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PubMed2004

Safety overview of new disease-modifying antirheumatic drugs.

Beginning in 1998, a surge of new agents has expanded treatment options for rheumatoid arthritis (RA) patients. Although the disease modifying potential of these agents is encouraging, their use must be weighed against an evolving array of new safety concerns. Because of the popularity of these agents with patients and rheumatologists alike, clinicians must be prepared to discuss the potential risks associated with novel disease-modifying antirheumatic drugs and biologic therapies as they begin to appear with greater frequency in practice. This article discusses the safety issues arising from clinical trial and postmarketing experience with several new and commonly used agents, with specific emphasis on adalimumab, etanercept, infliximab, anakinra, and leflunomide.

Antirheumatic Agents↗
PubMed1991

Disease-modifying agents and experimental treatments of rheumatoid arthritis.

The pharmacologic management of the rheumatoid arthritis (RA) patient involves the use of various classes of therapeutic agents to induce symptomatic relief and reduce disease activity. Aspirin and nonsteroidal antiinflammatory drugs are used initially to lessen the degree of pain and swelling associated with the inflammatory disease process. The addition of a heterogeneous class of compounds, "second-line" therapy (previously known as disease-modifying antiinflammatory rheumatic drugs), is advocated to modify the disease course itself. Second-line treatments include antimalarials, gold salts, D-penicillamine, azathioprine, and methotrexate. Randomized placebo-controlled trials ahve demonstrated the efficacy of these compounds in RA. Improvement in standard parameters of disease activity including the number of painful and swollen joints, duration of morning stiffness, and erythrocyte sedimentation rate has been noted with these second-line drugs. Whether they modify roentgenographic progression is under rigorous study. These agents alone or in combination rarely induce complete disease remission. Therefore, newer therapies are under intensive investigation and include sulfasalazine, cyclosporin A, and combination therapy.

Anti-Inflammatory Agents↗
PubMedDate not supplied

Treatment with immunosuppressive and disease modifying drugs during pregnancy and lactation.

Active rheumatic disease may necessitate the treatment of pregnant and lactating patients with disease modifying (DMARD) or immunosuppressive drugs. This review summarizes data from the literature, and attempts to give some recommendations. Possible teratogenic effects of gold, penicillamine, and chloroquine are still disputed. As long as the issue is not settled, it seems prudent to stop using these agents as soon as pregnancy is diagnosed. Hydroxychloroquine has been used by some rheumatologists for treating pregnant patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) without malformations detected in the neonates. Sulphasalazine does not increase the rate of congenital abnormalities. Selected case reports have not shown any teratogenicity of cyclosporine A so far. However, the drug may cause fetal retardation. The use of standard doses of azathioprine does not increase the risk of congenital anomalies. By contrast, the antitumor agents cyclophosphamide, chlorambucil, and methotrexate are possibly teratogenic when given during early pregnancy, but may be less harmful in late pregnancy. Data on the excretion of DMARD and the cytostatic drugs are sparse. Because of insufficient data, breast feeding is not recommended in patients on antimalarials, penicillamine, cyclosporine A, and cytostatic drugs. Intramuscular gold and sulphasalazine seem to impose no major risk on the nursing infant.

Abnormalities, Drug-Induced↗
PubMed2002

Identifying disease modifying genes in multiple sclerosis.

Evidence is mounting that genetic variation influences not only susceptibility to multiple sclerosis (MS), but also its course and severity. Identification of disease modifying genes, however, poses unique challenges, especially on how to classify the course and outcome of the disease in ways that may be relevant to analysis of biological factors that might be influenced by genes. The power of the statistical approaches to detect small effects of individual genes in complex disorders such as MS is problematic, and approaches to estimate power must be appropriate for the data. Nonetheless, using contemporary schemes of classification, genetic variants that influence disease course have been found; in fact, a small number have been confirmed to influence disease course in two or more independent studies. This review addresses strategies relevant to identification of disease modifying genes in MS, and summarizes and critically evaluates the current state of knowledge in this area.

Apolipoproteins E↗
PubMed2005

Cognitive evaluation of disease-modifying efficacy of galantamine and memantine in the APP23 model.

With increasing knowledge of molecular, biochemical and cellular events causing synaptic dysfunction and neurodegeneration in Alzheimer-diseased brain, preventive treatment strategies are emerging. Neuroprotective capacities have been attributed to galantamine and memantine. The age-dependent cognitive decline in the APP23 model was employed to evaluate disease-modifying efficacy of chronic treatment with both compounds. At age 6 weeks, heterozygous APP23 mice were subcutaneously implanted with osmotic pumps delivering saline, galantamine (1.3 or 2.6 mg/kg/day) or memantine (7.2 or 14.4 mg/kg/day). After 2 months of treatment, a 3-week wash-out period was allowed to prevent bias from sustained symptomatic effects. Subsequently, cognitive evaluation in the Morris water maze commenced. Galantamine low dose significantly improved spatial accuracy during probe trial. Memantine improved acquisition performance (path length) and spatial accuracy during probe trial in a dose-dependent manner. This is the first study reporting disease-modifying efficacy of galantamine and memantine in transgenic mice modeling Alzheimer's disease.

Alzheimer Disease↗
PubMed2002

Design and analysis of two-period studies of potentially disease-modifying treatments.

A number of two-period designs have been introduced in the neurological clinical trials literature to evaluate the effects of treatment on progressive diseases, using names such as withdrawal, active-extension, randomized withdrawal, randomized start, and staggered-start designs. After parallel groups complete the first period, treatment is either initiated or withdrawn in the second period in a subset of subjects. The purpose of the second period is to provide evidence of whether any effect of treatment observed during the first period is long-term ("disease-modifying") or short-term and transitory ("symptomatic"). A four-arm version, which we term a complete two-period design, has active/active, active/placebo, placebo/active and placebo/placebo respective treatment assignments in the two periods. We provide statistical models for these designs, describe some of the appropriate analyses, and investigate the relative efficiencies of various allocations and special cases. We describe extensions to full and partial factorial versions of such designs which permit efficient and simultaneous evaluation of disease-modifying and symptomatic effects of two or more treatments, along with possible interactions. Advantages and limitations of the various designs are discussed.

Alzheimer Disease↗
PubMed2004

Long-term treatment optimization in individuals with multiple sclerosis using disease-modifying therapies: a nursing approach.

The introduction of disease-modifying therapies (DMTs) for multiple sclerosis (MS) over the last 7 years has had a significant effect on the management of those living with this disease. Initially, the focus of improving treatment outcomes was on ensuring adherence to therapy by managing drug-related adverse events. However, treatment adherence is only one facet of ensuring optimal health outcomes for patients using DMTs. Therefore, a group of 80 nurses from Canada and the United States (The North American MS Nurses' Treatment Optimization Group) developed an evidence-based nursing approach to address the various factors involved in obtaining optimal patient outcomes. The goal of this nursing approach is to ensure the best possible clinical, subclinical, psychosocial, and quality-of-life outcomes for patients with MS using DMTs.

Adjuvants, Immunologic↗
PubMed1996

Disease-modifying activity of SK&F 106615 in rat adjuvant-induced arthritis. Multiparameter analysis of disease magnetic resonance imaging and bone mineral density measurements.

OBJECTIVE: To evaluate the effect of SK&F 106615 on joint integrity in rats with adjuvant-induced arthritis (AIA). METHODS: AIA was induced in Lewis rats on day 0, and the animals were treated either prophylactically (days 0-16 or days 0-23) or therapeutically (days 10-23) with SK&F 106615. Efficacy was determined by measurements of paw inflammation, bone mineral density (BMD) using dual x-ray absorptiometry, and magnetic resonance imaging (MRI). Joint integrity was also determined histologically, and serum interleukin-6 (IL-6) levels were measured as a marker of the antiinflammatory effects of the compound. RESULTS: Prophylactic treatment (days 0-16) of AIA rats with SK&F 106615 significantly inhibited paw volume at doses of 545 mg/kg/day given orally on 5 days each week. Extensive evaluation of joint integrity in rats treated with SK&F 106615 20 mg/kg/day orally for 23 days showed inhibition of paw volume, normalization of BMD, and significant improvement in disease by MRI and histologic assessment compared with the AIA controls. Elevated levels of serum IL-6 in AIA rats were reduced dramatically by SK&F 106615. Therapeutic treatment (days 10-23) resulted in similar protective effects measured by paw inflammation, BMD, and MRI. In the therapeutic protocol, serum IL-6 appeared to be a more sensitive marker of antiinflammatory activity than paw edema. CONCLUSION: Symptoms of AIA in rats are significantly reduced by prophylactic and therapeutic treatment with SK&F 106615. Of particular note, this compound appears to exert a protective effect on joint integrity and to have disease-modifying properties.

Absorptiometry, Photon↗
PubMed2004

Pharmacoeconomic considerations of multiple sclerosis therapy with the new disease-modifying agents.

Multiple sclerosis (MS) represents the second most common cause of neurological disability in young adults. The introduction of treatments that can change the natural course of the disease has focused attention on the economic burden of MS. There have been fears that the newly approved treatments for MS will ruin healthcare systems. Other published economic evaluations stress that the economic burden of a disease should be seen in a global perspective and that new treatments offer an opportunity to reduce the burden of the disease in the long-term. This paper reviews a number of key health economic studies in MS, which reveal the burden of MS on society and the cost-effectiveness of the new disease-modifying drugs, and highlight some unresolved issues. All relevant costs, including indirect costs and costs of informal care, should be taken into account for a global estimation of the cost/benefit balance. Further rigorous economic evaluations, focusing on the comparison of different available alternatives, are necessary. A major task will be the collection of data on the impact of the new disease-modifying therapies in reducing disability progression over the long-term, outside clinical trials. Gathering this kind of information is of critical importance in order to improve the precision of cost-effectiveness estimates in the future.

Adjuvants, Immunologic↗
PubMed2004

The cost of multiple sclerosis and the cost effectiveness of disease-modifying agents in its treatment.

Multiple sclerosis (MS) is one of the most common causes of neurological disability in young and middle-aged adults. The full economic cost of MS is substantial given that MS patients experience a major perturbation in their daily activities and the disease affects mainly young people who are obliged to restrict their levels of economic activity, either temporarily or permanently. A positive relationship exists between the direct and indirect costs of MS and its severity. Cost variations between countries exist because of differences in the costs of inpatient care, the number of ambulatory visits, drug usage and the extent and type of informal care. The development and availability of new agents has been accompanied by an increased optimism that treatment regimens for MS would be more effective. However, doubts have been expressed about the effectiveness of these treatments, which have compounded the problems associated with estimating the relative cost effectiveness of such interventions. In addition, variations in the utility scores associated with disease categories, the impact of relapses and the resulting utility losses, plus the speed of disease progression have all contributed to the difficulty of estimating the quality-adjusted life year (QALY) losses for a patient experiencing MS. Differences between studies with respect to the costs associated with each disability level, the timescale of the disease and the period over which costs and QALYs are to be measured, and the perspective employed in relation to costing have also resulted in a wide range of estimates being produced for the cost effectiveness of interferons and glatiramer acetate in the management of MS. These range from situations of cost savings, to over $US1.6 million (euro1.85 million) per QALY gained. Recent cost-effectiveness studies have benefited from more relevant and up-to-date data relating to disease progression and have generally produced more favourable cost-effectiveness ratios. However, the lack of homogeneity in the design of the studies partly accounts for the extent of variation in the estimates of cost effectiveness, and the difficulty of arriving at a consensus. The UK Department of Health has introduced a scheme that provides disease-modifying agents in the National Health Service for those patients with clinically active relapsing disease. Patients are monitored annually and payments to manufacturers are dependent on outcomes achieved. This initiative, although not without its detractors, will hopefully enhance the quantity and quality of evidence on the impact of drugs on disease progression and address some of the current difficulties with estimating the relative cost effectiveness of disease-modifying drugs in the treatment of patients with MS.

Cost-Benefit Analysis↗
PubMed2004

Disease modifying agent related skin reactions in multiple sclerosis: prevention, assessment, and management.

BACKGROUND: The objective for this article is to highlight some of the adverse skin manifestations associated with injectable disease modifying therapy for multiple sclerosis (MS). Early identification and intervention can often lead to minimal consequences and prolonged patient tolerance and compliance with these agents. At the University of Texas Southwestern Medical Center at Dallas and Texas Neurology in Dallas we actively follow approximately 5000 MS patients. The majority of our patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) are treated with one of the currently available disease modifying agents (DMAs). Our experience with these patients, and the challenges they face in continuing long-term treatment, constitutes the basis of our proposed treatment strategies. CONCLUSION: Skin reactions in response to injectable DMA therapy in MS are generally mild. However, some reactions can evolve into potentially serious lesions culminating in infection, necrosis, and in some circumstances requiring surgical repair.

Adjuvants, Immunologic↗
PubMed1999

[Disease modifying anti-rheumatic drugs(DMARDs)].

Several kinds of disease modifying anti-rheumatic drugs (DMARDs) can be utilized for the treatment of patients with rheumatoid arthritis (RA) to expect the prevention of joint damage progression and the improvement of quality of life. However, the methodology for the use of DMARDs is still controversial. On the basis of our prospective study, earlier introduction of DMARDs can be more efficient for the suppression of active disease. Thus, for the patients with more than three swollen joints, high ESR and CRP, immediate prescription of DMARD is recommended. And if these situation will not change even 6 months after starting the therapy, we should make all possible efforts to lead patients into remission using DMARD or corticosteroids, which would prevent patients from disability of joint function and thus would improve the quality of life of patients with early RA.

Antirheumatic Agents↗
PubMed2003

Disease-modifying antirheumatic drug therapy for spondyloarthropathies: advances in treatment.

The inflammatory arthritides included in the category of spondyloarthropathy (ankylosing spondylitis, psoriatic arthritis, reactive arthritis, undifferentiated spondyloarthropathy, and arthritis associated with inflammatory bowel disease) may cause significant, progressive morbidity. Therapy with nonsteroidal antiinflammatory drugs and traditionally used disease-modifying antirheumatic drugs, such as methotrexate, often fails in patients with more severe peripheral arthropathy and axial involvement, and alternative treatment options have been limited. With increased understanding of the pathologic processes involved in these disorders, new therapeutics have arisen and are being investigated in the various subtypes of spondyloarthropathy. This article reviews recent progress in disease-modifying therapy for spondyloarthropathy, including new biologic response modifiers, such as the tumor necrosis factor-alpha inhibitors etanercept and infliximab.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1986

Disease-modifying agents and immunosuppressive drugs in the elderly.

Disease-modifying and immunosuppressive therapies are required for elderly patients with rheumatic disorders. The evidence to date suggests that the criteria for choosing a particular drug is not vastly different from the choice in younger patients, and that the elderly have a similar response. More care is required in monitoring elderly patients on immunosuppressive drugs because of the potential for increased adverse reactions consequent on reduced functional capacity of major end organs. There is little data available to judge relative efficacy of these drugs in the elderly and with the 'greying' of the population these data should be sought after. With careful individual choice of drug and regular reassessment for effect and adverse drug reactions, many elderly patients with rheumatic diseases can obtain useful benefit from these agents.

Adrenal Cortex Hormones↗
PubMed1995

Disease-modifying antirheumatic drugs. Potential effects in older patients.

Disease-modifying antirheumatic drugs (DMARDs) are frequently used in rheumatoid arthritis. A number of physiological changes occur in the elderly which may modify the use of these medications. The most commonly used DMARDs are antimalarial drugs (particularly hydroxychloroquine), sulfasalazine and methotrexate. The principal mechanism of action of the antimalarials relates to the fact that they change intracellular pH, which downregulates numerous immune functions. Hydroxychloroquine is metabolised to 3 metabolites and has a very low clearance. It is moderately effective in dosages up to 6.4 mg/kg/day. While it is not the most effective of the DMARDs, it is the least toxic. Sulfasalazine is a prodrug which is enzymatically split in the bowel to form sulfapyridine (the principal active metabolite) and 5-aminosalicylic acid. The metabolism of sulfasalazine is complex and, to some extent, genetically determined. The mechanism of action of the drug is not well understood, but involves decreased production of cytokines and decreased proliferative response of lymphocytes. It may slow the rate of bony damage associated with rheumatoid arthritis. Nearly 50% of the patients who are prescribed sulfasalazine continue to receive the drug for up to 4 years. Sulfasalazine is not as well tolerated as hydroxychloroquine. Gastrointestinal toxicity, in particular, seems to be a problem in elderly patients taking this medication. Methotrexate is presently the most popular of the DMARDs for the treatment of rheumatoid arthritis. Methotrexate inhibits dihydrofolate reductase and adenosine release and has a secondary effect on cytokines and polymorphonuclear chemotaxis. It is highly metabolised within cells and remains there for prolonged periods. Up to 70% of patients who are prescribed methotrexate continue treatment for 5 years. Methotrexate treatment is associated with gastrointestinal, hepatic, cutaneous and, possibly, pulmonary adverse effects. The use of azathioprine, penicillamine and gold compounds is briefly reviewed in this article. Elderly patients have an increased incidence of rashes when using penicillamine, relative to young patients. There are no age-related differences in the efficacy and tolerability of azathioprine or gold therapy. The poor absorption and renal toxicity associated with cyclosporin, the new 'salvage' therapy in rheumatoid arthritis, make it generally unsuitable for use in the elderly, except under specialists' supervision.

Aged↗
PubMedDate not supplied

Disease-modifying antirheumatic drugs in rheumatoid arthritis: current concepts.

Disease-modifying antirheumatic drugs are used in virtually all patients with established rheumatoid arthritis. An increasingly large number of new drugs is now available. Furthermore, old therapies are being used in novel ways. Treatment is now begun earlier and patients are rarely left untreated. This report summarises recent developments regarding the drugs currently in use and those that may be available in the near future.

Anti-Inflammatory Agents↗
PubMed2026

Characteristics of early-onset, rapidly progressive scoliosis in spinal muscular atrophy type I treated with disease-modifying therapy -a multicenter retrospective study conducted in Japan.

In the era of disease-modifying therapy (DMT), almost all patients with spinal muscular atrophy (SMA) type I treated after onset, but before 6 months of age, develop early-onset, rapidly progressive scoliosis by 2 years of age, despite improvements in their motor function. Seven symptomatic patients with SMA type I who were treated before the age of 6 months were included in this retrospective observational study. Scoliosis had developed in all patients by 27 months of age. Among them, the patients who could stand with support or independently (standing patients; n = 3) tended to present with more progressive scoliosis than the sitters (n = 4). All standing patients demonstrated thoracic hyperkyphosis before or at the time of their scoliosis diagnosis. Despite receiving DMT, these patients continued to show residual key manifestations of SMA type I. Chronic difficulty maintaining posture due to trunk muscle weakness in the lying, sitting, or standing position was considered to be the main contributor to the development and progression of the scoliosis. The development and progression of such scoliosis, which begins in infancy, may be related to inappropriate postural management, which is not currently recognized as such by clinicians, caregivers, or guardians. In this population, it is important to closely monitor patients for such scoliosis from soon after the diagnosis of SMA. As this type of scoliosis progresses rapidly during the early developmental stage, when surgery is not possible, it is necessary to establish a proactive non-surgical management strategy for it.

Humans↗
PubMed2005

Trends in disease modifying antirheumatic drug prescription in early rheumatoid arthritis are influenced more by hospital setting than patient or disease characteristics.

OBJECTIVE: To characterise temporal trends and factors associated with the prescription of disease modifying antirheumatic drugs (DMARDs) at the initial consultation in early rheumatoid arthritis (RA). METHODS: Data from 2584 patients with early RA at 19 hospitals were extracted from the Swedish Rheumatoid Arthritis Register for the period 1997-2001. Disease characteristics and DMARD prescription at first consultation with the rheumatologist were investigated using cross tabulation and logistic regression. RESULTS: DMARD prescriptions, particularly for methotrexate, increased from 1997 to 2001 independently of patient characteristics. Stratification by hospital type showed that patients in district hospitals were less likely to be prescribed DMARDs than those in university hospitals (adjusted odds ratio (OR) = 0.53 (95% confidence interval (CI) 0.40 to 0.69), p<0.001), independently of confounding factors. Association of the DAS28 with the likelihood of DMARD prescription was greater among patients attending district hospitals (OR = 1.65 (1.34 to 2.02), p<0.001) than those at university hospitals (OR = 1.23 (1.07 to 1.41), p = 0.003) and county hospitals (OR = 1.34 (1.01 to 1.63), p = 0.003). Interaction testing indicated that the difference was significant (p = 0.007). CONCLUSIONS: Temporal trends in DMARD prescription indicate an increasingly aggressive approach to disease management among Swedish rheumatologists. However, the association of hospital type with DMARD prescription suggests that the adoption of research findings in clinical care varies considerably.

Adolescent↗