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Commonly used disease-modifying antirheumatic drugs in the treatment of inflammatory arthritis: an update on mechanisms of action.

Although disease-modifying drugs are extensively used in the treatment of inflammatory arthritides such as rheumatoid arthritis (RA), the actual underlying mechanisms of action of these agents remains somewhat unclear. Many investigators have studied the effects of these agents, often with particular attention being paid to alterations in inflammatory cytokine production, cell proliferation and activation, signal transduction pathways, and enzyme inhibition. By gaining a more complete understanding of these mechanisms, further information may be had regarding the pathophysiology of RA as well as other autoimmune diseases. In the following review we will examine some of the more recent studies of drug mechanisms, focusing on the most commonly used anti-rheumatic medications in the treatment of RA.

Antirheumatic Agents↗

Treating rheumatoid arthritis early with disease modifying drugs reduces joint damage: a randomised double blind trial of sulphasalazine vs diclofenac sodium.

BACKGROUND: Current disease management in rheumatoid arthritis (RA) has moved towards "inverting the therapeutic pyramid" by introducing disease-modifying anti-rheumatic drugs (DMARDs) early. Despite the logic of early DMARD therapy, there is a dearth of supportive evidence for this approach. We report a randomised controlled trial comparing sulphasalazine monotherapy with diclofenac monotherapy in early RA. The primary aim was to provide unequivocal evidence that early DMARDs prevent erosive damage. The secondary aim was to evaluate if sulphasalazine used alone has comparable symptomatic benefits to NSAIDs. METHODS: 117 patients with RA for under 12 months of diagnosis (mean 2 months) were randomised (62 sulphasalazine; 55 diclofenac). Sulphasalazine patients comprised 76% women, and 58% were rheumatoidfactor positive. Diclofenac patients comprised 74% women, and 54% were seropositive. 36% completed 12 months of therapy (16 sulphasalazine; 26 diclofenac); sulphasalazine was given for a mean period of 21 weeks and diclofenac for a mean period of 33 weeks. Results were analysed on an intention to treat basis. RESULTS: After 12 months the mean number of new erosions in patients randomised to receive sulphasalazine was 2.0 (95%CI 0.9, 3.1) and in patients randomised to receive diclofenac was 7.5 (95%CI 4.1, 10.9; p = 0.002 by Student's unpaired t-test). An analysis of valid compliant completers showed the mean number of new erosions in patients who received 12 months therapy with sulphasalazine was 2.3 (95%CI 0.6, 4.0) and in patients who received 12 months diclofenac was 10.5 (95%CI 5.0, 15.9; p = 0.018 by Student's unpaired t-test). The Ritchie articular index, swollen joint counts and pain scores decreased with both sulphasalazine and diclofenac, with mean falls in both groups of 15-20% at 2 weeks and 30-40% at 4 and 8 weeks. There were no differences between treatments. Disease activity scores showed similar highly significant mean decreases within both treatment groups (P < 0.001 in all cases) of 0.5 at 2 weeks and 1.0 at 4 weeks; at 12 and 26 weeks they were significantly lower with sulphasalazine (p = 0.036 and 0.045). 75% of the patients given sulphasalazine and 65% of those given diclofenac had one or more adverse events with no major differences between treatments. CONCLUSIONS: These results show that an accelerated dosing schedule of sulphasalazine has identical effects to diclofenac in reducing symptoms, indicating it is a rapidly effective DMARD. They also provide unequivocal evidence, analysed on an intention to treat basis, that early treatment with sulphasalazine significantly reduces the extent of radiological progression in active RA.

Anti-Inflammatory Agents, Non-Steroidal↗

Treating rheumatoid arthritis with new disease modifying drugs.

Rheumatoid arthritis (RA) is a serious illness that can only be controlled by the appropriate use of disease modifying anti-rheumatic drugs (DMARDs). In spite of the successful use of such substances, and of methotrexate in particular, a large number of patients still experience disease progression. Leflunomide and the two anti-TNF agents, infliximab and etanercept, were therefore warmly greeted as very welcome additions to the rheumatologist's armamentarium. These successful newcomers, their strengths and problems are the focus of the present review.

Adjuvants, Immunologic↗

Combination of disease-modifying antirheumatic drugs in the treatment of rheumatoid arthritis. A survey of Alabama rheumatologists.

Combinations of disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA) have been recently advocated. Efficacy and toxicity data are scant. We conducted a survey of Alabama rheumatologists to determine actual practice patterns regarding combined DMARD treatment for their patients with RA. No differences were found between academic and nonacademic rheumatologists nor between users and nonusers of combination DMARDs in demographics or practice pattern profiles. The majority did report use of combination DMARD treatment, though only in a small proportion of their patients for whom the pyramid approach had failed. The combination most often employed was gold salts and antimalarials. Users, as compared to nonusers, did favor changing the classic pyramid approach for the treatment of RA, but the differences did not reach statistical significance.

Antirheumatic Agents↗

Protocol development for combination therapy with disease-modifying antirheumatic drugs.

To date, it has been exceptionally difficult to prove that any combination of disease-modifying antirheumatic drugs is more effective than its components used one at a time. However, only a few of many possible combinations have been evaluated in clinical trials. Careful attention to the details of patient selection, study design and duration, and choice of primary outcome measures is essential. A logical strategy for protocol development emphasizes the use of multiple small pilot studies to screen series of combinations and doses to identify a few that appear to show clinical benefit. The most promising combinations can then be evaluated in large, double-blind, randomized, pivotal studies with a higher probability of success.

Anti-Inflammatory Agents↗

Laboratory screening for side effects of disease modifying antirheumatic drugs in daily rheumatological practice.

To observe the actual laboratory screening for side effects of disease modifying antirheumatic drugs (DMARDs) in daily rheumatological practice, a retrospective multi-center cohort study was performed on the laboratory tests in DMARD treated rheumatoid arthritis (RA) patients. RA patients were investigated by chart review if they started with a DMARD (cohort 1) or were treated with a DMARD for at least one year (cohort 2). Hematological, hepatic, and renal tests were collected. In cohort 1 and 2, 513 and 1209 patients were included, respectively. A fairly outlined screening profile was observed for each DMARD studied. Except for antimalarials, the testing frequency decreased with time in cohort 1. For all DMARDs the testing frequency in cohort 1 was higher than in cohort 2. In general, rheumatologists requested laboratory tests less frequently than is internationally recommended. This discrepancy raises questions about the relation between the efficacy and costs of laboratory screening for side effects of DMARDs in patients with RA.

Adolescent↗

Shared care between hospital and general practice: an audit of disease-modifying drug monitoring in rheumatoid arthritis.

To assess the correspondence between ideal and actual monitoring for disease-modifying anti-rheumatic drugs and the reasons for protocol failure, and the sharing of this task between primary and secondary care, we studied 249 patients with rheumatoid arthritis in a single district general hospital. Ideal monitoring protocols were derived from data sheets and from the rheumatological literature. Overall the ideal protocol was followed in 65% of cases: this ranged from 93% for methotrexate to 26% for sodium aurothiromalate. Most of the monitoring was done in general practice (e.g. 67% of all blood tests) and, with some exceptions, general practitioners (GPs) were willing to perform this task. However, many GPs reported logistic differences with specimen transfer and expressed the need for more information and support. Poor communication between hospital, patient and GP was also found to be a cause of protocol failure.

Antirheumatic Agents↗

Monitoring and assessing the safety of disease-modifying antirheumatic drugs: a West Midlands experience.

BACKGROUND: Serious adverse events may occur from the use of disease modifying antirheumatic drugs (DMARDs) used to treat rheumatoid arthritis. We describe preliminary data from a regional surveillance scheme. Our aims were to identify a broad range of potential adverse events, to identify deficiencies in care and examine the management of common events in order to improve care. METHODS: Adverse events were sought by regular postcards to clinicians in the West Midlands region of the UK. Each reported case was carefully described and the opinions of at least three peer-reviewers were sought on cause-effect relationships, the potential for prevention and the appropriateness of management. RESULTS: Forty-four serious adverse events associated with DMARD use were reported between December 1999 and October 2001. Events included eight patients with malignancies, two with pancytopenia taking methotrexate, three with septic arthritis, and two with septicaemias. Fifteen cases have been peer-reviewed in detail, so far. At least two reviewers thought that eight events were related to DMARD use and that two were preventable. Agreement between pairs of reviewers was fair or moderate (weighted kappa 0.23-0.5). DISCUSSION: We have successfully implemented a regional system for identifying potential drug-related serious adverse events. A diverse range of potential drug-related events has been seen. Early analyses have highlighted the difficulties of determining cause-effect relationships between a drug and an event.

Antirheumatic Agents↗

Disease-modifying therapies for osteoarthritis : current status.

Osteoarthritis, the most common form of arthritis, is a debilitating progressive disease principally affecting the elderly. Osteoarthritis therapy has evolved in the past few decades from symptomatic treatment to possible disease-modifying solutions. In this paper, the pathophysiology of osteoarthritis is first reviewed, including an examination of the mechanisms underlying osteoarthritis and discussions of the roles of cartilage, synovial fluid and subchondral bone. The remainder of the paper discusses therapeutic approaches in current use and those in development, with special attention given to pharmacological treatments. Current approaches to treating osteoarthritis--i.e. medications; nonpharmacological modalities, such as physical therapy, exercise, weight management and orthotics; and (as a last resort) surgery--focus on reducing pain and improving (or at least maintaining) mobility. Drugs currently used to treat osteoarthritis fall into several categories: analgesics, NSAIDs, cyclo-oxygenase-2 (COX-2) inhibitors, corticosteroids, viscosupplementation, and symptomatic slow-acting drugs ('nutraceuticals'). The analgesics (paracetamol [acetaminophen] and opiates) have demonstrated less symptomatic efficacy than NSAIDs, while the latter have displayed mixed results in terms of joint space narrowing. COX-2 inhibitors have been demonstrated to be equal to or superior to NSAIDs in effectiveness. However, once considered a safer alternative, COX-2 inhibitors have become the subject of intense scrutiny since recent clinical evidence has cast suspicion on their cardiovascular safety profile. Injectable therapies, such as corticosteroids and viscosupplementation have elicited favorable short-term response but no long-term structural modification. On the other hand, the slow-acting drugs, especially chondroitin and glucosamine sulfate, have shown promising results. Also reviewed are other established and experimental therapies that seek to modify and/or even reverse the course of osteoarthritis. These include such medications as colchicine, bisphosphonates and hormones; dietary therapeutics, such as ginger extract and green tea; and such truly experimental treatments as matrix metalloproteinase inhibitors, cytokines, nitric oxide, growth factors and gene therapy. Osteoarthritis continues to be a difficult disorder to treat, as there is no cure as such and current treatments focus mainly on relieving pain and maintaining joint function. The search nevertheless continues for management regimens that can slow, alter or reverse the degenerative processes of osteoarthritis.

Aged↗

Current concepts in clinical therapeutics: disease-modifying drugs for rheumatoid arthritis.

The epidemiology, pathophysiology, clinical features, diagnosis, and clinical course of rheumatoid arthritis (RA) and the role of disease-modifying antirheumatic drugs (DMARDs) in its treatment are reviewed. RA, a widespread disease affecting people of all races and sexes around the world, has an unknown and perhaps multifactorial etiology. Conflicting evidence supports an immune-complex, infectious, metabolic, or genetic basis for RA. The disease affects diarthrodial joints and begins as an immune response to unknown antigenic stimuli. A proliferative process ensues, leading to formation of a vascular lesion called a pannus, which then infiltrates into cartilage, subchrondral bone, and tendon. This destructive phase leads to classic RA symptoms of pain, limitation of motion, swelling, heat, and redness of the affected joint. Symptoms and laboratory tests form the basis for diagnosis. For most RA patients, conservative therapy provides substantial benefit. In those patients who suffer from unrelenting and progressively destructive disease, more aggressive intervention is necessary to prevent permanent disability. The DMARDs are reserved for treatment of this group of patients. DMARDs include such diverse agents as the gold compounds aurothioglucose, auranofin, and gold sodium thiomalate; the antimalarials hydroxychloroquine sulfate and chloroquine phosphate; penicillamine; and the cytotoxic agents azathioprine, methotrexate, and cyclophosphamide. DMARDs are effective but toxic therapeutic agents. Because of the toxicities of these agents, careful monitoring at regular intervals is necessary throughout the duration of therapy. For patients in whom these drugs demonstrate efficacy and are tolerated, the DMARDs may attenuate the disabling effects of long-term erosive disease.

Adrenal Cortex Hormones↗

Use of disease-modifying antirheumatic drugs in patients with psoriatic arthritis.

UNLABELLED: Few prospective placebo-controlled studies have evaluated disease-modifying antirheumatic drugs (DMARDs) in the treatment of peripheral psoriatic arthritis. OBJECTIVE: To evaluate second-line treatments used in clinical practice in patients with psoriatic arthritis. METHOD: We studied a cross-section of 100 consecutive patients seen by hospital-based or office-based rheumatologists for psoriatic arthritis. PATIENTS: The 55 men and 45 women had a mean age of 48 years (range, 17-79 years) and a mean disease duration of 7 years (range, 1-24 years). RESULTS: The most commonly used DMARDs were sulfasalazine, gold, methotrexate, and hydroxychloroquine (64, 43, 41 et 17 patients, respectively). These drugs had been stopped because of inefficacy in 31%, 31%, 12%, and 53% of patients, respectively, and because of adverse events in 23%, 44%, 22%, and 41% of patients, respectively. At the time of the study, mean treatment durations were 15, 21, 34, and 12 months, respectively, and the drugs were still being used in 45%, 21%, 66%, and 6% of patients. CONCLUSION: Our data confirm the value of methotrexate and salazopyrine. Methotrexate had the best risk/benefit ratio. Gold was often responsible for side effects. Hydroxychloroquine was inadequately effective and poorly tolerated.

Adolescent↗

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

Rheumatoid arthritis is a progressive inflammatory disease with evidence of early cartilage damage. Consequently, there is a trend toward earlier use of disease-modifying antirheumatic drugs. This review focuses on recent data on methotrexate, sulfasalazine, gold, hydroxychloroquine, D-penicillamine, and combination therapy. Methotrexate is focused on most, reflecting the increasing popularity of this agent; studies continue to show its good clinical efficacy. Combination therapy studies have been disappointing and are still marred by short duration and low power. Sulfasalazine has a fairly rapid onset of clinical effects and modulates immune function. Gold is still the subject of new studies, with evidence that clinical experience leads to improved patient efficacy. The beneficial effect of hydroxychloroquine in mild rheumatoid arthritis has been confirmed, and information on D-penicillamine suggests an effect on oxygen radical scavenging. Clinical studies are still required to ascertain the relative efficacy of these drugs, and potential long-term adverse effects remain a source of concern.

Anti-Inflammatory Agents↗

Early combination disease modifying antirheumatic drug treatment for rheumatoid arthritis.

Most people presenting with rheumatoid arthritis today can expect to achieve disease suppression, can avoid or substantially delay joint damage and deformities, and can maintain a good quality of life. Optimal management requires early diagnosis and treatment, usually with combinations of conventional disease modifying antirheumatic drugs (DMARDs). If these do not effect remission, biological DMARDs may be beneficial. Lack of recognition of the early signs of rheumatoid arthritis, ignorance of the benefits of early application of modern treatment regimens, and avoidable delays in securing specialist appointments may hinder achievement of best outcomes for many patients. Triage for recognising possible early rheumatoid arthritis must begin in primary care settings with the following pattern of presentation as a guide: involvement of three or more joints; early-morning joint stiffness of greater than 30 minutes; or bilateral squeeze tenderness at metacarpophalangeal or metatarsophalangeal joints.

Antirheumatic Agents↗

Selecting a disease-modifying agent as platform therapy in the long-term management of multiple sclerosis.

Multiple sclerosis (MS) is a complex, incurable disease. Treatment consists of lifelong disease and symptom management. FDA-approved therapies for relapsing MS include subcutaneous (SC) interferon beta-1b (IFNbeta1b, Betaseron), IM interferon-beta-1a (Avonex), SC interferon-beta-1a (Rebif), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone), all of which are known as disease-modifying agents (DMAs). DMAs that can be initiated and continued on a long-term basis can be referred to as platform therapies. During periods of disease instability with increased disease activity, corticosteroids or immunosuppressive agents can be used in combination with appropriate DMA platform therapy to help control symptoms. To date, long-term comparative studies of DMAs are not available. However, based on the effects of these agents on disability progression, relapse rates, MRI outcomes, and neutralizing antibodies observed in phase III randomized clinical trials, IFNbeta1a products are the DMAs of choice for platform therapy for MS. Evidence indicates that IFNbeta1a may also be beneficial in the early stages of the disease. Research is ongoing to identify other appropriate add-on agents (e.g., antigen-specific therapies) to be used in combination with existing DMAs to effectively manage MS.

Antibody Formation↗

Quantitative analysis of immunohistologic features of very early rheumatoid synovitis in disease modifying antirheumatic drug- and corticosteroid-naïve patients.

OBJECTIVE: To describe the immunohistochemical features of very early rheumatoid synovitis in disease modifying antirheumatic drug- and corticosteroid-naïve patients. METHODS: Eight patients presenting with oligoarthritis or polyarthritis, who later met American Rheumatism Association criteria for rheumatoid arthritis (RA), underwent needle synovial biopsies of a knee joint within the first 6 weeks after onset of disease symptoms. Using antibodies to CD3, CD8, L26, CD68, and von Willebrand factor, a detailed quantitative immunohistochemical analysis was done. RESULTS: CD3+ T lymphocytes, CD8+ T lymphocytes, L26+ B lymphocytes, and CD68+ macrophages were seen in 8/8 (100%), 7/8 (87%), 4/8 (50%), and 6/6 (100%) of synovial biopsies stained with the respective marker. There was a wide variation in number of positive cells between patients. CD3+ and CD8+ T cells were seen predominantly in perivascular areas, less often in a diffuse distribution, and not in aggregates. L26+ B lymphocytes were found in much smaller numbers compared with T lymphocytes. A mean of 67 vessels/mm2 was noted. No lymphoid aggregates were seen. In all cases, infiltration of macrophages and lymphocytes was limited mainly to relatively superficial parts of synovium, i.e., within 1 to 2 high power fields of the surface. CONCLUSION: An absence of lymphoid aggregates or dramatic vascularity and a predominantly superficial infiltrate consisting mainly of perivascular T cells with few B cells characterized our patients with very early RA of < 6 weeks' duration. Thus, there appear to be some potentially important differences from findings reported in well established disease.

Adrenal Cortex Hormones↗

Second line (disease modifying) treatment in rheumatoid arthritis: which drug for which patient?

OBJECTIVES: The objectives were to assess (a) the comparative merits of commonly used disease modifying drugs in the treatment of rheumatoid arthritis (RA) and (b) the influence of age, gender, and disease duration on the outcome of treatment. METHODS: Collected analysis (meta-analysis) was performed on results obtained during the first year of treatment in 1140 patients with RA treated with gold, penicillamine, sulphasalazine, or auranofin from a single centre. RESULTS: Gold, penicillamine, and sulphasalazine performed similarly, with about 60% of patients continuing to receive each of these drugs for at least one year. Neither gender nor age had an influence on the response to treatment, but patients with a longer disease duration showed a greater tendency to stop treatment. The median percentage improvement was 33% in visual analogue pain score and 50% in erythrocyte sedimentation rate. CONCLUSIONS: Routine use of these drugs should at least equal these results. Any new drug should either be substantially less toxic or at least as efficacious.

Adult↗

Toxicity profiles of traditional disease modifying antirheumatic drugs for rheumatoid arthritis.

BACKGROUND: The progression of rheumatoid arthritis (RA) can be retarded or halted by disease modifying antirheumatic drugs (DMARDs). Next to inefficacy, toxicity limits their use. OBJECTIVE: To explore the toxicity profiles of DMARDs in daily life. PATIENTS AND METHODS: Five hundred and ninety three patients with RA charts (>2300 patient years of treatment) were reviewed at two rheumatology outpatient clinics. All recorded data on toxicity and reasons for stopping treatment were collected. RESULTS: Adverse events were common reasons for treatment discontinuation (42% of treatments). In 70% they were subjectively reported at the clinical visit, while substantial laboratory abnormalities were seen relatively rarely (9% of treatments: abnormal liver function tests in 5%; haematological abnormalities in 3%; impaired renal function in 1%). No single case of retinopathy from antimalarial drugs (that is, an incidence of <0.3 events/1000 patient years) was found, although eye examinations by the specialists were abnormal 30 times per 1000 patient years, mostly revealing keratopathy. Most commonly reported symptoms per 1000 patient years were nausea (54 events), abdominal pain (37 events), and rashes (34 events). Adverse events were more likely to occur with increasing number of consecutive DMARD courses. CONCLUSION: The first DMARD course in a patient seems to be safer than the consecutive ones. In addition, the incidence of adverse events (AEs) seems to be similar for high and low dose treatment. Data are also provided on types and incidence of AEs that are consistent with previous studies in other countries and different settings.

Adult↗

Disease modifying antirheumatic drugs: longterm safety issues.

The trend for more aggressive management of rheumatoid arthritis includes earlier introduction of disease modifying antirheumatic drugs (DMARD). As patients may continue their therapy for several decades instead of several years, the evaluation of benefit versus risk of DMARD with particular emphasis on longterm safety is essential. Longterm safety assessment is difficult for a number of reasons: there are relatively few trials that have followed patients beyond 5 years and the use of a combination of DMARD therapy with nonsteroidal antiinflammatory drugs and corticosteroids complicates the assessment of an observed adverse event with a particular drug. This review of longterm studies incorporating DMARD provides insight into adverse events associated with currently available DMARD.

Antirheumatic Agents↗