Differentiation of patented crystalline glucosamine sulfate from other glucosamine preparations will optimize osteoarthritis treatment.

Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) are recommended for the medium- to long-term management of knee osteoarthritis (OA) due to their abilities to control pain, improve function and delay joint structural changes. Among SYSADOAs, evidence is greatest for the patented crystalline glucosamine sulfate (pCGS) formulation (Mylan). Glucosamine is widely available as glucosamine sulfate (GS) and glucosamine hydrochloride (GH) preparations that vary substantially in molecular form, pharmaceutical formulation and dose regimen. Only pCGS is given as a highly bioavailable once-daily dose (1500 mg), which consistently delivers the plasma levels of around 10 µmol/L required to inhibit interleukin-1-induced expression of genes involved in the pathophysiology of joint inflammation and tissue destruction. Careful consideration of the evidence base reveals that only pCGS reliably provides a moderate effect size on pain that is higher than paracetamol and equivalent to non-steroidal anti-inflammatory drugs (NSAIDs), while non-crystalline GS and GH fail to reach statistical significance for pain reduction. Chronic administration of pCGS has disease-modifying effects, with a reduction in need for total joint replacement lasting for 5 years after treatment cessation. Pharmacoeconomic studies of pCGS demonstrate long-term reduction in additional pain analgesia and NSAIDs, with a 50% reduction in costs of other OA medication and healthcare consultations. Consequently, pCGS is the logical choice, with demonstrated medium-term control of pain and lasting impact on disease progression. Physician and patient education on the differentiation of pCGS from other glucosamine formulations will help to improve treatment selection, increase treatment adherence, and optimize clinical benefit in OA.

2016 updated Thai Rheumatism Association Recommendations for the use of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis.

AIM: In June 2015, the Thai Rheumatism Association (TRA) approved an update of its recommendation for the use of biologic disease-modifying anti-rheumatic drugs (bDMARDs) and targeted synthetic (tsDMARD) in the treatment of rheumatoid arthritis (RA) to cover those currently available in Thailand (etanercept, infliximab, golimumab, rituximab, tocilizumab, abatacept and tofacitinib). METHOD: A search of the literature was performed between January 2000 and June 2015. Existing RA recommendations, in relation to the use of bDMARDs and tsDMARD, were identified and evaluated by the AGREE II instrument prior to their use as a 'guide' for developing this TRA recommendation. An additional literature search was performed in order to answer specific clinical questions that could not be found in existing guidelines. RESULT: Thirteen recommendations were developed. They covered the use of RA classification criteria, the aim of RA treatment, when to initiate bDMARDs/tsDMARD or taper or switch them to other medications, as well as monitoring these drugs during their use. In addition, specific issues including their use and vaccination, malignancies, pregnancy and lactation, and perioperative period also were addressed. Public hearings were performed at the annual meeting of the TRA and of the Royal College of Physicians of Thailand. The recommendations were distributed to other professional associations related to RA management, as well as government sectors associated with the reimbursement policy, prior to development of the final version. CONCLUSION: These recommendations will help Thai rheumatologists prescribe bDMARDs and tsDMARD more appropriately when treating RA patients.

Evidence-based recommendations for the diagnosis and management of rheumatoid arthritis for non-rheumatologists: Integrating systematic literature research and expert opinion of the Thai Rheumatism Association.

AIM: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease leading to joint damage, functional disability, poor quality of life and shortened life expectancy. Early diagnosis and aggressive treatment are a principal strategy to improve outcomes. To provide best practices in the diagnosis and management of patients with RA, the Thai Rheumatism Association (TRA) developed scientifically sound and clinically relevant evidence-based recommendations for general practitioners, internists, orthopedists, and physiatrists. METHODS: Thirty-seven rheumatologists from across Thailand formulated 18 clinically relevant questions: three for diagnosis, 10 for treatments, four for monitoring, and one for referral. A bibliographic team systematically reviewed the relevant literature on these topics up to December 2013. A set of recommendations was proposed based on the results of systematic reviews combined with expert opinions. Group consensus was achieved for all statements and recommendations using the nominal group technique. RESULTS: A set of recommendations was proposed. For diagnosis, either American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism 2010 classification criteria can be applied. For treatment, nonsteroidal anti-inflammatory drugs, glucocorticoid, and disease-modifying antirheumatic drugs, including antimalarials, methotrexate and sulfasalazine are recommended. Physiotherapy should be suggested to all patients. Tight control strategy and monitoring for efficacy and side effects of treatments, as well as indications for referral to a rheumatologist are provided. CONCLUSIONS: These evidence-based recommendations provide practical guidance for diagnosis, fundamental management and referral of patients with RA for non-rheumatologists. However, it should be incorporated with clinical judgments and decisions about care for each individual patient.

Pharmacogenetics of cyclophosphamide and CYP2C19 polymorphism in Thai systemic lupus erythematosus.

To assess whether the CYP2C19 polymorphism modified the effect of cyclophosphamide on ovarian toxicity in Thai patients with SLE. We performed a case-control study of female patients with SLE who were treated with cyclophosphamide at Ramathibodi Hospital, Bangkok, Thailand. Cases were patient who had ovarian toxicity (sustained amenorrhoea >12 months or lack of menstruation for >4 months). CYP2C19 polymorphism was genotyped using PCR-RFLP method. Logistic regression was applied to assess CYP2C19 polymorphism as an effect modifier of cyclophosphamide. Seventy-one patients with SLE were enrolled, of which 36 (59.7%) had ovarian toxicity. CYP2C19*2 allele frequencies were 27.8 and 21.4% in the ovarian and non-ovarian toxicity groups. Patients with CYP2C19*1/*1 genotype and higher cumulative dose of cyclophosphamide (>23.75 g) had the highest odds of ovarian toxicity, i.e. 11.0 (95% CI: 1.2-99.1) times higher than patients with the CYP2C19*1/*2 or *2/*2 genotypes who received less cyclophosphamide (<23.75 g). After adjusting for age at start of treatment, this risk increased to 13.6 (95% CI: 1.1-162.2). Our results suggest that a cumulative cyclophosphamide dose of 23.75 g or higher carries a twofold higher risk of ovarian toxicity and the CYP2C19*1/*1 genotype increases the risk of toxicity a further fivefold.

Risk factors of Pneumocystis jeroveci pneumonia in patients with systemic lupus erythematosus.

Pneumocystis jeroveci pneumonia (PCP) is an opportunistic infection which occurs mostly in the immune-deficiency host. Although PCP infected systemic lupus erythematosus (SLE) patient carries poor outcome, no standard guideline for prevention has been established. The aim of our study is to identify the risk factors which will indicate the PCP prophylaxis in SLE. This is a case control study. A search of Ramathibodi hospital's medical records between January 1994 and March 2004, demonstrates 15 cases of SLE with PCP infection. Clinical and laboratory data of these patients were compared to those of 60 matched patients suffering from SLE but no PCP infection. Compared to SLE without PCP, those with PCP infection have significantly higher activity index by MEX-SLEDAI (13.6 +/- 5.83 vs. 6.73 +/- 3.22) or more renal involvement (86 vs. 11.6%, P < 0.01), higher mean cumulative dose of steroid (49 +/- 29 vs. 20 +/- 8 mg/d, P < 0.01), but lower lymphocyte count (520 +/- 226 vs. 1420 +/- 382 cells/mm(3), P < 0.01). Interestingly, in all cases, a marked reduction in lymphocyte count (710 +/- 377 cells/mm(3)) is observed before the onset of PCP infection. The estimated CD4+ count is also found to be lower in the PCP group (156 +/- 5 vs. 276 +/- 8 cells/mm(3)). Our study revealed that PCP infected SLE patients had higher disease activity, higher dose of prednisolone treatment, more likelihood of renal involvement, and lower lymphocyte count as well as lower CD4+ count than those with no PCP infection. These data should be helpful in selecting SLE patients who need PCP prophylaxis.

Lupus nephritis and Raynaud's phenomenon are significant risk factors for vascular thrombosis in SLE patients with positive antiphospholipid antibodies.

This study is aimed to determine the predictors of nongravid vascular thrombosis in systemic lupus erythematosus (SLE) patients with positive antiphospholipid antibodies (SLE-aPL). A cohort of 67 SLE-aPL patients who had at least one positive test for lupus anticoagulant (LA), anticardiolipin (aCL), or anti-beta2glycoprotein-1(B2) was examined. Main outcome was the presence of vascular thrombosis. Association between thrombosis and risk factors was examined by contingency table. The odds ratio (OR) of significant predictors was determined by logistic regression. Three percent of patients were LA(+), 6% were aCL(+), 31% were B2(+), 3% were aCL(+)LA(+), 35.8% were aCL(+)B2(+), 7.5% were LA(+)B2(+), and 13.4% were positive for all tests. As for clinical manifestations, 79% had lymphopenia, 76% had lupus nephritis (LN), 41.8% had autoimmune hemolytic anemia, 34.3% had thrombocytopenia, 20.9% had abortion, and 19.4% had Raynaud's phenomenon (RP). Thrombosis occurred in 26 patients. The prevalence of thrombosis for SLE-aPL was 38.8%. Thrombosis was observed more frequently in patients with LA(+) (12 of 18) than the others (14 of 49; p = 0.01). Two-by-two table showed that oral contraceptive and LN were significantly associated with increased risk of thrombosis, while lymphopenia and antimalarials were significantly associated with decreased risk of thrombosis. Multivariate analysis confirmed that LN and RP were associated with increased risk of thrombosis (OR = 6.2 and 3.2; p = 0.005 and 0.008), while lymphopenia and antimalarials were associated with decreased risk of thrombosis (OR = 0.86 and 0.18; p = 0.02 and 0.034). LA is the strongest test to determine the risk of thrombosis in SLE-aPL. The presence of LN and RP strongly predicts thrombosis, while lymphopenia and antimalarials are protective. These findings help to identify patients who may benefit from prophylactic therapy.

Specificity and sensitivity of anti-beta2-glycoprotein I as compared with anticardiolipin antibody and lupus anticoagulant in Thai systemic lupus erythematosus patients with clinical features of antiphospholipid syndrome.

Antibodies to beta(2)-glycoprotein I (anti-beta(2)-GPI) have been reported to have stronger association with clinical antiphospholipid syndrome (APS) than anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). We investigated the sensitivity and specificity of ELISA for anti-beta(2)-GPI in Thai systemic lupus erythematosus (SLE) patients with clinical features of APS and compared the results with IgG/IgM aCL and LAC to find the test with the best association. The hospital records of 151 Thai SLE patients whose sera had been sent for either IgG/IgM anticardiolipin antibodies or lupus anticoagulant testing were reviewed. Sera of patients either without complete clinical records or those with APS-related manifestations other than vascular thrombosis and pregnancy morbidity (according to the international consensus statement on preliminary classification criteria for definite APS) were excluded. For the remaining subjects (112 patients), their sera were tested for anti-beta(2)-GPI antibody, IgG and IgM anticardiolipin, and lupus anticoagulant. The sensitivity and specificity of each method were compared by using the chi-square test. Among the 112 (74.2%) SLE patients in the study, 35 (31.3%) presented with preliminary clinical criteria for APS (i.e., vascular thrombosis and pregnancy morbidity) whereas 77 (68.7%) did not. The sensitivity and specificity of anti-beta(2)-GPI determination were 57.1 and 79.2%, respectively, whereas those of IgG aCL were 25.7 and 94.8%, of IgM aCL were 5.7 and 98.7%, and of LAC were 44.8 and 77.3%, respectively. The accuracy of the four tests showed similar association with clinical APS (accuracy of test = 72.3, 73.2, 69.6, and 68.3%, respectively). Concerning the sensitivity, specificity, and difficulty of the methods, the combination of anti-beta(2)-GPI and IgG aCL tests was the best for the diagnosis of APS in Thai SLE patients.

Vitamin D receptor gene BsmI polymorphisms in Thai patients with systemic lupus erythematosus.

The immunomodulatory role of 1,25-dihydroxyvitamin D3 is well known. An association between vitamin D receptor (VDR) gene BsmI polymorphisms and systemic lupus erythematosus (SLE) has been reported. To examine the characteristics of VDR gene BsmI polymorphisms in patients with SLE and the relationship of polymorphisms to the susceptibility and clinical manifestations of SLE, VDR genotypings of 101 Thai patients with SLE and 194 healthy controls were performed based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between VDR gene BsmI polymorphisms and clinical manifestations of SLE was evaluated. The distribution of VDR genotyping in patients with SLE was 1.9% for BB (non-excisable allele homozygote), 21.78% for Bb (heterozygote), and 76.23% for bb (excisable allele homozygote). The distribution of VDR genotyping in the control group was 1.03% for BB, 15.98% for Bb, and 82.99% for bb. There was no statistically significant difference between the two groups (p = 0.357). The allelic distribution of B and b was similar within the groups (p = 0.173). The relationship between VDR genotype and clinical manifestation or laboratory profiles of SLE also cannot be statistically demonstrated. In conclusion, we cannot verify any association between VDR gene BsmI polymorphism and SLE. A larger study examining other VDR gene polymorphisms is proposed.

Partial construction of apoptotic pathway in PBMC obtained from active SLE patients and the significance of plasma TNF-alpha on this pathway.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that affects various organs and systems. Increased apoptosis, together with defects in the uptake of apoptotic bodies, are thought to have a pathogenic role in SLE. By detection of chromatin condensation, 30% of apoptosis was detected in peripheral blood mononuclear cells (PBMC) from Thai patients with active SLE. Therefore, understanding of the molecular processes in PBMC apoptosis may allow us to gain insight into pathophysiology of SLE. Thus, genes involved in the apoptosis of PBMC from these patients were investigated ex vivo by cDNA array analysis. Seventeen apoptosis-related genes were stimulated in active SLE, more than twofold higher than in inactive SLE. These genes are classified into six groups, namely death receptors, death ligands, caspases, bcl-family, and neutral proteases and genes involved in endoplasmic reticulum stress-mediated apoptosis, such as caspase-4 and GADD153. Among those stimulated genes, tumor necrosis factor (TNF) and the TNF-receptor family were drastically up-regulated 60- and 19-fold higher than in healthy controls, respectively. Moreover, the degree of apoptosis correlated with the level of TNF-alpha in plasma, suggesting that the TNF family plays a role in the induction of apoptosis in SLE. To verify this hypothesis, PBMC from healthy individuals were treated with plasma from active SLE patients in the presence or absence of etanercept, a TNF inhibitor. In the presence of etanercept, active SLE plasma reduced the level of apoptosis to 26.43%. In conclusion, massive apoptotic death of PBMC occurred during the active stage of SLE. The molecular pathway of SLE-PBMC apoptosis was mediated at least via TNF/TNFR signaling pathway, which was confirmed by functional test of TNF-alpha in SLE patients' plasma.

Incidence and clinical correlation of anticentromere antibody in Thai patients.

Anticentromere antibodies (ACA) are useful in assessing and classifying patients with mild variant of systemic sclerosis called calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias (CREST) syndrome. From their prognostic significance, we are interested in the prevalence and disease correlation in Thai patients. A total of 3,233 serum samples of patients with any musculoskeletal symptoms were sent for antinuclear antibody determination at Ramathibodi Immunology Laboratory Service between the years 1998 and 2001. Forty sera (1.23%) were ACA positive. These sera were from 27 patients with autoimmune diseases and 13 with nonautoimmune diseases. Among autoimmune group, scleroderma was the most common diagnosis (33.3%) with limited sclerosis being the most frequent variant. The percentages of autoimmune disease were almost the same among the low-titer (1:40) and the high-titer (1:640) groups. The study suggests that the prevalence of ACA in Thai patients is low. The presence of ACA detected in patients with vague musculoskeletal symptoms does not suggest a diagnosis of CREST syndrome. Even high-titer ACA can be found in nonautoimmune diseases.

Complete deficiencies of complement C4A and C4B including 2-bp insertion in codon 1213 are genetic risk factors of systemic lupus erythematosus in Thai populations.

The complement component C4 is encoded by two genes: C4A and C4B on human chromosome 6p in the major histocompatibility complex (MHC). Most studies have linked the deficiencies in C4 with systemic lupus erythematosus (SLE) in Angio-Irish, North American, Black American, Mexican American, Australian and Japanese populations. Null alleles at either locus (C4AQ0 or C4BQ0) are relatively common in Americans occurring at the C4A and C4B loci in approximately 10% and 16% of normal individuals, respectively. In the present study, we extensively examined the possible association between homozygous C4Q0 and SLE in a large cohort of Thai populations diagnosed as SLE and further attempted to identify the genetic basis of C4Q0. One hundred and eighteen cases of SLE patients and 145 matched controls were genotyped by touchdown PCR. The results confirmed the previous studies that 5.93% (7/118) of C4 null genes: 2.54% (3/118) of C4AQ0 and 3.39% (4/118) of C4BQ0 were found in SLE patients. In contrast to other studies, we found no cases of C4 null genes in normal control (0 from 145 samples). To further investigate the genetic basis of C4 deficiency, all genomic DNAs were also analyzed for 2-bp (TC) insertion at codon 1213 in exon 29 which is a common mutation in many C4A null genes and a novel 1-bp deletion (C) at codon 522 in exon 13 that is common in most C4B null genes. Both mutation results in a flame-shift mutation and premature stop codon using sequence specific primers PCR (SSP-PCR) and direct sequencing. The results showed that there was 2-bp insertion in exon 29 of mutant C4B gene in one SLE patient carrying C4AQ0. There was no 2-bp insertion in exon 29 of both C4A and C4B genes in normal individual and the rest of SLE patients. All patients with C4AQ0 exhibited more than 5 ACR criteria including malar rash, oral ulcers, renal disorder, immunological disorder, anti-nuclear antibody, without hematological disorder. In contrast, all of C4BQ0 SLE patients showed 5 or 6 ACR criteria including hematological disorder, malar rash, oral ulcers, renal disorder, immunological disorder and anti-nuclear antibody. A patient who possesses C4AQ0 and 2-bp insertion in exon 29 of mutant C4B showed 9 ACR criteria but no discoid rash and hematological disorder. In conclusion, both C4AQ0 and C4BQ0 are the strong predisposing factors for SLE in Thais. It was supported by the absence of either C4A or C4B deletion in healthy control. We suggested that the different racial and genetic backgrounds could alter the thresholds for requirement of C4A or C4B protein levels in immune tolerance and regulation.

Reappraisal of cervical spine subluxation in Thai patients with rheumatoid arthritis.

Subluxation of the cervical spine is one of a number of devastating complications of rheumatoid arthritis. In spite of this, the features of cervical spine subluxation in Thai patients with rheumatoid arthritis have never previously been studied. We enrolled 134 patients with rheumatoid arthritis who were being followed at the rheumatology clinic, Ramathibodi Hospital, during 1978-2001. Radiological examinations were made in lateral neck flexion, extension and open-mouth views. Symptoms of neck pain and the results of relevant neurological examinations were recorded at the time of imaging. Other data on clinical features and treatments since diagnosis were reviewed retrospectively. The overall prevalence of cervical spine subluxation was 68.7%, which can be categorised into anterior (26.9%), posterior (14.9%), lateral (17.2%), vertical (16.4%) atlantoaxial and subaxial subluxation (28.4%). The percentages of cervical subluxation in patients who had suffered from the disease for 1, 5, 10 or more than 10 years were 77.8%, 64.9%, 70% and 64.7%, respectively. None of the patients had neurological deficits. No correlation between neck pain and cervical spine subluxation was established. The number of patients treated with corticosteroids was significantly higher in the subluxation group than in the non-subluxation group ( p=0.04). However, no difference in duration of treatment and cumulative dosages of steroids was displayed between the two groups. It was concluded that the prevalence of cervical spine subluxation in Thai patients with rheumatoid arthritis is much higher than the average, even in the early phase of the disease. Hence, radiological examination of the cervical spine should be included in the initial evaluation of Thai RA patients. Corticosteroid use was associated with cervical subluxation, regardless of dose and duration of treatment. The possible explanations are that steroids may directly cause ligament laxity, osteoporosis and decreasing muscle mass, which leads to accelerated subluxation, or that steroid treatments are used in more severe cases which have a higher tendency towards cervical subluxation.