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PubMedDate not supplied

The role of disease-modifying antirheumatic drugs in the treatment of giant cell arteritis.

Giant cell arteritis (GCA) is a vasculitis of unknown etiology that affects medium-sized and large arteries, and is the most common form of vasculitis in populations of predominantly Northern European ancestry. If left untreated, GCA can lead to significant morbidity including blindness, stroke, aortic aneurysm and dissection, as well as large-artery stenosis. Glucocorticosteroids are in general very effective in the treatment of GCA. Treatment with high dose glucocorticosteroids is associated with considerable morbidity and for some, but not all patients is required for prolonged periods sometimes exceeding several years. Numerous efforts have been made over the decades to optimize therapeutic outcomes and reduce the side effects of glucocorticosteroids by enlisting adjuvant and alternative therapies. This review focuses primarily on evidence from randomized controlled trials with the objective of efficacy assessment of the respective drugs and dosing regimens in the treatment of GCA. Various glucocorticosteroid dosing regimens including alternate-day dosing, disease-modifying therapies including methotrexate and azathioprine, and the prospect of using monoclonal anti-cytokine or anti-cytokine receptor antibodies in the treatment of GCA are addressed. Thus far, no disease-modifying antirheumatic drug therapy or alternative to daily glucocorticosteroid therapy has been found to be unequivocally effective in the treatment of GCA.

Antirheumatic Agents↗

PubMed1995

Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis.

OBJECTIVE: The development and validation of Modified Disease Activity Scores (DAS) that include different 28-joint counts. METHODS: These scores were developed by canonical discriminant analyses and validated for criterion, correlational, and construct validity. The influence of disease duration on the composition of the DAS was also investigated. RESULTS: No influence of disease duration was found. The Modified DAS that included 28-joint counts were able to discriminate between high and low disease activity (as indicated by clinical decisions of rheumatologists). CONCLUSION: The Modified DAS are as valid as disease activity scores that include more comprehensive joint counts.

Adult↗

PubMed2004

What do we know about the mechanism of action of disease-modifying treatments in MS?

Multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system (CNS), 2 results in damage to axons and their surrounding myelin sheath. The exact cause of inflammation remains unclear, but an autoimmune response directed against CNS antigens is suspected. MS can affect the brain, optic nerve and spinal cord, thus causing many neurological symptoms. These can include limb numbness or weakness, sensory or motor changes, ataxia, blurry vision, painful eye movements, bladder and bowel dysfunction, decreased memory, fatigue and effective disorders. This article will include a concise overview of the pathogenesis of MS in order to set the stage for subsequent discussion of the mechanisms of action of disease-modifying treatments, and whether these should influence our treatment choices. Although the exact pathogenesis of MS is not fully understood, current knowledge has already led to the development of effective treatments, namely interferon (IFN) 3 and glatiramer acetate, both of which have been shown to reduce relapse rates, while IFN 3- 1 a also reduces confirmed disability progression. Further increases in our understanding of the pathogenesis of MS are likely to assist in the identification of new targets for disease-modifying therapies and in the optimisation of current treatments..

Antigen-Presenting Cells↗

PubMedDate not supplied

Treatment of ankylosing spondylitis with disease modifying antirheumatic drugs.

Ankylosing spondylitis (AS) is a common (prevalence 0.2-0.9%) chronic inflammatory disease that mainly affects young males and is characterised by inflammatory back pain with sacroiliitis and often arthritis of the peripheral joints. The disease can lead to deformities of the vertebral column, joints and extra-spinal structures, e.g. the eye (uveitis). Non-steroidal anti-inflammatory drugs (NSAIDs) and physical therapy seem to improve the long-term outcome of AS. However, the effect of disease modifying antirheumatic drugs (DMARDs) is less impressive compared with other rheumatic diseases, such as rheumatoid arthritis (RA). In placebo controlled trials, sulfasalazine showed some improvement of disease activity, especially in spondyloarthropathy patients with peripheral arthritis. Altogether the number of therapeutic options for AS is limited and other drugs, such as leflunomide or thalidomide, should be explored further in placebo-controlled trials.

Adrenal Cortex Hormones↗

PubMed1988

Clonotypic heterogeneity in experimental interstitial nephritis. Restricted specificity of the anti-tubular basement membrane B cell repertoire is associated with a disease-modifying crossreactive idiotype.

Experimental anti-tubular basement membrane (anti-TBM) disease is an autoimmune interstitial nephritis elicited in susceptible rodents after immunization with renal tubular antigen. The nephritogenic antigen in the immunizing preparation is 3M-1, a 48,000 Mr noncollagenous glycoprotein. The hallmarks of the renal lesion are the presence of anti-TBM antibodies (anti-TBM-Ab) and a dense mononuclear cell infiltrate. The anti-TBM B cell repertoire in this disease was analyzed using a library of 22 anti-TBM mAbs generated in a prototypically susceptible Brown Norway rat. These anti-TBM mAbs were all demonstrated to be 3M-1 specific and their characterization formed the basis for the following observations: (a) The size of the anti-TBM B cell population is estimated at 58 distinct clones; (b) by competitive inhibition criteria, all anti-TBM mAbs recognize the same (or spatially close) epitope(s) on 3M-1. This focused recognition was maintained in spite of considerable variability in affinity. Epitopic dominance could also be demonstrated in human polyclonal anti-TBM antisera from a patient with anti-TBM disease; and (c) a crossreactive idiotype was documented, and antisera directed toward this set of variable region determinants was shown to be effective as a prophylactic regimen to abrogate disease, and as a therapeutic modality to arrest the progression of disease; (d) analysis of VH gene families suggested biased usage of Q52- and 7183-like families, although at least three gene families are used in the anti-TBM-Ab response. Thus, the anti-TBM B cell compartment in BN rats is moderately large, but is primarily focused to a single epitope on the nephritogenic antigen and is associated with a disease-modifying crossreactive idiotype.

Animals↗

PubMedDate not supplied

Role of cognitive testing in disease modifying AD trials.

Cognitive impairment is a key feature of Alzheimer's disease (AD). Cognitive performance will therefore be an important outcome measure in disease modifying drug trials. However, cognitive assessment also has several limitations such as a large inter and intra individual variability and floor and ceiling effects. To reduce the effect of these limitations on the accuracy with which drug-related changes can be detected, it is proposed to analyse cognitive change using a slope analysis. In addition, it is suggested to use as the main outcome measure for cognitive impairment a neuropsychological compound score that is based on a z-score transformation of a number of well-validated tests. The selection of these tests would depend on a number of study characteristics such as the inclusion criteria and the length of follow-up.

Alzheimer Disease↗

PubMed1993

The relative toxicity of disease-modifying antirheumatic drugs.

OBJECTIVE: To compare the toxicities of commonly employed disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA). METHODS: Toxicity Index scores, computed from symptoms, laboratory abnormalities, and hospitalizations attributable to DMARD therapy, were assessed in 2,747 patients with RA receiving 3,053 courses of 6 DMARDs and 1,309 courses of prednisone over 7,278 patient-years. Results were adjusted for severity of illness and other covariates. RESULTS: Least toxic was hydroxychloroquine (mean +/- SEM score 1.38 +/- 0.15), followed by intramuscular gold (2.27 +/- 0.17) and the closely grouped D-penicillamine (3.38 +/- 0.36), methotrexate (3.82 +/- 0.35), and azathioprine (3.92 +/- 0.39). Auranofin (5.25 +/- 0.32) was most toxic, but this toxicity resulted from a high frequency of minor complications. Hospitalizations because of auranofin or hydroxychloroquine therapy were not noted. Prednisone (3.83 +/- 0.39) was of comparable toxicity, although it is likely that not all events of prednisone toxicity were captured. For reference, the toxicity of methotrexate and azathioprine was similar to that of the most toxic nonsteroidal antiinflammatory drugs (NSAIDs) (indomethacin 3.99, tolmetin sodium 3.96, and meclofenamate 3.86). Hydroxychloroquine showed less toxicity than the most commonly used prescription NSAIDs. CONCLUSION: There are substantial differences in toxicity among DMARDs and less important differences in toxicity between specific DMARDs and specific NSAIDs.

Anti-Inflammatory Agents↗

PubMed1988

Antimalarial agents compared with or in combination with other disease-modifying antirheumatic drugs.

Available published comparisons of antimalarial drugs with other disease-modifying antirheumatic drugs (DMARDs) are reviewed, as well as reports of combinations of DMARDs, in the treatment of rheumatoid arthritis and juvenile rheumatoid arthritis. These reports suggest that antimalarial drug toxicity is less than that of parenteral gold, D-penicillamine, auranofin, or dapsone. Its efficacy appears to be equal to or slightly less than that of most comparison DMARDs. Combinations of DMARDs with antimalarials are probably used by a substantial proportion of rheumatologists, but the few prospective, double-blind studies with a balanced design show little or no advantage to combination DMARD therapy. Open, nonrandomized studies and preliminary reports suggest that combination therapy may be useful, usually when another DMARD is added to one or more DMARDs to which the patients did not have a satisfactory response. A few large, prospective, double-blind, randomized studies comparing hydroxychloroquine with several other DMARDs and placebo are needed to establish more confidence in the relative efficacy and utility of hydroxychloroquine. Although the rationale for combination DMARD therapy is attractive, additional preliminary studies of the various possible combinations and doses are needed before definitive trials of promising combinations can be justified.

Anti-Inflammatory Agents↗

PubMed2005

US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles.

Several disease-modifying agents (DMAs) are approved for the treatment of multiple sclerosis, including three interferon (IFN)-beta products, glatiramer acetate and mitoxantrone. This article reviews the adverse event profiles of these DMAs based on the pivotal phase III trials, and provides practical guidelines for managing adverse effects. In general, the most common adverse events associated with IFN beta therapy are flu-like symptoms, including fever, chills and myalgias, and headache. The flu-like symptoms typically resolve within 24 hours and may be mitigated by over-the-counter anti-inflammatory agents. Adverse events related to glatiramer acetate therapy include injection-site reactions and a systemic reaction consisting of flushing, chest tightness, palpitation, anxiety or dyspnoea. The systemic reaction is transient (30 seconds to 30 minutes) and self-limited. Mitoxantrone may cause nausea, vomiting, alopecia, amenorrhoea and myelosuppression; isolated cases of acute leukaemia and dose-related cardiotoxicity have been reported in the literature. Longer-term tolerability data on mitoxantrone as a treatment for multiple sclerosis are needed. It is important for physicians to counsel patients on DMA-related adverse effects, most of which are transient and of mild-to-moderate severity. Various strategies that can be employed to prevent or manage these adverse effects and lessen their impact on the patient are discussed.

Clinical Trials as Topic↗

PubMed2003

Patterns of disease modifying antirheumatic drug use in a Spanish cohort of patients with rheumatoid arthritis.

OBJECTIVE: To determine the adequacy of disease modifying antirheumatic drug (DMARD) prescription to disease activity in patients with rheumatoid arthritis (RA) and to assess whether the reasons for DMARD discontinuation agree with published evidence. METHODS: Cross-sectional analysis of the baseline year of a RA cohort (n = 788) randomly selected from the clinical registries of 34 centers. Data about current and previous DMARD use was collected from medical records and confirmed by the patient. Disease activity score (DAS), Health Assessment Questionnaire (HAQ) and Larsen scores, and other clinical data were obtained during the study visit. RESULTS: At baseline visit, 607 patients (77%) were receiving one or more DMARD. Mean DAS, HAQ, and Larsen scores (+/- SD) were: 3.40 +/- 1.22, 1.6 +/- 0.4, and 54.68 +/- 26.37, respectively. Methotrexate (MTX) was the most frequently prescribed DMARD and parenteral gold salts (GS) showed the highest rate of discontinuation. MTX was used as single therapy in a significantly higher proportion (64.3%) than other DMARD (< 50%) and treatment discontinuation due to inefficacy was significantly less frequent (25.5%) than with other DMARD (> 40%). However, the DAS28 was significantly worse in the group treated with MTX in single therapy than in the group treated with GS alone (4.13 vs 3.43; p = 0.032). CONCLUSION: Despite the high use of DMARD among Spanish patients with RA, a significant number of them still have poor control of the disease. In addition, our data show a different perception of ineffectiveness depending on the DMARD used. A non-systematic use of objective quantitative tools for assessment of RA activity and some non-evidence based decisions on the management of DMARD may account for these findings.

Activities of Daily Living↗

PubMed1997

Management of oral complications of disease-modifying drugs in rheumatoid arthritis.

Stomatitis is a troublesome adverse effect of disease-modifying anti-rheumatic drug (DMARD) therapy in rheumatoid arthritis (RA) patients. This review presents data to examine the incidence, clinical features and consequences of DMARD-related stomatitis, and suggests an algorithm for its clinical management. The specific objectives of the two studies presented here were to determine the incidence of DMARD-related stomatitis and its effect on DMARD continuation, and secondly to identify the clinical and laboratory risk factors. We investigated two cohorts of patients: (i) a retrospective survey of data collected from drug monitoring clinics run for patients on DMARDs from 1987 to 1994 involving 1539 patients and 2394 drug exposures; (ii) a prospective study of 25 consecutive RA patients presenting with DMARD-related stomatitis compared to 29 RA controls with no history of DMARD stomatitis. The retrospective survey showed that 2% of DMARD patients stopped therapy because of stomatitis, but 55% of these were able to resume the same therapy. In the case control study. 24% of patients discontinued temporarily and 8% permanently. Cases of DMARD-related stomatitis differed from controls in that they had a higher incidence of previous mouth ulcers (40% vs 14%), they smoked less (8% vs 31%) and Schirmer's test was more often abnormal (44% vs 21%). There were no differences in RA severity, disease activity or oral hygiene. Haematinic deficiencies were equally common in cases and controls: 30% for iron, 8% for vitamin B12 and 24% for folic acid. Herpes simplex virus was involved in a minority (8%) of cases. In conclusion, the occurrence of stomatitis in RA patients on DMARD should not lead to cessation of drug therapy, but to a careful evaluation so that patients may be maintained on effective treatment.

Aged↗

PubMed2006

Down regulation of multidrug resistance protein-1 expression in patients with early rheumatoid arthritis exposed to methotrexate as a first disease-modifying antirheumatic drug.

BACKGROUND: Methotrexate (MTX) is the current gold standard conventional disease-modifying antirheumatic drug (DMARD) and is effluxed from cells by several transmembrane proteins, including multidrug resistance protein-1 (MRP1). It is hypothesised that the overexpression of these proteins may mediate reduced efficacy of MTX. To date, it is unclear how expression of these proteins changes over time or after exposure to drugs. AIMS: To compare MRP1 expression in newly diagnosed patients with DMARD-naive rheumatoid arthritis with that in healthy controls and to investigate how MRP1 expression changed after exposure to MTX. METHODS: 18 newly diagnosed patients with DMARD-naive rheumatoid arthritis and 14 healthy controls were recruited. Peripheral blood mononuclear cell counts were taken at baseline and after 6 months' treatment with MTX. Cells were separated by density gradient centrifugation and MRP1 expression was measured using the QCRL-1 monoclonal antibody. RESULTS: MRP1 expression in patients did not seem to be up regulated compared with that in healthy controls. In patients who were positive for MRP1 at baseline (61%), treatment with MTX and folic acid led to a marked down regulation of MRP1 expression at 6 months. CONCLUSION: In patients with rheumatoid arthritis expressing MRP1, treatment with MTX and folic acid led to down regulation of MRP1 expression. Further studies are required to determine the mechanism behind this observation and whether MRP1 expression mediates altered efficacy to MTX.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Commentary: evaluating disease modifying treatments in multiple sclerosis.

OBJECTIVE: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from pound 42,000 (66,469 dollars; 61,630 euro) to pound 98,000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than pound 20,000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. CONCLUSIONS: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments.

Cost-Benefit Analysis↗

PubMed2002

[Pharmacogenetics of disease modifying anti-rheumatic drugs].

There are large differences in the effectiveness of disease modifying anti-rheumatic drugs(DMARD) from one person to the next. Adverse drug reactions caused by DMARD can also occur to some patients, but do not occur to others. One possible cause of the differences in the effectiveness and adverse drug reactions is genetic variation in how individuals metabolize drugs. The Human Genome Project heralds new opportunities for using information about genetic variation to predict responses to drug therapies, called pharmacogenetics. Based on pharmacogenetics, tailor-made drug therapy is going to be realized. Our recent studies revealed the relationship between genetic polymorphisms of drug metabolizing enzymes and the efficacy of methotrexate or sulfasalazine in patients with rheumatoid arthritis, suggesting pharmacogenetics is applicable to the treatment of rheumatoid arthritis.

Antirheumatic Agents↗

PubMed2026

Disease-modifying therapy uptake in a pediatric-onset multiple sclerosis population, British Columbia, Canada.

BACKGROUND: The treatment of pediatric-onset multiple sclerosis (POMS) is evolving as disease-modifying therapies (DMTs) undergo pediatric clinical trials. However, most DMTs remain off-label in children resulting in barriers to access and variability in treatment patterns across jurisdictions. The aim of this study was to describe trends in DMT uptake in POMS in British Columbia, Canada. METHODS: We utilized linked clinical and administrative datasets to identify MS with onset <18 years-of-age and assess DMT uptake from dispensed prescriptions between January 1, 1996 and March 1, 2020 in British Columbia, Canada. RESULTS: Of 173 POMS cases (median follow-up = 11.5 years), 32 (18%) filled a DMT prescription <18 years-of-age; 76 (44%) did so at any age. Moderate-efficacy therapies (beta-interferons/glatiramer acetate/teriflunomide/dimethyl fumarate) were the initial DMT in 60 cases (79%) overall, however by the end of follow-up a high-efficacy therapy was the most recent DMT dispensed for 52/76 cases (68%). After 2016, anti-CD20 monoclonal antibodies became the most common DMT class dispensed. CONCLUSIONS: Moderate-efficacy therapies were the more common initial DMT dispensed for individuals with POMS, but more than two-thirds eventually received a high-efficacy therapy. Only a minority of POMS cases were first dispensed a DMT under age 18 years.

Disease modifying therapies↗

PubMed2001

A clinical and economic review of disease-modifying antirheumatic drugs.

Rheumatoid arthritis is one of the most common chronic systemic inflammatory diseases, affecting approximately 1% of the adult population. Disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of treatment for rheumatoid arthritis when combined with physical therapy and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs. Recently, a number of new biological therapies have been introduced for the treatment of this condition and will have a major impact on the future management of this disabling disease. In this review, we summarise data on the efficacy and tolerability of the currently available DMARDs, including gold compounds, antimalarials, penicillamine, cytotoxic drugs (azathioprine and cyclophosphamide), sulfasalazine, methotrexate, leflunomide, cyclosporin, anti-tumour necrosis factor agents, combination therapy and apheresis. A literature review and quality assessment of economic evaluations of DMARDs is presented, illustrating that there has been a paucity of economic evaluations on these agents and showing the variable quality of those studies that are available. The manuscript also addresses the pharmacoeconomic implications of the new agents for rheumatoid arthritis; the need for formal long term economic evaluations in order to determine the cost effectiveness of these costly, but highly effective, new treatments is emphasised.

Antirheumatic Agents↗

PubMed1999

Disappointing longterm results with disease modifying antirheumatic drugs. A practice based study.

OBJECTIVE: To evaluate the longterm effectiveness of disease modifying antirheumatic drugs (DMARD) in an inception cohort of patients with rheumatoid arthritis (RA) seen by rheumatologists. METHODS: We performed a retrospective audit of the records of patients with onset of RA between January 1985 and June 1994. Charts were reviewed from the time of diagnosis to the last consult. Survival analysis was performed using Kaplan-Meier and Cox proportional hazard regression to adjust for potential confounders. RESULTS: A total of 2296 DMARD therapies were analyzed. Roughly half were started within 2 years of disease onset. By 16 months, 50% of the DMARD therapy courses had been discontinued, and after 4.5 years 75% had been discontinued. Over all, methotrexate (MTX) had the highest probability of continuation. After roughly 3 years 50% of patients were still receiving MTX, compared to one-third of patients who received antimalarials or intramuscular gold, 30% D-penicillamine, 25% sulfasalazine, and 18% oral gold. After 6 years, when considering all DMARD together, only 20% of the therapies had not been discontinued, with no substantial differences between drugs. Toxicity from gold compounds occurred within the first 18 months of therapy and stabilized thereafter. For MTX, withdrawals due to toxicity continued throughout therapy. CONCLUSION: This is the largest observational study examining the longterm termination rates of DMARD in patients followed from the time of their initial consult. Our results confirm previous reports of short therapeutic times, even for patients treated early in the course of their disease. MTX appears to be the best drug within the first 5 years of disease. These differences, however, decrease in the longer term. It is unclear whether the results observed for MTX within the first years of therapy translate to better health status in the longer term when compared to other DMARD.

Antirheumatic Agents↗

PubMed1995

Overview of combination second-line or disease-modifying antirheumatic drug therapy in rheumatoid arthritis.

This article discusses the use of combinations of disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). Patients with RA have a disease that can be disabling and life threatening and current therapies do not prevent these complications. The need for more aggressive therapy is apparent. The rationale for combinations of DMARDs is explored and the efficacy and safety of reported combinations is summarized. The variables to be reviewed in selecting a combination of DMARDs are examined. Newer approaches employing multiple DMARDs will be considered.

Antirheumatic Agents↗