Treatment of Rheumatoid Arthritis with Basic Therapeutic Combinations

Treatment of Rheumatoid Arthritis with Basic Therapeutic Combinations




MEDICINE
Wollenhaupt, Jürgen; Zeidler, Henning
Summary
The effectiveness of the treatment of rheumatoid arthritis with so-called basic therapeutics can be significantly increased by the combined use of two or more substances. Up to two-thirds of patients treated with combination basal therapy achieve clinical remission of the arthritis. Therefore, if there is insufficient response to monotherapy with a well-dosed basic therapeutic, especially methotrexate, and ongoing disease activity, combination therapy should be initiated. In view of the growing number of established basic therapeutics, the therapy strategy is selected on an individual basis. Nevertheless, based on recent study results, some guidance recommendations for the combined use of long-acting antirheumatics in the treatment of rheumatoid arthritis can be developed.

Keywords: rheumatoid arthritis, chronic polyarthritis, basic therapy, antirheumatic, combination therapy

Summary
Combination Therapy of Rheumatoid Arthritis with Disease Modifying Antirheumatic Drugs
The efficacy of pharmacological treatment of rheumatoid arthritis with disease-modifying antirheumatic drugs (DMARD) may be increased by using a combination of two or more DMARDs. As many as two out of three patients may remission their arthritis when DMARD therapy is used. Therefore, combination DMARD therapy is recommended if patients fail to respond to monotherapy, especially methotrexate. The selection of DMARD is presented individually. Recent studies suggest that recommendations for the use and selection of DMARD for combination therapy of rheumatoid arthritis can now be proposed.

Key words: disease modifying antirheumatic drug, rheumatoid arthritis, combination therapy

The treatment of rheumatoid arthritis has changed radically in recent years for various reasons. Epidemiological studies have shown that spontaneous remissions on symptomatic nonsteroidal anti-inflammatory or glucocorticoid therapy are rare and occur in less than 20 percent of patients with a confirmed diagnosis (5). In the majority of cases, the disease progresses rapidly and within a few years leads to functional deficits, joint destructions, severe limitations of ability to work and, when left untreated, soon to become disabled (12, 22). After many years of rheumatoid arthritis is characterized by the increasing disability, secondary diseases (for example, vasculitis, pulmonary fibrosis, amyloidosis) and increased mortality (9, 15).
The ideal therapy for rheumatoid arthritis should therefore be able to control the inflammatory disease process quickly and adequately, prevent bony destruction, maintain the quality of life and the ability to work and work in the long term, even in the early stages. This does not succeed with only symptomatic analgesic-anti-inflammatory treatment with, for example, non-steroidal anti-inflammatory drugs, physical therapy, diet or so-called natural healing methods, but - as has now been proven in many clinical studies - solely by drugs that are fundamental in the inflammatory and immunological Intervene processes, that is by so-called basic therapeutics. Accordingly, early use of the basic therapeutic agents (synonym: long-acting antirheumatic drugs, LARDHR, DMARD), which was started immediately at the time of diagnosis and adapted to the disease activity, is now considered the basic treatment rule. The early, adapted to the future course of disease base therapy no longer pursues the goal of adequate control of the disease symptoms and psychosocial consequences, but aims at inhibiting the radiologically detectable progression, achieving a complete remission of the disease and ultimately on a long-term reduction in mortality (Graphic 1).


In recent years, the number of long-acting anti-inflammatory drugs available for the basic therapy has increased (Table). However, their use in the form of conventional monotherapy is often inadequate even when supplemented with nonsteroidal anti-inflammatory drugs, optionally low-dose glucocorticoids and physical treatments. Although the basic effectiveness of individual basic therapeutics for influencing the long-term course and thus improving the prognosis of rheumatoid arthritis is now accepted, the medium and long-term benefits of using them in conventional monotherapy often become limited in practice due to intermittent relapses and toxic side effects are significantly limited (7). For example, inadequate efficacy or secondary efficacy in more than half of the patients force the drug to be discontinued and switched to another basic therapeutic agent (19, 20). The main goal of the therapy, the induction of remission with complete suppression of all clinical and laboratory signs of inflammation, is only achieved in 2 to 13 percent of patients on monotherapy with conventional basic therapies, and is usually short-lived and often followed by exacerbations (14). ,
Against this background, the simultaneous use of several long-acting antirheumatics in the form of so-called combination-based therapy is becoming increasingly important. By additive or synergistic effects, the disease activity should be better controlled and / or the toxicity of the individual substances should be reduced by a possible dose reduction.
Pharmacological basics
The knowledge of pharmacological effects and therapeutic approaches in the pathophysiology of rheumatoid arthritis are unfortunately incomplete for most basic therapeutics. Accordingly, pharmacological data from in vitro studies and animal studies are also insufficiently available for combination basal therapy of rheumatoid arthritis (23). Some pharmacokinetic considerations raised some doubts about the effectiveness of the combined use of several basic therapies, but other pharmacological arguments suggest that combination therapy is useful (3, 4, 17). This has led to an empirical approach to at least provisionally validate in clinical trials the hypothesis of a better efficacy of combined base therapy versus monotherapy.
Results of controlled studies
More recently, a number of controlled clinical trials have been published which investigated the effect of a dual or triple baseline therapy of rheumatoid arthritis compared to monotherapy of this disease. The design of the treatment forms differed in that in some cases a second basic therapeutic was added at baseline to a previously stable and side effect-free, but not sufficiently effective monotherapy (step-up design) or after a basal therapy-free phase initial combination therapy started and with monotherapy was compared (parallel design). For a complete overview of the published studies, please refer to various recent meta-analyzes (13, 26).
While the first controlled trials included predominantly patients with long-term disease after failure of several conventional basic therapies and came to different conclusions, recent studies consistently confirm the superior effect of early-onset combination therapy in rheumatoid arthritis. The percentage of patients who can achieve remission of their rheumatoid arthritis increases from 18 percent on monotherapy with methotrexate or sulfasalazine to 37 percent with early switch to combination therapy (10). With such a success rate of early combination therapy, remission of disease manifestations in rheumatoid arthritis, rather than just satisfactory control of disease symptoms, is at the center of realistic therapeutic goals (Figure 1).
However, not all previous studies have systematically investigated the effect of combination therapy on the radiologically detectable bony destruction in the course of the disease.


Recently, however, remission rates, the slowing of radiologically detectable progression, the influence on functional capacity and the improvement of quality of life have increasingly been taken into account as important clinical criteria in the effectiveness analyzes. Recent studies on the combination of methotrexate with the tumor necrosis factor (TNF) antagonists infliximab and etanercept now also prove the effectiveness of such a treatment to delay or arrest the radiologically detectable joint destruction.
If one summarizes the available study results from a practical point of view, the studies prove that both
In early rheumatoid arthritis, as well as in advanced stages of disease with persistent disease activity, combination-based therapy is more effective than the continuation of conventional monotherapy. In the case of partial but insufficient response to methotrexate monotherapy, the additional use of hydroxychloroquine and sulfasalazine (in triplicate) or cyclosporine (as a dual combination) leads to a significant and longer-term increase in response rate and intensification of therapy effect with a similar or even lower rate of side effects. All of these combination regimens include low - dose glucocorticoids (up to
7.5 mg prednisolone equivalent).
After two years of treatment with the triple combination of methotrexate, sulfasalazine, and hydroxychloroquine, 77 percent of patients had marked clinical improvement compared to baseline compared to only 40 percent of those receiving sulfasalazine plus hydroxychloroquine and 33 percent of patients receiving methotrexate alone (11).
There are also positive studies on double combinations. Thus, the activity score of rheumatoid arthritis improved by combination treatment with methotrexate and cyclosporine in 48 percent of patients treated compared to only 16 percent on methotrexate monotherapy (21). However, the number of side effects (for example, nephrotoxicity or increase in blood pressure), the associated close monitoring need and the high therapy costs limit the frequency of use of this dual combination in practice. As is also to be estimated effectively
the combination treatment of parenteral gold salts with hydroxychloroquine, whereby the relatively side-effect parenteral gold therapy is nowadays used much less frequently than other established basic therapeutics such as methotrexate or sulfasalazine (16).
Whether other combination-based therapies may also be more effective than the monosubstances can not be ruled out due to the still modest study data. Lack of evidence of superiority of combination therapy in some studies may also have methodological reasons, leaving further studies to be awaited.
A very important aspect of the recently published studies is the clear superiority of combination basic therapy in the treatment of early rheumatoid arthritis, ie with a disease duration of less than three years. The study by O'Dell (11) showed a clinically significant improvement of 50 percent of the activity parameters after three years in 73 percent of patients treated with a triple combination of methotrexate, sulfasalazine, and hydroxychloroquine. The significance of the study is limited by the comparatively small number of patients treated initially or over the entire 24-month period (31 or 24 patients). However, there are now a number of other studies that include larger patient numbers and also
emphasize the importance of early combination basic therapy.
In the studies of Boers (1997), Mottönen (10) and Calgüneri (2), remission was observed in 28-60% of patients, a remission rate several times higher than that achieved with monotherapy, for example with methotrexate. The radiologically detectable progression of joint destruction was also significantly reduced by combination of methotrexate and sulfasalazine and prednisolone and was only one third of the monotherapy group in the combination group (1). Based on this latest data, it will be possible to significantly improve therapy success through early combination therapy, thus increasing the chances of remission of the disease to up to two-thirds of the patients.



After decades of discussions, the joint-reducing effect of low-dose glucocorticoid treatment of rheumatoid arthritis has recently been clearly demonstrated by various studies in addition to the basic therapy.
It can now be taken for granted that low-dose glucocorticoids at a concentration of 5 to 7.5 mg prednisolone equivalent per day as a supplement to a basic therapy additionally delay the radiological progression and significantly reduce the clinical manifestations of rheumatoid arthritis. After two years of low-dose prednisolone therapy, the percentage of radiologically detectable erosions decreased from 46 percent in the placebo group to 24 percent in the treatment group (6) and the percentage of achievable remissions under parallel baseline therapy can be doubled (27).
Practical therapy recommendations
Based on the above-mentioned controlled studies, it is now considered certain that the combined use of so-called basic therapeutics in the case of inadequate response of rheumatoid arthritis to monotherapy with methotrexate or other basic therapeutics is promising.
The therapeutic goal of this approach should be the complete suppression of clinical, humoral and radiological manifestations. The authors of most recent publications on this topic agree on this general assessment of combination therapy, but due to the novelty of the data, concrete recommendations or even guidelines for practical use are lacking
this treatment procedure, which has fundamentally changed the hitherto customary procedure.
Data from the nationwide core documentation of the regional rheumatism centers point to a higher variability of monotherapy and combination therapy with long-acting antirheumatics (28). Thus, in 1997, in rheumatological practice, only four percent, but in patients with high inflammatory activity in rheumatism hospitals in 22 percent, a combination therapy.
In addition, there is a lack of international definition of treatment failure after monotherapy and combination therapy, and the indication for methotrexate or sulfasalazine as the first-line monotherapy varies. Most recently, English rheumatologists proposed an algorithm for treatment optimization, however, starting with sulfasalazine as a first-line therapeutic and then recommending the use of sulfasalazine plus methotrexate plus hydroxychloroquine if methotrexate is inadequate (Figure 2). As a further option, parenteral administration of methotrexate is recommended in the case of insufficient efficacy or gastrotoxicity, as well as the increase of the usual standard dose of methotrexate 15 mg once a week to 20 to 25 mg (or 0.3 mg / kg body weight) once a week. The scheme does not take into account that methotrexate is now the first-choice therapeutic drug worldwide and also in Germany. In addition, leflunomide, which was recently added as a new treatment option, is missing.
We have modified this algorithm and adapted it to the approach used in other rheumatological centers in Germany (26) (Figure 3). The spectrum of available long-acting antirheumatics is taken into account in order to demonstrate the variety of therapeutic alternatives and thus to make it clear that in the end, rheumatologists familiar with these substances should make the best possible indication taking into account previous basic therapies.
It is important to not lose time. With every month of disease activity, joint destruction and loss of function continue. If monotherapy with methotrexate or sulfasalazine, and possibly also other established basic therapies can not achieve an adequate therapy effect within two to three months, a double- or triple-combination treatment should be used according to Figure 3. The prerequisite for such a therapy intensification is always a reliable diagnosis, adequate complementary treatment by physiotherapy, optionally non-steroidal anti-inflammatory drugs or low-dose glucocorticoids, and of course the exclusion of contraindications to the substances mentioned.



Combination therapy should be considered most frequently in clinical practice when methotrexate monotherapy does not have a sufficient effect in terms of remission induction. In these cases, a combination of methotrexate in constant doses with hydroxychloroquine in standard dosage and / or sulphasalazine 1 000 to 2 000 mg per day, possibly 3 000 mg per day, is promising under cost-benefit aspects.
The combined treatment of methotrexate with ciclosporin (3.5 to a maximum of 5 mg per kg of body weight and day) is more costly and associated with an increased renal risk of side effects, so they may be considered only in case of failure of the latter triple combination or contraindications to sulfasalazine and hydroxychloroquine becomes. Although the other combinations listed in the table as alternatives have been investigated and described as effective in individual studies, their general effectiveness has not yet been sufficiently substantiated, so that their use is restricted to isolated cases and the indication by the rheumatologist.
It should not be forgotten that there are still a number of questions open, especially for the triple combination methotrexate, sulfasalazine and hydroxychloroquine. How early should this treatment be started? Is the direct primary use of combination therapy justified in patients with unfavorable prognosis? Should folic acid generally be added as with monotherapy with methotrexate to reduce the rate of side effects? Are higher doses of methotrexate greater than 15 mg and sulfasalazine (2 to 3 g instead of 1 g per day) equally compatible and more effective? At what time should the dose of methotrexate or sulfasalazine be reduced after shedding of remission, in what order and at what intervals?
As long as these questions have not yet been answered by desirably desirable controlled studies, the empirical application will have to show a tentative path.
outlook
Currently, the therapeutic repertoire of established basic therapeutics is expanding to include leflunomide (Arava) and the TNF antagonists etanercept and infliximab (Enbrel, Remicade). The combination of these new immunomodulatory substances with conventional basic therapies (8, 18, 24, 25) already opens up new perspectives and will in future expand the therapeutic possibilities of combination therapy. Thus, in the first studies, the combination of leflunomide and methotrexate appears to be very effective (25). However, further studies on larger groups of patients are needed to adequately assess the potential toxicity of this combination and to allow a benefit-risk assessment. The TNF antagonists are mainly used (etanercept) (24) or exclusively (infliximab) (8) in combination with methotrexate.
In summary, combination therapy today has an important place in the basic therapy of rheumatoid arthritis and represents a significant enrichment of the therapeutic options of this otherwise chronic progressive disease, which leads to inadequate medication to disability, early occupational disability and premature mortality.