Strategies

At present, traditional DMARDs remain the first choice for monotherapy or combination treatment in patients with RA. Although the new biologic DMARDs that block the activity of tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) have shown great promise in the treatment of RA, further evidence is needed to demonstrate their superiority over traditional DMARDs as initial therapy.

There are a number of key gaps in our knowledge about the new biologic agents and how they compare to traditional DMARDs. First, most patients treated in clinical practice would not meet the entry criteria employed in clinical trials of these new agents. Comparison of patients treated in practice with entry criteria for the Early Rheumatoid Arthritis (ERA) trial and the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial indicate that only 31% and 5%, respectively, would have qualified for these 2 studies.

A second important gap in our current data is that there has been only 1 study that directly compares a biologic against a traditional DMARD. Third, the effectiveness of biologic DMARDs has not been directly compared with those of alternative conventional DMARDs in patients who had less than optimal responses to methotrexate (MTX).

Finally, we continue to examine the long-term efficacy, safety, and cost of the new biologic treatments for RA. Optimal Use of Conventional DMARDs-Methotrexate. If one accepts the view that we do not have sufficient data to abandon traditional DMARDs in favor of biologic preparations, one should then ask what is the best way to treat RA patients with conventional DMARDs?

It is well established that MTX has the most durable efficacy of any single traditional DMARD in individuals with RA and it is now generally accepted as the gold standard for these patients. Recently published results have shown that MTX significantly decreases the overall risk for mortality and for cardiovascular death in a cohort of 1240 patients with RA. After adjustment for baseline prognostic factors, the mortality hazard ratio for MTX use compared with no MTX was 0.4.

The hazard ratios for cardiovascular death and noncardiovascular death in MTX-treated patients were 0.3 and 0.6, respectively. The potent disease-modifying activity of MTX is underscored by data from the ERA trial indicating that it is as effective as etanercept in slowing radiographic disease progression over 1 year.

The results from the ERA trial are also important because they demonstrated that high-dose MTX was significantly more effective than low-dose therapy for all key efficacy measures including American College of Rheumatology (ACR)-N, a continuous measure of clinical improvement derived from the ACR response criteria, the Health Assessment Questionnaire (HAQ), and Medical Outcomes Study Short Form-36 (SF-36).

These results support the view that the MTX dose should be increased to 20 to 25 mg/week in RA patients when necessary. Absorption of MTX may vary with oral delivery. Either intramuscular or subcutaneous administration should be used in patients who do not respond to oral therapy.

Neither high-dose MTX nor parenteral administration was employed in studies where patients received biologic DMARDs as a result of suboptimal responses to MTX. Folic or folinic acid should also be employed as supportive therapy to reduce toxicity in patients who experience side effects with MTX.

Combination therapy. The response to traditional DMARDs is often substantially enhanced by combination therapy, which has been repeatedly demonstrated to be superior to even optimal MTX monotherapy in controlled clinical trials.

Triple-drug therapy with MTX, sulfasalazine (SSZ), and hydroxychloroquine (HCQ) has also been shown to be significantly superior to the 2-agent combinations of MTX plus either SSZ or HCQ. This was demonstrated in a 2-year, double-blind, placebo-controlled trial of 171 RA patients.

Patients receiving the triple combination had the best response to therapy, with 78% achieving an ACR20 response at 2 years, compared with 60% of those treated with MTX and HCQ and 49% of those treated with MTX and SSZ. Similar trends were seen for the ACR50 response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years; and for the ACR70 response where the respective values were 26%, 16%, and 18%.

The sustained effectiveness of combination therapy with traditional DMARDs has been supported by the results of several long-term studies. Toxicities associated with this regimen are low with regular monitoring of patients and various laboratory parameters.

Aggressive early therapy. Recently updated treatment guidelines published by the ACR recommend prescribing DMARD therapy for patients with RA within 3 months of diagnosis. Selection of any pharmacotherapy is based on using the safest treatment plan that matches the aggressiveness of the disease. Agents can be used as monotherapy or in combination.

The effectiveness of early aggressive combination therapy is underscored by results from Calguneri and colleagues who treated 180 patients with early active RA with 1, 2, or 3 DMARDs and followed them for 2 years. There were significant improvements in clinical and laboratory parameters in all 3 groups, but they were greatest in the patients given the 3-drug combination .

How effective are the traditional DMARDs versus biologic preparations? The ERA trial is the only study that has addressed this question. In the first year of this trial, 632 patients with early RA were treated with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral MTX (mean dose = 19 mg/week) for 12 months. Study results showed that the effectiveness of MTX was very similar to that of etanercept.

There are several studies (some available only as abstracts) that have demonstrated the effectiveness of biologic DMARDs in patients who responded suboptimally to MTX (dosed at less than or equal to 20 mg/week with no patients switched from oral to either subcutaneous or intramuscular administration). These results make it difficult for the clinician to judge the relative effectiveness of the new preparations vs traditional DMARDs.

However, review of the literature suggests that treating patients who responded suboptimally to MTX with other traditional DMARDs or combinations of these drugs may be as effective as administration of biologic preparations.

Can Early Intervention Suppress Disease Progression in RA? A critical question in the long-term treatment of patients with RA is whether an aggressive, early, and temporary intervention can provide long-term benefit in patients with this disease. The results of the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial have provided some insight with respect to this issue.

The initial phase of this study demonstrated that step-down combination therapy with prednisolone, MTX, and SSZ was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of RA. Additional 4- to 5-year follow-up of these patients during treatment (all received "best available" therapy) showed that the patients who received combination therapy as initial treatment had significantly less disease progression than those treated with SSZ alone .

Thus, initial intensive combination treatment that included very short-term high-dose corticosteroids resulted in sustained suppression of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy

Management of Established RA: Dealing with Treatment Failure; Many RA patients will experience disease progression, particularly when treated with any single agent, and will require additional therapy to manage their clinical symptoms. A number of treatment options have proven effective for such patients, most of which entail the continuation of MTX therapy and/or addition of other DMARDs.

Both HCQ and SSZ are highly effective when used in combination with MTX and results reviewed above strongly support use of the triple combination of MTX, HCQ, and SSZ in patients who have had a suboptimal response to MTX. Other potentially effective combinations include MTX plus either cyclosporine or leflunomide, or MTX combined with etanercept, infliximab, or adalimumab. Comparison trials of these approaches are sorely needed. The results reviewed support the view that most patients with RA should be initially treated with MTX with rapid dose titration to 20 to 25 mg/week and switched to subcutaneous administration if oral therapy is not effective. If such treatment does not yield a satisfactory response, SSZ and HCQ should be added to the regimen.

Biologic agents can and should be added, preferably within the first year after diagnosis, if patients have not responded in a satisfactory fashion to optimal combination DMARD therapy.

Combination therapy with traditional DMARDs is often used in the management of patients with RA. However, such treatment is frequently limited by complicated drug regimens, low compliance associated with high pill burden, high incidence of side effects, requirement for complicated monitoring procedures, and the development of constitutional symptoms that can result in reduced quality of life (QOL), particularly in patients who are being treated with MTX.These limitations have led to the need for alternatives to existing treatment paradigms.

Biologic DMARDs: Elucidation of the key role of TNF-alpha in the pathogenesis of RA has led to the development of biologic DMARDs that block the activity of this cytokine. The use of these new preparations for the treatment of RA has a number of potential advantages over therapy with traditional DMARDs, including highly specific binding to target molecules that have key roles in the disease process, rapid onset of clinical action, reduced nonspecific toxicity, dosing intervals as long as every other week subcutaneously or every other month intravenously, possible long-term immunomodulatory effects, and improved QOL.

Effectiveness of biologic DMARDs in the treatment of early RA is particularly important for slowing and even potentially halting disease progression. The results of Genovese and colleagues provide strong support for the use of etanercept, the human recombinant version of TNFR1 that is linked to the Fc receptor of human immunoglobulin G1 (IgG1), in patients with early RA.

These investigators compared clinical and radiographic outcomes in 632 patients who received monotherapy with either etanercept or MTX for 2 years. Following at least 1 year of double-blind treatment, 512 patients continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner. At the end of 2 years, patients who received 25 mg etanercept twice weekly had a higher ACR20 response rate than patients who received 20 mg/week MTX .

Evaluation of radiologic disease progression over 2 years also indicated significant superiority of 25 mg etanercept over MTX. Results from this study showed further that significantly more patients in the 25 mg etanercept group (55%) than in the MTX group (37%) had at least 0.5 units of improvement in the HAQ disability index. In addition, fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events.

Since the initial studies with etanercept, there has been significant evolution in TNF-alpha antagonists . Monoclonal antibodies to TNF-alpha, which bind selectively to TNF-alpha but not to TNF-beta, are now available for the treatment of RA. Infliximab, a chimeric monoclonal antibody, is currently approved for use in combination with MTX. Adalimumab, the first fully human anti-TNF-alpha monoclonal antibody, is currently under regulatory review for the treatment of RA either in combination with MTX or other DMARDs or as monotherapy.

The efficacy and safety of adalimumab have been demonstrated in the Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Patients with Rheumatoid Arthritis (ARMADA) trial. This double-blind, placebo-controlled study included 271 patients with active RA who were partial-responders to MTX. They were randomized to receive placebo or adalimumab (20, 40, or 80 mg, injected subcutaneously every other week, for 24 weeks) with continued MTX.

Addition of 20, 40, or 80 mg adalimumab, respectively, to MTX resulted in ACR20 responses in 48%, 66%, and 66% of patients; ACR50 responses in 32%, 54%, and 43%; and ACR70 responses in 10%, 27%, and 19%. The ACR20, ACR50, and ACR70 response rates for patients who had placebo added to continued MTX were 15%, 8%, and 5%, respectively .These results thus show that the addition of a highly specific, fully human monoclonal anti-TNF-alpha antibody to continuing MTX in RA patients, who were partially responsive to this DMARD, provided clinically significant improvement in disease activity.

Results from the recently completed Safety Trial of Adalimumab in Rheumatoid Arthritis (STAR) trial also support the safety and effectiveness of adalimumab in patients with RA.The STAR trial is the first study designed to evaluate the safety of a biologic DMARD as part of standard antirheumatic care. It included 636 patients who had 40 mg adalimumab (injected subcutaneously every other week) or placebo added to ongoing therapy that included 1 or more conventional DMARDs in 83.5% of patients.

At the end of 24 weeks of follow-up, the ACR20, ACR50, and ACR70 response rates for patients who had adalimumab added to therapy were 52.8%, 29.2%, and 14.8%, respectively. The respective values for patients who received placebo in addition to their ongoing therapy were 34.9%, 11.1%, and 3.5%. Safety data from the STAR trial also indicated that adalimumab was safe and well tolerated when used in combination with multiple traditional DMARDs.

Results from other recent publications and presentations support the improved safety of biologic vs conventional DMARDs. Geborek and colleagues used a survival-on-drug analysis and showed that the TNF-alpha antagonists etanercept and infliximab had significantly better tolerability than leflunomide . At the end of 1 year, 82% of etanercept-treated patients remained on drug compared with only 36% of leflunomide-treated patients. In the above-cited 2-year comparison of etanercept and MTX carried out by Genovese and colleagues , 75% of patients remained on etanercept 25 mg compared with 59% of patients on MTX at the end of follow-up.

Taken together, the results summarized,indicate that addition or substitution of biologic DMARDs directed against TNF-alpha in the therapeutic regimens of patients with RA is significantly superior to continued MTX monotherapy for improving clinical and radiologic outcomes. Biologic DMARDs provide long-term improvement in signs and symptoms of RA, stop or greatly delay radiologic progression, and have a very good safety profile resulting in high patient compliance.

The efficacy, safety, and long administration intervals with these new preparations also support the prediction that they may become the treatment of choice, perhaps as monotherapy, for patients with early RA; new production processes that decrease their cost will increase their use. Treatment with highly specific biologic preparations also has the potential to revolutionize therapy for other difficult-to-treat conditions, such as ankylosing spondylitis.

Predicting responses to therapy. A number of issues regarding the optimal use of TNF-alpha antagonists remain incompletely defined, thereby providing key areas of focus for future research. For example, it has been demonstrated that some patients experience remission or near-remission as a result of using TNF-alpha antagonists. On the other hand, for some patients these agents are ineffective. Being able to prospectively identify patients with a tendency to experience outcomes at both ends of the response spectrum would be a tremendous advantage. Relevant information in this regard may come from pharmacogenetics, or "personalized medicine," which involves identifying the genetic polymorphisms and other factors associated with particular outcomes.

Defining the most appropriate therapeutic options for the majority of patients who experience significant benefit from TNF-alpha antagonists but still have some residual disease activity is also an important area for further study.

Determining the best approaches to combination therapy. Perhaps one of the most important priorities for future RA-related anticytokine research is determining the best combinations of biologic and traditional disease modifying antirheumatic drugs (DMARDs) for the early aggressive treatment of disease. Many different combinations of anticytokine therapies may be potentially useful. These include combinations of 2 anti-inflammatory molecules; anti-inflammatory plus immunomodulatory combinations (eg, inhibitors of co-stimulatory molecules, adhesion molecules, or angiogenesis). The potential benefits of such combination therapies include additive or synergistic efficacy that would permit treatment with low doses and reduced risk for toxicity and/or treatment resistance.

Exploration of combination anticytokine therapies is highly worthwhile because of their potential to completely suppress ongoing immune-driven inflammation, induce immunologic tolerance, prevent tissue damage, and promote healing. However, potential risks associated with these approaches include increased immunosuppression and elevated risk for both opportunistic infections and development of malignancies. There is also a potential for completely unanticipated outcomes due to the chaotic, nonlinear nature of cytokine networks/cascades. Ultimately, the objective of TNF-alpha antagonism and other immunomodulatory approaches in treating patients with RA is to completely suppress immune-driven inflammation, induce immunologic tolerance, prevent damage, and promote tissue healing, while minimizing any treatment-related side effects. Further study will hopefully enable us to achieve these goals.

Biologics VS Conventional:

For 60 to 90% of patients the disease is progressive despite treatment, leading to disability and early mortality. This group of patients often shows extra-articular manifestations of the disease (e.g. vasculitis which can involve skin, lung, heart, kidney and ocular vessels). In those with the poorest functional status and more involved joints the 5-year survival rate can be les than 50%; this is similar to mortality in other severe diseases such as stage IV Hodgkin's disease and 3-vessel coronary artery disease.

But Not for All. Nevertheless, for a small proportion of patients (5 to 20%) the disease is mild and symptoms resolve within 1 to 2 years after treatment with NSAIDs alone. For a further 5 to 20% of patients the disease progresses slowly and response to DMARDs is usually satisfactory. Although those with mild disease often have a smaller number of involved joints and rheumatoid factor is not detectable, there is no agreed prognostic marker(s) to determine which 'type' of rheumatoid arthritis a patient is likely to have at initial presentation.

Treatment is therefore usually 'stepped up' gradually to avoid exposing patients with milder types of rheumatoid arthritis to poorly tolerated therapies.

The goal of treatment is to control inflammation sufficiently to prevent or retard joint damage with the ultimate goal being to induce complete remission. Unfortunately complete remission is rarely achieved.

A number of criteria are used in clinical trials to measure response to treatment and are often combined to form a composite measure of treatment response, e.g. the American College of Rheumatology (ACR) criteria . Minimal clinical response is defined as a 20% improvement (ACR 20).

Try NSAIDs First: NSAIDs reduce joint pain and swelling and may improve function; however, they do not alter disease progression. Nevertheless, because of the unpredictable course of rheumatoid arthritis at presentation they are usually used as initial treatment. If patients continue to experience persistent joint symptoms, morning stiffness, and fatigue for more than 3 months, treatment with DMARDs is indicated.

Delaying treatment with DMARDs until joint damage is evident was found to be associated with poor long term outcomes. The current treatment strategy therefore involves the early use of DMARDs to limit joint damage and preserve function. The term DMARD applies to a diverse array of drugs such as penicillamine, oral or intramuscular gold, sulfasalazine, antimalarials (chloroquine and hydroxychloroquine) and immunosuppressants (methotrexate, azathioprine, cyclosporin, leflunomide). There is typically a delay in onset of clinical efficacy with these drugs which ranges from 4 weeks to 6 months depending on the DMARD being used.

Adverse events are a major limitation of the use of DMARDs and monitoring of complete blood counts is recommended for all DMARDs (except hydroxy-chloroquine and leflunomide). Additional monitoring of liver function tests, serum creatinine and urine proteins is required for some DMARDs.

The cost of adverse event monitoring adds significantly to the cost of treatment with these agents. Nevertheless, the consequences of rheumatoid arthritis are so severe that the efficacy/toxicity ratio of drugs such as methotrexate, sulfasalazine and hydroxychloroquine appears to be favourable. Such treatments are best administered by specialist rheumatologists.

Among the older DMARDs, methotrexate appears to have the best long term efficacy and is often selected as the initial DMARD. This observation conflicts with the registered indication which is for patients with severe, acute disease who do not respond to a course of NSAIDs and at least one other DMARD. This caution is a reflection of the potentially serious adverse events associated with this drug including an increased risk of lymphoma.

Despite methotrexate's ability to reduce disease activity and joint damage, it rarely leads to true remission and combination therapy is frequently required.

Leflunomide is a more recently introduced DMARD. Over longer treatment durations (24 months), leflunomide appeared to be at least as effective as methotrexate and more effective than sulfasalazine. Leflunomide also delayed radiological progression, assessed after 12 or 24 months of treatment, at least as effectively as methotrexate (in some patients ) or sulfasalazine and reduced functional disability (assessed using a Health Assessment Questionnaire) to a greater extent than either methotrexate or sulfasalazine after treatment durations of 6 to 24 months. The drug had a faster onset of action (4 weeks) than either methotrexate or sulfasalazine and was as well tolerated as both of these drugs in clinical trials.

Infliximab and etanercept have recently been approved for use in the treatment of rheumatoid arthritis ( 5 years ).Both drugs have been shown to reduce disease activity and joint damage so can be considered as DMARDs. However, unlike the more traditional DMARDs these drugs directly target TNF, a proinflammatory cytokine, which plays a key role in the pathological inflammatory process in rheumatoid arthritis. Both drugs have a faster onset of action (1 to 2 weeks) compared with other conventional DMARDs.

They have been associated with an increased risk of upper respiratory tract infection and more rarely with cases of serious infection. For this reason they should not be given to patients with active infections and should be discontinued if a patient develops a serious infection or sepsis. Approximately 10% of patients receiving infliximab have developed antibodies to the drug but the clinical significance of this is not yet known.

In contrast, etanercept antibodies have only rarely been reported in etanercept-treated patients. Antinuclear antibodies and anti-double-stranded DNA antibodies ( Lupus )have been reported to occur more frequently in both etanercept and infliximab treated patients compared with placebo recipients, although drug-induced lupus has been reported in only 2 rheumatoid arthritis patients (both of whom were receiving infliximab).

Etanercept approved for use alone. Etanercept was the first TNFinhibitor to be approved for rheumatoid arthritis. It produced improvements in all components included in the ACR core set of disease activity measures in patients who had failed to respond to conventional DMARD therapy, when used alone (at a dosage of 25mg subcutaneously twice weekly) or in combination with oral or subcutaneous methotrexate (10 to 25 mg/week).

Etanercept (25mg twice weekly) was also at least as effective and well tolerated as methotrexate (7.5 mg/week increasing to a maximum of 20 mg/week) in a large double-blind comparative trial of patients with active rheumatoid arthritis who had not previously received methotrexate. Furthermore, etanercept reduced joint erosion significantly more effectively than methotrexate after 6 and 12 months of treatment in the same study ( the curve seems to drop on a longer term trial ).

Overall, etanercept has been well tolerated with injection site reactions being the most frequently reported adverse event occurring in up to 49% of patients receiving the 25mg twice weekly dose.

Infliximab for use with methotrexate. Infliximab, a chimeric mouse-human monoclonal antibody directed at TNF, has primarily been evaluated in combination with methotrexate and is therefore only approved for use in combination with this drug. Infliximab (3 or 10 mg/kg intravenously every 4 or 8 weeks) plus methotrexate (15 mg/week orally) elicited a greater response in ACR criteria after 30 weeks of treatment than methotrexate alone in a double-blind, placebo-controlled trial.

All patients enrolled had failed to respond to more than 1 DMARD. Preliminary data indicate that response is sustained for up to 54 weeks and that joint damage is reduced compared with methotrexate alone. Adverse events, including serious events, occurred more frequently in infliximab-treated patients than in the placebo group ).

If residual inflammation remains after maximum doses of DMARD monotherapy, combinations of DMARDs should be considered. Methotrexate is the drug most commonly used in combination. These studies generally indicate increased efficacy for combination therapy compared with monotherapy and tolerability does not appear to be increased. The use of combination regimens is becoming more common for the treatment of patients with refractory rheumatoid arthritis but long term follow-up (5 years) is still needed to determine optimum strategies.

Low-dose oral glucocorticoids (> 10 mg of predisone daily,or the equivalent) and local injections of glucocortoids are highly effective for relieving symptoms in patients with active RA. A patient disabled by active poolyarthritis may experience marked and rapid improvement in functional status within a matter of days following initiation of low-dose glucocortoids.

Frequently,disabling synovitis recurs when glucocorticoids are discontinued,even in patients who are receiving combination therapy with one or more of the DMARDs, Therfore,many patients with RA are functionally dependent on glucocorticoids and continue them for a longer-term,then desired.

Recent evidence suggests that low-dose glucocorticoids slow the rate of joint damage and,therefore,appear to have disease-modifying potential. Joint damage may increase on discontinuation of glucocorticoids. The benefits of low-dose systemic glucocortoids,however,should always be weighed against their adverse effect.

The use of corticosteriod therapy should not be stopped abruptly-it should be tapered off ,gradually.

The improvement from an intraarticular injection of glucocorticoids helps to instill confidence that treatment can be effective. A patient who has a disease flare in only one or few joints can be treated successfully by injecting the particular joint(s),without requiring a major change in the prescribed treatment regimen. Local glucocorticoid injections may also allow the patient to participate more fully in rehabilitation programs to restore lost joint function.

Not all joint flares in RA patients are caused by the disease. Joint infection or microcrystalline arthritis must be considered and rukled out before local glucocorticoid injections are given.

In general,the same joint should not be injected more that once within 3 months. The need for repeated injections in the same joint or for injections in mutiple joints indicates the need to reassess the adequacy of the overall treatment program.

The Prosorba® column was approved by the FDA on March 16, 1999, for use in the treatment of moderate to severe adult rheumatoid arthritis in patients with longstanding disease who have failed or are intolerant of DMARDs.

The device had been previously approved in 1987 for treatment of idiopathic thrombocytopenia purpura. It consists of an inert silica matrix to which a component of Staphylococcus bacterium is covalently bound. This protein (protein A) has the propensity to bind immunoglobin G (IgG) and IgG bound to antigen. The standard course of treatment involves 12 weekly outpatient apheresis sessions, each of which takes approximately two hours.

The phase III clinical trial ended in January 1998 after an independent Data and Safety Monitoring Board recommended early cessation due to favorable safety and statistically significant efficacy data. The double-blinded, sham-procedure controlled multicenter trial enrolled 99 severely affected RA patients with average disease duration of approximately 15 years who had failed an average of five different DMARD regimens including methotrexate in 87% of patients.

Of these patients, 52 were randomized to Prosorba treatment and 47 to the sham procedure. After a wash-out period (one month for methotrexate, three months for other DMARDs), weekly treatments were initiated for 12 weeks. Corticosteroid and NSAID use could be continued but not adjusted during the study.

Using a 20% improvement rate to define a beneficial response (ACR 20), 29% of the Prosorba group responded as compared to 11% of the sham procedure group. The withdrawal rate in both groups was approximately 30%.

Among those completing the 12 treatments, 42% of Prosorba treated patients were responders as compared with 16% of sham-treated patients. Duration of response was 37 weeks for the Prosorba group.

Post-treatment flares were seen in approximately 1/3 of patients. The most frequent adverse events were hypotension and anemia. Five of nine patients who received central venous access developed significant complications including infection and thromboses. There is no data available regarding safety or efficacy when used in combination with conventional DMARD therapies.

In a study published in the July 20 issue of the New England Journal of Medicine, investigators have reported the benef1cial effects of the combination of cyclosporine (Cs) and methotrexate (MTX) in patients with rheumatoid arthritis.

This Sandoz-sponsored, multicenter, randomized, double-blind study compared the effects of Cs (2.5-5 mg/kg of body weight/day) plus MTX versus MTX plus placebo in a six-month trial in 148 RA patients who had achieved "partial but substantial" responses to MTX alone but who still had active disease and disability.

Cs doses could be altered depending upon changes in serum creatinine. MTX was administered at the maximum tolerated dose which did not exceed 15 mg/week. Outcome measures included tender and swollen joint counts, pain, patient and physician overall assessment, degree of disability, and ESR.

The two study groups were comparable at entry with the majority of patients having advanced disease. The number of early withdrawals was similar in both groups, and was usually secondary to an adverse reaction to treatment.

Statistically significant differences were noted between the two groups for all clinical measures. Patients in the Cs + MTX group versus the MTX + placebo group had a statistically more significant improvement in tender joint count, swollen joint count, physician and patient assessment, joint pain, and degree of disability. The ESR increased by 4.2 mm/hr in the CS group compared to a decrease of 4.8 mm/hr in the placebo group.

Additionally, 48 percent of the Cs-treated rheumatoids and I6 percent of the placebo group (p<0.001) satisfied the ACR criteria for improvement in RA.

Side effect profiles were generally similar between the two groups, although some significant differences were noted. In Cs-treated patients (mean dose approximately 3 mg/kg/day), the serum creatinine rose by 0.14 mg/dl by six months compared to an increase of 0.05 mg/dl in the placebo group. (p=0.02).

The authors correctly point out some concerns which will temper enthusiasm for this combination. Continued studies are obviously needed to determine if these results can be sustained with more prolonged treatment, and if the toxicity profiles change with chronic therapy. Furthermore, the effects of Cs + MTX versus MTX alone on mortality and disability will require long-term monitoring.

As is the case for all combination therapy in RA, usage should be reserved for patients failing to respond to monotherapy with a clear understanding of the potential toxicities and increased cost of these medications

James R. O'Dell, MD, and associates reported in the May 16, issue of the New England Journal of Medicine on the treatment of rheumatoid arthritis with triple combination therapy.

These researchers conducted a two-year, double-blind randomized study comparing methotrexate alone (7.5-17.5 mg/wk) with sulfasalazine (500 mg twice a day) and hydroxychloroquine (200 mg twice a day), or all three drugs. Methotrexate was adjusted to achieve remission. There was no difference in the groups at entry.

The major end point was whether the patients' conditions improved by 50 percent, as determined by whether three of the following requirements had been fulfilled: morning stiffness of less than 30 minutes duration or improved by 50 percent; joint tenderness improved by 50 percent; joint swelling improved by 50 percent; and erythrocyte sedimentation rate of less than 30 mm per hour in women and less than 20 mm in men. Patients that did not have this degree of improvement were considered failures.

Fifty of 102 patients had 50 percent improvement at nine months and maintained at least that for two years without major drug toxicity. Twenty-four of 31 (77%) of these patients were in the group taking all three drugs. Twelve of 36 patients (33%) were in the methotrexate group and 14 of 35 (40%) were in the sulfasalazine/hydroxychloroquine group.

Thirteen patients discontinued the study because of drug toxicity. Seven patients were in the methotrexate group, three were in the sulfasalazine/ hydroxychloroquine group, and three were in the three-drug group.

Disease modifying drugs currently available are frequently disappointing when remission is the end point. There is little data in the literature to suggest that combination therapy is better than a single drug.

The present study demonstrates that in patients with rheumatoid arthritis, the combination of methotrexate, sulfasalazine, and hydroxychloroquine is better than either methotrexate alone or a combination of sulfasalazine and hydroxychloroquine, and there is no increased toxicity with the combination compared to methotrexate alone.