Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
8995289 Up-regulation of the alpha2-macroglobulin signaling receptor on rheumatoid synovial fibrob 1997 Jan 3 In the present study, we demonstrate that the alpha2-macroglobulin (alpha2M) signaling receptor is up-regulated on rheumatoid synovial fibroblasts. In rheumatoid cells, 125I-alpha2M-methylamine bound to two sites; namely, one of high affinity (Kd approximately 52 pM) and the second of lower affinity (Kd approximately 9.7 nM). In normal synovial fibroblasts only one site for 125I-alpha2M-methylamine (Kd approximately 5.36 nM) was present. Receptor-associated protein did not inhibit the binding of alpha2M-methylamine to the high affinity binding sites, but it caused a 70-80% reduction in its binding to low affinity binding sites establishing its identity as the low density lipoprotein receptor-related protein/alpha2M receptor. Binding of alpha2M-methylamine to rheumatoid but not normal synovial fibroblasts caused a rapid rise in inositol 1,4,5-trisphosphate synthesis with a peak reached within 10 s of ligand exposure. Concomitantly, rheumatoid but not normal cells showed a rise in intracellular Ca2+. Pretreatment of rheumatoid cells with Receptor-associated protein or pertussis toxin did not affect the alpha2M-methylamine-induced increase in intracellular Ca2+. These are characteristic properties of ligation by alpha2M-methylamine of the alpha2M signaling receptor but not the lipoprotein receptor-related protein/alpha2M receptor. Binding of alpha2M-methylamine to rheumatoid synovial fibroblasts significantly increased the synthesis of DNA compared with normal synovial fibroblasts treated similarly.
9801212 Total hip arthroplasty with cement in patients who have rheumatoid arthritis. A minimum te 1998 Oct One hundred and six consecutive total hip arthroplasties with cement were performed by one surgeon, at least ten years before the time of the present clinical and radiographic review, in seventy-five patients who had adult-onset rheumatoid arthritis. Two patients (three hips) were lost to follow-up. Seven (7 per cent) of the remaining 103 hips were revised. The revisions were performed because of infection (three hips), dislocation (two hips), or aseptic loosening (two hips). Of the ninety-eight hips that were not lost to follow-up or revised because of infection or dislocation, eight (8 per cent) had radiographic loosening of the acetabular component and two (2 per cent) had radiographic loosening of the femoral component. Although the prevalence of radiographic loosening of the acetabular component was four times greater than the prevalence of radiographic loosening of the femoral component, the prevalence of revision because of aseptic loosening of the acetabular component was identical to that for the femoral component (one component each). These results compared favorably with those of total hip arthroplasty with cement, performed by the same surgeon, for the treatment of other diagnoses. Loosening of the acetabular component was significantly associated with a younger age at the time of the index operation (p = 0.03) and with acetabular osteolysis (p = 0.0006). Of forty-eight hips in thirty-two patients who survived for at least ten years, 96 per cent (forty-six hips) were considered by the patients to have a satisfactory result. At the time of the latest follow-up, twenty-four (75 per cent) of the patients had no pain in the hip. Although eighteen patients (56 per cent) could walk without support at a minimum of ten years after the operation, we found that the functional results for patients who had rheumatoid arthritis were inferior to those observed for patients who had had a total hip arthroplasty with cement, performed by the same surgeon, for the treatment of other diagnoses.
9297577 Cyclooxygenase inhibitors enhance the production of tissue inhibitor-1 of metalloproteinas 1997 Aug OBJECTIVE AND DESIGN: We investigated the influence of cyclooxygenase inhibitors against the production of tissue inhibitor-1 of metalloproteinases (TIMP-1) and pro-matrix metalloproteinase 1 (proMMP-1) in rheumatoid arthritis (RA) synoviocytes. MATERIAL: Synovial fibroblasts from RA patients were used. TREATMENT: The cells were treated with recombinant human interleukin 1 beta (rhIL-1 beta) (100 ng/ml) and/or indomethacin (0.1, 1, 10 microM) and diclofenac (0.1, 1, 10 microM) and/or prostaglandin E2 (PGE2) (1, 10 microM) for 72 h. METHODS: The amounts of TIMP-1, proMMP-1 and PGE2 was measured by enzyme linked immunosorbent assay (ELISA). Statistical significance was tested with Student's t-test and Dunnett test. RESULTS: RhIL-1 beta augments the production of TIMP-1 and proMMP-1 in synovial fibroblasts from RA patients, and this IL-1-induced production of TIMP-1 and proMMP-1 was further enhanced by treatment with the cyclooxygenase inhibitors, indomethacin and diclofenac. Exogenous PGE2 significantly suppresses indomethacin- and diclofenacenhanced TIMP-1 and proMMP-1 production. CONCLUSION: PGE2 down-regulates the production of TIMP-1 and proMMP-1 in RA synoviocytes, and cyclooxygenase inhibitors regulate the production of TIMP-1 and proMMP-1 through the inhibition of PGE2 production in inflammation.
9308131 An empirical comparison of two semi-parametric approaches for the estimation of covariate 1997 Sep 30 We conducted a simulation study to compare two semi-parametric approaches for the estimation of covariate effects from multivariate failure time data. The first approach was developed by Wei, Lin and Weissfeld (WLW) and the second by Liang, Self and Chang (LSC). Based on the simulation results we recommend Wei, Lin and Weissfeld's method for the situations with identical covariates and high correlations between the failure times. When the covariates are independent, LSC produces smaller mean squared errors than WLW, although at the expense of larger bias. We also compared four computer programs for implementing Wei, Lin and Weissfeld's approach: a FORTRAN program, MULCOX2; a SAS macro; the coxph function in S-plus, and a specialized software package for complex survey data (SUDAAN). Our comparison indicates that for large data sets, the speeds of the SAS macro and coxph are comparable, while MULCOX2- and SUDAAN took longer to run. However, MULCOX2 and coxph function in S-plus have the advantage of allowing time-dependent covariates, and SUDAAN has the advantage of handling complex survey data.
11409155 How do the biologics fit into the current DMARD armamentarium? 2001 Jun Most disease modifying antirheumatic drugs (DMARD) are discontinued within 5 years because of loss of clinical efficacy or toxicity. As a result, there has been a concerted effort to develop new immunomodulatory agents, particularly biological agents, that block the putative proinflammatory cytokines. Among the agents developed thus far, inhibitors of tumor necrosis factor (TNF) have shown perhaps the greatest promise as therapeutic agents for rheumatoid arthritis (RA). Two TNF-blocking agents, etanercept (Enbrel) and infliximab (Remicade), have been approved in the US and more recently in Europe, for the treatment of patients with RA. The results of randomized placebo controlled trials have shown that both agents significantly decrease the intensity of synovitis and prevent or retard the progression of cartilage destruction, especially when combined with methotrexate. Their side effect profiles appear to be acceptable, although rare cases of lupus-like diseases and of severe infections have been reported. Although the early clinical experience with these agents has been encouraging, their longterm safety and continuing efficacy in the general population with RA, as well as in high risk patient subsets (i.e., patients with malignancies or chronic infections), remain to be determined. In addition, the costs of these newer agents must be justified on clinical grounds. Because of the questions still surrounding these new treatment principles, several consensus conferences have been held in Europe and the US to address the role of the new biologicals in the current RA armamentarium.
11165996 Cyclooxygenase-2: a major therapeutic advance? 2001 Jan 8 The introduction of the highly selective cyclooxygenase-2 (COX-2) inhibitors (Coxibs) has resulted in the greatest new drug use ever. The hypothesis on which these drugs were developed was that COX-2-specific inhibitors would retain the advantageous aspects but restrict the deleterious effects of conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Current practice and evidence suggests that bleeding from the gastrointestinal tract is reduced to the level of placebo and that dyspepsia persists, and in other areas (particularly renal side effects), COX-2-specific inhibitors still have classic NSAID problems.
9476127 Elevated factor J levels in synovial fluid from patients with inflammatory arthropathies. 1997 Dec Factor J (FJ) is a complement inhibitor that is able to regulate in vitro both the classical and alternative human complement pathways. In the search of its biological significance, we have analyzed FJ levels in synovial fluid from patients with different arthropathies, in which IL-6 levels had been previously measured. The pathologies included in this study were: rheumatoid arthritis (RA) (n = 21), crystal deposition diseases (CDD) (n = 6), osteoarthritis (OA) (n = 23), spondyloarthritis (SpA) (n = 3) and other inflammatory arthropathies (OIA) (n = 4). We found a good correlation between IL-6 and FJ levels (r = 0.33, p = 0.0132) in the 57 processed samples. Synovial fluids had high levels of IL-6 (median: 3000 pg/ml). Besides, we found that FJ levels were elevated (241 +/- 429 micrograms/ml) when compared with NHS (5.32 +/- 2.82 micrograms/ml). Considering OA patients as control group for non-inflammatory situation, we found that FJ levels were significantly elevated in inflammatory patients only if RA patients were excluded. Furthermore, there were also significant differences with CDD patients. In addition, we have examined the presence of this inhibitor in synovial fluid by Western blot after running gels at acid pH and electrophoretical transference at the same pH. In these experiments, we evidenced the presence of a cationic protein immunoreactive with polyclonal and monoclonal anti-FJ antibodies. In conclusion, FJ levels are elevated in pathological synovial fluids. FJ could be an acute phase reactant as other molecules present in the synovial fluid, or could be shed from extracellular matrix as a consequence of the high enzymatic activity present in the articular fluid or as a response to the inflammatory stimulus.
11409154 Conventional DMARD options for patients with a suboptimal response to methotrexate. 2001 Jun Methotrexate (MTX) is one of the disease modifying antirheumatic drugs (DMARD) commonly used to treat rheumatoid arthritis (RA). However, MTX therapy alone rarely results in remission and frequently does not even produce 50% improvement. Therefore, over the course of their disease, many patients will require additional therapy to manage their clinical symptoms. A number of treatment options have proven effective for such patients, most of which entail the continuation of MTX therapy and the addition of other DMARD. Although the combination of MTX and hydroxychloroquine (HCQ) is the one most commonly used in the US, many clinicians (particularly in Europe) prefer the combination of MTX and sulfasalazine. In addition, excellent data now exist for the triple combination of MTX, HCQ, and sulfasalazine in patients who have had a suboptimal response to MTX, as well as in those with early or well established disease. Other combinations, including MTX + cyclosporine or leflunomide, have also been helpful in some patients. Most recently, the tumor necrosis factor blockers, etanercept and infliximab, have successfully been used to treat a number of patients resistant to MTX. The combination of MTX with DMARD or biological agents with different mechanisms of action greatly expands the treatment options for patients with RA.
9186666 Rheumatoid factor autoantibodies in health and disease. 1997 Apr 5 Recent advances in molecular biological and human cell hybridization technology have significantly advanced the knowledge of mechanisms that underlie human rheumatoid factor (RF) production. These advances have provided insight into the etiopathogenesis of synovial inflammation and lymphocyte recruitment in rheumatoid arthritis (RA) joints. We have examined the mechanisms that lead to RF production in RA patients and those that regulate RF production in normals. The studies revealed structural features that distinguish RF produced in normals from those produced in RA synovial tissue. There are significant differences in the use of VL and VH genes between the two RF populations. Furthermore, IgV genes encoding synovial RF in RA have extensive evidence for nucleotide changes, leading to amino acid replacement in the complementarity determining regions (CDRs). In addition, RF produced in RA synovia show evidence for affinity maturation, isotype switch to IgG RF, and repertoire shift indicative of a continued recruitment of B cells. Together with computer modeling and crystallographic studies, our data suggest that the mechanisms that operate on RF selection in RA synovia are similar to immune responses to exogenous antigens. In contrast, RF established from human immunized donors (HID) are characterized by a very low ratio of replacement to silent (R:S) nucleotide changes in the CDR1+2. In addition, there is little increase in affinity with increasing numbers of mutations. There is thus evidence for regulatory mechanisms that limit affinity maturation of RF in normals.
10505521 Short musculoskeletal function assessment questionnaire: validity, reliability, and respon 1999 Sep BACKGROUND: A short questionnaire on functional status was designed for use in community-based outcome studies and in the management of individual patients who have musculoskeletal disease. As most musculoskeletal care is delivered in community practices, short, validated instruments are necessary to perform clinical studies on the effectiveness of treatment in this setting. METHODS: A forty-six-item questionnaire was created as an extension of the work to develop the longer, 101-item Musculoskeletal Function Assessment (MFA) questionnaire. The Short Musculoskeletal Function Assessment (SMFA) questionnaire consists of the dysfunction index, which has thirty-four items for the assessment of patient function, and the bother index, which has twelve items for the assessment of how much patients are bothered by functional problems. The SMFA questionnaire was evaluated for reliability, validity, and responsiveness in a population of 420 patients who had a musculoskeletal disease or injury. RESULTS: The SMFA questionnaire demonstrated excellent internal consistency and stability, with most values greater than 0.90. Content validity for the dysfunction and bother indexes was supported with very little skew (less than 1.00), few ceiling effects (less than 5 percent), and no floor effects. Convergent validity was supported with significant correlations between the SMFA dysfunction and bother indexes and the physicians' ratings of patient function (for example, activities of daily living, recreational and leisure activities, and emotional function [rho > or = 0.40]) and standard clinical measures (for example, grip strength and walking speed [r > or = 0.401). Convergent and discriminant construct validity of the SMFA indexes were demonstrated (p < 0.01) in comparisons with clinical, demographic, Short Form-36 (SF-36), and life-change data. The responsiveness of the SMFA questionnaire to change over time was demonstrated with standardized response means ranging from moderate (0.76) to large (-1.14) for patients who had changes in health status. CONCLUSIONS: The SMFA questionnaire may be used for clinical assessments of the impact of treatment in groups of patients who have musculoskeletal disease or injury. It also may be used in clinical settings to provide reliable and valid assessments of the health status of an individual patient.
11197598 T cell chemokine receptor expression in human Th1- and Th2-associated diseases. 2000 The interaction between chemokines and their receptors is an important step in the control of leukocyte migration into sites of inflammation. Chemokines also mediate a variety of effects independent of chemotaxis, including induction and enhancement of Th1- and Th2-associated cytokine responses. Recent studies have shown that human Th1 and Th2 clones, activated under polarizing conditions with polyclonal stimuli in vitro, display distinct patterns of chemokine receptor expression: Th1 clones preferentially express CCR5 and CXCR3, while many Th2 clones express CCR4, CCR8 and, to a lesser extent, CCR3. These differential patterns of chemokine receptor expression suggest a mechanism for selective induction of migration and activation of Th1- and Th2-type cells during inflammation and, perhaps, normal immune homoeostasis. Studies have begun to examine T cell chemokine receptor expression in vivo to determine the relevance of these in vitro observations to human Th1- and Th2-associated diseases. In this review, we critically examine recent reports of T cell chemokine receptor expression in human autoimmune disorders (multiple sclerosis and rheumatoid arthritis) and atopic disorders (allergic rhinitis and asthma) which are believed to arise from inappropriate Th1- and Th2-dominated responses, respectively.
10225538 Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can w 1999 Apr Nonsteroidal antiinflammatory drugs (NSAID) are effective for the relief of pain and inflammation, yet their use is tempered by the development of side effects, primarily in the gastrointestinal (GI) tract. It is now known that inhibition of the enzyme cyclooxygenase (COX) is the principal mechanism for both the efficacy and the toxicity of NSAID. Recent research has shown that COX exists as at least two isoenzymes, COX-1 and COX-2. Compelling evidence suggests that COX-1 synthesizes prostaglandins that are involved in the regulation of normal cell activity (including G1 cytoprotection), whereas COX-2 appears to produce prostaglandins mainly at sites of inflammation. These findings led to the search for compounds that would inhibit COX-2 without affecting COX-1. Several agents are under investigation in this new therapeutic category, including celecoxib (SC-58635). Celecoxib was developed as an antiinflammatory and analgesic agent, and has been studied in preclinical studies and in clinical trials. This paper focuses on the results of 5 key clinical trials of celecoxib: an efficacy trial in dental pain, a 2 week osteoarthritis (OA) efficacy trial, a 4 week rheumatoid arthritis (RA) efficacy trial, a one week endoscopic study of GI mucosal effects, and a 10 day study of effects on platelet function. The arthritis trials identified celecoxib doses that were effective in treating OA and RA and that were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, no ulcers occurred in subjects receiving celecoxib or placebo, whereas 19% of subjects receiving naproxen developed gastric ulcers. In the platelet effects trial, no statistically significant difference from placebo was seen in the effect of celecoxib on platelet aggregation or bleeding time. In contrast, naproxen caused statistically significant reductions in platelet aggregation and a statistically significant increase in bleeding time. These preliminary trials show that celecoxib achieves analgesic and antiinflammatory efficacy in arthritis through specific COX-2 inhibition without showing evidence of two of the toxic effects of COX-1 inhibition associated with NSAID.
11249574 Vitaxin applied molecular evolution. 2000 Oct Vitaxin is a humanized version of LM-609 (an mAb licensed from the Scripps Research Institute and Dr David Cheresh in May 1994, which blocks the integrin receptor, alpha v beta 3) [172038]. It is in phase II trials for the potential treatment of leiomyosarcoma [316471] and is also being studied in phase I trials as an anti-inflammatory and potential rheumatoid arthritis therapy [364031,313665]. Vitaxin and non-peptides are under evaluation for use in the treatment of other diseases in which vitronectin is reputed to play a role, e.g., arthritis, psoriasis and other inflammatory diseases. Patent positions are being established on these and other applications, as well as on the structure and use of the non-RGD proteins [182507].
10366916 Gene expressions of antiinflammatory mediators in THR retrieved interfacial membranes. 1999 Apr We investigated gene expression of antiinflammatory mediators in the interfacial membranes retrieved at hip revision arthroplasty using reverse transcription-polymerase chain reaction (RT-PCR). Levels of RT-PCR products were compared with those of synovial tissue from patients with osteoarthrosis or rheumatoid arthritis. Antiinflammatory mediators such as type II interleukin (IL)-1 receptor, IL-4, IL-10, IL-1 receptor antagonist, and transforming growth factor-beta 1 (TGF-beta 1) were expressed in the interfacial membrane. In interfacial tissue, the level of IL-10 was lower, but that of the IL-1 receptor antagonist higher than in diseased synovial tissue.
11179015 Association between a single-nucleotide polymorphism in the promoter of the human interleu 2001 Mar Genetic variants of interleukin-3 (IL-3), a well-studied cytokine, may have a role in the pathophysiology of rheumatoid arthritis (RA); but reports on this association sometimes conflict. A case-control study was designed to investigate association between RA and a single-nucleotide polymorphism (SNP) in the IL-3 promoter region. Comparison of cases of RA versus control individuals yielded a chi(2) value of 14.28 (P=.0002), with a genotype odds ratio of 2.24 (95% confidence interval [95%CI] 1.44-3.49). When female cases with earlier onset were compared with female control individuals, the SNP revealed an even more significant correlation, with chi2=21.75 (P=.000004) and a genotype odds ratio of 7.27 (95%CI 2.80-18.89). The stronger association that we observed in this clinically distinct subgroup (females with early onset), within a region where linkage disequilibrium was not significantly extended, suggested that the genuine RA locus should locate either within or close to the IL-3 gene. Combined genotype data on SNPs on eight other candidate genes were combined with our IL-3 results, to estimate relationships between pairs of loci and RA, by maximum-likelihood analysis. The utility of combining the genotype data in this way to identify possible contributions of various genes to this disease is discussed.
10509845 Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthriti 1999 Sep Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs, despite their well-established association with gastroduodenal injury. Recent discovery of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2 has improved our knowledge of the action of NSAIDs. COX-1 is continuously expressed in almost all tissues, where it converts arachidonate to the prostaglandins (PGs) important in homeostatic function; COX-2 is present in immune cells, blood vessel endothelial cells, and synovial fibroblasts. Classic NSAIDs inhibit both COX isoenzymes by occupying the cyclooxygenase-active site, preventing access by arachidonic acid. In theory, a drug such as celecoxib that selectively inhibited COX-2 might block inflammation, pain, and fever while reducing the side effects (gastric erosions and ulcers) associated with inhibition of COX-1. In animal models of inflammation and pain, celecoxib has shown marked suppression of PG production and inflammation compared with indomethacin, the standard COX-1/COX-2 inhibitor. In clinical trials, celecoxib dosed at 100, 200, and 400 mg BID was found to significantly reduce the signs and symptoms of rheumatoid arthritis (RA) and osteoarthritis. In one RA study, celecoxib was found to be as clinically effective as diclofenac after 24 weeks of treatment; at the end of the study, gastroduodenal ulcers occurred significantly more frequently in the diclofenac group (15%) than in the celecoxib group (4%). In a 1-week endoscopy study comparing celecoxib with naproxen and placebo, the incidence of gastric erosions/ulcers was significantly greater in the naproxen group than in the celecoxib or placebo group. The most common adverse effects of celecoxib in clinical studies were headache, diarrhea, abdominal discomfort, and dizziness. Celecoxib has shown significant equivalent anti-inflammatory and analgesic efficacy and has produced less endoscopically apparent gastrointestinal (GI) ulceration or erosion than have 3 classic NSAIDs. Whether it will have long-term GI adverse effects or interact with other medications to cause serious adverse responses (eg, increased GI bleeding or rash in conjunction with other sulfonamide-like drugs) is unknown and remains to be established.
9443752 Pinhole SPECT imaging in normal and morbid ankles. 1998 Jan Pinhole SPECT can generate sectional nuclear images of a normal and morbid ankle and hindfoot with remarkably enhanced resolution by portraying the topography and pathological alterations in great detail. METHODS: Pinhole SPECT was performed using a commercially available single-head, rotating gamma camera system by replacing the parallel-hole collimator used for planar SPECT with a pinhole collimator. The images were reconstructed in the same way as in planar SPECT by using the filtered back-projection algorithm and a Butterworth filter. First, we compared the scan resolution between the planar and pinhole SPECT images of a thyroid phantom and a normal ankle and hindfoot by working out pinhole SPECT anatomy with CT validation. Second, the clinical usefulness was assessed in one case each of fracture, reflex sympathetic dystrophy syndrome and rheumatoid arthritis of the ankle with radiographic correlation. The resolution of the pinhole SPECT and planar pinhole images was compared for these diseases. RESULTS: The resolution of the pinhole SPECT of a thyroid phantom and of a normal ankle and hindfoot was significantly enhanced compared to the planar SPECT although image distortion was seen in the periphery of the field-of-view. The pinhole SPECT resolution was such that most of the anatomical landmarks were sharply delineated in the ankle and hindfoot and some useful diagnostic signs in the diseased ankle were visible. CONCLUSION: Pinhole SPECT can be performed using a single-head gamma camera system and filtered back-projection algorithm. It generates sectional scan images of both normal and morbid ankle and hindfoot with enhanced resolution portraying many anatomical landmarks and pathological signs in useful detail.
10352832 [D-penicillamine-induced pemphigus, polymyositis and myasthenia]. 1999 Feb BACKGROUND: D-penicillamine can induce autoimmune disease, particularly in patients with associated immune disorders. CASE REPORT: A 67-year old woman who had been taking D-penicillamine for 15 months for rheumatoid arthritis was hospitalized due to the development of a bullous eruption and proximal muscle deficiency. Search for intercellular antisubstance antibodies in serum was negative. The skin biopsy histology revealed intra-epidermal cleavage in the mucosal body and direct immunofluorescence revealed epidermal frame-marking with anti-IgG and anti-C3 antibodies. Other tests revealed muscular cytolysis, and anti-acetylcholine receptor antibodies. The electromyogram showed neuromuscular block without muscle deficiency and muscle biopsy showed moderate myositis. D-penicillamine was interrupted and was followed by cure of the pemphigus and aggravation of the myositis, requiring high-dose systemic corticosteroid therapy. DISCUSSION: This patient developed D-penicillamine induced pemphigus, a rather frequent observation. The desmoglein immunolabelling favored drug-induced pemphigus and the course was rapidly favorable after withdrawal. Pemphigus had developed simultaneously with signs of myasthenia and polymyositis. Polymyositis and myasthenia are also known complications of D-penicillamine therapy. The association of these three complications suggests that D-penicillamine can unmask certain antigens or have an immunomodulator effect.
11707862 DAB(389)IL-2 (denileukin diftitox, ONTAK): other potential applications. 2000 Nov DAB(389)IL-2 (denileukin diftitox, ONTAK) is an interleukin-2 receptor (IL-2R)-specific ligand fusion protein that may potentially be selective for IL-2R-expressing malignancies. The activity of DAB(389)IL-2 in the treatment of cutaneous T-cell lymphoma has established the feasibility of utilizing such a targeted therapeutic in disseminated disease with acceptable toxicity. Data from the phase I trial suggest that the definition of activity in other cancer types, including other non-Hodgkin's lymphomas (NHL), is warranted. Three NHL patients in this study responded, two of whom had follicular lymphomas, with the third having a primary intermediate-grade B-cell NHL that was refractory to chemotherapy and stem cell transplant. This patient has remained in complete remission over 3 years after treatment with DAB(389)IL-2. Patients treated to date have had IL-2R-positive tumors, but this remains a very complex clinical issue. The need for a threshold level of receptor expression, the difficulty in obtaining representative tissue, the lack of an assay that accurately reflects high-affinity receptor, and the potential difficulty of observer variability in evaluating the assays should point us toward examining response rates in cancer patients where IL-2R cannot be detected or is unknown. The potential to target the high-affinity IL-2R supports the development of this agent in transplantation and in autoimmune diseases. Targeting IL-2R-expressing lymphocytes may be an effective strategy for the prevention of graft rejection and to treat or prevent graft-versus-host disease. DAB(389)IL-2 has been examined in clinical trials of psoriasis and rheumatoid arthritis and has shown promising results. The potential utility in other autoimmune disorders is unknown, but diseases such as systemic lupus, scleroderma, and vasculitis also may be effective candidates for such ligand fusion therapy.
10319538 Ketotifen in prevention of indomethacin-induced gastropathy. 1999 Apr BACKGROUND: Therapeutic benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) are offset by their gastrointestinal side effects. We evaluated whether oral ketotifen, which prevents experimental NSAID-induced gastric mucosal injury, is superior to placebo in preventing NSAID-induced gastropathy. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: Rheumatology clinic in a tertiary care hospital. PARTICIPANTS: A majority of the 53 subjects had rheumatoid arthritis (n = 36) or osteoarthritis (12). Those with comorbidity, gastrointestinal (GI) symptoms or abnormal endoscopic findings at entry were excluded. Persons on steroids or NSAIDs in the previous month were also excluded. The subjects were started on indomethacin 25 mg thrice daily. INTERVENTION: Subjects were randomly allocated to receive 2 mg ketotifen or placebo tablets. Compliance was measured by tablet count. OUTCOME MEASURE: At the end of every week a questionnaire was administered to elicit GI symptoms or adverse effects. Every patient underwent endoscopy after four weeks. RESULTS: Of 53 patients recruited (27 drug, 26 placebo), three (2 drug, 1 placebo) dropped out. The age, sex, NSAID use and clinical conditions were similar in the two groups. Eight in the drug group and 16 in the placebo group developed GI symptoms and/or endoscopic lesions (relative risk 0.51, 95% CI 0.27-0.95). The difference was significant on intention-to-treat analysis. CONCLUSIONS: Ketotifen significantly reduced the risk of GI side effects in patients on indomethacin.