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PubMed2003

Update on disease-modifying antirheumatic drugs in the treatment of systemic sclerosis.

Treatment of systemic sclerosis has been somewhat haphazard and treatment has often been "borrowed" from the experience gained from treating other connective tissue diseases. There was a period of time that was focused mainly on organ-specific manifestations of systemic sclerosis and some advance in preventing vital organ damage (such as renal crisis) was achieved. The vast improvement in mortality from the use of ACE inhibitors raises one's hopes for other effective therapeutic interventions. At this juncture, the evidence is strong that the ACE inhibitors that are used in scleroderma renal crisis are disease-modifying, even without proving it by a randomized controlled trial. The evidence is strong that the use of epoprostenol for primary pulmonary hypertension is life-saving; however, whether epoprostenol is life-saving in the pulmonary hypertension in scleroderma remains to be proven. There are suggestions that bosentan (for the pulmonary hypertension of scleroderma), cyclophosphamide (for SSc alveolitis), stem cell transplant, interferon-gamma (for interstitial pulmonary fibrosis), and methotrexate (for the skin thickening of diffuse scleroderma) may improve organ function or functional activities, but whether they are truly disease-modifying remains to be proven. As we increase our understanding of the pathophysiology of systemic sclerosis and we learn how better to design trials for systemic sclerosis, we may be more successful in developing optimal disease-modifying therapy. Although the treatment of systemic sclerosis remains difficult, there are an increasing number of potentially effective regimens that are undergoing clinical investigations. A rational approach to therapy seems possible, based on a hypothesis of the pathogenesis of systemic sclerosis. Thus, there is accumulating evidence that supports the use of prostacyclin derivatives to treat systemic sclerosis, some evidence that antifibrotic regimens may be effective, and moderate evidence that immunosuppression also may be effective in certain stages of this disease.

Antirheumatic Agents↗

PubMed2002

International consensus statement on the use of disease-modifying agents in multiple sclerosis.

OBJECTIVE: To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. METHODS: An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment. RESULTS: A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. CONCLUSIONS: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available.

Adjuvants, Immunologic↗

PubMed2004

Neutralizing antibodies to disease-modifying agents in the treatment of multiple sclerosis.

Protein- and peptide-based disease-modifying agents for multiple sclerosis (MS), including interferon beta (IFNbeta) and glatiramer acetate (GA), have been associated with the formation of antibodies. Neutralizing antibodies (NAbs) block or neutralize the biological effects of the protein or polypeptide, potentially decreasing the therapeutic effects of these agents. Although the clinical relevance of antibodies against GA requires further investigation; both the incidence of NAbs to the three IFNbeta products (IFNbeta1b-Betaseron, IFNbeta1a-Rebif, and IFNbeta1a-Avonex) and the clinical relevance are quite clear. Data from clinical trials of IFNbeta products show that the immunogenicity of Betaseron > Rebif > Avonex and persistent NAbs reduce the clinical efficacy of IFNbeta. Because the initial detection of NAbs in the serum of patients receiving IFNbeta usually occurs between 6 and 15 months and appears to precede any apparent reduction in clinical efficacy by approximately 6 to 12 months, trials with a duration of less than 3 years are problematic when the clinical impact of NAbs is assessed. The potential development of NAbs is an important consideration in selection and monitoring treatment of MS. Long-term prospective studies are needed to further define the clinical effects of NAbs on patients receiving disease-modifying therapies for MS.

Antibody Formation↗

PubMed2004

Factors influencing the beliefs of patients with rheumatoid arthritis regarding disease-modifying medication.

OBJECTIVE: To investigate factors influencing the beliefs of patients with rheumatoid arthritis (RA) regarding disease-modifying medication. METHOD: Twenty-nine patients with RA either starting a disease-modifying anti-rheumatic drug (DMARD) for the first time or changing DMARD were recruited. Semi-structured interviews, activity diaries and focus groups were conducted over 9 months. A coding framework was developed and data analysed using the constant comparative method to identify key themes. RESULTS: DMARDs were perceived as central to the management of RA but strong concerns were expressed about potential long-term effects. Beliefs about DMARDs were informed by material from a wide range of sources. Judgements of efficacy were influenced by symptom relief, occurrence of side-effects and perception of alternative treatment options. Perception, reporting and tolerance of side-effects differed widely between individuals. The emotional impact of starting and being withdrawn from medication appeared stronger in people with more experience of DMARD use. CONCLUSIONS: Patients have complex and evolving belief systems relating to DMARDs. Understanding these systems will facilitate the provision of appropriate information and effective support not only in decision-making about treatment but also in relation to discontinuing treatment.

Adult↗

PubMed1992

Double blind, placebo controlled study of metronidazole as a disease modifying agent in the treatment of rheumatoid arthritis.

Anecdotal reports suggest that metronidazole may have disease modifying activity in the treatment of rheumatoid arthritis. To assess possible beneficial effects a double blind, comparative trial of metronidazole and placebo was performed. Fifty patients with active rheumatoid arthritis were randomly allocated to receive active drug (n = 24) or placebo (n = 26) and reviewed at weeks 0, 1, 4, 8, 12, 16, and 24. Detailed assessment of drug safety, biochemical and haematological parameters, and efficacy was made at these dates. Dose regimen was 400 mg twice daily from weeks 0 to eight, increasing to 400 mg three times a day from weeks nine to 24 provided that no adverse effects were recorded. Most patients were unable to tolerate metronidazole because of side effects or lack of efficacy, with only five (21%) continuing to take the drug at 24 weeks. For those patients attaining 12 weeks of treatment an overall improvement in articular index and morning stiffness was found. No improvement in laboratory indices of disease activity was seen, however. In this study metronidazole did not have disease modifying properties and was unacceptably toxic.

Adult↗

PubMed1996

[Development of standards by the Norwegian Society of Rheumatology. Control of disease modifying drugs].

Rheumatoid arthritis is a serious disease associated with increased morbidity and mortality, and requires adequate routines for therapy and follow-up examination. This article presents the work of the Norwegian Society for Rheumatology to improve the quality of the therapeutic assessment of patients with rheumatoid arthritis in Norway. The process of reaching an agreement involved a large number of rheumatologists. The final meeting included a variety of activities, plenary lectures, workshops, group discussions and opinion polls. A literature search through Medline was provided continuously. Agreement was achieved on a programme for monitoring therapy with disease-modifying antirheumatic drugs, which was to comprise visits to the physician and laboratory tests. This programme was later voted on and affirmed by the Annual Meeting of the Norwegian Society for Rheumatology. Proposals were issued regarding endpoint measures to assess progression of the disease. These proposals can be expected to improve the quality of treatment and management of patients with rheumatoid arthritis, both in primary health care and in the specialized rheumatological health service.

Antirheumatic Agents↗

PubMed1984

Possible disease-modifying effects of naproxen in the adjuvant-arthritic rat.

Naproxen was evaluated for possible disease modifying effects in the Freund's adjuvant injected rat (AIR). Oral administration of the clinical dose, 7 mg/kg/day, lead to an almost complete inhibition of hindpaw swelling and cartilage and bone erosion. This was noted in animals maintained on drug as well as those in which therapy was discontinued. AIR, comparable to arthritic patients, demonstrate a reduced lymphocytic response to T cell mitogens. This response was normalized in naproxen-treated rats. These results suggest that naproxen has a disease modifying effect in the AIR.

Animals↗

PubMed1999

Disease-modifying antirheumatic drugs.

Rheumatologists now seem to accept that early treatment of patients with rheumatoid arthritis with disease-modifying antirheumatic drugs is required if erosions are to be prevented. Methotrexate remains the most popular disease-modifying antirheumatic drug and is used in the most popular combination treatments, although the dose needs to be reduced in the elderly and those with renal dysfunction. The combination of sulfasalazine, methotrexate with reducing high-dose prednisolone, is demonstrated to be cost-effective in patients with rheumatoid arthritis, but although several other combinations have been reported effective in patients with rheumatoid arthritis, most trials do not have the power to provide a definitive answer as to the best combination available, if one exists.

Antirheumatic Agents↗

PubMed2004

Chinese herbs as immunomodulators and potential disease-modifying antirheumatic drugs in autoimmune disorders.

Autoimmune diseases are a group of illnesses with multiple organ involvement. The prototype of this group of disorders is rheumatoid arthritis (RA) that aside from systemic organ involvement mainly presents with progressive destruction of many joints. Both activation and defective apoptosis of immune effector cells like T and B lymphocytes and macrophages play critical roles in the pathogenesis of autoimmune disorders. Current therapy for autoimmune diseases recommends a combination of several disease-modifying antirheumatic drugs (DMARDs) that preserve different immunomodulatory mechanisms. Because of limited success in prevention of RA joint destruction for currently available DMARDs, the development of more effective and less toxic DMARDs has been one of the major goals for pharmaceutical companies. The introduction of leflunomide and anti-tumor necrosis factor alpha therapies to the market recently serves as examples. In this context, the experience from ancient Chinese medicine gives an alternative consideration looking for potential DMARDs. Two commonly prescribed Chinese antirheumatic herbs are Tripterygium wilfordii hook f (TWHf) and tetrandrine (Tet) that preserve both anti-inflammatory and immunosuppressive effects. Importantly, the TWHf- or Tet-mediated immunomodulatory mechanisms are evidently different from the known DMARDs. The synergistic effects have also been demonstrated between these two Chinese antirheumatic herbs and DMARDs like FK506, cyclosporin and possibly chloroquine. Another potential Chinese herb for this consideration is Ginkgo biloba. This review summarizes evidence-based in vivo and in vitro studies on Chinese herbs as immunomodulators and potential DMARDs.

Adjuvants, Immunologic↗

PubMed1991

Disease-modifying antirheumatic drugs: gold, penicillamine, antimalarials, and sulfasalazine.

In the assessment of the effects of disease-modifying antirheumatic drugs, three or four clinical measurements supported by the erythrocyte sedimentation rate, and sometimes radiographs, are generally agreed to be correct. Some advocate functional assessments also, or even alternatively. Several studies compared gold, penicillamine, antimalarials, and sulfasalazine either with each other or with placebo, and occasionally with methotrexate. No important differences between the general performance of the four drugs were found. More work was reported on sulfasalazine than on the other three drugs; the data support that it has a place in our armamentarium. Several important contributions concerned strategies of treatment. It is considered that disease-modifying antirheumatic drugs should be used earlier and more aggressively in rheumatoid arthritis. This aspect was perhaps the key note of the 1990 literature on this topic. As part of the new strategies, combination therapy is urged by some rheumatologists, whereas others urge caution on the grounds that we do not yet know enough about the effects of combinations, or by how much the risks of adverse effects are increased in combination.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

Exclusion of an extracolonic disease modifier locus on chromosome 1p33-36 in a large Swiss familial adenomatous polyposis kindred.

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited colorectal cancer predisposition syndrome, displays considerable inter- and intrafamilial phenotypic heterogeneity, which represents a major problem in genetic counselling of APC mutation carriers. The Min mouse model indicated a putative disease modifier locus on chromosome 4, which is syntenic to human chromosome 1p35-36. This finding was subsequently supported by parametric and nonparametric linkage analyses in FAP families, however, without identifying functional variants in candidate genes. Recently, germline mutations in the base-excision repair gene MYH (1p33-34) have been described in patients with multiple adenomas, pointing to a possible role as disease modifier in FAP. Here, we present critical reassessment of one of the largest FAP kindreds published, which was previously used in linkage mapping of 1p35-36. In this family, all affected members harbour the same APC germline mutation (5945delA), but display marked phenotypic variability, in particular regarding the occurrence of extracolonic disease that segregates in several branches of the family tree. Using updated clinical information, additional mutation carriers and polymorphic markers, fine mapping of the critical region as well as mutation analysis of the MYH gene were performed. These investigations allowed us to significantly exclude (i) the 1p33-36 region as a modifier locus and (ii) MYH as a modifier gene for extracolonic disease in this FAP kindred. Our results do not eliminate 1p33-36 from suspicion in other families, but clearly indicate that in our family linkage analysis of further putative candidate regions is necessary to identify a disease modifier locus in FAP.

Adenomatous Polyposis Coli↗

PubMed2003

Patients' willingness to participate in symptom-related and disease-modifying research: results of a research screening initiative in a palliative care clinic.

BACKGROUND: The growth of cancer symptom management research has been limited by challenges of slow recruitment and under-enrollment. One potential solution to this problem is the use of screening questions that identify patients who are interested in participating in research. The goal of this study was to evaluate this strategy in patients with cancer. METHODS: Two screening questions (for symptom management research and disease-modifying research) were integrated into the intake process of the palliative care clinic of an urban Veteran's Administration medical center. A chart review was conducted to extract patients' reported willingness to be recruited for research, explanations for their responses, demographic data, Memorial Symptom Assessment Scale Global Distress Index (GDI) subscale scores, and Eastern Cooperative Oncology Group performance score. RESULTS: Charts were reviewed for the first 100 patients seen for a palliative care clinic visit, 86 of whom had cancer. Patients were less likely to be interested in symptom-related research than in disease-modifying research (32 of 86 [37%] vs. 46 of 86 [54%]; sign test, P = 0.009). Patients' interest in each type of research was associated moderately (kappa = 0.41; P < 0.001). Independent predictors of interest in symptom management research included younger age, white race, and a lower GDI symptom distress score. Independent predictors of interest in disease-modifying research included only younger age and white race. CONCLUSIONS: Screening questions may be useful in identifying patients who are willing to be recruited for research. However, further study is needed to evaluate this process in other populations, as well as to determine whether screening questions introduce selection bias in the recruitment process.

Adult↗

PubMed1999

Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy.

The traditional "pyramid" or sequential approach to treatment of patients with rheumatoid arthritis involved use of a nonsteroidal anti-inflammatory drug for months to years while seeking to avoid use of second-line antirheumatic drugs until evidence of joint damage was seen. This approach led to short-term reduction of inflammation and a few remissions. However, long-term remissions were rare, and most patients experienced poor long-term outcomes, including joint destruction, severe functional declines, considerable economic losses, work disability, and premature mortality. At this time, a "preventive" strategy is evolving in which early aggressive treatment with disease-modifying antirheumatic drugs is used, seeking to minimize long-term joint damage. When residual inflammation remains after maximum doses of single agents, as is usually the case, combinations of disease-modifying antirheumatic drugs appear to be a reasonable consideration for many patients. Methotrexate is the most commonly used "anchor drug" in combination therapy. Evidence from randomized, controlled clinical trials and observational studies have indicated increased efficacy and acceptable (and often lower) toxicity for combinations of methotrexate plus cyclosporine, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, and infliximab. Further studies lasting 5 years or more are needed to determine the long-term effectiveness, toxicities, and optimal clinical use of disease-modifying antirheumatic drug combinations. At this time, such combinations are taken by at least some patients under care of almost all rheumatologists, and it appears likely that they will be used increasingly in the coming decades.

Antirheumatic Agents↗

PubMed2001

Combination therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis.

There is increasing interest in using combinations of two or more disease modifying anti-rheumatic drugs to treat rheumatoid arthritis. The use of such combinations is increasing in routine clinical practice. We have identified 18 well-conducted, randomised controlled trials of the use of combinations of disease modifying drugs, and a number of open studies that provide helpful supportive information. The 18 trials involved 2221 patients. Two trials reported strongly positive results, six reported moderately positive results and ten gave largely negative results. The combination of methotrexate, sulfasalazine and hydroxychloroquine appears to be effective with an acceptable level of adverse effects. There is also evidence that the combination of methotrexate and cyclosporin is advantageous. With both combinations, there appears to be further advantages from using corticosteroids in addition to the combination, although the evidence for this is incomplete. The use of other combinations is of less value, and in particular combinations involving parenteral gold, penicillamine and azathioprine are best avoided. Finally, there is growing evidence from randomised trials that the combination of anti-tumour necrosis factor (TNF) therapy with methotrexate is effective and well tolerated. We have identified four randomised controlled trials of the use of combinations of anti-TNF with methotrexate that all reported results favouring this combination. There is insufficient evidence to support the use of other combinations involving immunotherapies at the present time.

Animals↗

PubMed1996

Disease-modifying antirheumatic drugs, including methotrexate, gold, sulfasalazine, antimalarials, and D-penicillamine.

The class of agents known as disease-modifying antirheumatic drugs remains the predominant treatment for rheumatoid arthritis. Methotrexate has again demonstrated efficacy in long-term studies, and more reports on its pharmacokinetics and possible mechanism of action have been published. Renal impairment has been highlighted again as a major risk factor for methotrexate toxicity, and studies have supported the American College of Rheumatology guidelines concerning elevated transaminases as a warning sign for liver toxicity. Although questions about the long-term efficacy of gold have again been raised, some interesting reports have focused on its mechanism of action. The sulfasalazine literature includes reports on possible immunomodulatory roles for the drug in the gastrointestinal tract. The usefulness of hydroxychloroquine has been confirmed in a large study of early rheumatoid arthritis. The minimal effective dose of D-penicillamine has been questioned in a clinical study. Combination therapy using existing disease-modifying antirheumatic drugs has not demonstrated major benefits over single-drug therapy.

Antimalarials↗

PubMed2002

Longterm maintenance therapy with disease modifying antirheumatic drugs.

Longterm safety and efficacy of disease modifying antirheumatic drugs (DMARD) have been challenging to assess. There are few studies that have evaluated patient outcome beyond 5 years. As patients may receive several DMARD over the course of their disease a long with nonsteroidal antiinflammatory drugs, corticosteroids, and other drugs for comorbidities, it is difficult to design and implement a trial to define a specific drug's longterm effect. Based on the findings of several key studies, however, it does appear that DMARD are safe when taken longterm, and that they are more likely to be discontinued because of inefficacy than toxicity. Although DMARD are often discontinued because of lack of efficacy, 12 year data suggest that DMARD can provide benefit over this period. The toxicity profiles vary significantly between DMARD. In addition, the time during therapy when the majority of these adverse effects most frequently appear is DMARD-specific. Prospective studies are needed to further clarify longterm safety and efficacy of the newer DMARD.

Adult↗

PubMed1990

Double blind placebo controlled trial of pulse treatment with methylprednisolone combined with disease modifying drugs in rheumatoid arthritis.

OBJECTIVE: To assess whether monthly treatment with intravenous methylprednisolone enhances or accelerates the effect of disease modifying drugs in patients with rheumatoid arthritis. DESIGN: A 12 month double blind, placebo controlled, multicentre trial in which patients with active rheumatoid arthritis were randomly allocated to receive pulses of either methylprednisolone or saline every four weeks for six months. At the start of the pulse treatment all patients were started on penicillamine or azathioprine. SETTING: Four rheumatology departments in Denmark. PATIENTS: 97 Patients (71 women, 26 men) aged 23-84 (mean 60) who had active rheumatoid arthritis of at least four weeks' duration despite treatment with non-steroidal anti-inflammatory drugs. MAIN OUTCOME MEASURES: Monthly clinical recording of morning stiffness, number of tender and swollen joints, blinded observers' evaluation of therapeutic effect, and patients' self assessed condition. Concomitant laboratory measurements of erythrocyte sedimentation rate and concentrations of C reactive protein and haemoglobin. Radiography to determine the number of erosions at the start of treatment and after 12 months. RESULTS: 57 Patients completed the trial, taking the same disease modifying drug throughout. Evaluation four weeks after each pulse treatment and at 12 month follow up showed no significant differences between the methylprednisolone and placebo groups in any of the clinical or laboratory variables. Radiography showed the same degree of progression of erosions in both groups. Evaluation of the total data on 97 patients and on the 57 who completed the trial showed the same lack of significance between the treatment groups. CONCLUSIONS: Intravenous pulse treatment with steroids can be recommended only for rapid temporary relief of flares of disease in patients with rheumatoid arthritis. The response is short lived. Repeated pulses of methylprednisolone at four week intervals do not improve the results of treatment with drugs that induce remission such as penicillamine and azathioprine.

Adult↗

PubMedDate not supplied

Predictive value of the CES-D in detecting depression among candidates for disease-modifying multiple sclerosis treatment.

The presence of depression is an important concern for patients with multiple sclerosis who are candidates for disease-modifying treatment, since depression may affect treatment adherence. The authors evaluated the positive predictive value of the Center for Epidemiologic Studies Depression Rating Scale (CES-D) in detecting depression among patients who were candidates for disease-modifying multiple sclerosis treatment. Of 47 patients who scored >/=16 on the CES-D, 74.5% (N=38) were found to have a depressive disorder. The results of the study indicate that case-finding for depressive disorders among multiple sclerosis patients can be facilitated by use of the CES-D scale.

Adolescent↗