SEARCH · PubMed Health

Results for “Disease modifying”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources

PubMed1990

Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. The Cooperative Systematic Studies of Rheumatic Diseases Group.

A composite index for estimating improvement in individual rheumatoid arthritis (RA) patients during trials of slow-acting, disease-modifying antirheumatic drugs (DMARDs) was developed by analyzing the responses of 130 placebo-treated participants in Cooperative Systematic Studies of Rheumatic Diseases studies. If responses in 4 of 6 selected measures were required for improvement (by greater than or equal to 20% for morning stiffness, Westergren erythrocyte sedimentation rate, joint pain/tenderness score, and joint swelling score, and by greater than or equal to 2 grades on a 5-grade scale, or from grade 2 to grade 1 for patient's and physician's overall assessments of current disease severity), few placebo-treated patients qualified as improved, whereas significantly more DMARD-treated patients demonstrated improvement. The proposed index appears to be useful in estimating the probability that an RA patient will improve if taking a placebo during a DMARD trial, and may be a useful tool for analysis of DMARD studies.

Anti-Inflammatory Agents↗

PubMed2003

Current disease-modifying therapies in multiple sclerosis.

In recent years, the usefulness of interferon beta and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis (RRMS) has been established. Interferon beta has also been shown to be efficacious in secondary-progressive multiple sclerosis (SPMS) as well as in patients with isolated syndromes at risk to develop clinically definite multiple sclerosis (MS). Mitoxantrone is another disease-modifying drug that is available for SPMS and severe cases of RRMS. The clinical utility of disease-modifying agents in MS will be reviewed with respect to the anti-inflammatory, immunomodulatory, and immunosuppressive treatments that are currently available. Symptomatic therapies will not be considered.

Adjuvants, Immunologic↗

PubMed2001

New disease modifying agents in adult rheumatoid arthritis.

In recent years, new disease modifying agents including leflunomide and tumour necrosis factor (TNF) antagonists have been used to treat patients with rheumatoid arthritis (RA). Leflunomide prevents proliferation of activated lymphocytes by inhibiting dihydroorotate dehydrogenase, a critical step in de novo pyrimidine synthesis. Leflunomide has been shown to be as effective as sulfasalazine and methotrexate (MTX) in placebo-controlled trials. It also improves physical function, quality of life measures and retards radiographic progression. TNF antagonists include infliximab and etanercept. Infliximab is a chimeric TNF monoclonal antibody. Repeated infusions of low dose infliximab (1 mg/kg) are ineffective if given alone. Addition of MTX to infliximab has been shown to prolong the duration of clinical response. Etanercept is a human TNF receptor p75 Fc fusion protein. In active RA patients with suboptimal response to MTX, additional clinical benefit was obtained by the addition of infliximab or etanercept to MTX. The main side effect of etanercept is injection site reaction. However, the long-term effect of TNF antagonists in the development of infection, malignancy and autoimmune disease remains unknown.

Adult↗

PubMed2006

Therapy-related lymphomas in patients with autoimmune diseases after treatment with disease-modifying anti-rheumatic drugs.

Ten patients developing lymphomas after disease modifying anti-rheumatic drugs (DMARD) (methotrexate, n = 3, mean cumulative dose = 3.4 g; cyclophosphamide, n = 2, mean dose = 70 g; azathioprine, n = 6, mean dose = 243 g) were investigated. Methotrexate-related lymphomas were Epstein-Barr virus (EBV)-positive, had infrequent aberrant methylation of p15 and p16, and responded well to methotrexate withdrawal or anti-CD20 antibody (rituximab) alone without concomitant chemotherapy, implying that defective immunosurveillance was important in lymphomagenesis. However, 75% of cyclophosphamide/azathioprine-related lymphomas were EBV-negative, had frequent p15 and p16 methylation, and responded poorly to drug withdrawal and chemotherapy, implying that direct drug-induced mutagenesis might be involved in lymphomagenesis.

Adult↗

PubMed2006

Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthritis drug.

Pulmonary alveolar proteinosis is an uncommon disorder marked by the abnormal accumulation of surfactant within the alveoli. Secondary pulmonary alveolar proteinosis develops in patients who are immunosuppressed, usually with corticosteroids. We present a case of biopsy-proven pulmonary alveolar proteinosis in a patient undergoing therapy with the disease-modifying antirheumatoid arthritis drug leflunomide (Arava; Aventis Pharmaceuticals, Bridgewater, NJ). He was treated with whole lung lavage and discontinuation of leflunomide with good results. This is the first reported association of secondary pulmonary alveolar proteinosis with leflunomide therapy. Pulmonary alveolar proteinosis should be considered in patients with diffuse lung disease that develops while on disease-modifying antirheumatoid arthritis drug therapy.

Adult↗

PubMed1990

Rational use of disease-modifying antirheumatic drugs.

The currently available, most frequently used disease-modifying antirheumatic drugs (DMARDs) include auranofin, azathioprine, D-penicillamine, gold sodium thiomalate, hydroxychloroquine, methotrexate (amethopterin) and sulphasalazine. Controlled trials of these agents are reviewed to compare their relative efficacy and tolerability. Tender joint counts decreased with all drugs, as did joint swelling (measured as the percentage of patients with greater than or equal to 50% improvement in joint swelling). Tender joint count decreased by 8 to 57% in drug-treated patients, compared with 3 to 30% (1 study exceeded this degree of placebo response) in the placebo groups. The ratio of drug to placebo improvement usually averaged greater than 2. A 50% improvement in joint swelling occurred in between 15 and 65% of drug-treated patients. Time to onset of response varied from 6 weeks (with methotrexate) to as long as 18 months (some patients on hydroxychloroquine). The remission rate was inconsistent and unusual in controlled studies (5 to 7%), but very high in some open studies (e.g. 43%). While up to 8% of patients on DMARDs stopped therapy secondary to unsatisfactory therapeutic response (with 1 exception) up to 43% of placebo patients discontinued therapy for this reason. The ratio of dropouts for unsatisfactory therapeutic response for DMARD compared to placebo was less than 1 in 16 of 22 studies, and it was usually less than 0.5. Laboratory data examined include ESR, rheumatoid factor (RF), immunoglobulins and radiographic data. Ratios of decreases in ESR, comparing drug and placebo, were usually greater than 2. ESRs decreased from 3.6 to 27 mm/h, with gold sodium thiomalate, auranofin and methotrexate being most effective relative to placebo. RF decreased by greater than or equal to 2 tube dilutions in 15 to 53% of the DMARD groups but also decreased in up to 26% of placebo patients, with ratios of drug: placebo usually greater than 2. Immunoglobulins tended to decrease with DMARDs but the data are fragmentary. Radiographic evidence that a drug slows the rate of bony damage is strong evidence that it is a DMARD. These data, however, are not easily available because measurements of bony damage is insensitive and difficult. The best evidence of radiographic efficacy exists for gold, although the data are not uniform even here. Studies with other DMARDs suffer from lack of convincing control populations, methodological failures or small numbers, although trends exist showing that azathioprine and D-penicillamine (and perhaps sulphasalazine and methotrexate) may also slow bony deterioration. The other side of efficacy, of course, is tolerability.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Inflammatory Agents↗

PubMed1999

[Disease-modifying treatments in multiple sclerosis].

The number of available disease-modifying agents in multiple sclerosis has been increasing dramatically since 1993. First, interferon beta-1b has been licensed for exacerbating-remitting forms. Then, efficacy has been demonstrated for intramuscular or subcutaneously administered interferon beta-1a in the same indication. More recently, utility of interferon beta-1b in secondary progressive forms has also been proved. Concomitantly, with glatiramer acetate, the concept of a specific intervention on myelin auto-reactive T-cells been validated. Lastly, the classical approach of a global immunosuppression is still of interest. A better utilization of the currently available medications, an improvement of their efficacy/tolerance ratio, the exploration of new concepts such as neuro-protection and remyelination may soon lead to more significant advances.

Glatiramer Acetate↗

PubMed1992

Mechanisms of action of disease modifying antirheumatic drugs.

The relationship between the biologic activities of disease modifying antirheumatic drugs (DMARD) and their therapeutic effects are complex. Some DMARD are prodrugs, e.g., azathioprine; others may act in combination with endogenous substances, e.g., D-penicillamine and copper salts. Gold compounds, antimalarials, sulfasalazine, azathioprine and methotrexate affect various phagocytic cell functions. Most DMARD inhibit the immune responses of monocytes and of T and B lymphocytes. Gold, sulfasalazine, D-penicillamine also affect fibroblast and/or endothelial cell proliferation. Many DMARD inhibit responses to, or production of, cytokines. Several DMARD have overlapping biologic effects but differ in their therapeutic efficacy in individual patients for unknown reasons.

Anti-Inflammatory Agents↗

PubMed1987

An investigation of the action of disease modifying antirheumatic drugs on the rheumatoid synovial membrane: reduction in T lymphocyte subpopulations and HLA-DP and DQ antigen expression after gold or penicillamine therapy.

Synovial needle biopsy specimens from the knee joints of seven patients with rheumatoid arthritis (RA) were examined immunohistochemically before and after six months' treatment with either gold or penicillamine (disease modifying drugs, DMDs). There were significant reductions in the numbers of infiltrating T lymphocytes and a disproportionate fall in the numbers of lymphocytes of the helper/inducer subset when compared with those of the suppressor/cytotoxic subset. This resulted in a fall in the ratio of helper/inducer to suppressor/cytotoxic cells. The immunohistological changes correlated with improvements in erythrocyte sedimentation rate (ESR), serum immunoglobulins, visual analogue pain assessment, grip strength, and Ritchie articular index. A second group of nine patients with RA, already well established on DMD therapy, did not show similar changes after the six month period. The HLA class II antigens DR, DQ, and DP were widely expressed on lymphocytes, macrophages, and synovial lining cells of a group of patients with RA who had never received disease modifying drug therapy. After treatment there was a significant reduction in the expression of HLA-DP and DQ antigens.

Adult↗

PubMedDate not supplied

Structural neuroimaging outcomes in clinical dementia trials, with special reference to disease modifying designs.

In the past clinical trials in dementia, symptomatic or disease modifycing in nature, relied mostly on clinical/neuropsychological endpoints. In the recent past much effort has been put into incorporating imaging, notably MRI, into trials in order to provide a surrogate marker for progression and measure a disease modifying effect, and to provide more insight into the homogeneity, or absence of, the included sample. In the following review an update will be given on the current thinking on how and when MRI should be used in the design of a clinical trial in Alzheimer's disease and mild cognitive impairment, with particular emphasis on trials focusing on disease modification.

Alzheimer Disease↗

PubMed2002

"5D" Outcome in 52 patients with rheumatoid arthritis surviving 20 years after initial disease modifying antirheumatic drug therapy.

OBJECTIVE: Evaluation of a complex and variable disease such as rheumatoid arthritis (RA) poses a challenge particularly over the medium to long term. A practical framework to evaluate clinically relevant outcomes over the long term is the "5D" approach of Fries, described in 1980. We describe the 20 year outcome in 52 survivors of a 123 patient cohort in terms of change in discomfort, disability, drug side effects, dollar costs, and deaths. METHODS: We studied 123 patients with RA allocated to their first disease modifying antirheumatic drug (DMARD) between 1977 and 1979. All were under the overall care of one physician over the 20 years and were maintained where possible taking a single DMARD. Baseline demographic variables, the Ritchie Articular Index (RAI), Lee functional index, and erythrocyte sedimentation rate (ESR) were initially recorded. The extent to which the demographic and disease variables contributed to need for joint replacement surgery was assessed. Therapies for comorbidity were also documented. RESULTS: At cohort inception mean age was 50 years, RAI was 35, and median disease duration 5.5 years. F:M ratio was 90:33; 96% of patients were positive for rheumatoid factor (RF). Initial median ESR was 55 mm/h. At 20 years, 9 patients (7% of original cohort, 14% of survivors) were lost to followup and 62 (50%) had died. In the 52 survivors RAI, a surrogate for disability, showed a significant improvement (p < 0.0001), but disability measured by Lee functional index showed a deterioration (p = 0.018); 50% underwent joint replacement surgery. Initial ESR and mean ESR over the first 10 years of followup were significantly higher in those who required surgery. Nonsteroidal antiinflammatory drug (NSAID) use declined, but at least 2 deaths and 4 renal deaths that may have been related to therapy were attributed to NSAID use. No unexpected DMARD toxicity or mortality occurred. Concomitant therapy for comorbidity, in particular for cardiovascular disease, osteoporosis, and gastrointestinal disease, increased: more than 60% were on these therapies at 20 year followup. CONCLUSION: Strategies to improve the outcome of RA in all dimensions should include: earlier referral for expert assessment; avoidance of NSAID gastrointestinal and nephrotoxicity; a more intensive effort to identify effective management of comorbidity and those likely to have a poor outcome. Such patients require sustained, intensive therapy to minimize later disability.

Adult↗

PubMed2004

Pharmacogenetics of disease-modifying anti-rheumatic drugs.

The outcome of treatment with disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients is considerably variable and is also unpredictable. It would be useful clinically if physicians were able to predict responses to DMARDs prior to their administration. One possible cause of differences in efficacy and adverse drug reactions is genetic variation in how individuals metabolize drugs. Based on pharmacogenetics, tailor-made drug therapy, also called personalized drug therapy or individual drug therapy, will be possible with analysis of genetic polymorphism, such as single nucleotide polymorphism (SNP), and analysis of haplotype and diplotype configuration. Several studies of the correlation between the genetic polymorphism of enzymes metabolizing several DMARDs and efficacy or adverse drug reactions have already been reported, suggesting that pharmacogenetics will be applicable to the treatment of RA in the near future.

Antirheumatic Agents↗

PubMed2002

[Combination therapy of disease-modifying antirheumatic drugs(DMARDs) in rheumatoid arthritis].

The early suppression of disease activity during the first 2 years in rheumatoid arthritis (RA) has been reported to be exclusively important to prevent joint destruction and functional decline. Since single disease-modifying antirheumatic drugs(DMARDs) therapy is still disappointing, many rheumatologists today advocated a more aggressive approach using combinations of classic DMARDs. Many clinical trials on combination therapy have been reported and most studies of combination therapy focused on the efficacy of a treatment strategy. Therefore, the possible synergistic action of combination of drugs has not been demonstrated. Among combination of therapy of classical DMARDs, only few trials demonstrated the efficacy of combination therapy. The incidence of adverse effects among 341 RA patients was investigated by our department. The incidence of adverse effect in combination therapy revealed 36.4% which was not statistically different from that in monotherapy(33.6%, p = 0.41). The recent studies on combination therapy on classical DMARDs are not encouraging, however, the combination therapy for patients with early RA, drugs utilizing immunosuppressant, biologics and other newly developed drugs will still have a chance to expect a potent efficacy for RA.

Antirheumatic Agents↗

PubMedDate not supplied

Regulation of in vitro anti-DNA antibody production by a novel disease modifying anti-rheumatic drug, Lobenzarit.

Lobenzarit (CCA) is a novel disease modifying anti-rheumatic drug. Although CCA has been shown to prevent the development of the autoimmune disorders in NZB/W F1 mice and in MRL/l mice, the precise mechanism of its action has not yet been clarified. The current study examined the effect of CCA on the in vitro production of anti-DNA antibody, a hallmark of the autoimmune disorders. In vitro anti-DNA antibody production was induced from highly purified B cells of normal human individuals by stimulation with Staphylococcus aureus and CD4+ T cells or with immobilized anti-CD3 activated CD4+ T cells. CCA suppressed the production of anti-DNA antibody as well as IgM at pharmacologically obtainable concentrations (10-50 micrograms/ml). CCA did not inhibit the initial stages of B cell activation in either culture system, but rather suppressed the maturation of previously activated B cells. Although CCA suppressed IL2 production by immobilized anti-CD3 activated CD4+ T cells, its suppressive effects on B cells were not overcome by the addition of IL2 or factors generated from mitogen activated T cells (TF). CCA did not suppress IL6 production by immobilized anti-CD3 activated CD4+ T cells nor that by B cells activated with SA+ IL2. These results indicate that CCA suppresses the production of anti-DNA antibody by directly inhibiting activated B cells. The data therefore suggest the possible efficacy of CCA in suppressing the function of activated B cells in human SLE patients.

Adult↗

PubMed1991

Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis.

The toxicity profiles of 7 disease modifying antirheumatic drugs (DMARD) (hydroxychloroquine, intramuscular (im) gold, D-penicillamine, oral gold, methotrexate (MTX), azathioprine and cyclophosphamide) were evaluated in 2,479 patients with rheumatoid arthritis consecutively enrolled at 5 centers in the Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) program. Incidence rates for side effects are reported as events/1000 patient-years. Our descriptive study revealed an individual profile of prevalent toxicities for each drug. Oral gold was characterized by substantial lower gastrointestinal (GI) toxicity (diarrhea 391 events/1000 patient-years, loose bowel movement 148, lower abdominal pain 76), MTX by hepatotoxicity (47) while D-penicillamine had the only clinically significant incidence of altered taste (40). MTX users reported the most mucosal ulcers (87), followed by oral gold (76), im gold (55) and D-penicillamine (38). Rash was frequently seen with gold compounds and D-penicillamine, while upper GI toxicity was common with immunosuppressive agents. Cyclophosphamide had 48% discontinuations within 6 months. MTX had the lowest discontinuation rate in the first 6 months, but then showed little difference from im gold. A preliminary similarity index was developed to compare the toxicity profiles of various DMARD. Close similarities were found between toxicity profiles of im gold and D-penicillamine, and between azathioprine and MTX. Oral gold had a unique toxicity pattern. Knowledge of these different toxicity patterns can enable more appropriate selection of agents for particular patients.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1990

Biologic properties of romazarit (Ro 31-3948), a potential disease-modifying antirheumatic drug.

The biologic effects of a new potential disease-modifying antirheumatic drug, romazarit (Ro 31-3948, 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropio nic acid), have been investigated. In a 5-day adjuvant arthritis model, romazarit inhibited the development of hindpaw inflammation with a minimum effective dose of 30 mg kg-1. Plasma levels of the acute phase reactants seromucoid and haptoglobulin were also significantly reduced. Romazarit was equally effective in adrenalectomized animals, indicating that the compound is not acting via stimulation of the pituitary/adrenal axis. When the developing adjuvant arthritis was extended to 15 days romazarit showed dose-related improvements of all the symptoms of arthritis with a minimum effective dose of 25 mg kg-1. Romazarit caused a dose-dependent (range 20-250 mg kg-1) reduction in both the inflammatory and bony changes occurring during collagen arthritis in the rat, without any significant effect on anticollagen antibody titers except at the highest dose. Collagenase and prostaglandin E2 production in cultures of talus bones taken from rats with collagen arthritis were reduced by romazarit. In vitro romazarit was an extremely weak inhibitor of prostaglandin synthetase activity in both sheep seminal vesicle (IC50 6500 microM) and rat renal medulla (IC50 greater than 300 microM) cell-free preparations. Romazarit showed little or no activity in models of acute inflammation such as rabbit skin edema, carrageenan pleurisy or UV-induced erythema. In both acute and chronic tests romazarit displayed no ulcerogenic potential. In comparison with the structurally similar compound clobuzarit, hepatic changes such as increases in catalase and peroxisome proliferation-associated 80,000 mol.wt. protein were markedly less with romazarit. Clinical studies with romazarit are currently in progress.

Animals↗

PubMed1996

The use of antimalarials in combination with other disease modifying agents in RA--the British experience.

Antimalarial drugs are effective disease modifying agents in RA with a low incidence of serious toxic effects. Recently, combinations of second-line agents have been used in RA in attempts to treat patients with no response to a number of single agents, or suboptimal response to a single agent. Combinations of drugs have been selected for maximum efficacy and minimum toxicity, but clinical trials are difficult to design and interpret. In particular, ensuring adequate power to detect small differences in response poses a major problem. Antimalarials are an attractive choice for combination therapy due to their efficacy, mechanisms of action and toxicity profile. In this review, the evidence for the use of antimalarials in combination in RA is examined. No advantage has been shown in combining antimalarials with gold, penicillamine or sulphasalazine compared with monotherapeutic regimens. There is some evidence to suggest a beneficial combination of antimalarials with methotrexate, but this is as yet inconclusive. Open non-randomised uncontrolled studies have shown that antimalarials combined with cytotoxic agents are effective but highly toxic. The authors conclude that there is little good evidence to support the introduction of combination second-line drug therapy for RA into widespread therapeutic use.

Antimalarials↗

PubMed2007

Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs--from bench to bedside.

The chronic nature of rheumatoid arthritis (RA) means that patients require drug therapy for many years. Many RA patients, however, have to discontinue treatment because of drug-related toxic effects, loss of efficacy, or both. The underlying molecular cause for loss of efficacy of antirheumatic drugs is not fully understood, but it might be mediated, at least in part, by mechanisms shared with resistance to anticancer drugs. This Review outlines molecular mechanisms that could be involved in the onset of resistance to, or the loss of efficacy of, disease-modifying antirheumatic drugs in RA patients, including methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, and leflunomide. The mechanisms suggested are based on findings from experimental laboratory studies of specific drug-uptake and drug-efflux transporters belonging to the superfamily of multidrug-resistance transporters, alterations in intracellular drug metabolism, and genetic polymorphisms of drug transporters and metabolic enzymes. We also discuss strategies to overcome resistance and the current clinical studies aiming to predict response and risk of toxic effects. More in-depth knowledge of the mechanisms behind these features could help facilitate a more efficient use of disease-modifying antirheumatic drugs.

Antirheumatic Agents↗