Reference intervals for CTX and P1NP in a multi-ethnic Malaysian cohort.

BACKGROUND: Well defined reference intervals are central to the utility of serum C-terminal telopeptide of type 1 collagen (CTX) and N-terminal propeptide of type I procollagen (P1NP), designated as reference markers in osteoporosis, and useful for monitoring therapeutic response in that condition. This study reports the reference intervals for plasma CTX and serum P1NP in a multi-ethnic Malaysian population. METHODS: Ethnic Malay, Chinese or Indian subjects aged 45-90 years old were recruited from Selangor, Malaysia from June 2016 to August 2018. Subjects with known medical conditions (e.g., bone disorders, malnutrition, immobilisation, renal impairment, hormonal disorders) and medications (including regular calcium or vitamin D supplements) that may affect CTX and P1NP were excluded. Additionally, subjects with osteoporosis or fracture on imaging studies were excluded. The blood samples were collected between 8 a.m. and 9 a.m. in fasting state. The CTX and P1NP were measured on Roche e411 platform in batches. RESULTS: The 2.5th-97.5th percentiles reference intervals (and bootstrapped 90%CI) for plasma CTX in men (n = 91) were 132 (94-175) - 775 (667-990) ng/L; in post-menopausal women (n = 132) 152 (134-177) - 1025 (834-1293) ng/L. The serum P1NP reference intervals in men were 23.7 (19.1-26.4) - 83.9 (74.0-105.0) µg/L, and in post-menopausal women, 25.9 (19.5-29.3) - 142.1 (104.7-229.7) µg/L. CONCLUSION: The reference intervals for plasma CTX and serum PINP for older Malaysian men and post-menopausal women are somewhat different to other published studies from the region, emphasising the importance of establishing specific reference intervals for each population.

Association between bone characteristics and cardiovascular risk factors among adults in selected urban areas in Selangor, Malaysia.

INTRODUCTION: Cardiovascular disease and osteoporosis (OP) have been shown to have similar risk factors but studies have demonstrated contradictory results with regards to their associations. This study evaluated relationships between bone characteristics and cardiovascular risk factors among adults in selected urban areas in Malaysia. MATERIALS AND METHODS: A cross-sectional study was performed involving 331 subjects between 45-90 years recruited at a health screening programme. Sociodemographic and clinical characteristics were recorded. Biochemical analyses on fasting blood samples and dual energy X-ray absorptiometry scan to determine bone mineral density (BMD) were performed. RESULTS: Increased waist circumference (WC) was protective for abnormal BMD status (osteopenia and OP). Males with increased high-density lipoprotein cholesterol (HDL) were more likely to be osteoporotic. WC, fasting blood glucose (FBG) and triglyceride (TG) were positively associated with BMD at all sites but was gender specific. In contrast, WC was negatively associated with trabecular bone score (TBS) for females but this association became attenuated when adjusted for fat percentage. HDL and MetS were negatively and positively associated with BMD, respectively in males. CONCLUSION: The cardiovascular risk factors of raised WC, FBG, TG and low HDL were significantly associated with increased BMD with skeletal site and gender specific differences after adjusting for confounders. However, a higher WC was associated with a weaker skeletal microstructure reflected by lower TBS in females driven by fat percentage. A higher BMD was demonstrated among MetS individuals. These findings suggest that adiposity may have a protective effect on BMD.

Calculation of free and bioavailable vitamin D and its association with bone mineral density in Malaysian women.

INTRODUCTION: Low 25-hydroxyvitamin D [25(OH)D] levels have not been consistently associated with bone mineral density (BMD). It has been suggested that calculation of the free/bioavailable 25(OH)D may correlate better with BMD. We examined this hypothesis in a cohort of Malaysian women. MATERIALS AND METHODS: A cross-sectional study of 77 patients with rheumatoid arthritis (RA) and 29 controls was performed. Serum 25(OH)D was measured using the Roche Cobas E170 immunoassay. Serum vitamin D binding protein (VDBP) was measured using a monoclonal enzyme-linked immunosorbent assay (ELISA). Free/bioavailable 25(OH)D were calculated using both the modified Vermuelen and Bikle formulae. RESULTS: Since there were no significant differences between RA patients and controls for VDBP and 25(OH)D, the dataset was analysed as a whole. Calculated free 25(OH)D by Vermeulen was strongly correlated with Bikle (r = 1.00, p < 0.001). A significant positive correlation was noted between measured total 25(OH)D with free/bioavailable 25(OH)D (r = 0.607, r = 0.637, respectively, p < 0.001). Median free/bioavailable 25(OH)D values were significantly higher in Chinese compared with Malays and Indians, consistent with their median total 25(OH)D. Similar to total 25(OH)D, the free/bioavailable 25(OH)D did not correlate with BMD. CONCLUSION: In this first study of a multiethnic female Malaysian population, free/bioavailable 25(OH)D were found to reflect total 25(OH)D, and was not superior to total 25(OH)D in its correlation with BMD. Should they need to be calculated, the Bikle formula is easier to use but only calculates free 25(OH)D. The Vermuelen formula calculates both free/bioavailable 25(OH)D but is more complex to use.

Influences on bone mineral density in Malaysian premenopausal systemic lupus erythematosus patients on corticosteroids.

The aim of this study was to assess the bone mineral density (BMD) of premenopausal patients with systemic lupus erythematosus (SLE) on corticosteroids (CS) and to determine the influence of CS and other risk factors on BMD. A total of 98 premenopausal patients with SLE were recruited from outpatient clinics in two teaching hospitals. Risk factors for osteoporosis were determined, and BMD was measured using dual-energy x-ray absorptiometry. The mean age of the patients was 30.05 +/- 7.54 years. The mean dose of prednisolone at time of BMD measurement was 18.38 +/- 10.85 mg daily. Median duration of CS use was 2.5 years (range 0-20). Median cumulative dose of CS was 9.04 g (range 0.28-890.0). Six patients (6.1%) had osteoporosis, 41 (41.9%) had osteopenia and 51 (52.0%) had normal BMD. Lumbar spine T score correlated with cumulative CS dose (P = 0.019). Duration of CS intake correlated with femoral neck T score (P = 0.04) and trochanter T score (P = 0.008). There was no correlation between BMD and race, SLE Disease Activity Index score, smoking and self-reported calcium intake or exercise. Only 52% of these patients had normal BMD. The duration and cumulative dose of CS intake was significantly correlated to BMD, but not the other commonly assessed risk factors. These findings suggest that premenopausal patients with SLE on CS should have their BMD measured at regular intervals to fully assess their osteoporosis risk.

The association between HLA genes and radiological erosions in Malaysian patients with rheumatoid arthritis.

OBJECTIVE: To assess the relationship between the HLA-DRB1 genes with disease severity as assessed by radiological erosions in Malaysian patients with rheumatoid arthritis (RA). METHODS: In this cross-sectional study, we studied 61 RA patients who fulfilled the ACR criteria for the diagnosis of RA. HLA-DRB1 genotyping was performed by sequence specific primer (SSP) - PCR. Radiological grading and erosive score of the hands and wrists was calculated according to the Larsen-Dale method. Demographic data and treatment given to the patients were obtained from their case records. RESULTS: Fifty-six females and five males were studied from three ethnic groups. In 57 patients with erosions, rheumatoid factor was detected in 80%, HLA-DR4 in 40%, HLA-DRB1*0405 in 24% and shared epitope (SE) in 31%. The median delay in starting DMARDs was 24 months. The presence of rheumatoid factor, HLA-DR4 and HLA-DRB1*0405 were not significantly associated with a worse erosive score. Patients who possessed the SE had a higher erosive scores, compared to those who did not (p = 0.05). Concurrently, a delay in starting DMARD was associated with a high erosive score (p = 0.023, r = 0.348). However, after adjustment for the delay in starting DMARD, SE was no longer significantly associated with the erosive score. CONCLUSIONS: In these patients, the delay in starting DMARDs had a greater influence on the erosive score than SE alone. Whilst we cannot discount the contribution of the SE presence, we would advocate early usage of DMARDs in every RA patient to reduce joint erosions and future disability.

Dietary calcium and bone mineral density in premenopausal women with systemic lupus erythematosus.

The primary objective of this study was to determine the relationship between dietary calcium intake and bone mineral density (BMD) in premenopausal women with systemic lupus erythematosus (SLE) on corticosteroids (CS). The secondary aim was to identify other risk factors for osteoporosis in these patients. A cross-sectional sample of patients attending the SLE Clinic at a teaching hospital was recruited. BMD was measured using dual-energy X-ray absorptiometry. Daily dietary calcium intake was assessed using a structured validated food frequency questionnaire, in which patients were asked to estimate their food intake based on their recent 2-month dietary habits. Sixty subjects were recruited with a mean age of 33.70+/-8.46 years. The median duration of CS use was 5.5 years (range 0.08-24). The median cumulative dose of steroids was 17.21 g (range 0.16-91.37). The median daily dietary calcium intake was 483 mg (range 78-2101). There was no significant correlation between calcium intake and BMD, even after correcting for CS use. There were also no correlations between BMD and the duration of SLE, cumulative CS use, duration of CS use, smoking, alcohol intake, and SLE disease activity index score. Twenty-eight (46.7%) patients had normal BMD, 28 (46.7%) had osteopenia, and four (6.6%) had osteoporosis. Duration of SLE significantly correlated with cumulative CS dosage. In conclusion, 6.7% of these Asian premenopausal SLE women had osteoporosis and only 46.7% had normal BMD. Daily dietary calcium intake did not correlate with BMD.

Cerebral infarction and cerebral salt wasting syndrome in a patient with tuberculous meningoencephalitis.

A 38-year old female with underlying systemic lupus erythematosus was admitted with tuberculous meningoencephalitis. After an initial good response to anti-tuberculous treatment, she developed cerebral infarction and profound hyponatremia. This was due to cerebral salt wasting syndrome, which has only previously been described in 2 cases. The difficulties in diagnosis and management of this case are discussed.

HLA-DRB1 genes and susceptibility to rheumatoid arthritis in three ethnic groups from Malaysia.

Worldwide population studies have generally agreed that rheumatoid arthritis (RA) is associated with a group of HLA-DRB1 alleles which share a common amino acid sequence at residues 70-74. This represents the first study to investigate the association of HLA-DRB1 genes with susceptibility to RA amongst Malay, Chinese and Indian ethnic groups in Malaysia. One hundred and thirty three RA patients and one hundred and sixty seven healthy controls were recruited. The HLA-DRB1 alleles were studied using the Phototyping method. The subtypes of HLA-DR4 were detected by "high resolution" PCR-SSP DRB1*04 typing techniques. The prevalence of HLA-DRB1*0405 was significantly higher in Malay patients with RA than in healthy controls (28.9 vs. 8.3%, p = 0.0016, OR = 4.48, 95% CI = 1.26-16.69). Similarly, DRB1*0405 was more common in Chinese RA patients than in controls (30.0 vs. 6.7%, p = 0.0029, OR = 6.00, 95% CI = 1.67-23.48). In addition, DRB1*0901 was a predisposing factor (32.0 vs. 6.7%,p = 0.0015, OR = 6.59, 95% CI = 1.85-25.64) and *0301/04 had a protective role (4.0vs. 25.0%, p = 0.00562, OR = 0.13, 95% CI = 0.02-0.62) in Malaysian Chinese RA. RA in Indians was associated with DRB1*1001 (51.1 vs. 8.5%,p = 0.00002, OR = 11.24, 95% CI = 3.13-44.18). DRB1*0701 (13.3 vs. 42.6%,p = 0.0022, OR = 2.73, 95% CI = 1.40-5.37) may have a protective effect. Therefore, in the Malaysian population, RA is primarily associated with the QRRAA motif, and we suggest that genetic factors play a crucial role in the pathogenesis of RA, compared to environmental factors.

Traditional medicine and food supplements in rheumatic diseases.

This was a prospective survey using a standard questionnaire to determine the prevalence of use of oral traditional medicine and food supplements among patients with rheumatic diseases. Among the 141 patients surveyed, we found that 69% of the patients were consuming food supplements, 35% were using traditional medicine and 45% had used traditional medicine at some time or other. Females were more likely to use food supplements (P < 0017); especially among those with higher education (p < 0.036). There was no statistical difference between those who had ever consumed compared to those who never used traditional medicines. The Chinese were more likely than others to be using traditional medicine (p < 0.007). Vitamin C and B were the most commonly used food supplements. More than two thirds of the patients obtained their traditional medicine from non-medical personnel. More than half of them used 2 or more types of traditional medicine for more than two months. Spending on traditional medicine was noted to be modest with 73% spending less than one hundred ringgit a month for their traditional treatment. Doctors need to be aware of the possible interactions between these 'self-medications' and the conventionally prescribed medication.

Comparison of treatment regimes for lupus nephritis.

The best therapeutic choice in the treatment of lupus nephritis remains open to debate. In addition, there have been little data on the treatment of lupus nephritis in Asian patients. The objective of this study was to look at the response rate and complications of treatment given for lupus nephritis in a group of South East Asian patients with systemic lupus erythematosus (SLE). This was a retrospective, cross-sectional study of 103 patients with lupus nephritis. Detailed analysis was done on 58 patients with Class IV disease. The median time to remission was 12.1 months for azathioprine (AZA), 15.01 months for oral cyclophosphamide (CPM) and 15.25 months for intravenous (i.v.) CPM. The percentage of patients achieving remission after the first course of treatment was 42.9% with AZA, 83.3% with oral CPM and 90.9% with i.v. CPM. Overall, 41/58 (70.7%) of patients went into remission following the first course of treatment. Seventeen (41.5%) subsequently relapsed, requiring a second course of treatment. Fifty-two (50.5%) of all patients had drug-related complications from their treatment. The most frequent complication for the group was amenorrhoea (23.3% of all patients, 40% of those who had CPM previously), which was significantly more frequent in patients given CPM. In conclusion, more patients achieve remission when treated with CPM compared with AZA alone but this is associated with a higher complication rate, especially amenorrhoea.

Management of corticosteroid-induced osteoporosis.

Corticosteroid (CS) therapy is widely used in the treatment of rheumatic diseases. Osteoporosis remains one of its major complications. The risk of low bone mineral density (BMD) and fracture may be already increased in some of the rheumatic diseases, regardless of CS therapy. However, in spite of this, preventative treatment for osteoporosis in patients on CS remains low. Patients on or about to start CS use for more than 6 months are at risk of corticosteroid-induced osteoporosis (CIOP). The pathogenesis of CIOP differs from post-menopausal osteoporosis in that bone formation is said to be more suppressed compared with bone resorption. The diagnosis of CIOP can be made on clinical risk factors and may not require measurement of BMD. Many agents used in post-menopausal osteoporosis such as activated vitamin D products, hormone replacement therapy, fluoride, calcitonin and the bisphosphonates have been shown to maintain or improve BMD in CIOP. However, there are few data on the reduction in fracture rates in CIOP, but the bisphosphonates seem the most promising in this regard.

IgG anti-beta(2) glycoprotein I antibodies in Malaysian patients with antiphospholipid syndrome and systemic lupus erythematosus: prevalence and clinical correlations.

The aim of this study was to investigate the incidence of IgG anticardiolipin antibody (ACL) and IgG anti-beta(2) glycoprotein I antibody (anti-beta2GPI) positivity in patients with primary or secondary antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), to assess the association between IgG ACL and anti-beta2GPI, and the relationship between the presence of ACL and anti-beta2GPI with the clinical manifestations of APS. IgG ACL and IgG anti-beta2GPI levels were measured in 51 SLE patients, 20 patients with SLE and APS (secondary APS) and 11 primary APS patients using commercially available ELISA kits. Relationships between laboratory data and clinical manifestations of the patients were examined. The incidence of IgG ACL positivity was significantly higher in primary (36.4%) and secondary (40%) APS than in SLE (13.7%) patients (P = 0.02). The incidence of IgG anti-beta2GPI positivity was significantly higher in primary (54.5%) and secondary (35%) APS than in SLE (7.8%) patients (P = 0.0006). Mean levels of IgG ACL and anti-beta2GPI were significantly higher in the primary and secondary APS than in the SLE patients (P = 0.002 for both). A significant relationship was found between IgG ACL and IgG anti-beta2GPI (P = 0.01, R(2) = 0.56). There was a significant correlation between the presence of IgG ACL and a history of thrombosis in the combined primary and secondary APS group, but not in SLE patients. In conclusion, in this study IgG ACL and IgG anti-beta2GPI are closely related and mean levels of IgG ACL and IgG anti-beta2GPI are higher in patients with either primary or secondary APS than in SLE patients.

Mortality patterns in Malaysian systemic lupus erythematosus patients.

A retrospective analysis of the case records of 494 systemic lupus erythematosus (SLE) patients under follow-up at University Hospital, Kuala Lumpur during 1976-1990 was performed. Overall mortality was 20.2% (100 patients). The causes of death were infection (30%), renal (15%), respiratory (14%), neurological (5%), cardiovascular (7%), other causes (2%) and unknown (27%). Active SLE was a contributing factor in 19% of the deaths. The patients who died had significantly more renal disease, neurological disease, serositis or thrombocytopenia by the end of the first year of disease compared to the survivors. As in other series, infection and active SLE remain important causes of death.

The spectrum of ocular involvement in patients with systemic lupus erythematosus without ocular symptoms.

The aim of the study was to determine the spectrum of clinical ocular involvement in patients with inactive systemic lupus erythematosus (SLE) who have no ocular symptoms. Patients with a diagnosis of SLE based on the 1982 revised American College of Rheumatology criteria and with no ocular complaints were recruited from the SLE clinic. Clinical data regarding their systemic disease and disease activity were recorded and a full ophthalmic examination carried out. 52 patients of mixed ethnicity comprising of 75% Chinese, 19% Malays and 6% Indian patients were recruited. Of these, 51 (98%) were female with a mean age of 34+/-11 (range 16-74 y). 16 (31%) patients had dry eyes while corticosteroid induced glaucoma and cataract was detected in 1 (2%) and 7 (14%) patients, respectively. No patients were found to have sight-threatening ocular conditions such as cotton wool spots, vasculitis, optic neuropathy or uveitis. Patients with clinically inactive disease were found not to have sight-threatening ocular diseases that are known to be associated with SLE. Although they have no ocular complaints, nearly one-third of these patients have dry eyes. Ocular examination may be unnecessary when the disease is clinically inactive and in the absence of ocular symptoms.

Amyopathic dermatomyositis and pulmonary fibrosis.

'Amyotrophic dermatomyositis' (ADM) is used to describe a small subgroup of patients with the typical skin rash associated with dermatomyositis but without muscle involvement. Lung involvement in ADM is rare. We report on the management of a patient with ADM associated with pulmonary fibrosis at presentation, and her response to corticosteroid treatment.

Genetic and environmental factors affecting bone mineral density in large families.

This study assessed whether relatives with low bone mineral density (BMD) could be identified in five large families using historical, biochemical, and genetic markers for osteoporosis. Fifty of 65 relatives had their bone density and bone turnover markers measured, together with an assessment of their risk factors for osteoporosis. Only 33% (5/15) of siblings, 50% (6/12) of children and 43% (10/23) of nephews and nieces had entirely normal BMD. There was no difference in life-style risk factors for osteoporosis, history of previous fractures or body mass index between normal subjects and those with osteopenia or osteoporosis. Osteopenic individuals had a significantly higher than normal osteocalcin value. Within families, there was no clear association between BMD and any of the genetic markers (vitamin D receptor gene polymorphisms, COL 1A1 and COL 1A2 polymorphisms of the collagen gene), either alone or in combination. The addition of genetic markers to the other risk factors for low BMD did not improve the prediction of BMD. In conclusion, we suggest that the presence of osteoporosis in a first degree relative should be one of the clinical indications for bone density measurement as the individuals at risk would not be picked up by other methods.

The relationship between bone mineral density and ultrasound in postmenopausal and osteoporotic women.

The aim of this cross-sectional study was to use a novel method of data analysis to demonstrate that patients with osteoporosis have significantly lower ultrasound results in the heel after correcting for the effect of bone mineral density (BMD) measured in the spine or hip. Three groups of patients were studied: healthy early postmenopausal women, within 3 years of the menopause (n = 104, 50%), healthy late postmenopausal women, more than 10 years from the menopause (n = 75, 36%), and a group of women with osteoporosis as defined by WHO criteria (n = 30, 14%). Broadband ultrasound attenuation (BUA), speed of sound (SOS) and Stiffness wer measured using a Lunar Achilles heel machine, and BMD of the lumbar spine and left hip was measured using dual-energy X-ray absorptiometry (DXA). SOS, BUA and Stiffness were regressed against lumbar spine BMD and femoral BMD for all three groups combined. The correlation coefficients were in the range 0.52-0.58, in agreement with previously published work. Using a calculated ratio R, analysis of variance demonstrated that the ratio was significantly higher in the osteoporotic group compared with the other two groups. This implied that heel ultrasound values are proportionately lower in the osteoporotic group compared with the other two groups for an equivalent value of lumbar spine and femoral neck BMD. We conclude that postmenopausal bone loss is not associated with different ultrasound values once lumbar spine or femoral neck BMD is taken into account. Ultrasound does not give additional information about patterns of bone loss is postmenopausal patients but is important in those patients with osteoporosis and fractures.