A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis.

OBJECTIVE: Lorecivivint (LOR; SM04690), an investigational Wnt pathway modulator, previously demonstrated patient-reported and radiographic outcome improvements vs placebo in clinically relevant subjects with moderate to severe knee osteoarthritis (OA). This study's objective was to identify effective LOR doses. DESIGN: Subjects in this 24-week, Phase 2b, multicenter, randomized, double-blind, placebo (PBO)-controlled trial received an intra-articular injection of 2 mL LOR (0.03, 0.07, 0.15, or 0.23 mg), PBO, or dry-needle sham. The primary efficacy endpoints were changes in Pain NRS [0-10], WOMAC Pain [0-100], WOMAC Function [0-100], and radiographic mJSW outcomes, which were measured using baseline-adjusted analysis of covariance at Week 24. Multiple Comparison Procedure-Modeling (MCP-Mod) was performed for dose modeling. RESULTS: In total, 695/700 subjects were treated. Pain NRS showed significant improvements vs PBO after treatment with 0.07 mg and 0.23 mg LOR at Weeks 12 (-0.96, 95% CI [-1.54, -0.37], P = 0.001; -0.78 [-1.39, -0.17], P = 0.012) and 24 (-0.70 [-1.34, -0.06], P = 0.031; -0.82 [-1.51, -0.12], P = 0.022). Additionally, 0.07 mg LOR significantly improved WOMAC Pain and Function subscores vs PBO at Week 12 (P = 0.04, P = 0.021), and 0.23 mg LOR significantly improved both WOMAC subscores at Week 24 (P = 0.031, P = 0.017). No significant differences from PBO were observed for other doses. No radiographic progression was observed in any group at Week 24. MCP-Mod identified 0.07 mg LOR as the lowest effective dose. CONCLUSION: This 24-week Phase 2b trial demonstrated the efficacy of LOR on PROs in knee OA subjects. The optimal dose for future studies was identified as 0.07 mg LOR.

A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study.

OBJECTIVE: To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA). DESIGN: Subjects with Kellgren-Lawrence grade 2-3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT-OARSI Response), OA-related biomarker (P1NP, ß-CTX, and cartilage oligomeric matrix protein [COMP]), and radiographic/imaging data were collected at baseline and during 24-week follow-up. RESULTS: 61 subjects (SM04690 n = 50; PBO n = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort (P = 0.02 vs PBO). CONCLUSION: SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties. CLINICALTRIALS. GOV REGISTRATION: NCT02095548.

Morning stiffness response with delayed-release prednisone after ineffective course of immediate-release prednisone.

OBJECTIVE: To assess morning stiffness in rheumatoid arthritis (RA) patients switched from immediate-release (IR) to delayed-release (DR) prednisone. METHOD: Circadian Administration of Prednisone in Rheumatoid Arthritis-1 (CAPRA-1) is a 12-week, randomized, multicentre, active-controlled study of morning stiffness that consisted of a double-blind phase and a 9-month open-label extension. Patients receiving IR prednisone with no significant improvement after the double-blind study were switched to DR prednisone. Morning stiffness duration and median absolute and relative changes in pain and global assessment were evaluated (3, 6, and 9 months). RESULTS: In patients switched from IR to DR prednisone (n=110), statistically significant reductions in morning stiffness occurred over 3 months and were sustained for 9 months. Absolute reduction of morning stiffness was ~50 min with >40% relative reduction at each visit. Interleukin (IL)-6 levels were reduced by the same amount. Statistically significant and clinically meaningful mean reductions in morning stiffness were maintained at >67 min at each visit along with significant improvements in pain and patient global assessment. There was no evidence of tachyphylaxis seen over the 9-month study. CONCLUSIONS: Patients receiving disease-modifying anti-rheumatic drugs (DMARDs) and IR prednisone who had not had significant reductions in morning stiffness demonstrated statistically significant and clinically meaningful improvements when switched to DR prednisone.

Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database.

INTRODUCTION: Treatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs. OBJECTIVE: To assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA. SEARCH STRATEGY: The Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications. DATA COLLECTION AND ANALYSIS: Data collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e., <10 categories or ≥10 categories). The treatment effect (difference in mean change from baseline between the placebo and active therapy arms) and standardized effect size (SES) were estimated for each measure in a meta-analysis using a random effects model. RESULTS: There were 125 RCTs with data to compute the treatment effect for at least one measure; the majority evaluated non-steroidal anti-inflammatory drugs (NSAIDs), followed by opioids, glucosamine and/or chondroitin, and acetaminophen. In general, the patient-reported pain outcome measures had comparable responsiveness to treatment as shown by the estimates of treatment effects and SES. Treatment effects and SESs were generally higher for patient-reported global measures compared with clinician-rated global measures but generally similar for the WOMAC and Lequesne composite measures. CONCLUSIONS: Comparing different outcome measures using meta-analysis and selecting those that have the greatest ability to identify efficacious treatments may increase the efficiency of clinical trials of treatments for OA. Improvements in the quality of the reporting of clinical trial results are needed to facilitate meta-analyses to evaluate the responsiveness of outcome measures and to also address other issues related to assay sensitivity.

Impaired fc-mediated mononuclear phagocyte system clearance in HLA-DR2 and MT1-positive healthy young adults.

Normal individuals with an HLA haplotype containing either DR2, MT1, or B8/DR3 are more likely to have abnormally prolonged Fc receptor-mediated mononuclear phagocyte system (MPS) clearance of IgG-sensitized autologous erythrocytes than their normal counterparts without such haplotypes. Although measurement of Fc receptor binding by rosette formation and saturable IgG aggregate binding revealed no differences among groups, Fc receptor-mediated phagocytosis of IgG-sensitized bovine erythrocytes by monocytes was decreased in the DR2-positive and MT1-positive individuals. The basal in vivo MPS clearance in normal individuals may be immunogenetically determined and may reflect differences in phagocytic rates.

Disease associations of the Ia-like human alloantigens. Contrasting patterns in rheumatoid arthritis and systemic lupus erythematosus.

Increasing evidence has been obtained of the special value of Ia-like B-cell alloantisera for demonstrating disease associations with histocompatibility antigens. This was particularly evident for the study of the immunogenetics of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), two conditions frequently considered related. The profiles of antigens recognized by the alloantisera in patients from each disease group was distinctive. Two types of alloantisera were obtained that illustrated the divergence between the twod iseases. One type showed a higher than normal incidence in RA but lower than normal in SLE; the other showed a higher incidence in SLE. While these sera were not totally defined, evidence was obtained that the SLE-reactive alloantiserum related to two alleles of the major histocompatibility complex DRw2 and DRw3, while the RA-reactive alloantiserum related to a common specificity shared by cells positive for either DRw4, DRw7, or DRw10. The data indicate that immunogenetic factors are relevant to the development of both RA and SLE, but that these are distinct for each disease.

Peripheral blood Ia-positive T cells. Increases in certain diseases and after immunization.

The Ia antigens, usually expressed primarily on B lymphocytes, are found on a small percentage of normal peripheral blood T cells (average 2.6% by fluorescence and 10.8% by rosette assay). Elevated levels up to 40% by both assays were observed in a high proportion of patients with rheumatoid arthritis. Increases also were found in patients with systemic lupus erythematosus and various types of infections. The increases were evident with a specific heteroantiserum, a hybridoma reagent, and DR specific alloantisera. Normal levels were present in multiple sclerosis and an assortment of metabolic and other disorders. A rise in similarly positive T cells occurred in normal individuals after immunization with tetanus toxoid or PPD. The cells primarily involved in all of these instances were small lymphocytes, which stained relatively weakly with the fluorescent reagents and were readily distinguishable from T-cell blasts. They were found to be enriched in isolated T gamma fractions but were also found in other T cells. The accumulated evidence indicated that these cells represent an expansion of one or more subsets of T cells found in normal individuals, and that their level in the peripheral blood may serve as an index of immunological stimulation.

Association of HLA-DRw2 with autoimmune thrombocytopenic purpura.

Peripheral blood lymphocytes from 38 patients with autoimmune thrombocytopenic purpura (AITP) were tested for HLA-A, -B, and -C alloantigens. Isolated B lymphocytes from 20 of these patients were tested for HLA-DRw (Ia) alloantigens. The profile of HLA alloantigens in the patients with AITP was significantly different from that of a matched control population. The most significant finding was the presence of the HLA-DRw2 alloantigen in 75% of patients as compared with 23% in the control population, P less than 0.001, relative risk 10.0 (A relative risk of 1 would indicate no association between the presence of the antigen and the disease.) The co-occurrence of either A3 and B7 (known to be in linkage disequilibrium with DRw2) or A26 and Bw38 was significantly increased as compared with the control population (P less than 0.001). Of the patients positive for DRw2, 47% had the association A26 and Bw38 as compared with the control population association incidence of 21% (P less than 0.1). Thus, in the patient population, A26-Bw38 appears to be a haplotype that is in linkage disequilibrium with DRw2 (as presumably is the case with A3-B7). These data indicate that a predisposition to AITP is inherited with a DRw2 gene of the major histocompatibility system.

Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody.

Numerous investigators have suspected that there is a genetic predisposition to rheumatic fever (RF). In this context we have recently produced a series of monoclonal antibodies directed against B cells obtained from RF patients one of which, labeled D8/17, identifies a B cell antigen present in 100% of all RF patients studied. While the highest percentage of positive cells were exhibited by RF probands (33.5% +/- SE), the percentage of cells in unaffected siblings and parents was 14.6 and 13%, respectively. The percentage of positive cells in APSGN probands, unaffected siblings, and parents was 2.96, 3.86, and 2.8%, respectively. A low level of B cells (5-7%) bearing the D8/17 marker was seen in control patients. The segregation pattern of the phenotypes defined by the percentage of D8/17 positive cells within HLA-typed RF families are consistent with an autosomal recessive mode of inheritance not associated with the human MHC system. We postulate that these phenotypes indicate the presence of at least one necessary genetic factor for susceptibility to RF.

Liability issues in the treatment of patients with rheumatic diseases.

In clinical practice, risk management focuses primarily on concerns regarding adverse occurrences and the possibility of resulting civil litigation. Tort law, one of the major branches of civil law, is most relevant to clinical risk management. Duty, breach, causation, and damages are the four elements of the tort of professional liability, i.e., medical malpractice. Liability concerns in clinical practice commonly involve adverse drug reactions. Other potential liability concerns include informed consent, adverse outcomes, and economic considerations.

The arthritogenic properties of microbial antigens. Their implications in disease states.

The sharing of antigenic determinants between host and microbe is a common event and new microbial-tissue cross-reactions are being recognized each year. Almost every human organ has been implicated as a possible target. The purpose of this article is to examine the arthritogenic properties of these microbial antigens and to explore the mechanisms by which they induce pathologic damage and disease.

Rheumatic fever. The relationships between host, microbe, and genetics.

Acute rheumatic fever is a delayed, nonsuppurative sequela of a pharyngeal infection with the group A streptococcus. The onset of the disease is usually characterized by an acute febrile illness; however, there may be chronic involvement of the heart and/or central nervous system. The article explores the relationship between the initial infection and host-microbial interactions that may be operative in disease pathogenesis.

Assessing the impact of self-efficacy beliefs on adaptation to rheumatoid arthritis.

This article examines the influence of self-efficacy beliefs on problem-solving coping, functional disability, and psychological well-being for 101 recently diagnosed adult patients with rheumatoid arthritis (RA). Data were drawn from a longitudinal study of psychosocial adaptation to the onset of RA. Self-efficacy beliefs were associated with less functional disability assessed concurrently and 1 year later. Self-efficacy beliefs were also associated with greater use of problem-solving coping 1 year later. There was an interaction between pain and self-efficacy beliefs in the prediction of depression 1 year later: at low pain, self-efficacy beliefs were unrelated to depression, but at higher levels of pain, greater self-efficacy was related to greater depression. Finally, problem-solving coping mediated the relationship between disability and initial self-efficacy beliefs. The distinct patterns that emerge for pain, self-efficacy beliefs, and coping, with respect to functional status as compared to psychological status, are discussed.

The role of Fc gamma receptors in mononuclear phagocyte system function.

Abnormalities in host mechanisms for the handling of immune complexes (IC) may promote both tissue deposition of pathogenic complexes and interaction of complexes with other immunocompetent cells. Although immune adherence of complexes to erythrocytes may be decreased in patients with autoimmune disease, the significance of this decrease for overall immune complex handling is unclear since many IC release rapidly from the erythrocytes. Little is known about the role of complement receptors in IC uptake by phagocytes. In contrast, the observations of defective Fc gamma receptor-mediated uptake of IgG ligand-coated erythrocytes (one model for erythrocyte-bound complexes) by fixed tissue macrophages in SLE patients demonstrate the role of Fc gamma receptors in the uptake of these complexes. Although partly acquired and related to disease activity in SLE, the Fc-mediated clearance defect may also have a genetic component. Inherited differences in Fc gamma function may reflect structural polymorphisms of the involved Fc receptors. The emerging picture of Fc gamma receptor structural diversity - several different receptor families (Fc gamma RI, Fc gamma RII and Fc gamma RIII) each with different isoforms, the potential for different glycoforms and cell anchoring mechanisms, and allelic variations within the isoforms - provides the basis for structure/function relationships which have clear implications for autoimmune diseases with abnormal Fc receptor function.

Risk management in endoscopic practice.

As illustrated, the practice of gastrointestinal endoscopy is not without risks. All physicians who perform endoscopy should be mindful of the tenets of risk management and how they apply to their endoscopic practices. Retrospective review of individual endoscopic practice habits should be performed yearly and modifications made where necessary. Hospital quality assurance committees should have gastrointestinal endoscopist representation. These committees should have as a component of their responsibilities a commitment to physician education.

Social support as a double-edged sword: the relation of positive and problematic support to depression among rheumatoid arthritis patients.

This study considers social network interactions as a potential source of both stress and support for individuals coping with a chronic illness. The sample consisted of 101 recently-diagnosed rheumatoid arthritis patients. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression scale. Hierarchical multiple regression analyses examined the conjoint effects of social support and problematic interactions on symptoms of depression. Receipt of positive or helpful support from close friends and family was related to lower depression; receipt of problematic support was related to increased depression. A positive x problematic support interaction suggested that the costs of problematic support do not cancel out the benefits of positive support. Patients who reported both little support and a greater degree of problematic interactions experienced the highest level of symptoms. The findings emphasize the need to consider positive and negative aspects of support transactions conjointly in assessing their stress-reducing and health-protective potential.

A diagnostic approach to musculoskeletal pain.

Musculoskeletal pain or inflammation is one of the most common causes of primary care office visits. Musculoskeletal disorders exact a high toll in distress, disability, and direct health care costs. Given the wide range of disorders that may cause or contribute to musculoskeletal symptoms, differential diagnosis is challenging and a systematic approach is necessary. Patient history is the single most valuable source of diagnostic information, followed by a careful physical examination. The history also suggests which laboratory tests and imaging studies, if any, are indicated. The chronology, duration, and pattern of pain distribution offer clues to establishing an accurate diagnosis, along with evidence of other organ system involvement or underlying disease. Helpful distinctions are those between articular and nonarticular pain, between monarthritis and multiple joint involvement, and between inflammatory and noninflammatory conditions.