Biomedical subjects

Grace S Park

Publications and source records attributed to Grace S Park.

10 recordsLinked to original sources

PubMed2006

Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis.

OBJECTIVE: Methotrexate (MTX) is an antifolate agent that is often associated with toxicity. This study investigated whether risk genotypes for folate-dependent enzymes are associated with the toxicity of MTX in patients with rheumatoid arthritis (RA). METHODS: Blood was collected for analysis in a muticenter, cross-sectional study of RA patients who had been receiving MTX for at least 1 month prior to enrollment, and side effects occurring at the time of a single study visit were recorded. Low-penetrance risk genotypes in methylenetetrahydrofolate reductase (MTHFR) 677TT, thymidylate synthase (TSER) *2/*2 (variable number of tandem repeats), amino imidazole ribonucleotide transformylase (ATIC) 347GG, and serine hydroxymethyltransferase (SHMT1) 1420CC were measured and summed to constitute the toxicogenetic index specific to each patient. Statistical analyses consisted of logistic regression models with clustered-center effects, and associations with risk genotypes were expressed as adjusted odds ratios (ORs). RESULTS: Among 214 patients enrolled at 4 study sites, a total of 67 patients (31%) presented with a side effect (gastrointestinal event, headache, lethargy, alopecia, cough, or dyspnea). Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05). ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia. The toxicogenetic index ranged from 0 to 3 (median 1). An index of 3 was associated with an approximately 7-fold higher likelihood of having a side effect compared with an index of 0 (P < 0.01). CONCLUSION: These data suggest that a composite index of the cumulative risk genotypes in folate-dependent enzymes may be an effective means of profiling RA patients who develop side effects to MTX.

Aged↗

PubMed2006

Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus.

OBJECTIVE: To study 5 type I interferon (IFN)-inducible genes (LY6E, OAS1, OASL, MX1, and ISG15) in patients with systemic lupus erythematosus (SLE) and to correlate expression levels with disease activity and/or clinical manifestations. METHODS: Peripheral blood cells were obtained from 48 SLE patients, 48 normal controls, and 22 rheumatic disease controls, and total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by real-time polymerase chain reaction, standardized to a housekeeping gene, and summed to an IFN score. Disease activity was determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) composite. RESULTS: Each gene was highly expressed in SLE patients compared with normal controls (P < or = 0.0003) or disease controls (P < or = 0.0008 except for MX1). IFN scores were positively associated with the SELENA-SLEDAI instrument score (P = 0.001), the SELENA-SLEDAI flare score (P = 0.03), and the physician's global assessment score (P = 0.005). Compared with patients without nephritis, lupus nephritis patients had higher IFN scores (overall P < 0.0001), especially during active renal disease. IFN scores were weakly associated with neurologic manifestations. Elevated IFN scores were positively associated with the current presence of anti-double-stranded DNA (anti-dsDNA) antibodies (P = 0.007) or hypocomplementemia (P = 0.007). LY6E expression levels distinguished active from inactive lupus nephritis (P = 0.02) and were positively associated with proteinuria (P = 0.009). CONCLUSION: The 5 IFN-inducible genes were highly expressed in SLE patients, and increased levels were correlated with disease activity defined by several methods. IFN scores, or LY6E levels, were elevated in lupus nephritis patients, especially during active renal disease, and in patients with anti-dsDNA antibody positivity and hypocomplementemia. IFN scores, or LY6E levels, may be useful as a biomarker for lupus nephritis therapy.

Adult↗

PubMed2005

Increased radiographic damage scores at the onset of seropositive rheumatoid arthritis in older patients are associated with osteoarthritis of the hands, but not with more rapid progression of damage.

OBJECTIVE: To investigate the impact of patient age at symptom onset on radiographic joint damage at study entry, and on subsequent progression of damage in a cohort of patients with early seropositive rheumatoid arthritis (RA). METHODS: We studied 186 patients with RA of <15 months' duration. All patients had active disease and had not received disease-modifying antirheumatic drugs. At study entry and during followup, total Sharp scores (TSS), RA-associated joint space narrowing (RA-JSN), and erosions were determined on hand and foot radiographs. Baseline radiographs were also scored for osteoarthritis (OA)-related JSN (OA-JSN) and osteophytes. Older patients (>55 years) and younger patients (</=55 years) were compared by t-test, Mann-Whitney U test, chi-square, or Fisher's exact test. Multiple linear regression models were also constructed. RESULTS: The older group (n = 74) had a higher baseline total Sharp score (median 6.21) compared with the younger group (n = 112) (median 2.33) (P = 0.0002). This was mainly due to a higher baseline JSN score in the older group (median 3.96 versus 1.08) and not to differences in erosion score (median 0.91 versus 0.70). Disease activity and duration of RA symptoms were similar in the 2 groups, as were progression rates of the TSS, JSN score, and erosion score. At baseline, 26% of patients had osteophytes, with a prevalence of 13% in the younger age group and 50% in the older group. The presence of OA-JSN was highly correlated with the presence of osteophytes (r = 0.72). Also, increased age and RA-JSN were associated with increased severity of osteophytes and OA-JSN at baseline. Multiple linear regression analysis showed that both age and hand osteophytes contributed to the increase in baseline RA-JSN score and TSS, but not to erosion score. CONCLUSION: In a cohort of patients with early RA, an increase in the baseline RA-JSN score and TSS can be accounted for in part by the presence of hand OA.

Adult↗

PubMed2005

Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies.

OBJECTIVE: To examine the effect of folic acid on the efficacy of methotrexate (MTX) treatment in rheumatoid arthritis (RA) at 12 months in 2 phase III randomized controlled trials (RCTs) of leflunomide in which MTX was used as a comparator. METHODS: Analyses were restricted to patients randomized to receive MTX who had rheumatoid factor data. The US study recruited 482 patients with active RA; 179 received at least 1 dose of MTX, and all were mandated to receive 1 mg of oral folic acid once or twice daily. The multinational European study recruited 999 patients with active RA; 489 received at least 1 dose of MTX, and oral folic acid was not required, although 50 received folate after developing an adverse event. Because of similar entry criteria for both studies, the data for patients with available primary outcome data at week 52 were pooled (n = 668), and the patients were grouped by folic acid use (n = 225) and nonuse (n = 443). To account for the significant between-study differences in the MTX groups, baseline covariates were adjusted using propensity scores so that folic acid users could be matched with nonusers. This allowed for a comparison of differences in American College of Rheumatology (ACR) 20% improvement criteria at week 52. RESULTS: At study entry, non-folic acid users had a significantly lower mean body weight, shorter mean RA duration, and higher mean disease activity (measured by joint counts, patient's and physician's global assessments, and acute-phase reactant levels). The mean MTX dosage at week 52 was similar in the 2 RCTs. Using propensity score matching techniques, the proportion of patients achieving an ACR 20% response at week 52 averaged 17% higher in the non-folic acid group than in the folic acid group (range 15-21%). Similarly, the proportion of patients achieving ACR 50% and ACR 70% responses averaged 14% (range 12-16%) and 12% (range 9-14%) higher, respectively, in the non-folic acid group. Adverse events were reported in 93% of US study patients and 94% of the multinational study patients. Elevated liver transaminase levels (above the upper limit of normal) were reported in 29% of the US study patients (majority receiving folic acid) and 62% of the multinational study patients (majority not receiving folic acid). CONCLUSION: After using propensity scores to adjust for differences in the baseline characteristics of folic acid users and non-folic acid users, 9-21% fewer MTX-treated RA patients taking folic acid had ACR 20%, 50%, or 70% improvement at 52 weeks compared with those who did not receive folic acid in the 2 phase III RA clinical trials. As a post hoc analysis, the results of this data analysis should be considered "hypothesis generating" and an impetus for future studies regarding the effects of folic acid on the efficacy of MTX in RA.

Adult↗

PubMed2005

Telephone reminder calls increased response rates to mailed study consent forms.

BACKGROUND: This study assessed the impact of follow-up reminder phone calls on response rates to a mailed consent form packet. METHODS: Patients with rheumatoid arthritis were invited to enroll in a study by signing and returning consent forms by mail. Patients not returning completed study consent forms were called and reminded to return the signed consent forms. RESULTS: Among 724 mailed consent form packets, 376 (52%) were returned without further follow-up. Follow-up reminder calls were made to 220 of the 348 patients who did not return signed consent forms. Among subjects contacted by phone, 67 (31% of those called) returned signed consent forms. CONCLUSION: Follow-up reminder phone calls raised the overall consent rate of 52 to 61%, suggesting that they can be an effective technique in increasing response rates.

Arthritis, Rheumatoid↗

PubMed2005

Responsiveness of the SF-36 and the Health Assessment Questionnaire Disability Index in a systemic sclerosis clinical trial.

OBJECTIVE: This study compares the responsiveness to change of the Medical Outcomes Study Short Form Health Survey (SF-36), a measure of health related quality of life (HRQOL), and the Health Assessment Questionnaire Disability Index (HAQ-DI), a function instrument, in a randomized clinical trial for treatment of systemic sclerosis (SSc). METHODS: A phase 2/3, multicenter, prospective, placebo controlled trial was conducted to evaluate human recombinant relaxin treatment in patients with diffuse SSc over 24 weeks. At baseline, subjects had stable, moderately severe, diffuse SSc of disease duration < or = 5 years, modified Rodnan skin score > or = 20, serum creatinine < 2.0 mg/dl, percentage forced vital capacity (% FVC) predicted > or = 50%, and % DLCO predicted > or = 40% and were not receiving concomitant disease modifying therapies. Internal consistency reliability of multi-item scales was estimated using Cronbach's alpha. Responsiveness to change of the SF-36 and HAQ-DI was computed between Weeks 0 and 24. Subjects were classified as unchanged or having a meaningful change in 4 different external measures: Change in (1) skin score > or = 30%; (2) % FVC predicted of > or = 15%; (3) self-reported patient global assessment by visual analog scale (VAS) > or = 20%; and (4) physician global assessment by VAS of > or = 20%. Responsiveness indices were computed and Cohen's effect size criteria were used to assess the magnitude of change. RESULTS: A total of 239 patients participated in this trial, with 196 completing the 24 week trial. Cronbach's alpha for the SF-36 scales ranged from 0.76 to 0.93 and for the HAQ-DI ranged from 0.69 to 0.91 (good to excellent). The SF-36 had a larger magnitude of responsiveness in overall disease (patient and physician global assessment) compared to the HAQ-DI, while the HAQ-DI had a larger magnitude of responsiveness in clinical measures (i.e., change in skin score and % FVC predicted) than the SF-36. CONCLUSION: These data support inclusion of both the SF-36 and HAQ-DI as outcome measures in future clinical trials of diffuse SSc.

Adult↗

PubMed2004

Classifying structural joint damage in rheumatoid arthritis as progressive or nonprogressive using a composite definition of joint radiographic change: a preliminary proposal.

OBJECTIVE: To categorize radiographic joint damage as progressive or nonprogressive in individuals with rheumatoid arthritis (RA) participating in clinical studies. METHODS: Using the total Sharp radiographic damage score, erosion score, and joint space narrowing (JSN) score for 751 serial films of the hand/wrist and forefoot obtained from 190 patients with early RA during 6-60 months of followup (mean 31 months), various threshold values for progression of joint damage were evaluated singly and in various combinations. For each patient, the progression rate was estimated from the linear regression line for all available radiographic time points. After preliminary screening, 23 candidate definitions were tested to select a definition that discriminated well between radiographic progression and radiographic nonprogression. RESULTS: The definition selected describes radiographic nonprogression in individual patients as an increase of < or =0.1 in the standardized response mean of the trimmed population (the central 95% of patients) for > or =5 of 6 change measures (erosion scores and JSN scores for the fingers, wrists, and feet). Using this definition, 59% of the 190 patients with early RA were defined as having nonprogressive radiographic damage. Moreover, 95% of 95 patients with progression of the total Sharp score at or below the median and 24% of 95 patients with progression of the total Sharp score above the median were defined as having nonprogressive joint damage (chi(2) = 98, P < 0.0001), as were 97% of patients in the lowest quintile of total Sharp score progression rates and none of the patients in the highest progression quintile. Patients defined as nonprogressors had significantly lower baseline levels of C-reactive protein and lower erythrocyte sedimentation rates compared with patients defined as progressors, and those patients in the nonprogressive joint damage group more frequently had American College of Rheumatology 20% and 50% improvement criteria responses, "good" improvements (decrease of > or =1.2) in the Disease Activity Score, and > or =50% decreases in the swollen joint counts during the first 2 years of followup. CONCLUSION: RA joint damage in an observational cohort can be classified as progressive or nonprogressive with the use of a composite definition. Validation and/or refinement of this definition is needed by utilizing the data from controlled clinical trials that compare placebo with active treatment.

Antirheumatic Agents↗

PubMed2004

Dating the "window of therapeutic opportunity" in early rheumatoid arthritis: accuracy of patient recall of arthritis symptom onset.

OBJECTIVE: A "window of therapeutic opportunity" has been hypothesized to be present in early rheumatoid arthritis (RA). To determine the date of this window, we must know the symptom-onset date of the RA. Patients participating in an observational study of early aggressive rheumatoid factor (RF) positive RA were evaluated to assess the accuracy of their recall of symptom-onset date by comparing the onset date they reported at the first visit with that reported on subsequent 6-monthly questionnaires. METHODS: One hundred eighty-six patients with early RA (at entry: median disease duration 5.8 mo, mean RF 413.8 +/- 630.7 IU/ml, 20.6 +/- 10.9 swollen and 23.7 +/- 13.4 tender joints) completed a self-reported mailed questionnaire every 6 months for up to 5 years. As a part of each questionnaire, patients were asked to recall their RA symptom-onset date. These dates were then compared to the dates reported on the initial questionnaire. RESULTS: Thirteen months after symptom onset (i.e., about 6 mo after study entry) 61% of patients recalled the symptom-onset date (within 1 mo) that they had reported at baseline; the proportion decreased to 39% at 31 months and 25% after 70 months. During this period, the proportion overestimating RA duration remained about 20%, but the proportion underestimating it increased from 23% at 13 months to 39% at 31 months, and to 50% after 56 months. Patients with longer disease duration, less disease activity, and higher pain levels tended to be less accurate. CONCLUSION: Accuracy of recall of RA symptom-onset date by patients tends to decline over a period of 5 years. This should be taken into consideration when enrolling patients, when interpreting the findings of early RA clinical trials, and when attempting to ascertain the presence of a window of therapeutic opportunity.

Arthritis, Rheumatoid↗

PubMed2003

Correlation of single time-point damage scores with observed progression of radiographic damage during the first 6 years of rheumatoid arthritis.

OBJECTIVE: Aggressive treatment of early rheumatoid arthritis (RA) is recommended to prevent irreversible joint damage. We evaluated the usefulness of single time-point joint radiographs for deciding whether early RA is erosive or nonerosive. METHODS: In an observational study, 179 patients with recent onset of RA symptoms (median 5.1 mo), positive rheumatoid factor, and active polyarthritis had 2 to 8 radiographic observations of hands, wrists, and forefeet during 6 to 60 months of followup. Linear regression lines for all available radiographs were used to determine progression rates of total Sharp score (TSS), erosion score (ES), and joint space narrowing score (JSNS) of each patient. RESULTS: Using the average of 2 readers' scores, intraclass correlation coefficient was 0.97 and smallest detectable difference was 3.07 for ES, 0.93 and 7.52 for JSNS, and 0.90 and 12.71 for TSS. Mean progression rates per year were 1.20 (ES), 0.67 (JSNS), and 1.85 (TSS). Single time-point radiographs taken within 6 months of symptom onset did not correlate with progression rates (r = 0.01 to 0.07); between 7 and 18 months correlations were weak (r = 0.23 to 0.35), but were better for ES between 19 and 72 months (r = 0.60 to 0.81). Among 53 patients (31%) with no progression of TSS, only 10 of them had zero scores at baseline. Among all 630 radiographs with TSS > or = 1, 25% were associated with progression rates < or = 0. CONCLUSION: Erosion scores of single radiographic examinations done > 18 months after onset of RA symptoms correlated with progression rates, but earlier radiographs did not sufficiently predict erosive or nonerosive status to guide disease modifying antirheumatic drug treatment decisions.

Adult↗

PubMed2002

Autoantibodies in early seropositive rheumatoid arthritis, before and during disease modifying antirheumatic drug treatment.

OBJECTIVE: Autoantibodies observed in patients with rheumatoid arthritis (RA) during clinical trials of immunomodulating agents may cause concern about possible induction of autoimmunity by the therapeutic intervention. We determined the frequency and variability of selected autoantibodies in patients with early rheumatoid factor (RF) positive RA during a prospective observational study. METHOD: The study cohort consisted of 276 patients with active RA and with RF > or = 40 IU, who were enrolled between January 1, 1993, and April 1, 2000, before starting disease modifying antirheumatic drug (DMARD) therapy (average duration of symptoms, 7 mo). During an average of 3.5 years followup, a panel of autoantibodies was determined at entry, 6 months, 12 months, and yearly thereafter, in addition to routine clinical, radiographic, and laboratory assessments. After enrollment, patients were treated with DMARD at the discretion of their rheumatologists. RESULTS: At entry before any DMARD therapy, antinuclear antibody (ANA; by HEp-2) values were negative in 31%, borderline (8 IU/ml) in 26%, and > 8 (mean 65.5 IU/ml) in 41%. Tender and swollen joint counts, Disease Activity Score, and RF values were significantly higher in those with ANA > 8. During followup 726 paired serial specimens were available; 12.5% changed from negative to positive ANA and 12.3% from positive to negative. Additional autoantibodies were present in specimens of 20% of the subjects; 8% had 2 and 1.4% had 3 other autoantibodies. Anti-dsDNA was detected in 13 (5.5%) patients; 4 changed from negative to positive and one from positive to negative. SSA IgG and SSB IgG autoantibodies were both present in one of these patients. Ribosomal P protein autoantibodies were noted in 2 other patients, but Sm (Smith) and uRNP/snRNP IgG autoantibodies were not present in any patient. No patient had a diagnosis of systemic lupus erythematosus. Antithyroid peroxidase (20 patients), parietal cell (15), smooth muscle (14), reticulin (9), mitochondrial (5), striational (2), SSB (2) and SCL-70 (1) autoantibodies were detected in some specimens. Seven patients were diagnosed with hypothyroidism, one with chronic thyroiditis, one with hepatitis C, and 9 with malignancies. CONCLUSION: In patients with early RF positive RA the frequent occurrence of autoantibodies before and during treatment with standard DMARD may make it difficult to attribute their presence to new therapies.

Adult↗