cofactors on the outcomes using sub-group meta-regression. DATA SYNTHESIS: We conducted a systematic review and meta-analysis to measure the effect sizes of changes in CMRF in healthy adult Muslims observing RDIF. Ten scientific databases (EBSCOhost, CINAHL, Cochrane, EMBASE, PubMed/MEDLINE, Scopus, Google Scholar, ProQuest Medical, ScienceDirect, and Web of Science) were searched from the date of inception (1950) to the end of November 2020. The CMRF searched and analyzed were total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), diastolic blood pressure (DBP), and heart rate (HR). We identified 91 studies (4431 adults aged 18-85 years) conducted between 1982 and 2020 in 23 countries distributed over four continents. RDIF-induced effect sizes for CMRF were: TC (no. of studies K = 77, number of subjects N = 3705, Hedge's g = -0.092, 95% confidence interval (CI): -0.168, 0.016); TG (K = 74, N = 3591, Hedge's g = -0.127, 95% CI: -0.203, 0.051); HDL-C (K = 68, N = 3528, Hedge's g = 0.138, 95% CI: 0.051, 0.224); LDL-C (K = 65, N = 3354, Hedge's g = -0.115, 95% CI: -0.197, -0.034); VLDL-C (K = 13, N = 648, Hedge's g = -0.252, 95% CI: -0.431, 0.073), DBP (K = 32, N = 1716, Hedge's g = -0.255, 95% CI: -0.363, 0.147), and HR (K = 12, N = 674, Hedge's g = -0.082, 95% CI: -0.300, 0.136). Meta-regression revealed that the age of fasting people was a significant moderator of changes in both HDL-C (P = 0.02) and VLDL-C (P = 0.01). Male sex was the only significant moderator of changes in LDL-C (P = 0.055). Fasting time duration was the only significant moderator of HDL-C (P = 0.001) at the end of Ramadan. CONCLUSIONS: RDIF positively impacts CMRF, which may confer short-term transient protection against cardiovascular disease among healthy people.

Prevalence of Musculoskeletal Manifestations in Adult Kidney Transplant's Recipients: A Systematic Review.

Background and Objectives: The musculoskeletal (MSK) manifestations in the kidney transplant recipient (KTxR) could lead to decreased quality of life and increased morbidity and mortality. However, the prevalence of these MSK manifestations is still not well-recognized. This review aimed to investigate the prevalence and outcomes of MSK manifestations in KTxR in the last two decades. Materials and Methods: Research was performed in EBSCO, EMBASE, CINAHL, PubMed/MEDLINE, Cochrane, Google Scholar, PsycINFO, Scopus, Science Direct, and Web of Science electronic databases were searched during the years 2000-2020. Results: The PRISMA flow diagram revealed the search procedure and that 502 articles were retrieved from the initial search and a total of 26 articles were included for the final report in this review. Twelve studies reported bone loss, seven studies reported a bone pain syndrome (BPS) or cyclosporine-induced pain syndrome (CIPS), and seven studies reported hyperuricemia (HU) and gout. The prevalence of MSK manifestations in this review reported as follow: BPS/CIPS ranged from 0.82% to 20.7%, while bone loss ranged from 14% to 88%, and the prevalence of gout reported in three studies as 7.6%, 8.0%, and 22.37%, while HU ranged from 38% to 44.2%. Conclusions: The post-transplantation period is associated with profound MSK abnormalities of mineral metabolism and bone loss mainly caused by corticosteroid therapy, which confer an increased fracture risk. Cyclosporine (CyA) and tacrolimus were responsible for CIPS, while HU or gout was attributable to CyA. Late diagnosis or treatment of post-transplant bone disease is associated with lower quality of life among recipients.

Therapeutic regimens for vitamin D deficiency in postmenopausal women: a systematic review.

INTRODUCTION: We reviewed the most effective vitamin D3 regimen for vitamin D deficiency in postmenopausal women. MATERIAL AND METHODS: We searched for studies and clinical trials conducted on healthy postmenopausal women published on PubMed from 2000 to 2018 using the term "Vitamin D deficiency" combined with the following terms: "dose", "supplement", "supplementation", "cholecalciferol" or "cholecalciferol dose". We identified 1376 articles which matched the search criteria. Based on reviewing the title and abstract, 17 articles were eligible for a full-text review. Of those, 12 manuscripts were ultimately included. RESULTS: A majority of the studies (75%) reported using daily maintenance doses which were predominantly administered orally (83.3%). Two studies reported favorable results following therapy with a single oral dose of 300,000 IU. After one month, however, 25-hydroxy vitamin D [25(OH)D] was satisfactory; both studies failed to maintain adequate responses after 60 and 90 days. One study found that loading oral doses of 50,000 IU/day for 2 weeks followed by the same doses every 2 weeks for one year were effective. Five studies employed oral doses of 800 IU/day but none of them reported that this dose was adequate. Three studies used doses of 1000 IU/day but only two of them reported positive results. Three trials examined oral doses of 2000 IU/day and another 3 studies tested oral doses of 4000-4800 IU/day. All of them reported acceptable responses that lasted with continued treatment. CONCLUSIONS: Oral maintenance doses of 2000-4800 IU/day satisfactorily corrected vitamin D deficiency and maintained 25(OH)D levels in postmenopausal women with continuous therapy.

Therapeutic and maintenance regimens of vitamin D3 supplementation in healthy adults: A systematic review.

Studies carried out assessing the effect of different doses of cholecalciferol (vitamin D3) on correcting serum 25-hydroxyvitamin D deficiency in healthy adults are limited and review studies are lacking. Moreover, the maintenance dose and its duration offered by these few studies are inconsistent. We performed a systematic review of randomized clinical controlled trials (RCTs) that assessed the effect of different doses of vitamin D3 on serum 25(OH)D in healthy adults. PubMed database was searched from 2010 to 2018 using the following search terms: "vitamin D deficiency", "Cholecalciferol", "vitamin D3 dose", "vitamin D supplement", "vitamin D therapy". RCTs and original articles that evaluated different doses of vitamin D3 were identified. A total of sixteen (out of 3016) acceptable studies fulfilling our inclusion criteria were included in the current systematic review. Our results revealed that supplementation with vitamin D3 had a significant positive effect in raising serum 25(OH) D concentrations. Our findings indicated that the best regimen of vitamin D3 supplement consisted of an initial large bolus dose either IM injection of 600.000 IU monthly or oral dose of 200.000 IU monthly or 50.000 IU weekly for 8 weeks, followed by a maintenance dose of 50.000 IU monthly or bimonthly. A large bolus therapeutic dose of vitamin D3, frequently or infrequently for 8 weeks, followed by long-term oral maintenance dose of 50.000 IU monthly or bimonthly optimiz and manitain vitamin D serum levels year round.

Prevalence of Vitamin D Deficiency in Adult Patients with Systemic Lupus Erythematosus in Kingdom of Bahrain.

Vitamin D deficiency (VDD) has been implicated as an important factor in the development or aggravation of systemic lupus erythematous (SLE). Patients with SLE are especially prone to the development of VDD due to the nature of their illness and avoidance of sun exposure. The prevalence of VD status in Bahraini patients with SLE has not been studied. Our aim is to study the prevalence of VDD in Bahraini cohort with SLE. Fifty-eight Bahraini patients with SLE were included retrospectively in this study. Most of the patients were females 50/58. The patients were followed at the rheumatology department at "Salmanyia medical complex". Controls were fifty-eight age-matched healthy Bahraini subjects. Serum levels of 25 (OH) vitamin D were estimated using chemilumenescence immunoassay. Chi Square and T-Test were used for analysis a p value of ≤ 0.05 was considered significant. There was statistically significant difference (P ≤ 0.05) in the mean serum levels of vitamin D between patients (30.67 nmol/l) and controls (39.95 nmom/L). In the SLE patients there were 49.1% deficient, 47.1% insufficient and 3.8% were Optimal. In the controls; 27% was deficient, 52% insufficient and 21% optimal. In conclusion, There was high prevalence of VDD in Bahraini patients with SLE. Both patients and controls had low vitamin D serum levels, however the patients had statistically significant lower levels. Our study also highlights the need for studying the effects of correcting hypovitaminosis on the disease activity in SLE patients.

Hormonal and echocardiographic abnormalities in adult patients with sickle-cell anemia in Bahrain.

BACKGROUND: Adrenal, thyroid, and parathyroid gland hormonal changes are recognized in children with homozygous (HbSS) sickle-cell anemia (SCA), but are not clear in adult patients with SCA. AIM: To assess the metabolic and endocrine abnormalities in adult patients with SCA and evaluate left ventricular (LV) systolic and diastolic functions compared with patients with no SCA and further study the relationship between serum levels of cortisol, free thyroxine (T4), and testosterone with serum ferritin. MATERIALS AND METHODS: The study was conducted on 82 patients with adult HbSS SCA compared with a sex- and age-matched control group. The serum levels of cortisol, parathyroid hormone (PTH), testosterone, thyroid-stimulating hormone (TSH), and free T4 were compared. Blood levels of hemoglobin, reticulocyte count, lactate dehydrogenase (LDH), calcium, alkaline phosphatase (ALP), vitamin D3, and ferritin were also compared. Pulsed Doppler echo was performed to evaluate the LV mass, wall thickness, and cavity dimensions with diastolic filling velocities of early (E) and atria (A) waves. Biometric data were analyzed as mean ± standard deviation between the two groups. Multiple regression analysis was performed between serum levels of ferritin as independent variable and testosterone, cortisol, and thyroid hormones. RESULTS: A total of 82 adult patients with HbSS SCA were enrolled who had a mean age of 21±5.7 years, with 51 males (62%). Patients with SCA compared with the control group had significantly lower hemoglobin, body mass index, cortisol, vitamin D3, testosterone, and T4. Furthermore, there were significantly high levels of reticulocyte count, PTH, TSH, ferritin, LDH, ALP, and uric acid. The incidence of subclinical hypothyroidism and adrenal insufficiency was 7% and 4.8%, respectively, with hypogonadism 9.8% and vitamin D3 deficiency 61%. There were inverse relationships between ferritin as independent variable and serum levels of testosterone, T4, and cortisol, with regression coefficients of -0.49 (P<0.001), -0.33 (P<0.001), and -0.11 (P<0.92), respectively. CONCLUSION: Patients with adult SCA had a high prevalence of in vivo hypoadrenialism (4.8%), hypogonadism (9.8%), and hypothyroidism (7%). There were significant inverse relationships between serum ferritin as independent variable and cortisol, testosterone, and T4. Pulsed Doppler echocardiography showed increased LV mass, with a restrictive LV diastolic pattern suggestive of diastolic dysfunction.

Pain frequency, severity and QT dispersion in adult patients with sickle cell anemia: correlation with inflammatory markers.

BACKGROUND: Inflammatory markers are increased during vaso-occlusive crisis (VOC) in adult patients with sickle cell anemia (SCA), but this is not clear in clinical steady state. AIM: The present study aims to establish the frequency and intensity of bone pain episodes in adult patients with SCA in clinical steady state and to determine the correlation between different inflammatory markers, other variables including QT dispersion (QTd) and pain frequency and intensity in SCA. PATIENTS AND METHODS: Patients were classified into two groups: group 1, those with more than three hospital admissions in the last 6 months, and group 2, those with no hospital admission. Pearson correlation between variables such as body mass index (BMI), level of tumor necrosis factor (TNF-α), interleukin-1 (IL-1), C-reactive protein (CRP), hemoglobin (Hb), reticulocyte count, white blood cell count (WBC), ferritin, lactate dehydrogenase (LDH), parathormone (PTH), vitamin D3 (25-OH cholecalciferol) and bone pain frequency with severity was evaluated. RESULTS: Forty-six patients were enrolled in this study with a mean age of 18.47±5.78 years, with 23 patients in each group. Vitamin D3 and Hb were lower (17.04±5.77 vs 37.59±4.83 ng/L, P<0.01 and 7.96±0.3 vs 8.44±0.27 g/dL, P<0.01, respectively); the inflammatory markers showed significantly higher level of TNF-α, IL-1 and CRP (56.52±5.43 pg/ml, 44.17±4.54 pg/ml and 3.20±0.72 mg/L, respectively, P<0.05); WBC, LDH and reticulocyte count were also significantly higher and the QTd was higher (45.0±2.22 vs 41.55±0.8 ms, P<0.05) in group 1 when compared with group 2. Pearson correlation coefficient showed significant positive correlation between serum level of TNF-α and bone pain frequency (r=0.414, P<0.005) and serum level of IL-1 (r=0.39, P<0.008). CONCLUSION: There is a strong positive correlation between TNF-α, IL-1 and WBC and bone pain frequency in steady state in adult patients with SCA. CRP and low hemoglobin had weak positive correlation. QTd was significantly longer in patients who had hospitalizations with VOC.

Generalisability theory analyses of concept mapping assessment scores in a problem-based medical curriculum.

CONTEXT: In problem-based learning (PBL), students construct concept maps that integrate different concepts related to the PBL case and are guided by the learning needs generated in small-group tutorials. Although an instrument to measure students' concept maps in PBL programmes has been developed, the psychometric properties of this instrument have not yet been assessed. OBJECTIVES: This study evaluated the generalisability of and sources of variance in medical students' concept map assessment scores in a PBL context. METHODS: Medical students (Year 4, n = 116) were asked to construct three integrated concept maps in which the content domain of each map was to be focused on a PBL clinical case. Concept maps were independently evaluated by four raters based on five criteria: valid selection of concepts; hierarchical arrangement of concepts; degree of integration; relationship to the context of the problem, and degree of student creativity. Generalisability theory was used to compute the reliability of the concept map scores. RESULTS: The dependability coefficient, which indicates the reliability of scores across the measured facets for making absolute decisions, was 0.814. Students' concept map scores (universe scores) accounted for the largest proportion of total variance (47%) across all score comparisons. Rater differences accounted for 10% of total variance, and the student × rater interaction accounted for 25% of total variance. The variance attributable to differences in the content domain of the maps was negligible (2%). The remaining 16% of the variance reflected unexplained sources of error. Results from the D study suggested that a dependability level of 0.80 can be achieved by using three raters who each score two concept map domains, or by using five raters who each score only one concept map domain. CONCLUSIONS: This study demonstrated that concept mapping assessment scores of medical students in PBL have high reliability. Results suggested that greater improvements in dependability might be made by increasing the number of raters rather than by increasing the number of concept map domains.

Predictors of abnormal bone mass density in adult patients with homozygous sickle-cell disease.

BACKGROUND: Adult patients with sickle-cell disease (SCD) often have multiple bone compactions causing tissue hypoxia and osteonecrosis. The impact on bone abnormalities lesion detected by bone mass density is not well defined. AIM: The study is a cross sectional, perspective was designed to assess the prevalence of abnormal BMD in adult Bahraini patients with SCD and to assess the predictive risk of different metabolic variables such as serum level of vitamin D3, testosterone, and parathyroid hormone in addition to lactate dehydrogenase (LDH), hemoglobin (Hb), and reticulocyte count for the development of abnormal bone density on dual X-ray absorptiometry (DXA) scan. METHOD: The study was conducted over the period of 12 months from first of January 2012 to end of December 2012. All patients were evaluated clinically for severity of SCD and abnormal bone mass density (BMD) using DXA scan. Blood samples were withdrawn for measuring the serum level of vitamin D3, testosterone, and parathyroid hormone in addition to Hb, LDH, and reticulocyte count. Multiple logistic regression analysis was used to assess risk prediction of different variables for the development of abnormal BMD on DXA with T-score ≤-2.5 standard deviation (SD). RESULTS: The study included Bahraini patients with SCD (n = 55, age 29.24 ± 9.47 years, male 60% and female 40%) compared with an age-matched healthy control group (n = 55, age 28.82 ± 8.64 years, with 62% male and 38% female). Of the 55 patients with SCD compared with the control group, there were 33 (58%) patients with low BMD and 2 (3%) in the control. Among the 33 patients with SCD and with low BMD, there were 20 (36%) with osteoporosis (T-score of ≤-2.5 SD) and 13 (24%) with osteopenia (T-score of <-1 to -2.5 SD). The most affected site of low BMD was lumbar spine (55%), followed by the radius (30%) and neck of the femur (15%). SCD patients with osteoporosis compared with the healthy subjects had significantly lower body surface area (BSA, m(2)) of 1.4 ± 0.3 vs. 1.63 ± 0.5 BMI, low level of vitamin D3 of 21.11 ± 6.95 ng/mL vs. 46.2 ± 15.19 (P < 0.001), lower testosterone level of 1.34 ± 0.54 vs. 2.18 ± 0.56 ng/mL (P < 0.001), higher reticulocyte count (P < 0.001), and higher LDH level (P < 0.001). The low serum level of vitamin D3 (<20 ng/mL) and low testosterone of <0.9 ng/mL had risk prediction (odds ratio) of 1.14 and 1.2, respectively, for abnormal BMD in SCD. In the risk prediction of other variables of parathormone (PTH), LDH, and reticulocyte, were not significant. CONCLUSION: The prevalence of abnormal bone mass density (BMD) is high (60%) in Bahraini patients with SCD. There is significant low serum level of vitamin D3 and low testosterone hormone in those with very low bone mass density (BMD) (osteoporosis and T-score <-2.5). The low serum level of vitamin D3 (<20 ng/mL) and low testosterone of <0.9 ng/mL had risk prediction (odds ratio) of 1.14 and 1.2, respectively, for abnormal BMD in SCD.

Immunological aspects of biopsy-proven lupus nephritis in Bahraini patients with systemic lupus erythematosus.

Lupus nephritis (LN) is a frequent and potentially serious complication of systemic lupus erythematosus (SLE) that may influence morbidity and mortality. Immunological investigations are aiding tools to the kidney biopsy findings in early diagnosis, in addition to monitoring the effect of therapy. The aim of the present study is to highlight the role of these investigations in a group of Bahraini patients and to determine whether there is any positive association between these findings and the outcome of LN. The current study is a retrospective case-control study of randomly selected 88 SLE patients, 44 with biopsy-proven LN and 44 without, acting as controls. All renal biopsies performed during the period from 1996 to 2012 were classified according to the World Health Organization classification. Immunological investigations analyzed are: Antinuclear antibodies (ANA), anti-ds DNA, anti-ENA, anti-cardiolipin antibodies (abs) and complement components C3, C4. Human leukocyte antigen (HLA) typing class II was performed on selected cases. All patients had positive ANA (100%). A significantly high frequency of anti-Smith abs among the non-LN group (43.18%) compared with the LN group (18.18%) was found (P <0.001). On the other hand, the anti-Ro/SSA abs in the non-LN group was also found at a statistically higher frequency (20.45%) compared with that in the LN group (4.54%) (P <0.01). Anti-ds-DNA abs were found to be higher in the LN group (84.09%) compared with the non-LN group (70.45%), but the difference was not statistically significant (P = 0.082). There was a positive association of ANA positivity and low C3 and or C4 in the studied group. In our study, 88.2% of the HLA typed patients had HLADR2, DR3 or both. In conclusion, in our Arabic Bahraini SLE patients, the presence of anti-Smith, anti-Ro/SSA and anti-RNP antibodies and the absence of anti-dsDNA antibodies are independent predictive markers for renal involvement. However, more prospective studies with a larger number of patients are essential to ascertain those findings.

Genetically determined imbalance between serum levels of tumour necrosis factor (TNF) and interleukin (IL)-10 is associated with anti-Jo-1 and anti-Ro52 autoantibodies in patients with poly- and dermatomyositis.

Our aim was to investigate presence of tumour necrosis factor (TNF) and interleukin (IL)-10 in serum and their relation to different genotypes as well as to clinical and laboratory phenotypes in patients with polymyositis and dermatomyositis. In 65 patients with poly- or dermatomyositis the inflammatory cytokine balance was evaluated by the assessing absolute levels as well as the ratio between TNF and IL-10 in serum. These levels were correlated to the G-308A TNFA, G-1087A IL10 and G915C TGFB1 gene polymorphisms and haplotype frequencies, gender, autoantibody profiles and clinical manifestations. Increased serum levels of TNF and IL-10 were observed in patients compared to controls. A significantly higher TNF:IL-10 ratio was detected in female poly- and dermatomyositis patients carrying the TNF2 allele compared to female patients with the TNF1/TNF1 genotype (median+/-IQR 1.513+/-0.0.679 vs. 0.950+/-1.173, p=0.021). This ratio was also significantly higher in patients with the extended MICA5.1/TNF2/TNFa2/DRB1*03 haplotype compared to patients lacking this haplotype. A significantly higher TNF:IL-10 ratio was recorded in sera of patients with anti-Ro52 (1.513+/-1.275 and 1.276+/-0.671, positive vs. negative, p=0.010) antibodies and in women with anti-Jo-1 (1.919+/-0.918 and 1.281+/-0.790, positive vs. negative, p=0.041). Our data suggest that a genetically programmed cytokine imbalance exists in patients with poly- or dermatomyositis and that this imbalance is related to the presence of disease-associated autoantibodies.

MICA4/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease in Swedish patients.

In order to investigate major histocompatibility complex (MHC) class I chain-related gene A (MICA), tumor necrosis factor (TNFa), -308TNFA, and human leukocyte antigen (HLA-DR/DQ) polymorphisms in mixed connective tissue disease (MCTD), we analyzed 24 patients and 229 healthy controls from Sweden. MICA and TNFa typing was performed by polymerase chain reaction (PCR) and genotyping. HLA-DR and -DQ were genotyped using PCR-sequence specific primers (PCR-SSP) and PCR-sequence-specific oligonucleotide probe (PCR-SSOP), respectively. For analysis of -308TNFA polymorphisms we performed PCR with restriction endonuclease enzymes. We found that the MICA5.1-5.1 genotype was positively associated with MCTD. Shared epitope genes (DRB1*01 and DRB1*04) were also significantly positively associated with MCTD. Polymorphism of -308TNFA was not differently distributed in MCTD patients compared with controls. Furthermore, we demonstrated that frequencies of three estimated haplotypes were increased in MCTD patients compared with controls. Interestingly, the haplotype with MICA allele 4 together with DRB1*04 and TNF1 alleles gives the most specific pattern for MCTD patients compared with controls. Our study demonstrates a clear contribution of HLA loci in susceptibility to MCTD in the Swedish population. Susceptibility to MCTD may be linked to the MICA4/HLA-DRB1*04/TNF1 haplotype and MICA 5.1-5.1 genotype. Mixed connective tissue disease was also associated with shared epitope genes, which in RA has been associated with a more severe disease. Whether these genotypes affect the clinical phenotype of MCTD needs to be determined.

Serial analysis of Ro/SSA and La/SSB antibody levels and correlation with clinical disease activity in patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the temporal correlation between anti-Ro/SSA and anti-La/SSB antibody levels and compare them with variation in clinical disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Sequential serum samples collected over 18-44 months from 18 anti-Ro/SSA positive patients with systemic lupus erythematosus were analysed by ELISA with recombinant Ro60, Ro52 and La antigens. Disease activity was assessed by the BILAG index. RESULTS: Limited antibody level variation over time was found in most patients, but a subset displayed more changes and a co-variation between the levels of separate specificities was found in 40% of patients. In two patients antibody levels fluctuated with the global score. Antibodies also correlated with separate organ/systems involvement in individual patients. CONCLUSION: The Ro60, Ro52 and La antibody profile is fixed at an early stage of disease and in most patients hardly changes. Patients with fluctuating levels tend to have a co-ordinated expression of these autoantibodies.