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PubMed2005

A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer's disease.

Increased levels of alpha-1-antichymotrypsin (ACT), a protease inhibitor and an acute phase protein, have been found in the brain and peripheral blood of patients with Alzheimer's disease (AD). Patients from northern Italy with a clinical diagnosis of probable AD, and patients with early onset AD (EOAD) from UK with AD neuropathological diagnosis were genotyped for a new polymorphism in the promoter region of the ACT gene which has been shown to affect ACT expression. A subset of patients with clinical AD from northern Italy was also followed up for 2 years and monitored for cognitive decline. The ACT TT promoter genotype was associated with an increased risk of EOAD independently from the presence of the apolipoprotein E (APOE) epsilon 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele epsilon 4. The ACT gene appears to influence the early clinical development of the disease, and the interaction of the ACT and APOE genes affects clinical progression of AD.

Aged↗

PubMedDate not supplied

Imaging-based measures of disease progression in clinical trials of disease-modifying drugs for Alzheimer disease.

The authors review and assess imaging-based strategies for measuring the rate of progression of Alzheimer disease (AD). Such techniques may be useful in addition to the behavioral instruments typically used in these studies and may be more sensitive to treatment-related change. MEDLINE searches obtained relevant published literature. Articles were reviewed with particular attention to assessments of rate of disease progression and the effects of investigational drugs. Authors studied a variety of techniques, including volumetric magnetic resonance imaging, functional MRI, fluorodeoxyglucose positron emission tomography, and several target-specific radiopharmaceuticals. In cross-sectional as well as small longitudinal trials, many of these show promise not only in diagnosis, but also as measures of disease progression. The effects of drugs that provide symptomatic relief on these measures have not been fully characterized. Even less is known about the effects of investigational drugs that may slow disease progression. Several neuroimaging techniques have been studied that could improve the ability of clinical trials to quantify the rate of progression of AD. Clinical trials of investigational drugs would benefit from more systematic validation of image-based outcome measures. Several choices of imaging techniques are available. An understanding of the relationship between a statistically significant effect size in an imaging marker and a clinically significant change in rate of disease progression will require additional studies.

Aged↗

PubMed1997

Disease-modifying antirheumatic drugs.

The case for early intervention with disease-modifying antirheumatic drugs is strengthened by published reports during the past year. These drugs include methotrexate, gold sulfasalazine, and antimalarial agents. The American College of Rheumatology issued guidelines for the management of rheumatoid arthritis and for monitoring the toxicity of antirheumatic drugs. Studies on the mechanisms of action of disease-modifying antirheumatic drugs focused on their effects on cytokines and their receptors. The toxic effects of disease-modifying antirheumatic drugs remained an important issue, especially the adverse pulmonary effects of methotrexate. An important trial demonstrated a beneficial effect of triple disease-modifying antirheumatic drug therapy (methotrexate, sulfasalazine, and hydroxychloroquine) over individual agents.

Antimalarials↗

PubMed1992

Clinical research in osteoarthritis: design and results of short-term and long-term trials with disease-modifying drugs.

Putative disease-modifying drugs are usually clinically used in osteoarthritis with two main aims: not only stopping or reducing the cartilage degenerative process after a long-term treatment, but also controlling the symptoms of the disease within a few days or weeks, thus avoiding or diminishing the use of symptomatic medications. Due to the difficulties of implementing the first aim, the latter aim was more often investigated, even if most often with inadequate study design and insufficient numbers of patients. We have recently carried out three double-blind, controlled, parallel groups, randomized, 4-6 week trials of glucosamine sulphate versus placebo or the NSAID ibuprofen on a total of 606 gonarthrosic out-patients. Movement limitation and pain were scored according to the Lequesne index, and the efficacy goals were strictly pre-determined. Access to other medications was not allowed. Glucosamine was significantly more effective than placebo, while no difference was detected in comparison with the NSAID (p < 0.025 and p = 0.77, respectively: Fisher's two-tailed exact test). On the other hand, glucosamine was as well tolerated as placebo, while the percentage of patients suffering adverse drug reactions was higher in the ibuprofen group (37% vs 7%: p < 0.001). Long-term trials are in progress and several aspects are to be considered in their design: they must be double-blind, placebo-controlled, randomized, continued for a period of years and (most importantly) with the careful use of imaging and biochemical techniques capable of generating objective evaluation criteria.

Clinical Trials as Topic↗

PubMed1998

Disease-modifying antirheumatic drugs.

Disease-modifying antirheumatic drug (DMARD) therapy is now clearly accepted as the primary treatment for rheumatoid arthritis, with an increasing emphasis on use of combination therapy. Data on combination therapy have highlighted the difficulties in performing these studies and the large number of patients required to produce meaningful results. Combination studies have focused on use of rapidly decreasing high-dose steroids as a part of the combination and emphasize the importance of using patients with early rheumatoid arthritis. Even with relatively aggressive use of DMARDs, the majority of patients develop erosions. Adverse reactions to DMARDs continue to concern clinicians, although evaluation of the frequency of these events has led to a reappraisal of previously accepted monitoring strategies in some cases. For example, it may not be cost-effective to subject patients on antimalarials to regular review by an ophthalmologist because of the low frequency of serious eye defects. Studies have also identified risk factors for the development of pulmonary toxicity in association with methotrexate. That DMARDs are effective in treating rheumatoid arthritis is beyond question-just how effective they are and what combinations of DMARDs will show improved efficacy will provide data for the next annual review.

Antimalarials↗

PubMed2002

Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Oral glucocorticoids combined with disease-modifying antirheumatic drugs are beneficial and retard radiologic joint damage in rheumatoid arthritis. OBJECTIVE: To investigate the clinical efficacy, disease-modifying properties, and side effects of low-dose glucocorticoids as monotherapy for previously untreated patients with early active rheumatoid arthritis. DESIGN: 2-year randomized, double-blind, placebo-controlled clinical trial. SETTING: 2 outpatient rheumatology clinics. PATIENTS: 81 patients with early active rheumatoid arthritis who had not been treated with disease-modifying antirheumatic drugs. INTERVENTION: 41 patients were assigned to 10 mg of oral prednisone per day, and 40 were assigned to placebo. Nonsteroidal anti-inflammatory drugs were allowed in both groups. After 6 months, sulfasalazine (2 g/d) could be prescribed as rescue medication. MEASUREMENTS: Clinical variables were assessed at baseline and every 3 months; radiologic studies were performed every 6 months. Adverse effects were documented every 3 months. RESULTS: In the first 6 months, the prednisone group showed more clinical improvement than the placebo group. This effect was not seen after 6 months except in grip strength and the 28-joint score for tenderness. Use of additional therapies was significantly less common in the prednisone group, particularly in the first 6 months. More than 65% of those who completed the study were not taking sulfasalazine. After month 6, radiologic scores showed significantly less progression in the prednisone group than in the placebo group. No clinically relevant adverse effects were observed, except for a higher incidence of osteoporotic fractures in the prednisone group. CONCLUSIONS: Prednisone, 10 mg/d, provides clinical benefit, particularly in the first 6 months, and substantially inhibits progression of radiologic joint damage in patients with early active rheumatoid arthritis and no previous treatment with disease-modifying antirheumatic drugs. Because of their limited disease-modifying effects, glucocorticoids should be combined with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

Administration, Oral↗

PubMed1998

Disease-modifying antirheumatic drugs. Using their clinical pharmacological effects as a guide to their selection.

Rheumatoid arthritis is a disease of unknown aetiology characterised by persistent joint swelling, functional disability and increased mortality. No curative therapy exists at present but some therapeutic agents, commonly referred to as disease-modifying drugs, offer the potential for suppression of the inflammatory activity and attenuation of the disease process. Since the precise mechanism of action of most disease modifying drugs is uncertain, the selection of a particular therapy must at present be based on the pharmacologic properties of each available agent, appropriately individualised for each clinical setting. The toxicity of disease-modifying agents often limits the dose and/or duration of therapy and makes careful monitoring mandatory. No consensus exists as to the order in which disease-modifying agents should be employed. Less toxic disease-modifying drugs such as auranofin, hydroxychloroquine, minocycline, and sulfasalazine are usually used in early and mild disease. Azathioprine, penicillamine (D-penicillamine), methotrexate and parenteral gold are usually considered to be more toxic and are most often used in the setting of progressive disease while the most toxic agents, such as chlorambucil and cyclophosphamide, are reserved for life-threatening manifestations such as vasculitis. Newer therapeutic approaches presently under study include the use of existing drugs in combination and novel biologic agents which selectively inhibit lymphocyte and cytokine activity. These strategies offer the hope of more efficacious and less toxic therapy in the future.

Animals↗

PubMed1988

Can 'disease modifying' drugs influence outcome in rheumatoid arthritis?

The treatment of rheumatoid arthritis with disease modifying drugs is based on the hypothesis that they exert a more profound effect on the disease process than non-steroidal anti-inflammatory drugs. Short-term studies of disease modifying drugs show significant clinical and laboratory improvements in comparison to placebo. Longer-term studies suggest that this improvement is not maintained. Attempts to assess the effect of disease modifying and immunosuppressive drugs on radiological progression suggest that they may have a week protective effect, but there is no evidence to suggest that this is maintained in the long term. Studies of corticosteroid therapy indicate that in large doses it possesses disease modifying properties and is capable of retarding radiological progression. The benefit-risk ratio of such doses is unacceptable. Lower doses have not yet been adequately investigated. Rheumatologists should regard existing suppressive agents as moderately effective in the short term. Few patients remain on single drug therapy for prolonged periods and available evidence does not suggest that these drugs are capable of altering the long-term outcome of rheumatoid arthritis.

Adrenal Cortex Hormones↗

PubMed2004

The use of disease-modifying new drugs for multiple sclerosis treatment in private-sector health plans.

OBJECTIVES: The aims of this study were to estimate the effects of demographics, location, severity of multiple sclerosis (MS), comorbidities, plan type, coinsurance levels, and time of entry into the sample on the use of disease-modifying agents. METHODS: A retrospective analysis of medical claims data from 1996 through 2000 was conducted with a sample of MS patients covered by self-insured, employer-sponsored health plans. Proportional hazard analysis with the SAS procedure for proportional hazards regression was used to estimate the impact of the factors of interest on the use of disease-modifying agents. A simulation was conducted to assess the impact of changing drug copayments on the use of disease-modifying agents for MS. RESULTS: The sample included 1807 patients. Patients were followed for as long as possible, but most were observed for <3 years; the mean (SD) follow-up time was 972.88 (440.59) days. Most factors associated with the use of disease-modifying agents were immutable. They included the following: high severity of illness (only marginally related; P = NS); history of seizures (P = 0.03), depression (P < 0.01), or heart disease (P = 0.01); census region of location (P < 0.01); union membership or association with a union member (P < 0.01); drug copayment requirements (P < 0.05); and year of entry into the sample (P < 0.01). In the simulation, a 50% reduction in drug copayments was associated with an increase of the proportion of patients treated with disease-modifying drugs from 41.2% to 54.7%. Patients' and physicians' preferences for treatment could not be measured directly. The true onset of MS may be unknown for many patients, but this would be the case even if medical records or other data were used for this study. CONCLUSIONS: Our analyses showed an association between copayments and the use of disease-modifying drugs for MS. Insurance policies can be tailored to influence the use of disease-modifying drugs, enhancing the quality of care for MS patients and reducing price-related barriers to beneficial treatment. Future research should test whether reducing copayments for MS treatment would reduce the use of other health care services (via better MS treatment that modifies the course of illness), or whether the use of disease-modifying drugs would increase total costs to the plan, resulting in slightly higher premiums.

Adolescent↗

PubMed2000

Multiple sclerosis, disease modifying treatments and depression: a critical methodological review.

BACKGROUND: Major depression affects one in two patients with multiple sclerosis (MS) during the course of their lifetime. This adds to the morbidity associated with the disorder and may contribute to an increased mortality rate because of suicide. Over the past few years, with the advent of disease modifying treatments for MS, a new concern with respect to mood has arisen, namely the possibility that some of these drugs may have depression as a clinically significant side effect. OBJECTIVE: To ascertain whether disease modifying treatments in MS are associated with the development of depression or the worsening of a depressive illness. METHODOLOGY: A MEDLINE and PSYCHLIT search focusing on depression and disease modifying treatments going back to 1993 (the publication date of the results of the first randomised, placebo controlled trial). The methodology pertaining to the assessment of depression is critically reviewed. Furthermore, a critical summary is provided of treatment modalities for the depressed MS patient. RESULTS: There are conflicting data that depression may occur with some disease modifying drugs, particularly interferon beta-1b. However, all studies reveal limitations with respect to the assessment of mood. Some reports, despite omitting details of how mentation was assessed, still comment on the presence or absence of depression. Others suffer from one or more of the following shortcomings: a failure to assess premorbid risk factors for mood disorder; a reliance on one question to assess depression; the utilisation of self report mood rating scales of questionable validity; neglecting to distinguish depression as a symptom from depression as a syndrome (i.e. major depression as defined by the DMS-1V). CONCLUSIONS: Given the many methodological pitfalls inherent in all studies to date, it is premature to conclude that disease modifying drugs are associated with depression. Evidence suggests that treatment of depression, irrespective of a putative association with a disease modifying agent, is frequently effective. This applies to pharmacotherapy or psychotherapy, although the former may be preferred should depression arise during a course of treatment with a disease modifying agent. Multiple Sclerosis (2000) 6 343 - 348

Major Depressive Disorder↗

PubMed2005

Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the beta-amyloid peptide.

AD (Alzheimer's disease) is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles and profound grey matter loss. The 'amyloid' hypothesis postulates that the toxic Abeta (amyloid beta) peptide, enzymatically derived from the proteolytic processing of a larger protein called APP (amyloid precursor protein), is one of the principal causative factors of neuronal cell death in the brains of AD patients. As such, methods for lowering Abeta levels in the brain are of significant interest with regard to identifying novel disease modifying therapies for the treatment of AD. In this review, we will review a variety of approaches and mechanisms capable of modulating levels of Abeta.

Alzheimer Disease↗

PubMed1983

Rheumatoid arthritis: disease-modifying antirheumatic drugs.

A review of the trials in which 'disease-modifying' drugs have been tested leads to the following conclusions: (a) Most of these trials do not provide acceptable evidence of the efficacy of these drugs. (b) A well-designed, placebo-controlled, study of gold (Empire Rheumatism Council, 1960, 1961) provides strong evidence that the drug has a beneficial effect lasting about 18 months. It does not establish any advantage beyond that period. Two reports which claim to show a favourable influence of gold on radiological progression are suspect because of faults in trial design. (c) There has been only one placebo-controlled study of penicillamine (Multicentre Trial Group, 1973). This also provides evidence of medium-term efficacy. No information is available about x-ray progression. (d) Studies of other drugs for which 'disease-modifying' activity has been claimed (antimalarials, antiproliferative agents, corticosteroids, etc.) have similarly provided evidence only of medium-term efficacy. With information now available it is possible to identify some of the reasons why these trials have failed to answer the fundamentally important question of whether the drugs can modify the long-term course of RA. (a) Trial designs have concentrated on following process measures (e.g., ESR) rather than outcome measures (e.g., disability and deformity). Observers have thus come to accept the former as being important in themselves, to the neglect of the latter. (b) Psychological pressures to provide relief for patients, combined with unjustified assumptions about the long-term efficacy of these drugs, have produced a climate of expectations amongst both clinicians and patients which makes it difficult to sustain long-term trials against placebo. (c) Traditional radiological assessment methods have proved insensitive. (d) Recent advances in clinical trial design and analysis (developed largely in specialties outside rheumatology) were not available at the time of most of these trials. At this stage clinical trials of 'disease-modifying' drugs should seek to answer the following questions: (a) Is it worth giving drugs such as gold and penicillamine for periods longer than 6 months? (b) How long does the effect of such treatment last? (c) Is any information obtainable before or during treatment which predicts favourable or unfavourable responses? To answer these question, trial designs, will need to include: (a) Larger numbers of patients. (b) Longer duration of treatment and follow up.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗

PubMed1989

Relationships between knowledge and experience in the use of disease-modifying antirheumatic agents. A study of primary care practitioners.

The timely dissemination of new medical information is a complex and often faulty process. We surveyed primary care physicians to determine their knowledge and use of disease-modifying antirheumatic agents for the treatment of rheumatoid arthritis. Only 26.2% of patients hospitalized for rheumatoid arthritis had been treated with disease-modifying antirheumatic agents in the past, and 13.9% were presently receiving them. When responding to a clinical vignette on rheumatoid arthritis, only 12% (10/84) of practitioners would implement therapy with disease-modifying antirheumatic agents, while the majority would refer the patient to a rheumatologist. Experience with similar patients was clearly the factor that led to initiation of therapy. While 73% of practitioners were aware of the value of disease-modifying antirheumatic agents, only 14% prescribed them in the last year. These findings suggest that dissemination of information concerning disease-modifying antirheumatic agents has been successful, but the problems inherent in their use result in referral rather than initiation of therapy.

Adult↗

PubMed1982

An overview of benefit/risk of disease modifying treatment of rheumatoid arthritis as of today.

In chronic rheumatoid arthritis (RA), disease modifying drugs are used in an attempt to suppress the progressive damage to tissues and joints that is associated with active disease. Their success in achieving this goal is variable; responses vary from complete suppression of all signs and symptoms of RA to continued active disease, with progressive disability, despite prolonged therapy. Because disease activity almost always recurs after the therapy is stopped, early interruption of an effective therapy for any reason will make its benefit insignificant in a lifelong disease such as RA. Similarly, short-term sequential use of multiple disease modifying therapies is unlikely to be beneficial. The immediate problems with these therapies are substantial. In general, fewer than 50% of patients are able to continue a particular drug for more than one year. Since it takes three to 12 months or longer to achieve maximum effects, those patients who are unable to continue the drug receive little benefit from it. Inevitable delayed side-effects, such as those associated with chronic corticosteroid therapy, may make the benefit/risk ratio unacceptable. Potential late lethal adverse effects, such as malignancy, weight the benefit/risk ratio to varying extents for individual patients, depending on the relative probability that the adverse effect will occur during the remainder of the patient's anticipated life span, and are of greater importance in younger patients. In that minority of patients who achieve remission or near remission and are able to tolerate a disease modifying treatment for many years, it is of truly significant benefit. We are still searching for a therapy that will reliably achieve this goal for most patients with RA.

Arthritis, Rheumatoid↗

PubMed2003

Is there still a role for traditional disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis?

Rheumatoid arthritis is a chronic and debilitating disease, affecting an estimated 1% of the population worldwide. The past decade has witnessed an explosion in our understanding of the pathophysiology of rheumatoid arthritis and therefore in our ability to more effectively target the disease process. Although a cure remains elusive, remission is an approachable goal. There has been a complete remodeling of the traditional "pyramid" by rheumatologists, who now treat rheumatoid arthritis earlier and more aggressively than ever before. Standard single therapy with disease-modifying antirheumatic drugs, which was previously the final step in treating rheumatoid arthritis, is now practically bypassed in the deluge of information suggesting that combinations of disease-modifying antirheumatic drugs or newer biologic therapy is more effective. It is difficult to assimilate all the data and develop a rational approach; however, the bottom line is often the deciding factor: the newer agents are tremendously expensive. The intent of this article is to review recent and relevant trials in the treatment of rheumatoid arthritis, suggest a treatment algorithm, and argue that traditional disease-modifying antirheumatic drugs continue to play a pivotal role.

Anti-Inflammatory Agents↗

PubMed2005

Emerging prospects for the disease-modifying treatment of Alzheimer's disease.

The currently approved therapies for Alzheimer's disease (AD) in the US are designed to modify the function of specific neurotransmitter systems in the brain. While these palliative treatments can benefit some patients for a period of time, they do not halt the relentless cognitive and behavioral deterioration that characterize this neurodegenerative disorder. Consequently, much current research on AD is directed toward illuminating the disease process itself, particularly the abnormal accumulation of certain proteins in brain: the amyloid-beta protein (Abeta) in senile plaques and cerebral blood vessels, and the tau protein in neurofibrillary tangles. Genetic, biochemical and pathologic evidence now favors a primary role of Abeta aggregation in the Alzheimer proteopathic cascade, and studies in mice indicate that lowering the amount of this protein in brain can be beneficial. Recently, Abeta-immunization therapy has emerged as a particularly promising therapeutic option for treating Alzheimer's disease, but unexpected treatment-related side-effects are an overriding issue. These adverse events were not anticipated from preclinical studies with rodents; hence, more biologically relevant models, such as nonhuman primates, are needed to test the safety and efficacy of novel therapies for Alzheimer's disease.

Alzheimer Disease↗

PubMed2005

[Examination of the escape phenomenon in disease modifying antirheumatic drugs].

Although disease-modifying antirheumatic drugs (DMARDs) are used in the treatment of rheumatoid arthritis (RA), the selection of agents in the case of relapse (escape phenomenon) lacks clear-cut standards. Therefore we investigated the rate and conditions of escape as well as the agents used after escapes had occurred. Outpatients of the Matsubara Mayflower Hospital with a history of DMARD administration during the 4 years prior to May 2003 were studied. Those receiving salazosulfapyridine (SASP) had a high escape rate and those receiving methotrexate (MTX) and bucillamine (BC) had a low rate. The continuous duration of administration was long for MTX and BC, but short for sodium aurothiomalate (GST). BC and Actarit (AR) gradually elevated C-reactive protein (CRP) levels and the erythrocyte sedimentation rate (ESR). In patients receiving SASP and MTX, a high level of CRP and high ESR was seen 2 months prior to the occurrence of escape and remained unchanged after escape. With respect to the agents used after escape, SASP and BC were substituted with other DMARDs. A combination with other DMARDs was usually administered to patients who had been receiving MTX. Taken together, the present results clarified the characteristics of DMARD escape and will contribute to the appropriate pharmacotherapy for RA.

Aged↗

PubMed1995

Management of adverse effects of disease-modifying antirheumatic drugs.

Therapy with disease modifying antirheumatic agents (DMARDs) is often complicated by the occurrence of adverse effects. Although risk factors for several DMARDs have been reported, the prediction of adverse drug reactions is not yet possible. Therefore regular monitoring remains mandatory. Monitoring for adverse effects to DMARDs usually includes one or more of the following: blood count, liver, kidney, urine or ophthalmologic tests. Since most adverse reactions occur during the first few months of treatment, monitoring should be more intense and frequent in this initial phase. Some adverse effects are dose-dependent, and therefore dosage reduction may help alleviate these. Others are idiosyncratic, and often necessitate drug withdrawal. Except for (hydroxy)chloroquine-induced retinopathy and methotrexate-induced liver cirrhosis, most adverse reactions to DMARDs are fortunately reversible.

Antirheumatic Agents↗