Q J Med 2000; 93: 757-760
© 2000 Association of Physicians
Commentary papers |
A new era in rheumatoid arthritis treatment—time to introduce a modified treatment pyramid
From the Department of Medicine, Kaplan Medical Center, Rehovot, and the Hebrew University-Hadassah Medical School, Jerusalem, Israel
The traditional stepped-up therapy in rheumatoid arthritis (RA)—prescribing non-steroidal anti-inflammatory drugs (NSAIDs) for a long time and only eventually adding a second-line agent (the so-called ‘pyramid’) has long been abandoned, and for very good reasons. Several important insights have been gained in recent years which have led to an entirely different approach to RA treatment. First, long-term studies of the natural history and outcomes of large cohorts of RA patients have revealed that RA is not the benign disease it was once considered to be. Rather, it is often an aggressive, relentless disease culminating in substantial disability and premature mortality in as many as 50% of the patients at 20 years from diagnosis, with only about 1 in 5 patients leading a normal life.1,2 Second, sequential sensitive imaging studies revealed that significant joint damage occurs early in most patients, often within the first year or two of synovitis, and once established, it is irreversible.2–4 Third, the amount of inflammation correlates with articular damage;5 therefore, symptom control is not enough and the treatment goal in RA should be clearly defined as an urgent suppression of inflammation maintained over long periods of time.6,7 Periodic assessment of pain, physical function and quality-of-life scores are useful in follow-up, but study results must include objective measurements such as involved joint count, acute-phase reactants and new bone erosions.8
All this knowledge translates into an important lesson: RA patients should be identified early, assessed comprehensively and followed meticulously. Treatment should not only be started quickly and tailored to the patient's response, but usually has to be aggressive and prolonged. Mild treatment would not adequately suppress inflammation9 and discontinued treatment would usually herald a disease flare.7 A delay in treatment would allow joint damage to become established, missing the small window of opportunity for the successful treatment of RA.10 Disease-modifying anti-rheumatic drugs (DMARDs) should therefore be administered from the start. Furthermore, since single-drug therapy may take months to become effective and even fail to benefit many patients, (perhaps due to the multiple pathways of immune-mediated attack upon the synovia), combination therapy may be a more rational, effective, and rapid approach, and does not apparently increase the occurrence of adverse events.11–14 Thus, many rheumatologists adopt a strategy of starting treatment with multiple DMARDs and supporting it with the use of NSAID coverage, oral corticosteroids (using either short 15–25 mg/day courses of prednisone to control flareups until DMARDs take effect, or long-term 
7.5 mg/day treatment to reduce joint damage), interventions to prevent bone loss, patient counselling and support, as well as intra-articular injections of methylprednisolone where specific joints are severely affected and resistant to systemic therapy.15
To evaluate the effectiveness of new treatment regimens in patients with RA, large controlled trials (RCTs) are required, that focus on patients with early disease and their long-term outcomes. Unfortunately, not many studies comply with these essential demands. One recently published trial, however, met all these criteria: 199 patients with early RA were randomized and 178 completed the trial; American College of Rheumatology (ACR) criteria8 to assess disease activity and clinical improvement were used; duration of follow-up was 2 years; and finally, a DMARD combination of methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ) was used in a flexible manner which closely imitates clinical practice. The results however, while supporting the use of combination therapy in early RA (more than twice the patients were in remission compared with the single-drug group, with no increase in adverse drug reactions), still strike a dismal note. Despite a timely start, combination therapy and intensive follow-up in the ideal circumstances of a trial setting, 30% of RA patients failed to achieve significant improvement and over 60% were not in remission after 2 years.16 Other studies also reveal that a substantial proportion of patients are not improved despite an appropriate selection of patients and the use of aggressive treatment.17,18 Patient withdrawal is also a common problem.18 Thus new modes of treatment are urgently needed to target as many as 50% of patients with early RA, whose synovitis cannot be adequately suppressed by current combination therapies.
Three relatively recent additions to the ‘DMARD shelf’ may soon change the treatment paradigm because of their proven efficacy and safety in well-conducted controlled trials. Minocycline, for example, was significantly more effective in RA than placebo and generally safe in three separate RCTs, although only one study targeted patients with early disease.19 A favourable and objective response (defined as >50% improvement in at least three parameters—morning stiffness; joint tenderness; joint swelling; ESR) was noted in 65% of the minocycline group vs. 13% on placebo. The beneficial effect of minocycline in RA seems remarkable even 4 years after treatment, and may not necessarily relate to its antimicrobial activity.20 However, the small number of patients examined (n=46) makes further studies necessary before antibiotic treatment can be intelligently incorporated in RA therapy. Leflunomide (Arava) was recently approved by the US FDA, and its clinical efficacy and safety appear promising and comparable to SSZ, possibly MTX.21,22 The mechanism of action appears to be inhibition of de nova pyrimidine synthesis and interference with immune cell activation and adhesion. Additional studies are required, however, to assess the impact of leflunomide in early RA. Cyclosporine (CSA) has well established efficacy in RA, despite the controversial role of T cells and T cell cytokines such as IL-2 and IFN-
in the pathogenesis.10,23 The first trials evaluated patients with long-standing established disease, and used a high dose which often resulted in renal toxicity. However, important advances in CSA administration, have resulted in an improved safety profile. These include excluding patients who have a history of malignancy, renal/liver dysfunction or uncontrolled hypertension; using a microemulsion formulation (Neoral) with better bioavailability at the lowest efficacious dosage (usually 3.5 mg/kg/day) and careful adverse event monitoring.24 Patients with early severe aggressive disease are candidates for CSA treatment, often in combination with MTX and/or another DMARD.13 Blinded evaluation of radiographs of 91 erosion-free patients after 12 months of treatment showed appearance of erosions in only 10.8% of CSA-treated patients vs. 51.8% of patients treated with other DMARDS—an impressive result. Moreover, on average, no more than 10–20% of patients discontinue CSA because of inefficacy or adverse events.25
Thus, despite concern for the long-term safety of RA treatments which cannot at present be dispelled,26 severely ill RA patients should be identified within the first year of illness and closely monitored by experienced clinicians while a combination immunomodulatory and immunosuppressive treatment is selected, titrated and tailored to the individual patient's needs.9,26 Nevertheless, a sizeable proportion of patients achieve only a temporary remission, or worse, symptoms are ameliorated without a true control of underlying disease activity. These patients must become candidates for novel, hopefully more potent interventions, preferably in the setting of carefully conducted clinical research trials.
High-dose immunosuppressive therapy (HDIT) for RA—usually cyclophosphamide-based, followed by autologous stem-cell transplantation to shorten hematopoietic recovery time, has been performed in about 24 adult patients thus far.27 Due to its significant toxicity, an almost 10% mortality risk and associated prolonged and profound immunosuppression, this regimen cannot be considered unless other options have failed. Perhaps equally disturbing are the observations of recurrence of disease activity in several RA patients suggesting that few patients are likely to be cured by this aggressive therapy, as it appears to be incapable of reinstituting self tolerance.27
With careful analysis of joint tissues from patients with RA, important insights into the pathogenesis of synovitis have been gained, leading to potentially new methods of therapy. Despite our lack of knowledge of putative environmental factors, it is now clear that proliferation of synovial macrophages and fibroblasts, angiogenesis, perivascular infiltration and endothelial activation occur early. This process is driven by locally-produced pro-inflammatory cytokines which set off a vicious cycle of inflammation and mediator discharge. Progressive cartilage and bone destruction may rapidly develop.18 Realization of the central and deleterious part of cytokines, particularly tumor necrosis factor (TNF) in RA, as well as major advances in deciphering their structure and binding sites, have led to important practical results. Thus, anticytokine interventions in RA have finally left the bench for the bedside, with intriguing initial results in recent clinical trials. One of the most promising of these is a recombinant fusion protein that consists of the soluble TNF receptor p75, linked to the Fc portion of human IgG1 (TNFR:FC; etanercept) which acts as a TNF antagonist. In a recent RCT of patients with persistent active RA despite MTX treatment, twice weekly subcutaneous injections of TNFR:Fc led to a remarkably rapid and sustained improvement. Measured parameters included all indicators of disease activity. At 24 weeks, 39% of the patients on TNFR:Fc/MTX met the ACR criteria for 50% improvement (ACR 50) vs. 3% of those receiving placebo/MTX (p<0.001). Toxicity was minimal, and no patient withdrew from the study.28 In another 30-week RCT of 428 patients which also targeted MTX-resistant patients, a chimeric anti-TNF monoclonal antibody infusion (infliximab) +MTX, achieved ACR 50 in 28%, vs. 5% among placebo+MTX (p<0.001). In this trial there was no excess of withdrawals or serious adverse events in the anti-TNF arm.29 Despite ample evidence demonstrating rapid down-regulation of a spectrum of cytokines, acute-phase reactants and vascular adhesion molecules, as well as parallel improvement in synovial histology,30,31 these results must be interpreted with caution. The fact that only short-term studies are currently available, that an effect on bone erosions has yet to be proved, and that continued administration of the agent is apparently needed for effect, (indicating that disease activity may be suppressed but not actually eliminated), must raise a note of caution. Nevertheless, the ability to favourably affect the course of DMARD-refractory patients, which is strongly indicated in these studies, is definitely encouraging. Anti-TNF interventions, IL-1 receptor antagonist32 as well as other promising anticytokine agents about to be examined in vivo, may well signify an important advance in controlling RA synovitis,33 especially when coupled to DMARDs.28,29 Other future strategies which appear intriguing but require much further investigation before they can translate into actual patient benefit include non-depleting monoclonal antibodies to CD4, induction of T-cell tolerance by oral feeding of putative antigens, administration of anti-inflammatory cytokines—especially IL-4 and IL-10, and the development of drugs designed to reinduce apoptosis of immune and endothelial cells within the inflamed synovium.34
In conclusion, intensive and prolonged DMARD treatment, often given in combination, is beneficial for many RA patients provided it is started early (preferably within weeks of the initial symptoms and diagnosis), and provided careful attention is given to adjunctive non-pharmacological and symptom-modifying strategies. However, the physician who takes care of an RA patient needs to be vigilant and ready to add or change treatment should significant disease activity be detected despite treatment. Refractory patients must be identified as soon as possible and referred for additional therapies whether by anticytokine agents or other interventions. Thus, the old pyramid of RA treatment should perhaps be recreated and modified (Figure 1
) to emphasize that patients who continue with refractory disease must be considered for early more aggressive or experimental treatments aiming at achieving a complete and long-term remission of this devastating disease.
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30/68), presence of extra-articular manifestations and high-titre rheumatoid factor positivity indicate increased risk for adverse prognosis (reference
Notes
Address correspondence to Professor A. Schattner, Department of Medicine, Kaplan Medical Center, Rehovot 76100, Israel. e-mail: amiMD{at}clalit.org.il 
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