Slow-acting Antirheumatic Drugs Research Articles

The use of immunomodulators in early rheumatoid arthritis

Immunomodulators represent a unique class of drugs that are not biologics, usually are isolated from nature, and have relatively specific noncytotoxic effects on the immune system. Although most slow-acting antirheumatic drugs (SAARDs) have effects on the immune system, these effects usually are not specific, often are cytotoxic, are not associated with specific cellular binding proteins, and their effect on immunity is difficult to correlate with their clinical effects. Most immunomodulators primarily affect T cells; because of their apparent role in rheumatoid arthritis (RA), studies of these agents are appropriate. Cyclo-sporine, the most widely tested of the immunomodulators, has shown significant efficacy in established RA in studies worldwide. However, only one study using cyclosporine has been performed in relatively early RA, in which the most positive effects might be expected. FK506 and rapamycin, agents similar to cyclosporine, are being tested in human transplantation; the only arthritis studies have been performed in animals. Tilomisole, imuthiol, and mycophenolate mofetil have been studied in limited RA trials, with positive effects. However, no trials have been conducted in early RA. Although promising, this class of drugs will require more studies to establish their efficacy and safety, especially in early RA.

Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate.

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (-)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration-effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease.

Methotrexate in rheumatoid arthritis. An update.

Methotrexate has been approved for the treatment of refractory rheumatoid arthritis by several regulatory agencies, including the Food and Drug Administration. The tendency is now to prescribe it at earlier stages of the disease. Methotrexate is a well known antifolate. Its exact mechanism of action in rheumatoid arthritis remains uncertain. The polyglutamated derivatives of methotrexate are potent inhibitors of various enzymes, including dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Inhibitory effects on cytokines, particularly interleukin-1, and on arachidonic acid metabolism, as well as effects on proteolytic enzymes, have been reported. Some of them may be linked to the antifolate properties of methotrexate. Overall, the drug appears to act in rheumatoid arthritis as an anti-inflammatory agent with subtle immunomodulating properties. Direct inhibitory effects on rapidly proliferating cells in the synovium have also been suggested. Methotrexate is usually given orally. Marked interindividual variation in its bioavailability has been found. Food intake has no significant effect on the pharmacokinetics of oral methotrexate. Methotrexate undergoes significant metabolism. The functionally important metabolites are the polyglutamated derivatives of methotrexate, which are selectively retained in the cells. Less than 10% of a dose of methotrexate is oxidised to 7-hydroxy-methotrexate, irrespective of the route of administration. This metabolite is extensively (91 to 93%) bound to plasma proteins, in contrast to the parent drug (35 to 50% bound). Methotrexate is mainly excreted by the kidneys. It undergoes tubular secretion and may thereby compete with various organic acid compounds. Early placebo-controlled trials demonstrated that weekly low dosage methotrexate produced early symptomatic improvement in most rheumatoid arthritis patients. Two meta-analyses showed that methotrexate is among the most efficacious of slow-acting antirheumatic agents, together with parenteral gold (sodium aurothiomalate), penicillamine and sulfasalazine. Furthermore, in the short term context of clinical trials, methotrexate has one of the best efficacy/toxicity ratios. There is little evidence that methotrexate, or any available slow-acting antirheumatic agent, is a true disease-modifying drug. However, the probability that a patient will continue methotrexate therapy over time appears quite favourable compared with any other slow-acting antirheumatic drug. Combination therapy with slow-acting drugs has been advised for the management of rheumatoid arthritis, but the evidence currently available does not support general use of combination therapy including methotrexate. Almost all investigations indicated that toxic effects, rather than lack of response, were the major reason for discontinuing methotrexate therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical pharmacokinetics of slow-acting antirheumatic drugs.

The pharmacokinetics of the slow acting antirheumatic drugs (SAARDs), hydroxychloroquine, chloroquine, penicillamine, the gold complexes and sulphasalazine, in humans have been studied. For all these drugs, both in controlled clinical trials and in empirical observations from rheumatological practice, delays of several months are reported before full clinical effects are achieved. Variability in response is also characteristic of these agents. Pharmacokinetic factors may partially explain these clinical observations. Delays in the achievement of steady-state concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentrations may arise after standard administered doses because of interindividual pharmacokinetic variability. These factors are likely to contribute to the delay in response and the variable response, respectively. Pharmacokinetics of the antimalarials, hydroxychloroquine and chloroquine, are characterised by extensive tissue sequestration with reported volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fold range occurs in the fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hydroxychloroquine and chloroquine are administered as racemates. Enantioselective disposition of both compounds occurs, again with notable interindividual variability. Sulphasalazine is split in the large intestine into sulphapyridine, proposed to be the active compound in rheumatoid arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine is metabolised partly by acetylation, the rate of which is under genetic control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexes are administered either intramuscularly or in an oral form (auranofin). Gold is widely distributed in the body. Very long terminal elimination half-lives and slow accumulation rates are reported. Penicillamine is administered orally. Its bioavailability is variable and may decrease by as much as 70% in the presence of food, antacids and iron salts. Penicillamine forms disulphide bonds with many proteins in the blood and tissues, creating potential slow release reservoirs of the drug. Like the other SAARDs, gold complexes and penicillamine are found in a wide range of blood concentrations after administration in standard doses to different individuals. More research must be conducted into the concentration-effect relationships of the SAARDs before the pharmacokinetic characteristics of these drugs can be used effectively to optimise patient therapy.

Non-steroidal anti-inflammatory drugs and slow-acting anti-rheumatic drugs in juvenile rheumatoid arthritis.

The preferred drugs for the initial treatment of juvenile rheumatoid arthritis (JRA) are salicylates or other non-steroidal anti-inflammatory drugs (NSAID) such as tolmetin or naproxen. If the disease activity does not respond adequately to the treatment, slow-acting anti-rheumatic drugs (SAARD) such as oral gold agents, low-dose D-penicillamine, or sulfasalazine should be given in addition to NSAID. If the systemic manifestations are severe, corticosteroid therapy may be commenced. Furthermore, if the joint destruction is progressive, immunosuppressants such as methotrexate would be selected as the third-line drugs of choice. The safety and efficacy of SAARD and immunosuppressants for the treatment of children with JRA, however, have not yet been confirmed, as the adverse effects such as bone marrow suppression, oncogenicity and mutagenicity are sometimes intense. Consequently, the strict indications for use and new therapeutic concepts for the management of JRA based on its pathogenesis are required.

Effects of sulphasalazine in experimental arthritis

The effects of sulphasalazine and related drugs on various models of arthritis are reviewed. Dosage regimen and duration of the treatment are of importance, as is the animal species, in determining clinical, biological, or radiological responses. Considering these parameters together with differences in administration protocols, it is not surprising that various drug effects are reported in the published studies. There is some evidence that sulphasalazine displays beneficial activity in attenuating experimental synovitis, but its influence only becomes apparent after a few weeks of therapy, thus functioning as a slow-acting antirheumatic drug. In contrast, sulphasalazine does not seem to be effective on the cicatricial ossifying process. Nevertheless, the respective therapeutic and remission-inducing effects of the parent drug, sulphasalazine, and its main moieties, 5-aminosalicylic acid and sulphapyridine, remain controversial.

Rheumatoid arthritis: opposing actions of haemopoietic growth factors and slow-acting anti-rheumatic drugs

The pathogenesis of rheumatoid arthritis and the mode of action of anti-rheumatic drugs are unknown. This hypothesis proposes that haemopoietic growth factors (colony stimulating factors [CSFs]) have an important role in rheumatoid arthritis as regulators of myelopoiesis and as activators of inflammatory leucocytes. It also suggests that slow-acting anti-rheumatic drugs may work by inhibiting myelopoiesis. This opposition to one of the actions of the CSFs would result in fewer inflammatory cells in the inflamed joints.

The use of suppressive agents for the treatment of rheumatoid arthritis

This paper addresses the issue of slow-acting anti-rheumatic drugs as well as complementary therapies.

Antirheumatic drug side-effects alert.

Potentially fatal side-effects of slow acting antirheumatic drugs (SAARDs) mean comparative drug trials are needed to answer 'fundamental' questions about their longterm efficacy, says a report in Drug and Therapeutics Bulletin.

Slow-acting antirheumatic drugs

Rheumatoid arthritis (RA) is common and debilitating. It affects approximately 1% of adults in the UK, with a prevalence which increases with age; over the age of 60 years roughly 2% of men and 5% of women are affected.1 Early in the disease most patients will receive analgesics and NSAIDs, which relieve symptoms but do not affect the underlying disease process.2 Slow-acting antirheumatic drugs (SAARDs) – gold, penicillamine, hydroxychloroquine/chloroquine or sulphasalazine – have conventionally been used later.3 These drugs act slowly, improve symptoms and suppress clinical and serological markers of RA activity. Moreover they appear to slow progression of the disease, although whether they modify disease outcome in the long term is not clear. Many rheumatologists now advocate their earlier use in some patients. We review the place of SAARDs, including methotrexate and immunosuppressants, in the treatment of RA.

The effect of slow acting antirheumatic drugs on the production of cytokines by human monocytes

The mode of action of slow acting antirheumatic drugs (SAARDs) is poorly understood. Interleukin (IL)-1α, IL-1β, IL-6 and tumour necrosis factor (TNF)α are pleiotropic cytokines produced predominantly by macrophages which have been implicated in the pathogenesis of rheumatoid arthritis. We have investigated the potential of the following drugs to modulate the production of those cytokines by purified human monocytes stimulated by either lipopolysaccharide (LPS) or cytokines in vitro: gold sodium thiomalate (GST), auranofin, hydroxychloroquine (HCQ),d-penicillamine (d-Pen), sulphasalazine and its metabolites, sulphapyridine and 5-aminosalicylic acid (5-ASA).

Targetting cytokines in rheumatology

Pharmacological intervention to specifically block cytokine action may become a useful means of managing autoimmune diseases in the future. Cytokine inhibition has already been implicated as a potential common mode of action in a number of slow-acting antirheumatic drugs currently used in the treatment of RA. This idea is now being taken one step further and several companies are hot in pursuit of agents specifically designed to interrupt the rheumatic disease process via their effect on cytokines.

Angiogenesis and rheumatoid arthritis: pathogenic and therapeutic implications.

Rheumatoid arthritis can be considered as one of the family of 'angiogenesis dependent diseases'. Angiogenesis in rheumatoid arthritis is controlled by a variety of factors found in the synovial fluid and pannus tissue. Modulation of the angiogenic component of the disease may alter the pathogenesis of the condition, and subsequent cartilage and joint destruction, by reducing the area of the endothelium in the pannus and restricting pannus growth. Current therapeutic strategies exert, to varying extents, an inhibitory effect on the angiogenic process. In particular, the mode of action of the slow acting antirheumatic drugs may be due to their effect on the angiogenic response. The development of novel angiostatic treatments for chronic inflammatory joint disease may lead to a new therapeutic approach in controlling disease progression.

The long-term outcome and justification for early treatment

The therapeutic options for rheumatoid arthritis (RA) remain disappointing, and the continued lack of overall progress in altering the course of the disease is frustrating. Whilst numerous trials demonstrate the benefits of slow-acting antirheumatic drugs (SAARDs) in the short term over 1-2 years (Research Subcommittee of the Empire Rheumatism Council, 1960; Huskisson et al, 1974; Pinals et al, 1986; Hamdy et al, 1987), there is little evidence for an overall effect on the ultimate outcome of rheumatoid disease determined over 15-25 years or longer (Scott et al, 1987; Pincus, 1988; Kushner, 1989). It is appropriate therefore to reappraise current rationale for treatment. Early active treatment of synovitis with SAARDs before radiological signs appear and irreversible destruction of cartilage and bone have occurred would seem the optimum time to commence therapeutic intervention. Studies have shown that disability develops most rapidly during the first years of disease, and thereafter is relatively slow (Sherrer et al, 1986). Radiological deterioration also occurs at a maximum rate at the onset of disease and parallels functional disability (Brook and Corbett, 1977; Beltran et al, 1987). This indicates that, despite the chronic nature of RA, a large amount of the ultimate functional deterioration may be determined over a relatively short time span at the beginning of the disease. A therapeutic implication is that treatment with SAARDs in an attempt to achieve 'disease modification' should precede the period of rapid disease progression to be effective. Such concepts have given the impetus and provided the logic for the establishment of early arthritis clinics. These exist at a number of centres. How successful are these early clinics and do they justify the investment of time and staff involved? This question is the background to this present volume; it is a specific and major issue which may alter the present conventional treatment of RA. In this chapter we present a synopsis of the outcome of conventionally treated RA and consider how this could be influenced by early treatment; we also examine the ways in which treatment policies, and especially the use of SAARDs, could be altered and tailored for the

Short-term effects of antirheumatic drugs

Antirheumatic drugs fall into four categories: non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting antirheumatic drugs (SAARDs), corticosteroids, and cytotoxic drugs. NSAIDs are useful in controlling the symptoms and signs of inflammation. They work within a few days but patients' response varies widely and is unpredictable. Hence there is a wide choice of agent. Anxiety about the side-effects of NSAIDs, particularly on the stomach and kidney, is growing and their use is likely to decline, especially in the elderly. SAARDs are being used increasingly early in the disease. It is realized that there is only a small window of opportunity (2 years) in which to get the disease into remission before irreversible damage is done to the joints. Thus, there is a growing tendency to use combinations of SAARDs together with steroids early in the disease. The most appropriate treatment for established RA (of more than 2 years duration) is less easy to discern. It is important to define realistic treatment goals on an individual basis and to tailor the medication accordingly. Cytotoxic drugs are still reserved for severe aggressive joint disease or for systemic manifestations. Once we are able to predict outcome more accurately, the stage will be set for a trial of combination chemotherapy in severe early RA.

Rheumatoid nodules do not predict response to treatment with slow-acting anti-rheumatic drugs

Rheumatoid nodules have been associated with a poor long-term prognosis. We investigated whether they predict a poor response to treatment with slow-acting anti-rheumatic drugs (SAARDs). Two hundred and twenty-eight patients with rheumatoid arthritis (RA) were treated for six months with a SAARD. Clinical and laboratory assessments of disease activity were made initially and after 6 months' treatment. Patients were divided into two groups according to the presence or absence of nodules at entry. Twenty-one % had nodules before treatment but their response was no different to patients without nodules (79%), both groups showing improvements in all variables. Males were more likely to develop nodules and had a relative risk of 1.7. High titres of rheumatoid factor correlated with nodules and no sero-negative patients had nodules. We conclude that nodules are not predictive of poor response to treatment with a SAARD, despite their presence being associated with a poor long-term prognosis. One possible implication is that SAARDs themselves, despite an early response, may not effect long-term outcome.

Adult-onset Still's disease

Adult onset Still's disease seems to be the adult form of Still's disease in children. The key symptoms of the disease are high spiking fever, arthritis and a macular or maculopapular, salmon-pink evanescent rash, almost always accompanied by neutrophilic leukocytosis and frequently by sore throat, intense myalgias, lymphadenopathy, splenomegaly and signs of serositis. Tests for IgM rheumatoid factor and antinuclear antibody are characteristically negative. With respect to haematologic abnormalities, the disease may give rise to several problems. First, there is a neutrophilic leukocytosis, which currently is unexplained, and often a normocytic normochromic anaemia, that may be profound. The anaemia has the characteristics of anaemia of chronic inflammatory disease. Both abnormalities disappear after effective treatment of the disease or at spontaneous remission. Secondly, there might be a problem to differentiate AOSD from malignant haematological disorders, including malignant lymphoma and leukaemia, especially when the picture is dominated by lymphadenopathy, splenomegaly, fever and leukocytosis. Although in rare cases the differential diagnosis is extremely difficult, diagnosis can mostly be made or excluded by peripheral blood smear staining, bone marrow biopsies and occasionally lymph node biopsy. Finally, like the juvenile counterpart, AOSD is occasionally complicated by sometimes life-threatening diffuse intravascular coagulation. Factors that might be important in the development of this complication include severe disease activity, liver abnormalities and particular drugs including salicylates, other NSAIDs and some slow-acting antirheumatic drugs. Prompt therapy, including withdrawal of the drug, corticosteroids and sometimes anticoagulant therapy have been successfully applied to most patients.

ブシラミンの腎毒性

Bucillamine [N- (2-mercapto-2-methylpropanoyl) -L-cysteine, Rimatil (R) ] is a new slow-acting antirheumatic drug developed in Japan. The chemical structure of Bucillamine is similar to that of D-penicillamine except that it has two rather than one SH-bond in the molecule. As it is generally accepted that the SH-bond plays a role in the antirheumatic effect of D-penicillamine, the effectiveness of Bucillamine on rheumatoid arthritis has been proved in several studies.We administerd Bucillamine to 87 cases of rheumatoid arthritis patients for about 5 years, during which it became apparent that Bucillamine has the nephrotoxic potential to cause proteinuria. The frequency of bucillamine-induced proteinuria reached 12.6% in our study. Males were more susceptible to proteinuria than females (20.0% vs 11.1%), but its occurrence was not related with the dosage of bucillamine, disease duration, or the anatomical stage of disease.Other side effects, such as eruptions, itching, oral aphtha, malaise, and dysgeusia, also occurred, but no patient with proteinuria showed skin symptoms and/or dysgeusia.As bucillamine has the potential to cause proteinuria, similar to other antirheumatic drugs such as D-penicillamine and gold, special attention must be paid to renal involvement.

Assessment of antirheumatic activity in man

Although so-called disease-modifying antirheumatic drugs (DMARDs) have been trialled in a number of chronic arthropathies, including psoriatic arthritis, Reiter's syndrome and ankylosing spondylitis, it is their application in the treatment of rheumatoid arthritis (RA) that has attracted the greatest attention. The drugs of interest are slower in their onset of action than the non-steroidal anti-inflammatory drugs (NSAIDs) and appear to differ in the dimensionality of the response induced, producing less dramatic effects on pain and swelling but possibly having long-term advantage with respect to physical function and radiographic progression of disease. There has been much debate as to the correct terminology for this class of drugs, which in Canada includes the antimalarials, chloroquine and hydroxychloroquine, as well as sulphasalazine, sodium aurothiomalate, auranofin, D-penicillamine, methotrexate, azathioprine and cyclophosphamide. Other drugs in this group that have been tested but are not in routine use include levamisole and cyclosporin A. Some authors have favoured the term remission-inducing drugs (RIDS) or slow-acting remission-inducing drugs (SARIS), although others contend that, since a complete remission is rarely achieved, DMARDs is a better eponym. However, it is clear that compared to a placebo or no treatment, even NSAIDs modify the disease process. While it may be suggested that such a response leaves the long-term consequences of disease unaltered, it is hard to accept that the long-term outcome of RA is not improved in some way for those patients who demonstrate a substantial and sustained response in pain, swelling, stiffness, range of movement and activities of daily living to either a single trial or serial trials of several NSAIDs prescribed over time. Given the aforementioned problems, the term 'slow-acting antirheumatic drugs' or SAARDs is to be preferred (Currey, 1984). The majority of SAARDs appear at least in vitro to modulate the immune response, although some have received the specific designation of immunosuppressive or cytotoxic agents. It is because NSAIDs modify the symptoms of disease and SAARDs differ in their induction-response interval and may affect aspects of disease relatively untouched by NSAIDs that clinical trials of SAARDs differ in certain respects from those of NSAIDs. Furthermore, until recently, drugs such as methotrexate, azathioprine and cyclophosphamide were regarded as drugs

Azathioprine, cyclophosphamide and chlorambucil

Immunosuppressive agents serve a major role in the management of once-fatal conditions such as the systemic necrotizing vasculitides, but they are also being used in more common, chronic inflammatory disorders such as rheumatoid arthritis. The drugs are all capable of reducing cell division but they differ in their modes of action. This is in keeping with their differing rates of action, and different indications. Azathioprine is a valuable alternative to slow-acting antirheumatic drugs in older patients with rheumatoid arthritis. Cyclophosphamide has transformed the outlook of many forms of vasculitis. Chlorambucil is particularly useful in improving the prognosis for children with amyloidosis secondary to juvenile chronic arthritis. We have tried to highlight the role of these drugs in a number of rheumatic diseases. We have emphasized their clinical applications, with some laboratory evidence for their effects. The major side-effects are reviewed. Finally, we have discussed their possible mechanisms of action.