Adverse drug events in rheumatoid arthritis and osteoarthritis ambulatory patients.

AIM: We aimed to determine the prevalence and characteristics of adverse drug events (ADE) in rheumatoid arthritis (RA) and (osteoarthritis) OA patients. METHOD: A cross-sectional study at rheumatology clinics, was performed by random selection of RA and OA out-patients by a research pharmacist. All suspected ADEs occurring during the last hospital visit and the subjects were identified by retrospective chart review and direct patient interview. ADE characteristics, including causative drug groups, affected organ severity and patient outcomes, were recorded. RESULTS: One hundred and forty-three patients consisting of 129 RA and 14 OA were recruited. The patients' mean ages were 54.3 ± 14.3 years and 121 (84.6%) patients were female. A total of 68 ADEs were detected in 51 patients. The prevalence and rate of ADE were 35.7% and 47.6 events per 100 patients, respectively. Thirty out of 68 ADEs (44.1%) were preventable. Disease-modifying anti-rheumatic drugs and non-steroidal anti-inflammatory drugs resulted in ADEs by 41 (59.4%) and 10 (14.5%) events, respectively. Common affected organs were skin, gastrointestinal tract and eyes which accounted for 20 (29.4%), 18 (26.5%) and eight events (11.6%), respectively. Continuation of the suspected drug was noted in 42 ADEs (61.8%), classified as severity level 1 and 2a-b, and 43 ADEs (63.2%) were completely or partially resolved during the study period. CONCLUSION: ADEs are common in RA and OA patients with prevalence of 35.7%. High exposure to potentially harmful drugs might explain the higher rate of ADE in these patients.

Primary prophylaxis for Pneumocystis jirovecii pneumonia in patients with connective tissue diseases.

OBJECTIVES: The aim of our study was to examine the primary prophylactic effect of sulfamethoxazole/trimethoprim single strength (SMZ/TM SS) against Pneumocystis jirovecii pneumonia (PCP) in connective tissue disease (CTD) patients with immune dysfunction induced by the long-term use of prednisolone. Prevalence of adverse drug reactions (ADRs) to sulfonamide in these patients was the secondary outcome. METHODS: This was a retrospective cohort study. Medical records of CTD patients who were treated with prednisolone ≥20 mg per day or equivalent doses of corticosteroid for more than 2 weeks and were followed for at least 12 weeks after receiving this dosage of corticosteroids at the Rheumatology clinic of Ramathibodi Hospital between October 2006 and September 2007 were reviewed. Information regarding clinical status, laboratory features, and clinical course of the enrolled subjects was recorded. RESULTS: There were 138 episodes of PCP risk in 132 CTD patients; 59 episodes received SMZ/TM SS, while 79 episodes did not. All 6 PCP cases developed in patients without prophylaxis with an overall incidence of 4.3%. The incidence of PCP between the 2 groups was significantly different (P = 0.038). Absolute risk reduction and relative risk reduction were 7.3% and 100%, respectively. All ADR developed in 5 systemic lupus erythematosus patients (8.5%): 4 had drug rashes and 1 had mild hepatitis. There was no correlation between the use of, or allergic reactions to, SMZ/TM and lupus flare. CONCLUSIONS: Sulfamethoxazole/trimethoprim single strength can be used effectively as a primary prophylaxis against PCP in high-risk CTD patients. Only mild ADR developed at this dosage. Further evaluations in larger groups of CTD patients are warranted.

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.

Possible protective effects of the Glu27 allele of beta2-adrenergic receptor polymorphism in Thai asthmatic patients.

The genetic polymorphisms at the 16th (Arg--> Gly) and 27th (Gln-->Glu) amino acid positions of the beta2-adrenergic receptor (ADRB2) may be linked to various asthma-related phenotypes. These include the adverse effects on lung function known to occur following the regular use of albuterol. The study aimed to determine the association between these two ADRB2 SNPs, their haplotypes and the phenotypes in Thai asthmatic patients. One-hundred and thirty asthmatic patients were genotyped at the Arg16Gly and Gln27Glu polymorphisms. Demographic data, disease severities, pulmonary function tests and medication usages were recorded for each patient. The frequencies of the Arg16 and Gln27 alleles were found to be 56.9% and 91.2%, respectively, while the linkage disequilibrium coefficient between the two SNPs was 0.36. Three haplotypes were estimated, i.e., Arg-Gln, Gly-Gln and Gly-Glu with frequencies of 148 (56.9%), 89 (34.2%) and 23 (8.9%), respectively. The mean percentages for predicted FEV1 (%FEV1) for these corresponding haplotypes were 73.5 (SD = 16.3), 72.4 (SD = 17.4) and 80.7 (SD = 13.1), respectively (p = 0.258). Additionally, the number of hospitalizations, emergency visits and inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) usages were lower in Gln/Glu subjects than for Gln/Gln genotyped patients, with values of 0% versus 11.9% (p = 0.122) for hospitalizations; 4.5% versus 18.8% (p = 0.121) for emergency visits; and 50% versus 76.6%, (p = 0.042) for ICS/LABA usages. The presence of the Glu27 allele in Thai asthmatic patients is associated with a decreased asthma severity, higher %FEV1 values, less frequent hospitalizations and emergency visits, and decreased ICS/LABA usage.

The effect of religious practice on the prevalence of knee osteoarthritis.

The aim of this study is to evaluate the effect of religious practice on the prevalence, severity, and patterns of knee osteoarthritis (OA) in a Thai elderly population with the same ethnicity and culture but different religions. A house-to-house survey was conducted in two subdistricts of Phranakhon Sri Ayutthaya province where inhabitants are a mixture of Buddhists and Muslims. One hundred fifty-three Buddhists and 150 Muslims aged >or= 50 years were evaluated demographically, physically, and radiographically. Those suffering knee pains were questioned about severity using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores and examined for their range of knee motion. Radiographic knee OA (ROA) was defined as Kellgren-Lawrence radiographic grade >or=2 while symptomatic knee OA (SOA) was defined as knee symptoms of at least 1 month in a knee with ROA. Muslims had on average a higher number of daily religious practices than their Buddhist neighbors (p < 0.001). The prevalence of knee pain and ROA was significantly higher in Buddhists than in Muslims (67.11 vs. 55.80, p = 0.02 for knee pain; 85.62 vs. 70.67, p = 0.02 for ROA). For SOA, Buddhists showed a trend towards higher prevalence than Muslims (47.71 vs. 37.32, p = 0.068). No significant difference was found when the range of motion and WOMAC scores were compared between the two groups. Muslims had a lower prevalence of OA than their Buddhists counterparts with the same ethnicity but different religious practice. The Muslim way of praying since childhood, forcing the knees into deep flexion, may stretch the soft tissue surrounding the knee and decrease stiffness and contact pressure of the articular cartilage.

Are anti-citrulline autoantibodies better serum markers for rheumatoid arthritis than rheumatoid factor in Thai population?

The aim of the study is to evaluate the prevalence of anti-citrulline antibodies (anti-CCP) versus rheumatoid factor (RF) in a cohort of Thai patients with rheumatoid arthritis (RA), a variety of rheumatic diseases other than RA and healthy controls. The association between anti-CCP and RA disease activity was also examined. Serum from 125 RA patients, 60 from other rheumatic diseases (non-RA) and 60 from healthy controls were tested for IgM RF and second generation anti-CCP. The association between anti-CCP, RF, the Disease Activity Score (DAS 28) and other relevant laboratory tests (CBC, ESR and CRP) were assessed. The sensitivity and specificity of anti-CCP antibody were 58.7 and 100% when compared with 63.5 and 98.3% for RF. These differences were not statistically significant. The anti-CCP outperformed RF in terms of the positive-predictive values (100 vs. 97.6%); however, the negative-predictive values were 72.4% for RF and 69.6% for anti-CCP. The sensitivity when either anti-CCP or RF was positive increased to 71.2%. Nine out of 45 RF-negative patients had a positive anti-CCP test. Anti-CCP was significantly correlated with parameters of inflammation, but not with DAS 28. In conclusion, although anti-CCP is better than RF in distinguishing RA from other rheumatic diseases, its cost, which is 3.3 times higher than the RF test precludes it from replacing RF as a serum marker for Thai patients with RA. The treatment decisions cannot be based on the test alone, as it has no correlation with DAS 28. Its usefulness is in patients with suspected RA who have had a negative RF test.

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.

Asymptomatic avascular osteonecrosis of the hip in new patients diagnosed as systemic lupus erythematosus in Ramathibodi Hospital.

OBJECTIVE: To determine asymptomatic avascular osteonecrosis (AVN) of the hip in new patients diagnosed as Systemic Lupus Erythematosus (SLE) in Ramathibodi Hospital. MATERIAL AND METHOD: A prospective descriptive study of new SLE patients with asymptomatic hip at the Rheumatology clinic of Ramathobodi Hospital was conducted from February 2005 to November 2005. The information of steroid and immunosuppressive drug treatment was recorded Plain film (AP and frog leg views) and MR study of both hips were analyzed. RESULTS: Twenty-two hips (II patients) were enrolled in the present study (women 100%; mean age 27.8 years; range 16-50). Four hips (2 patients, 18%) had A VN, without other abnormal imaging findigs of the hips and pelvis. Seventeen hips of nine patients hadjoint effusion; none of them had AVN. No marrow edema, secondary osteoarthritis, collapsed femoral head or pelvic insufficiency fracture in allpatients is detected. In the present study, the 2 AVN patients had longest duration of steroid treatment before MR study (105 & 99 days) and rather high cumulative dose of prednisolone or its equivalent dose (4920 & 4540 mg), compared to non-AVN patients. CONCLUSION: SLE patients without hip pain may have AVN of the hips. Joint effusion and marrow edema do not necessarily associate with early AVN, and the authors found early AVN without joint effusion. Cumulative dose and duration of steroid treatment seem to relate to AVN in the present study. However a larger number of cases, prospective clinical data, and long-term follow up will help better evaluate the prevalence of asymptomatic AVN of the hips, as well as to evaluate the benefit of MRI as a screening tool for patients at risk of AVN.

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.

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.

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.