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Larry Moreland

Publications and source records attributed to Larry Moreland.

15 recordsLinked to original sources
PubMed2026

Multimodal Integration of Protein Interactomes With Genomic and Molecular Data Discovers Distinct Rheumatoid Arthritis Endotypes.

OBJECTIVE: Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease characterized by clinical and molecular heterogeneity, notably in the presence of anti-cyclic citrullinated peptide (CCP) antibodies. Patients with CCP+ RA exhibit more severe disease progression and distinct treatment responses compared to patients with CCP- RA. Although previous studies have investigated cellular and molecular differences between these subtypes, their genetic differences are understudied. METHODS: We leveraged the Rheumatoid Arthritis Comparative Effectiveness Research cohort, comprising 555 patients with CCP+/rheumatoid factor (RF)+ RA and 384 patients with CCP-/RF+ RA. Using a novel framework, we integrated a network-based genome-wide association study (GWAS) with multiomic data to uncover corresponding genetic and molecular differences. RESULTS: We uncovered a significant heritability difference between these disease groups. Network-based GWAS uncovered 14 putative gene modules, including many genes outside the HLA loci, that explained genetic differences between CCP+/RF+ and CCP-/RF+ RA. Heritability partitioning and multivariate expression analyses validated four modules, highlighting novel genetic loci underlying phenotypic differences. Module functional significance was established using multiple orthogonal cohorts, underscoring their biologic relevance. CONCLUSION: Our findings demonstrate the use of network-based approaches in revealing differential genetic risk factors underlying CCP+/RF+ and CCP-/RF+ RA. Disease-associated gene modules detected in synovial tissue were also observed in peripheral blood, indicating joint-specific molecular programs are reflected systemically. This cross-tissue concordance highlights the potential for blood-based assays to capture pathogenic mechanisms active in the joints, enabling practical patient stratification. Our findings highlight why patients with CCP+/RF+ and CCP-/RF+ RA exhibit distinct clinical courses and therapeutic responses, supporting precision-guided treatment strategy development in RA.

Humans↗
PubMed2006

Abatacept.

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Abatacept↗
PubMed2005

Unmet needs in rheumatoid arthritis.

Until the pathophysiology/etiology of rheumatoid arthritis (RA) is better understood, treatment strategies must focus on disease management. Early diagnosis and treatment with disease-modifying antirheumatic drugs (DMARDs) are necessary to reduce early joint damage, functional loss, and mortality. Several clinical trials have now clearly shown that administering appropriate DMARDs early yields better therapeutic outcomes. However, RA is a heterogeneous disease in which responses to treatment vary considerably for any given patient. Thus, choosing which patients receive combination DMARDs, and which combinations, remains one of our major challenges in treating RA patients. In many well controlled clinical trials methotrexate and other DMARDs, including the tumor necrosis factor-alpha inhibitors, have shown considerable efficacy in controlling the inflammatory process, but many patients continue to have active disease. Optimizing clinical response requires the use of a full spectrum of clinical agents with different therapeutic targets. Newer therapies, such as rituximab, that specifically target B cells have emerged as viable treatment options for patients with RA.

Antirheumatic Agents↗
PubMed2004

Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate.

OBJECTIVE: To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra. METHODS: Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed. RESULTS: Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent. CONCLUSION: Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.

Adult↗
PubMed2004

High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned.

OBJECTIVES: To review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d-penicillamine. METHODS: One hundred thirty-four patients with early (< or =18 months), diffuse systemic sclerosis (SSc) were entered into an RCT (high-dose [822 mg daily] vs low-dose [120 mg every other day] D-penicillamine) and were followed up regularly for up to 4 years. Because analysis failed to show efficacy for D-penicillamine in early diffuse SSc, all data were pooled for additional secondary analyses. RESULTS: This RCT showed that trials of potential disease-modifying interventions can be completed in SSc using the American College of Rheumatology guidelines. This RCT used an active control. After analysis, we were not able to tell whether either dose was effective or ineffective. That experience argues in favor of using placebo controls until such time as an active control can be found that truly modifies the disease. Skin score and the disability index of the Health Assessment Questionnaire (HAQ-DI) were valid predictors of outcome. Along with the physician global assessment, they also were valid measures of response. CONCLUSIONS: Even in studies that are therapeutically "negative," careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct.

Adult↗
PubMed2003

Domains of health-related quality of life important to patients with giant cell arteritis.

OBJECTIVE: To determine aspects of quality of life (QOL) important to people with giant cell arteritis (GCA). METHODS: We explored the domains of QOL affected by GCA in audiotaped focus groups. We then created an Importance Rating Questionnaire (IRQ) by constructing questions related to the domains most frequently mentioned. Of 214 GCA patients to whom the IRQ was sent, 145 (68%) responded. We calculated frequencies of responses and then ranked items by the proportion selecting the top category of importance and also according to a mean item rank. We compared the domains of QOL covered by the IRQ with those in the Short Form 12 (SF-12). RESULTS: The highest rated QOL item was "losing sight in both eyes permanently." Of the top 20 items, 12 were in domains not covered directly by the SF-12. CONCLUSION: We have identified aspects of QOL important to GCA patients. Assessment of QOL in GCA should include vision and other domains that are not included in standard QOL questionnaires.

Activities of Daily Living↗
PubMed2003

The use of rheumatoid arthritis health-related quality of life patient questionnaires in clinical practice: lessons learned.

OBJECTIVE: The utilization of health-related quality of life (HRQOL) patient questionnaires by clinical rheumatologists is limited. Yet, considerable literature exists defining the value of such data. In an effort to understand this apparent paradox, we performed a literature review and conducted a survey to describe what has been learned over the past 2 decades concerning the use of these measures in clinical care and explore the reasons for their underutilization. METHODS: A panel of rheumatologists with extensive clinical experience was convened to review the relevant literature pertaining to the use of HRQOL patient instruments in clinical practice. Additionally, a survey of all American College of Rheumatology practicing clinicians was conducted to assess the use of and beliefs about these measures. RESULTS: The literature provided evidence to support the use of HRQOL patient measures in clinical practice. Forty-seven percent of the responding rheumatologists stated that none of their patients complete HRQOL patient questionnaires. The majority of respondents (63%) reported that such information is "somewhat valuable." The most frequently reported reason for the underutilization was that such instruments "require too much staff time." CONCLUSIONS: The literature supports the potential value of HRQOL patient questionnaires in clinical practice. Few rheumatologists routinely gather such information as part of patient care. Reasons for this discrepancy between utility and use are given along with recommendations intended to help increase their utilization in clinical care.

Arthritis, Rheumatoid↗
PubMed2003

The effects of physician specialty and patient comorbidities on the use and discontinuation of coxibs.

OBJECTIVE: To examine the effects of physician specialty and comorbidities on cyclooxygenase 2-selective nonsteroidal antiinflammatory drugs (NSAIDs; coxibs) utilization. METHODS: Medical records of 452 patients from a regional managed care organization with >/=3 consecutive NSAID prescriptions from June 1998 to April 2001 were abstracted. Multivariable adjusted associations between coxib initiation and discontinuation and patient and provider characteristics were examined. RESULTS: A total of 1,142 NSAID prescriptions were written over 9,398 total patient-months of followup. Compared with patients seeing family or general practitioners, patients seeing rheumatologists (odds ratio [OR] 3.4, 95% confidence interval [95% CI] 2.1-5.7) and internists (OR 2.3, 95% CI 1.5-3.6) were significantly more likely to receive a coxib, as well as patients with a history of osteoarthritis (OR 2.6, 95% CI 1.7-3.8), gastrointestinal disease (OR 2.3, 95% CI 1.2-4.5), and congestive heart failure (OR 4.1, 95% CI 1.0-16.4). Although specialists were more likely than generalists to prescribe coxibs, only family or general practitioners were significantly more likely to selectively use coxibs among their patients with a history of gastrointestinal disease. Fifty-four percent of NSAID prescriptions were discontinued, and coxibs were significantly less likely to be discontinued than were traditional NSAIDs (OR 0.6, 95% CI 0.5-0.8). CONCLUSION: Our findings suggest significantly greater, but perhaps less selective use of coxibs among specialists, even after accounting for important covariates. The initiation and discontinuation of coxibs was influenced by physician specialty and by patient risk factors.

Aged↗
PubMed2003

Nonsteroidal antiinflammatory drug toxicity monitoring and safety practices.

OBJECTIVE: Nonsteroidal antiinflammatory drug (NSAID) related gastrointestinal (GI) and renal adverse events are commonly reported. Although published guidelines recommend periodic laboratory monitoring, NSAID safety practices of physicians have not been investigated at a population level. We examined the associations of physician specialty and patient characteristics with NSAID safety practices. METHODS: Using administrative data and medical record review from a regional managed care organization, we studied a retrospective cohort of 373 frequent NSAID users (> or = 3 consecutive NSAID prescriptions and > or = 1 month of continuous NSAID use and followup). NSAID safety measures included: complete blood count (CBC) testing, creatinine testing, use of GI cytoprotective agents, and lack of simultaneous prescriptions for different NSAID (NSAID overlap). RESULTS: The mean duration of cumulative NSAID use was 14.4 +/- 7.7 months/patient, patient age was 62.0 +/- 11.4 years, and 63% were women. About two-thirds of patients received CBC (238, 63.8%) and creatinine monitoring (263, 70.5%), one-third (120, 32.2%) were prescribed cytoprotective agents, and one-fourth (97, 26%) had at least one NSAID overlap. After multivariable adjustments, concomitant use of disease-modifying antirheumatic drugs (OR 2.5, 95% CI 1.1-5.8), longer NSAID exposure (OR 1.3, 95% CI 1.1-1.4), and a greater number of physician visits/year (OR 1.1, 95% CI 1.0-1.2) were significantly associated with receipt of a CBC. A history of hypertension (OR 2.0, 95% CI 1.2-3.2), longer NSAID exposure (OR 1.3, 95% CI 1.2-1.4), and more physician visits/year (OR 1.1, 95% CI 1.0-1.2) were significantly associated with serum creatinine testing. Rheumatologists, and to a lesser extent internists, trended toward more NSAID toxicity monitoring than family/general practitioners. However, family/general practitioners and internists were more likely to monitor creatinine than rheumatologists among patients with renal risk factors. CONCLUSION: While rheumatologists and internists trended toward more CBC and creatinine testing, visit frequency, duration of NSAID use, and comorbidities were the factors most consistently associated with safety monitoring.

Adolescent↗
PubMed2002

Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial.

OBJECTIVE: The reported frequency of scleroderma M01-R renal crisis (SRC) in diffuse systemic sclerosis (SSc; scleroderma) is 15-20%. Early use of angiotensin-converting enzyme (ACE) inhibitors has markedly improved outcome. The present analysis reexamines the prognostic factors for and outcome of SRC in a prospective cohort of patients with early diffuse SSc. METHODS: We retrospectively evaluated the cohort of SSc patients who participated in the High-Dose Versus Low-Dose D-Penicillamine in Early Diffuse SSc trial. Patients with diffuse cutaneous scleroderma were enrolled if their disease duration was <18 months. Because the trial failed to show a difference between treatment groups, the data were pooled. RESULTS: One hundred thirty-four SSc patients entered the observation period a mean +/- SD of 0.8 +/- 0.3 years after onset of SSc. SRC occurred in 18 patients a mean +/- SD of 0.9 +/- 1.1 years after entry. During a mean +/- SD 4.0 +/- 1.1 years of followup after entry, 9 of the 18 patients died (mean +/- SD 0.6 +/- 0.9 years after SRC onset). Baseline characteristics that predicted SRC included a modified Rodnan skin thickness score of >or=20 (P < 0.01), enlarged cardiac silhouette on radiograph (P = 0.04), large joint contractures (wrist, elbow, knee) (P = 0.008), and prednisone use at entry (P = 0.01). Baseline characteristics that did not predict SRC included age, sex, race, Health Assessment Questionnaire score, fist closure, handspread, lung involvement, muscle weakness, erythrocyte sedimentation rate, and platelet count. In 5 of 10 subjects for whom at least 2 sequential skin scores were available, skin scores increased significantly (P = 0.012) in the 6 months before onset of SRC. CONCLUSION: SRC occurred in 13% of patients soon (mean 11 months) after entry into the cohort. Predictors of SRC identified in this study included higher than average skin score, prednisone use at study entry, large joint contractures, and heart enlargement. Our data suggest, however, that low-dose prednisone alone was not associated with the onset of SRC, except in the appropriate clinical setting. Although ACE inhibitors and dialysis are now readily available, SRC continues to be associated with poor survival (in this study, 50% of patients with SRC died).

Adult↗