SLCO1B1 Gene Polymorphisms (rs2306283 and rs4149056) and Statin-Induced Myopathy in Jordanian Diabetics.

BACKGROUND: The use of statins to lower high serum cholesterol levels may be associated with a number of adverse reactions, including severe myopathy. The solute carrier organic anion transporter 1B1 (SLCO1B1) gene, which encodes the organic anion-transporting polypeptide OATP1B1, is related to the intracellular transport of statins. The aim of this research was to study the association of rs2306283 and rs4149056 genetic polymorphism of the SLCO1B1 gene with the development of statin-induced myopathy in Jordanian diabetics receiving statins. METHODS: We included 413 patients attending the Diabetes Clinics of the National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan. The study was approved by the Institutional Review Board of NCDEG. Myopathy was defined as the elevation of creatine kinase more than 3 times the upper limit of normal. Every subject signed an informed consent form and donated 3-5 mL of venous blood. Genome DNA was extracted from lymphocytes of peripheral blood. Genotypes were identified using the Tetra Amplification Refractory Mutation System of SLCO1B1. RESULTS: The minor allele frequencies of rs2306283 [G] and rs4149056 [C] were 0.38 and 0.23, respectively. The two SNPs followed the Hardy-Weinberg equilibrium. The development of SIM was significantly associated with the homozygous and heterozygous minor allele genotype of rs4149056 (CC and CT), and the homozygous wild type allele genotype of rs2306283 (AA). There was no linkage disequilibrium between the two SNPs in the studied subgroups. CONCLUSION: Genetic polymorphism in the SLCO1B1 Gene is a risk factor for the development of SIM in Jordanian patients.

In-hospital mortality in patients with systemic lupus erythematosus: a study from Jordan 2002-2017.

We aimed to study the mortality among hospitalized patients with systemic lupus erythematosus (SLE). We performed a retrospective cross-sectional study and identified patients with SLE who were hospitalized at Jordan University Hospital (JUH) between 2002 and 2017.There were 990 admissions among which 283 were SLE patients. The mean age at disease onset was 34 ± 12.5 years and the female to male ratio was 8.4:1. Forty patients died during the 15-year period. In-hospital case fatality was 14% over 15 years. For the deceased patients, the female to male ratio was 3.4:1, mean age at disease onset was 27.8 ± 11.5 years, mean age at death was 35.1 ± 12 years, and mean disease duration was 7.5 ± 6.9 years. Twenty patients had disease duration ≤ 5 years. Infection and SLE-related complication contributed equally to mortality in hospitalized SLE patients (42.5% [CI 27.5%-59%] and 40% [95% CI 25%-56.5%], respectively). Infection related mortality compared to SLE-related mortality was associated with younger age and shorter disease duration (29.5 years versus 38.3 years and 6.4 versus 8.7 years, respectively). CRP was higher in infection related mortality compared to SLE-related mortality (131.4 mg/dl versus 87.6 mg/dl, respectively). Most SLE-related deaths were secondary to pulmonary disease. Renal disease did not contribute directly to mortality. No fatalities were attributed to cardiovascular disease (CVD) or cancer. Infection and active SLE accounted for the majority of deaths at a young age. Significant pulmonary related deaths may indicate a change in trends in SLE mortality, as renal related mortality is expected to decline due to proper management.

Musculoskeletal disorders of the hand in type 2 diabetes mellitus: prevalence and its associated factors.

AIM: To assess the prevalence of musculoskeletal disorders of the hand among adult patients with type 2 diabetes mellitus (T2DM) and their relation to disease duration, glycemic control and microvascular complications. METHODS: A cross-sectional study was conducted at the National Center for Diabetes, Endocrinology and Genetics in Amman, Jordan. RESULTS: One thousand patients with T2DM were included in this study (mean age 57.8 ± 9.5 years, 52.2% females and 47.8% males). Hand disorders were seen in 69.5% of patients, limited joint mobility (LJM) was the most prevalent (63.1%) condition followed by Dupuytren's contracture (DC) (18.6%). Trigger finger, thick skin and carpal tunnel syndrome (CTS) were found in 7.2%, 6.2% and 5.5% of patients, respectively. One disorder was seen in 45.4% of patients, two in18.2%, three in 4.9%, four in 0.9%, while only 0.1% of patients had all disorders. Female gender, age over 60 years and long duration of diabetes were associated with hand abnormalities. Hypertension was significantly associated with DC while retinopathy was associated with increased odds of thick skin, DC and CTS with P-values 0.037, < 0.005 and 0.002, respectively. CONCLUSION: Hand disorders are very common in T2DM. Female gender, old age, duration of diabetes, retinopathy and hypertension were significantly associated with hand disorders in T2DM.

Low prevalence of malignancy in patients with idiopathic inflammatory myopathies in Jordan.

OBJECTIVES: To estimate the frequency of malignancy among patients with idiopathic inflammatory myopathies (IIM) in Jordan. METHODS: This was a retrospective review of case records of patients with IIM in Jordan. RESULTS: We identified 94 cases of IIM, (47 polymyositis (PM) and 47 dermatomyositis (DM)). Sixty-seven (71%) were females and 27 (29%) were males. The mean age at diagnosis was 39.7± 15.7 years (range 17-72), median 40 years and the mean follow-up was 5.05±4.03 years (0.2-19). Malignancy was diagnosed in only 4 patients (4.25%) with IIM. Among patients with DM, malignancy was found in three patients (6.4%).The age-standardised rate was 2.7% (95% confidence interval: 0. 6% to 7.1%). The standardised incidence ratio was 0.998. Diagnosis of associated malignancy was made close to the time of IIM diagnosis. Two male patients had nasopharyngeal carcinoma at the ages of 51 and 59 years, while the other two were female with breast and ovarian cancer at the ages of 40 and 45 years, respectively. CONCLUSIONS: Malignancy in association with IIM was found to be low in our cohort in comparison to reports from other countries. The observed number of cancer cases in this group of patients is similar to the expected number of cases that would occur in general population of Jordan. This could be related to younger age of disease onset. The benefits of long-term screening for malignancy in our population are not clear.

Methylene tetrahydrofolate reductase genotypes frequencies: association with toxicity and response to methotrexate in rheumatoid arthritis patients.

OBJECTIVES: The purpose of this study was to determine the genotype/allele frequencies of C677T and A1298C polymorphisms of methylenetetrahydrofolate (MTHFR) gene in Jordanian rheumatoid arthritis (RA) patients. In addition, the association between MTHFR gene C677T and A1298C polymorphisms and response to and toxicity of methotrexate (MTX) was evaluated. METHODS: 159 adult rheumatoid arthritis ent Rheumatology Clinic at The Jordan University Hospital, between December, 2011 and April, 2012 were recruited into the study. Genomic DNA was extracted from leukocytes using Wizard Genomic DNA extraction Kit. The DNA extracts were amplified by polymerase chain reaction (PCR), and the PCR products were subjected to restriction enzymes to identify the C677T and A1298C genotypes. Genotype frequencies were identified and their relationship to some measures of MTX response and toxicity were evaluated. RESULTS: The 677 TT genotype frequency was higher in RA patients (15.1%) compared to the healthy control group (5.9%) (odds ratio 3.09, 95% confidence interval (CI) 1.39-6.87, p-value=0.0056). No such differences were seen with the A1298C genotypes. The frequencies of 677T and 1298C variant alleles were 0.346 and 0.296, respectively. None of the change-in-disease-activity measurements in MTX-treated patients has a significant association with the various genotypes. There was no significant association between A1298C genotypes and "œany MTX toxicity", but there was an association between C677T polymorphism and "œany MTX toxicity" (p=0.037). In addition, there was no association between both SNPs and specific MTX adverse effects. However, some haplotypes or combinations of the C677T and A1298C genotypes were associated with certain MTX side effects. CONCLUSIONS: More data from a larger number of RA patients are needed to evaluate the role of pharmacogenetic studies of MTHFR gene in predicting MTX response and toxicity.

Spinal cord infarction in giant cell arteritis associated with scalp necrosis.

Spinal cord infarction is extremely rare in patients with giant cell arteritis (GCA). There are only four case reports in the literature. We describe a 65-year-old man who presented with sudden paraplegia and back pain of 4-days duration with sensory loss below the umbilicus and bilateral scalp necrosis. Magnetic resonance imaging finding was consistent with dorsal spinal cord infarction. Biopsy of the temporal artery confirmed the diagnosis of GCA. The patient was treated with high dose of corticosteroids, which resulted in healing of the scalp ulcerations in 3 weeks, but the paraplegia was irreversible. To our knowledge, this is the first report of spinal cord infarction and simultaneous occurrence of bilateral scalp necrosis in a histopathologically proven GCA. Although literature about spinal cord involvement in GCA is very limited, cord infarction is associated with high mortality and therapeutic challenges since little is understood regarding the pathogenesis that leads to infarction.

Association of MDR1 C3435T and RFC1 G80A polymorphisms with methotrexate toxicity and response in Jordanian rheumatoid arthritis patients.

OBJECTIVES: Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1 G80A) and multi-drug resistance-1 (MDR1 C3435T) might affect MTX response and/or toxicity. The aim of this study was to find out if there is an association between those polymorphisms and MTX toxicity and/or response in Jordanian RA patients. METHOD: A genotyping approach was used to determine the studied polymorphisms in 159 RA patients. RESULTS: There was an association between RFC1 G80A and MDR1 C3435T polymorphisms with MTX toxicity. Patients with RFC1 80GG genotype were at higher risk for gastrointestinal toxicity (p = 0.036). Patients carrying at least one MDR1 3435T variant allele were at higher risk for MTX overall toxicity (p = 0.04), especially hepatotoxicity (p = 0.028). Furthermore, the distribution of RFC1 G80A polymorphism between males and females was significantly different. The variant genotype 80AA was found to be more in males than in females (60% vs. 31%) (p = 0.011). CONCLUSIONS: Our results suggest that genetic polymorphisms in methotrexate transporters affect the toxicity but not the response of MTX treatment. Further studies should be performed to have more conclusive results.

Takayasu's arteritis in Arabs.

The objective of this study was to describe epidemiological and clinical features of Takayasu's arteritis (TA) among Arab populations and to compare it to other populations. We conducted a systematic review of reports about TA from Arab countries published in English and French until 2013. All published papers were reviewed including original research and case reports. There were 197 patients (176 females) reported in 28 publications that comprised 8 original research publications (with a total of 163 patients) and 20 case reports (reporting 34 patients). These patients were from countries with a total population of approximately 80 million (Tunisia, Morocco, Jordan, Lebanon, Kuwait, Saudi Arabia, and Bahrain). The female to male ratio was 7:1. Mean age at disease onset was 28 years, and the mean delay in diagnosis was 3.5 years. Clinical manifestations are constitutional symptoms in 44 %, limb claudication in 64 %, Raynaud's in 6 %, erythema nodosum in 3.6 %, visual disturbances in 30 %, carotidynia in 7 %, neurologic manifestations in 56 %, and hypertension in 34.5 % of patients. Involvement of the aortic arch and its branches were observed in about 80 % of patients. The overall mortality was very low over a period of 5.4 years of follow-up, and the course of the disease was quite stable in about 50 % of patients. The demographical and clinical findings of TA in Arabs are similar to what has been reported from different parts of the world. A relatively long delay in diagnosis may be in part due to low awareness of a relatively rare disease.

Thiopurine S-methytransferase gene polymorphism in rheumatoid arthritis.

BACKGROUND AND AIMS: Thiopurine S-methyltransferase (TPMT) is responsible for inactivation of thiopurine drugs which are commonly used in leukemia, organ transplantation and autoimmune diseases. The gene encoding TPMT is polymorphic, and both phenotyping and genotyping studies have shown ethnic variations in gene sequence and enzyme activity worldwide. The aim of this study is to identify the most common genetic polymorphisms of TPMT in healthy Jordanian volunteers and patients with rheumatoid arthritis (RA). METHODS: A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to identify the frequency of TPMT (*2, *3A, *3B, and *3C) polymorphisms in 250 healthy Jordanian volunteers and 110 RA patients. RESULTS: Only four healthy subjects (1.6%) and one RA patient (0.9%) with variant alleles were identified in this study. Two healthy subjects had the TPMT*3A allele and the other two had the TPMT*3B allele, whereas the one RA patient had the TPMT*3A allele. No homozygous polymorphisms were detected and all genotypes detected were heterozygous (*1/*3A) (*1/*3B). None of the subjects had TPMT*2 or TPMT*3C variant alleles. CONCLUSIONS: Mutant alleles identified in this study have a low frequency. TPMT (*3A and *3B) were the only detected heterozygous alleles. No homozygous variant allele was detected. Further studies are necessary to identify other variant alleles that might uniquely occur in Jordanians.

HLA-B27 Prevalence in Arab Populations and Among Patients with Ankylosing Spondylitis.

OBJECTIVE: To investigate prevalence of HLA-B27 among general Arab populations and among patients with ankylosing spondylitis (AS), and to review published data. METHODS: The prevalence of HLA-B27 was studied among 2579 unrelated healthy Jordanians, almost equally divided among Palestinian refugees and natives of Jordan, reflecting the general population of Jordan. The prevalence of HLA-B27 was also studied among 129 patients with AS, 70 from Jordan, and the remaining 59 from Qatar. HLA typing was performed by standard 2-stage micro-lymphocytotoxicity method. We also reviewed published English language studies of HLA-B27 in Arab patients with AS and general populations retrieved through Medline and cross-reference search. RESULTS: We observed that the general prevalence of HLA-B27 among Jordanians is 2.4%; while the reported prevalence ranges between 2% and 5% among major Arab populations. The prevalence of HLA-B27 among patients with AS is 71% in Jordan and 73% in Qatar, while the reported prevalence from pooled published data from various Arab populations is 64%. CONCLUSION: From these data one can conclude that HLA-B27 is present in about 2% to 5% among major Arab populations and that its prevalence in Arab patients with AS is closer to 70%.

N-acetyltransferase-2 genotypes among patients with rheumatoid arthritis attending Jordan University Hospital.

AIM: To determine the frequency of major N-acetyltransferase (NAT2) alleles and genotypes among Jordanian patients with rheumatoid arthritis (RA). METHODS: The study was approved by the IRB of the Jordan University Hospital. An informed consent was signed by every patient. DNA samples from 150 healthy volunteers and 108 patients with RA were analyzed by polymerase chain reaction followed by a restriction fragment length polymorphism assay (PCR-RFLP) to determine the frequency of four major alleles: NAT2*4, NAT2*5, NAT2*6, and NAT2*7. RESULTS: The most prevalent genotypes are those that encode the slow acetylation phenotype. About 59.3% of the patients with RA carried the slow, 33.3% the intermediate, and 7.4% the fast-encoding genotypes. The frequency of NAT2 alleles was 0.241 (95% confidence interval [CI] 0.184-0.298) for NAT2*4, 0.449 (95% CI 0.383-0.515) for NAT2*5, 0.273 (95% CI 0.214-0.332) for NAT2*6, and 0.037 (95% CI 0.012-0.062) for NAT2*7 allele. The overall frequency of the slow acetylation genotype in patients with RA is similar to that in healthy Jordanian volunteers. However, the NAT2*5/7 genotype was found in seven patients (6.5%) with RA and was absent in Jordanian volunteers, and the z test revealed that the difference was statistically significant. This genotype constituted 10.9% of the genotypes encoding slow acetylation. CONCLUSION: The overall acetylator genotype in RA is similar to that in healthy volunteers. The overall slow acetylator genotypes do not seem to be a genetic risk factor for RA among Jordanians. However, the NAT2*5/7 genotype seems to be related to RA. The nature of this relationship needs further clarification.

Clinical characteristics and outcomes of patients with idiopathic inflammatory myopathies from Jordan 1996-2009.

To describe demographic characteristics, clinical features and outcome of Jordanian patients with idiopathic inflammatory myopathies (IIM), a retrospective chart review of all patients diagnosed with IIM at Jordan University Hospital between 1996 and 2009 was carried out. Thirty patients with IIM were identified. Female to male ratio was 1.7:1, with mean age at diagnosis 34.3 ± 9.2 (10-72) years with bimodal presentation at 21 and 49 years and a mean follow-up of 6.5 ± 5.7 years. Eleven patients had polymyositis (PM); 19 patients had dermatomyositis (DM); 1 patient had DM with malignancy; 2 patients had juvenile DM; and 2 patients had DM/PM with other rheumatologic diseases. Raynaud's phenomenon was present in 26% of patients, dysphagia in 40%, fever in 16%, arthralgia/arthritis in 26%, and dyspnea was present in 26% patients. Positive muscle biopsy and EMG were present in 81% and 92% of patients, respectively. Elevated serum creatinine kinase (CK), AST/ALT and LDH were found in 90%, 72%, and 88% of patients at presentation, respectively. Interstitial fibrosis identified on high-resolution computed tomography (HRCT) was found in 7/14 (50%) patients. Restrictive lung disease was present in 16/21 (76%), low diffusion capacity of lung of carbon monoxide (DLCO) in 10/17 (59%) and pulmonary hypertension in only 3/19 (16%) patients tested. Arab Jordanian patients with IIM showed very low prevalence of malignancy, lower mean age than previous reports, and similar other clinical, laboratory and serologic markers, and survival rate to previous reports. Of interest, we found that extra-muscular manifestations were mainly associated with dermatomyositis.

Clinical and radiological features of Takayasu's arteritis patients in Jordan.

The prevalence of Takayasu's arteritis (TA) varies greatly among world populations, and little is known about this disease in Eastern Mediterranean Arab populations. We conducted a retrospective chart review of patients diagnosed with TA from 1996 to 2008 at a single large referral center in Jordan. Eight patients (seven females, one male) with angiographically diagnosed TA were seen at the Jordan University Hospital between 1996 and 2008. All patients were of Arabic ethnicity. The age at presentation ranged from 14 to 50 years, and delay in diagnosis ranged from 1 to 10 years. Extra-vascular manifestations included nodular episcleritis, elevated liver enzymes, erythema nodosum, inflammatory-bowel-disease-like illness, Raynaud's phenomena, and constitutional symptoms. Vascular symptoms included postural dizziness, central nervous system deficits, amauroses fugax, and transient ischemic attacks. Aortic arch vessels were involved in all patients, the abdominal aorta was involved in five patients, and the renal arteries in four patients. Major clinical events including severe stroke and cardiac failure were associated with mortality in two patients. Treatment with corticosteroids and immunosuppressive agents resulted in improvement in five patients with follow-up ranging from 3 to 12 years. In conclusion, TA is seen in Arabs, and the clinical spectrum of TA in Arabs in Jordan is similar to that reported in other countries. Increased awareness of the disease may shorten the time to diagnosis and result in a more reliable estimate of disease prevalence.

Polyarthritis with chondronecrosis associated with osteonecrosis, panniculitis and pancreatitis.

Arthritis associated with panniculitis complicating pancreatitis is well described in the literature, usually associated with osteonecrosis. Chondronecrosis has not been reported before in association with pancreatitis. We report a patient with chronic pancreatitis who presented with polyarthritis, panniculitis, osteonecrosis, but in addition had clear evidence of chondronecrosis. We suggest that direct extension of noxious materials from nearby subchondral osteonecrotic bone lesion could be the cause of the osteonecrosis and one of the pathological mechanisms leading to arthritis in patients with pancreatitis.

Prevalence of cigarette smoking and khat chewing among Aden university medical students and their relationship to BP and body mass index.

To evaluate the smoking and khat chewing habits in male Aden University medical students and correlate them with blood pressure (BP), body mass index (BMI), and year of training, we randomly selected 100 students of different levels of training and measured their BP, height, and weight, and evaluated their cigarette smoking and khat chewing habits. The mean age of the whole group was 31.8 years. The mean BMI was 23.24 with a range from 22.6 in the in first year medical students to 24.7 (4.4) in 5 th year medical students (P= 0.127). The mean SBP, DBP, and MBP were 120.35, 70.47 and 87.1 mmHg, respectively, and did not change over the years of training. Preva-lence of smoking increased from 20% to 40% and khat chewing from 35% to 90% over the 5 years of training (P= 0.0003). There was a tendency for positive correlation between age and weight, BMI and frequency of khat chewing, and BMI and MBP. We found high prevalence of smoking and khat chewing among the medical students at Aden University and their prevalence increases with student seniority with no significant changes in BMI, SBP, DBP or MBP. There was a weak positive correlation between BMI with SBP, MBP and frequency of Khat chewing.

Perceived benefit after participating in positive or negative/neutral heart failure trials: the patients' perspective.

BACKGROUND: Clinical trials, the gold standard for the evaluation of new therapeutic strategies, may prove a drug to be beneficial, harmful or neutral according to its effect on the end-point(s) under study. AIMS: To study the reaction and perspective of the patients participating in a clinical heart failure trial, particularly in relation to whether the trial subsequently proved to be positive, negative or neutral. METHODS: Anonymous self-completed questionnaire was sent to 78 and returned by 70 consecutive patients 1--6 months after participating in six clinical heart failure trials. The trial was neutral or negative regarding the primary end-point in four (47 patients) of the six studies (MACH-1 trial of mibefradil, REACH trial of bosentan, CASCO trial of calcium sensitizer, ecadotril trial of neutral endopeptidase inhibitor) and positive in two (23 patients) (ICARUS Israel carvedilol study, exercise study of candesartan cilexetil). RESULTS: Most patients reported subjective global clinical benefit (78% for positive, 74% for negative or neutral trial, NS) after participating in a clinical trial. After adjustment for age, sex, level of education, previous research, perceived comprehension, and treatment allocation (active drug/placebo) in a stepwise regression model, perceived global improvement was greater in older patients (P=0.02), after participation in a positive trial (P=0.05) and in females (P=0.07). The major reason given by the patient for perceived clinical improvement was better follow-up, some believed it was due to change in medication, particularly those who had participated in a positive trial. CONCLUSIONS: More than 70% of patients participating in clinical trials of new drugs for heart failure reported perceived global improvement. Clinical improvement was greater in, but not limited to, patients who participated in positive trials. These salutary findings support the continued recruitment of patients to clinical heart failure trials.

Patient comprehension and reaction to participating in a double-blind randomized clinical trial (ISIS-4) in acute myocardial infarction.

BACKGROUND: Although randomized clinical trials are currently the standard for the evaluation of new therapeutic strategies, little attention has been paid to the viewpoint of the patients recruited to these trials. OBJECTIVES: To examine the perspective of the Israeli patient cohort who participated in the Fourth International Study of Infarct Survival, a randomized trial in acute myocardial infarction. METHODS: A patient questionnaire was mailed to 360 Israeli patients who participated in the Fourth International Study of Infarct Survival and was returned by 150 of them. Main outcome measures included patient perception of consent procedures, comprehension of the study, subjective reaction to participating in the trial, and interest in present and future trials. RESULTS: Forty (31%) of 129 patients perceived that they had full comprehension of the trial, while 64 (50%) claimed partial understanding and 25 (19%), no understanding at all. Comprehension was related to a recollected explanation of 5 minutes or more (P<.001) and to an opportunity for discussion at the time of consent (P<.001). Most patients recollected the oral explanation; fewer, the written material. Patient consent was given by 64 (43%) of 150 patients in the hope of better treatment. In 36 cases (25%), the patients felt they received better treatment because of participation in the trial. CONCLUSIONS: Despite proper attention to accepted ethical and legal standards, perceived patient comprehension in this trial in acute myocardial infarction was incomplete or lacking in a considerable number of subjects. Much progress must be made toward the goal of true informed consent in clinical trials.