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CURRENT CONTROVERSIES IN RHEUMATOLOGY

THE USE OF COMBINATIONS OF DISEASE-MODIFYING ANTIRHEUMATIC AGENTS IN RHEUMATOID ARTHRITIS HAROLD E. PAULUS

Rheumatologists are expressing increased interest in the use of combinations of disease-modifying antirheumatic drugs (DMARDs) to treat patients with rheumatoid arthritis (RA). This interest has been motivated by published reports ( 1 4 ) and personal experience that strongly suggest that the sequential use of available DMARDs, added to standard background therapy with nonsteroidal antiinflammatory drugs (NSAIDs) and/or low-dose corticosteroids, prevents progressive joint damage and eventual disability in only a very few patients, if the patients are followed for 5 or 10 years, or longer. Moreover, published evidence indicating that RA decreases not only the patient’s functional ability but also the lifespan (5) further motivates us to find treatment regimens that favorably alter the long-term outcome of our RA patients. A number of drugs have been demonstrated to be more effective than placebo when added to a regimen of NSAID therapy in 3-12-month studies. During the last 20 years, D-penicillamine, azathioprine, auranofin, methotrexate, and sulfasalazine have been added to previously available injectable gold preparations and antimalarial drugs as useful agents for the treatment of RA. Cyclophosphamide, chlorambucil, cyclosporin A, levamisole, total nodal irradiation, antithymocyte globulins, lymphocyte apheresis, thoracic duct drainage, and other regimens also appear From the University of California, Los Angeles, School of Medicine, Los Angeles, California. Harold E. Paulus, MD. Address reprint requests to Harold E. Paulus, MD, Professor of Medicine, UCLA School of Medicine, Los Angeles, CA 90024. Submitted for publication August 4, 1989; accepted August 14, 1989. Arthritis and Rheumatism, Vol. 33, No. 1 (January 1990)

to partially suppress some of the manifestations of RA, at least in some patients, for variable periods of time (6). Thus, even if we limit ourselves to this list of therapies and use only rational dosages and dosage schedules, a large number of therapeutic permutations and combinations are available for investigation. It is not unusual for practicing rheumatologists to add a second DMARD to a patient’s treatment regimen while continuing the first, using the drugs cumulatively rather than sequentially. For example, gold, methotrexate, or D-penicillamine may be added to an antimalarial agent, or methotrexate may be added to D-penicillamine therapy (7-9). A survey (by mail) of 92 Canadian and 77 Australian rheumatologists, published in 1986 (lo), reported that the combination of an antimalarial agent and gold was prescribed by 45% of the Canadian rheumatologists and 31% of the Australian rheumatologists, and the combination of an antimalarial agent and D-penicillamine had been used by 3 1% of the Canadian rheumatologists and 18% of the Australian rheumatologists. Indeed, Wilske and Healey (1 1) have recently proposed that patients with early RA who continue to have active disease after 1 month of treatment with prednisone or an NSAID should immediately be started on combination DMARD therapy, and they suggest that methotrexate, injectable gold, oral gold, and antimalarial agents are a reasonable combination. Their rationale for this approach is that RA inflammation would be quickly and completely suppressed with prednisone and methotrexate,.which can then be sequentially withdrawn as the injectable gotd, then the otal gold, and finally, the antimalarial drug control the inflammation, This down bmdge” therapy should Prevent early joint damage and, after the first year, provide sustained com-

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plete suppression of RA inflammation (thus preventing joint damage ,.and subsequent disability) with prolonged antimalarial therapy alone. Brief courses of prednisone andor methotrexate can be repeated if needed for intermittent flares.

RATIONALE FOR COMBINED DMARD THERAPY Wilske and Healey’s proposal admirably expresses the goals of DMARD therapy: to suppress RA inflammation as completely as possible for the patient’s entire lifetime and, thereby, to prevent the initial, and then progressive, joint damage that leads to eventual disability. Up to the present time, therapy with a single DMARD has only very rarely achieved this goal for the entire lifetime of the patient. Various rationales can be used to justify combining DMARDs in an attempt to better achieve this goal (12). The selected DMARDs may have different sites of action, such that the efficacy of the combination is greater than that of either drug alone. Combining drugs with different toxicities or using lower doses of toxic drugs in combination may decrease the risks associated with DMARD therapy while maintaining or increasing the efficacy. Alternatively, high doses of toxic drugs with presumably different mechanisms of action may be used in an attempt to eradicate the disease, considering the RA to be a “non-malignant B-lymphoproliferative disease,” and adopting the oncologist’s approach to the treatment of malignant lymphoproliferative diseases (13). Often, however, combinations of DMARDs have been resorted to in desperation, in a random search for an effective therapy for particular patients who have not responded to standard therapy. What evidence supports the hope that some combination of DMARDs will effectively produce long-term, sustained suppression of RA inflammation without unacceptable short-term or long-term toxic effects? Oncologists have had considerable success treating malignancies of lymphocytes, monocytes, granulocytes, and their precursors with combined chemotherapy. Since these cells are intimately involved in inflammation, one logical question is: What would happen to rheumatoid inflammation if oncologic regimens were used to treat RA patients? Roubenoff et a1 (14), in 1987, described 2 women who developed acute myelogenous leukemia after 3 years and 6 years, respectively, of active classic, seropositive, erosive RA. Complete remission of the leukemia occurred in

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both patients after marrow aplasia was induced with a protocol that combined cytosine arabinoside, daunorubicin hydrochloride, and m-AMSA (amsacrine) administration over a 10-day period. The first patient received 2 courses of this regimen and experienced complete clinical and serologic remission of RA, with negative results on tests for rheumatoid factor and disappearance of rheumatoid nodules. The second patient also experienced remission of the RA, and remained in remission for 8 months, after a single course of this chemotherapy. The RA recurred after 13 months of remission in the first patient, however, and treatment with prednisone and D-penicillamine was necessary. If prolonged remission of RA occurs following drug-induced bone marrow aplasia, perhaps complete ablation of the marrow, with marrow transplantation from a healthy donor, would produce a permanent remission of RA by eliminating the disease-producing clones of inflammatory cells. Jacobs et al(15), in 1986, described a 33-year-old woman with seropositive, erosive RA of 6 months duration who developed aplastic anemia during treatment with NSAIDs, prednisone, gold salts, and then D-penicillamine. After administration of 200 mg/kg of cyclophosphamide, she received a transplant of bone marrow from an HLA-identical brother. Engraftment occurred, and cyclosporine was given for 1 year to prevent graft-versus-host disease. All signs and symptoms of the RA disappeared, and rheumatoid factor, which had been positive at a titer of 1 :512, became negative. Results of skin tests for the delayed hypersensitivity reaction and in vitro tests of lymphocyte responses became normal. However, af-

ter 2 years of RA remission, arthritis recurred and the rheumatoid factor titer again became strongly positive. NSAIDs, prednisone, and azathioprine were given to control the symptoms, and 3 years after transplantation, the patient was functioning well; cytogenetic studies demonstrated only donor cells, with no reconstitution of any of the patient’s marrow constituents.

DMARD COMBINATIONS STUDIED Combinations including low-dose cyclophosphamide or methotrexate. DMARD combinations that include daily low doses of cyclophosphamide have been reported to induce complete or nearly complete remissions in most of the patients with previously refractory RA who were chosen for inclusion in these practice-based clinical trials (no control groups); approximately 50% of the patients demonstrated recortication of some erosions (16-18). In a study by

DMARDs IN RA

McCarty et al, of 31 patients (mean disease duration 9.9 years) (17), gold therapy was changed to cyclophosphamide (average dosage 30 mg/day), and hydroxychloroquine therapy (210 mg/day) was continued. Nine patients also continued to take azathioprine, and azathioprine (74 mg/day) was added to the cyclophosphamide and hydroxychloroquine regimen in the others. Dosages were manipulated to attempt to decrease toxic events. After 12-102 months of treatment (mean 43 months), 16 of the 31 patients were in complete remission, and 7 were in near remission. Sixteen patients demonstrated recortication of some erosions, although in 9 of those patients, progression of other erosions was evident on the same radiographs. Only 6 patients had no adverse reactions. Three patients died of malignancies (colon carcinoma, endometrial and colon carcinoma, and erythroleukemia); 1 patient with carcinoma of the lung was still living. Antimalarial drugs were discontinued in 5 patients because of early macular changes. Herpes zoster developed in 5 patients, pneumonia in 4, and other infections in 4. Cystitis in 5 patients subsided with a decrease in the cyclophosphamide dosage. All patients who discontinued therapy while in remission had subsequent recurrences of RA, although disease control with standard DMARDs was often possible. Because of concern about the number of malignancies, the investigators have since changed this DMARD regimen to include methotrexate instead of the cyclophosphamide. Tiliakos (18) has reported similar levels of improvement in 12 patients who were treated with hydroxychloroquine (400 mg/day), cyclophosphamide (25 mg/day), and methotrexate (5 mg/week) for 16-25 months. There was recortication of erosions in 7 of the 12 patients. Walters and Cawley (19), however, did not find any additional benefit from a single I-gm pulse of intravenous cyclophosphamide added to the regimen of 8 of 17 patients (average disease duration 12 years) who were treated with a 1-gm pulse of intravenous methylprednisolone. The addition of 24 weekly injections of gold prolonged the improvement induced by the pulse steroid. Biro and coworkers (20) and Wilke et a1 (21) have reported their experience with the use of the combination of methotrexate, azathioprine, and hydroxychloroquine therapy in the treatment of 20 RA patients (average disease duration 10 years), at the Cleveland Clinic. The patients had failed to respond to initial hydroxychloroquine treatment and had experienced continued active RA 12 weeks after the addition

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of methotrexate (17 patients) or azathioprine (3 patients). Azathioprine was then added for the patients receiving methotrexate, and methotrexate for those receiving azathioprine. The 3 drugs were continued in combination for a mean of 14.7 months. Two patients were lost to followup, and 1 discontinued therapy because of stomatitis. The remaining 17 patients experienced marked improvement, with final observations demonstrating a mean erythrocyte sedimentation rate of 23 mmhour, mean grip strength of 161 mm Hg, and mean joint count of 3.3 tender or swollen joints. Brawer (22) described 7 patients whose RA relapsed after 4 years of intramuscular gold therapy. The gold was continued and methotrexate was added (10-15 mg/week) for 17-22 months. All patients had a good response, without toxic events. Antimalarial agents plus gold. There have been several reports of the use of combined therapy with an antimalarial drug plus gold. Sievers and Hurri (23), working in Heinola, Finland, compared 240 RA patients who were treated with an antimalarial drug (between 1957 and 1959) with 248 RA patients who were treated with a combination of an antimalarial drug and gold (during 1960 and 1961). Their mean disease duration was 5.3 years. All patients were hospitalized for an average of 3.4 months, and were treated with rest, splints, salicylates, physical therapy, and corticosteroid injections into the joint, in addition to the drugs of interest. Chloroquine dosages were 200-400 mg daily and the hydroxychloroquine dosage was 400 mg daily; SO-mg injections of gold sodium thiomalate or gold sodium thiosulfate were given weekly for at least 12 weeks. During the 3-6 months of hospitalization, remission or major improvement occurred in 36% of the patients treated with only an antimalarial drug, compared with 43% of those treated with an antimalarial drug plus gold. A subgroup of 177 patients with less severe (stage I or 11) RA had better results: 49% treated with antimalarial agents alone and 66% treated with combination therapy experienced remission or major improvement. Sievers and Hurri’s study was not blinded or randomized, and it was unbalanced, in that there was no group receiving gold treatment alone to serve as a comparison group. Scott et a1 (24) have done a complementary study, in which gold therapy alone was compared with combined therapy with gold plus hydroxychloroquine, although without a hydroxychloroquine treatment alone comparison group. They treated 101 RA patients (average disease duration 24 months) with sodium aurothiomalate at a dosage of 50 mg

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weekly for 20 weeks and then 50 mg every 2 weeks for the remainder of the 1-year study. In addition, patients were randomly assigned to double-blind treatment with hydroxychloroquine or placebo at a dosage of 400 mg daily for 6 months, followed by 200 mg daily for the other 6 months, as well as taking the background NSAIDs and analgesics. Corticosteroids were not permitted. Combined goldhydroxychloroquine treatment was more toxic, with 18 patients (of 52) withdrawing because of toxic events compared with only 10 (of 49) similar withdrawals among those taking gold alone. Ten patients taking the combination withdrew because of rashes, compared with 4 taking gold alone, but only 2 taking the combination withdrew because of lack of benefit, compared with 5 taking gold alone. Comparing the 27 patients who completed 1 year of gold/ hydroxychloroquine treatment with the 32 who completed 1 year of gold treatment, the C-reactive protein levels (P = 0.04) and overall disease activity index (P = 0.05) were statistically significantly better in those receiving the combination therapy. Eleven other clinical, laboratory, and radiologic variables favored combination therapy by 20-25%, but the differences did not achieve statistical significance. These findings suggest that hydroxychloroquine plus sodium aurothiomalate is somewhat more effective and more toxic than gold alone, although a n intent-to-treat analysis was not done. Singleton and Cervantes (25) treated 22 patients with hydroxychloroquine, 200 mg/day, for early, preerosive, classic or definite RA. After an average of 6 months of hydroxychloroquine therapy, 18 patients had exacerbations, and aurothiomalate, 50 mg/week, was added to the regimen. Complete or partial remissions were achieved in 16 of these 18 patients after 15 weekly injections of gold. Antimalarial agents plus D-penicillamine. A balanced, 2-year, randomized, double-blind comparison of hydroxychloroquine, D-penicillamine, and a combination of the 2 was reported by Bunch and associates in 1984 (26). The average duration of RA in those patients was 6.1 years. Eighteen patients were randomized to receive hydroxychloroquine (2.2 mg/ kg/day), 21 to take D-penicillamine (7 mg/kg/day), and 17 to take the combination. Only 1 of the 17 patients was markedly improved after 6 months of combined therapy, compared with 17% of the group taking hydroxychloroquine alone and 43% of those taking D-penicillamine alone. Forty percent of the patients taking the combination were no better after 6 months,

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and 50% were classified as “no better” after 24 months, suggesting that patients receiving combination therapy did less well than those receiving either D-penicillamine or hydroxychloroquine alone. Surprisingly, toxic events occurred less frequently (29%) in those receiving both drugs than in those treated with only D-penicillamine (48%), but with similar frequency in those taking only hydroxychloroquine (22%). The reasons for the apparent decreased efficacy and toxicity of combined hydroxychloroquine/D-penicillamine therapy are not clear, but the relatively small sample size in this study mandates caution in attempts to generalize its findings. A similar balanced, 1-year study comparing chloroquine (200 mg/day), D-penicillamine (250 mg/ day increasing to 750 mg/day), and the combination was done by Gibson et al(27), but it was not a blinded study. Seventy-two patients were prospectively recruited and randomly assigned to 1 of the 3 treatment groups; clinical assessments were made by a blinded, independent assessor, but the patients knew what treatment they were receiving. The mean disease duration range for the 3 treatment groups was 1-3 years. After 1 year of treatment, there were no significant differences in the clinical responses of the 3 groups, but side effects (57%) and treatment withdrawals because of side effects (23%) were more frequent with the combined therapy. Erythrocyte sedimentation rates improved more in the groups receiving D-penicillamine than in those treated with chloroquine alone. D-penicillamine plus gold. Forty-five patients with active RA were prospectively randomized to blindly receive sodium aurothiomalate injections (50 mg/week) plus placebo capsules, D-penicillamine (500 mg/day) plus placebo injections, or both active drugs for 6 months (28). Clinical and biochemical improvements were seen within 4 weeks in patients receiving the combination of gold and D-penicillamine, but were not seen until after 8 weeks of treatment with either drug alone. Otherwise, efficacy and toxicity appeared to be similar among the 3 groups. Bitter (13), in an open study, sequentially assigned 42 patients whose RA was intractable after 1 year of aurothiopropanol injections (150 mg/week) to 1 of 4 groups: aurothiopropanol alone or aurothiopropanol plus either D-penicillamine (1 gm/day), chlorambucil (5 mg/day), or levamisole (150 mg/day for 3 dayslweek). Another similar group of 29 patients with refractory RA had received D-penicillamine (1 gnd day) for 1-2 years; they either continued this therapy

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DMARDs IN RA alone or added levamisole or chlorambucil. Patients who discontinued the therapy were replaced. At the end of at least 18 months of treatment, there were 12 patients each in the groups receiving gold alone, D-penicillamine alone, gold plus D-penicillamine, gold plus levamisole, and D-penicillamine plus levamisole. Six patients were receiving gold plus chlorambucil, and 5 were receiving D-penicillamine plus chlorambucil. Only 2 of the 24 patients who continued taking high doses of gold or D-penicillamine alone achieved remission, and 6 had to withdraw because of toxicity. In contrast, 8 of the 12 who received high doses of combined gold and D-penicillamine achieved remission, although 5 of the original 12 patients withdrew because of toxicity. Fifty percent of the patients who received levamisole in addition to either gold or Dpenicillamine achieved remission, although 4 of the original 12 patients withdrew because of toxicity. The author concluded that the combination of high-dose gold and high-dose D-penicillamine appeared to induce remissions in many patients with intractable RA, without unacceptable levels of toxicity. Combination therapies with sulfasalazine. In an open study, Taggart et a1 (29) randomly assigned 30 patients with active RA (average 2.5 years) to a regimen of either sulfasalazine (2 gdda y) or a combination of sulfasalazine plus D-penicillamine (500 mg/ day) for 6 months. Five of the 15 patients receiving combination therapy, and 3 of the IS receiving sulfasalazine alone, dropped out because of side effects, and 1 patient receiving combination therapy withdrew because of a lack of response. Six patients taking sulfasalazine alone, and 9 patients taking sulfasalazine/ D-penicillamine improved substantially. These results suggest that the Combination is somewhat more effective and somewhat more toxic than sulfasalazine alone. Unfortunately, there was no comparison group assigned to receive D-penicillamine alone. In another report (30), 38 RA patients with an average disease duration of 9 years had tolerated 0.8-5 years of treatment with sulfasalazine (1.5-3.0 gm/day) but after a good initial response, experienced continued active synovitis or a relapse. D-penicillamine (125-1,000 mg/day) was then added to the sulfasalazine therapy in 29 patients, and aurothiomalate (50 mg/week tapering to 50 mg/month) was added to the sulfasalazine therapy in 9 patients. During the first year of combined therapy, 70% of the patients had an overall favorable response, including 2 patients who had remissions of RA. The gold and the D-penicil-

lamine were each discontinued because of adverse reactions in one-third of the patients receiving them, but only 1 patient had to stop taking the sulfasalazine because of toxic effects. STUDIES IN PROGRESS

The ideal study design for assessing a combination of 2 established drugs is a 3-group, balanced, double-blind, randomized study comparing each drug individually with the combination, in a patient sample large enough to detect modest intergroup differences. Such a study should permit one to statistically detect clinically meaningful synergistic, as well as additive or antagonistic, effects of the combination as compared with each drug alone, with respect to both benefit and toxicity. None of the above studies fully satisfies this standard. The publication by Bunch et al (26) and the abstract by McKenna et a1 (28) report well-designed, balanced, double-blind studies, but their sample sizes of 15-21 patients per treatment group are not large enough to permit adequate statistical assessment. We are aware of 2 large well-designed studies of combination DMARD therapy that are currently in progress. One, being conducted by the Cooperative Systematic Studies of Rheumatic Diseases Study Group, is comparing low-dose weekly methotrexate plus auranofin with methotrexate alone and with auranofin alone (Williams HJ: personal communication). Another, being sponsored by Burroughs Wellcome Laboratories, is comparing low-dose weekly methotrexate plus azathioprine with methotrexate alone and with azathioprine alone (Grossman SH: personal communication). It will be several years before the results of these studies are available, but they set a standard for future definitive evaluations of combination therapy.

CONCLUSIONS

There is a great deal of interest in, and considerable tentative use of, various combinations of available DMARDs for treatment of RA. Review of the published evidence (Table 1) indicates that in spontaneous reports of clinical experience, DMARD combinations appear to be especially effective therapy, particularly if the combination includes cyclophosphamide or methotrexate. Two unbalanced but complementary studies of antimalarial agents plus gold suggest that the combination may be more effective and more toxic than gold alone (24), and slightly more effective than an antimalarial drug alone (23). Non-

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Table 1. Previous studies of combinations of disease-modifying antirheumatic drugs (DMARDs) for the treatment of intractable rheumatoid arthritis*

Study type, DMARDs studied (ref.) Double-blind, randomized HCQ + DP (26)

HCQ DP

+ gold (24)

+ gold (28)

Nonblinded, randomized CQ + DP (27)

DP

+ gold @ugh doses) (13)

SSZ

+ DP (29)

Nonblinded, nonrandomized Antimalarial + gold (23) Uncontrolled studies and case reports CYC + AZA + HCQ (16.17) CYC + MTX + HCQ (18) Marrow-ablative chemotherapy

(14,15)

Gold + MTX (22) MTX + AZA + HCQ (20,21) HCQ + gold (25) SSZ + DP or gold (30)

Findings Combination less efficacious than HCQ alone, both less efficacious than DP alone; combination as toxic as HCQ alone, both less toxic than DP alone Combination more effective and more toxic than gold alone Combination as efficacious as DP alone, both as efficacious as gold alone Combination as efficacious as CQ alone, both as efficacious as DP alone; combination more toxic than DP alone, both more toxic than CQ alone Combination more effective than DP or gold alone Combination more effective and more toxic than SSZ alone Combination slightly more effective than antimalarial alone Combination effective but toxic Combination effective Combination induced 12-year remissions Combination effective Combination effective Combination effective Combinations moderately effective; combinations moderately toxic

* HCQ = hydroxychloroquine; DP = D-penicillamine; CQ = chloroquine; SSZ = sulfasalazine; CYC = cyclophosphamide; AZA = azathioprine; MTX = methotrexate.

blinded, random assignment comparison studies suggest that chloroquine plus D-penicillamine is more toxic but not more effective than D-penicillamine or chloroquine alone (27), and that sulfasalazine plus D-penicillamine is more effective and more toxic than sulfasalazine alone (29). Two relatively small welldesigned, balanced, double-blind randomized studies have been done, but their findings do not support the use of combination DMARD therapy (26,28). Two

larger well-designed balanced studies are currently being done (Williams HJ: personal communication and Grossman SH: personal communication). There is as yet no evidence that the efficacy of combinations of DMARDs is synergistic, and there is very little suggestion that it is additive. On the other hand, unanticipated catastrophic toxicity has not been noted in the considerable body of published reports, and in general, the adverse effects have been those that could be anticipated from the previous single-drug experience with the DMARDs being used. COMMENTS At present, essentially all of the pharmaceutical interventions for rheumatoid arthritis seem to work by altering, to various degrees, the normal host inflammatory and/or immunologic protective responses, thereby decreasing the destructive host-mediated inflammation associated with the manifestations of the disease. Interventions that produce more profound alterations in these defense mechanisms tend to relieve RA to a greater extent. Indeed, bone marrow ablation was associated with complete clinical and serologic remission of RA in several cases, as described above (14,15). If RA is a nonmalignant lymphoproliferative disease, driven by an abnormal, inadequately controlled element in the immunoinflammatory response, perhaps it could be cured by identifying and eradicating that element, just as certain patients with leukemia or lymphoma can be cured by intensive combination chemotherapy or radiation therapy. Unfortunately, although chemotherapy-induced bone marrow aplasia was associated with cure of the leukemia in the cases cited, RA recurred after 13 months of complete remission (14). Even complete and permanent destruction of a patient’s bone marrow, along with the associated host immune defense mechanisms sufficient to permit successful replacement by normal donor marrow, produced only a 2-year remission of the patient’s RA (15). These case reports strongly suggest that RA is not a nonmalignant B (or T) lymphoproliferative disease, but rather, that its destructive inflammatory manifestations are unfortunate byproducts of a chronically stimulated, but otherwise normal, host response. If this is the case, and our treatment efforts continue to be directed toward altering the normal host defenses, then increased benefit will continue to be associated with increased risk, and the long-term

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DMARDs IN RA management of RA will continue to require delicate balancing of benefit and risk. While we are waiting for molecular-based research to provide sufficient knowledge to permit more direct and precise control of RA, it is possible that combination DMARD therapy and “step-down bridge” combination therapy may prove to be useful refinements of current practice. However, evidence presently available does not support the general use of any of these regimens. Numerous well-designed, large, long-term, carefully controlled clinical trials will be needed to determine which, if any, combinations, dosage schedules, and sequences of administration are most beneficial and least toxic. Designing studies to test the hypotheses proposed in the complex combinations in “step-down bridge” therapy, of which prednisone is a component, will be particularly difficult. Nevertheless, rheumatologists should continue their traditional adherence to the principles of controlled clinical studies to develop evidence with which to judge the value of new therapeutic approaches. The rheumatologic community contains many conscientious, experienced clinical investigators who can perform the appropriate studies; the National Institutes of Health must be convinced that they must extend to rheumatologic problems (as they have to problems related to hypertension, diabetes, stroke, coronary artery disease, and cancer) sufficient resources to perform the needed long-term definitive, controlled clinical studies. Until we develop treatment regimens that reliably induce and sustain acceptable control of RA manifestations in all patients for the rest of their natural lifespan, daily oral prednisone will continue to be a troublesome component of “bridge” therapy, as it becomes the sole surviving constant in complex regimens whose other components are eventually discontinued because of toxicity, lack of efficacy, or noncompliance. Meanwhile, can the available knowledge about combinations of DMARDs be applied to current management of RA patients? We have often seen patients in whom the replacement of a welltolerated but presumably ineffective DMARD with another DMARD has led to worsening of the RA, when the modest benefits of the discontinued DMARD were lost before the hoped-for onset of benefit from its replacement became evident. Since the toxicity of combinations of DMARDs has not appeared to be excessive, one can reasonably add the second DMARD to the first, while carefully monitoring for adverse effects and planning to continue the combination until increased benefit

occurs. Then, if the second DMARD is not tolerated, the partial benefit from the first DMARD haFnot been given up, and a longer duration of treatmexwith the initial DMARD is sometimes associated with satisfactory improvement in the RA. If better control of the RA is evident after 3-6 months of treatment with the combination of DMARDs, one must still decide whether to stop the first DMARD, stop the second, or continue with the combination. In the absence of major toxicity, we are most likely to choose to continue the combination if the patient has had a good response, thus inadvertently embarking on prolonged combined DMARD therapy. REFERENCES 1. Hoh K-F, Dwosh IL, Ford PM, Anastassiades TP, Kelly

2.

3.

4.

5.

6. 7. 8. 9. 10. 11.

12. 13.

HG: Drug-related disease remission in rheumatoid arthritis (abstract). Arthritis Rheum 24 (suppl4):S72, 1981 Husain Z, Runge LA: Treatment complications of rheumatoid arthritis treated with gold, hydroxychloroquine, D-penicillamine, and levamisole. J Rheumatol 7:825830, 1980 Scott DL, Coulton BL, Symmons DPM, Popert AJ: Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet I: 1108-1 11 1, 1987 Epstein WV, Henke CJ, Yelin EH: Gold salt therapy does not alter the course of rheumatoid arthritis in adults (abstract). Arthritis Rheum 32 (suppl 4):S62, 1989 Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughan WK: Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 27:864-872, 1984 Klippel JH, Strober S, Wofsy D: New therapies for rheumatic diseases. Bull Rheum Dis 38:1-8, 1989 Mackenzie AH: Antimalarial drug therapy, Rheumatic Therapeutics. Edited by SH Roth. New York, McGrawHill, 1985 Wilke WS, Kroll PL: Refractory RA patients: give cytotoxics next? J Musculoskeletal Med 150-58, 1984 Cheatum DE: Use of antimalarials in the treatment of rheumatoid arthritis. Intern Med Specialist 7:67-74, 1986 Bellamy N, Brook PM: Current practice in antimalarial prescribing in rheumatoid arthritis. J Rheumatol 13: 55 1-555, 1986 Wilske KR, Healey LA: Remodeling the pyramid: a concept whose time has come. J Rheumatol 16565-567, 1989 Paulus HE: Antimalarial agents compared with or in combination with other disease-modifying antirheumatic drugs. Am J Med 85 (suppl4A):45-52, 1988 Bitter T: Combined disease-modifying chemotherapy for

120

14.

15.

16.

17.

18.

19.

20.

21. 22.

intractable rheumatoid arthritis. Clin Rheum Dis 10: 413-428, 1984 Roubenoff R, Jones RJ, Karp JE, Stevens MB: Remission of rheumatoid arthritis with the successful treatment of acute myelogenous leukemia with cytosine arabinoside, daunorubicin, and m-AMSA. Arthritis Rheum 30:1187-1190, 1987 Jacobs P, Martell V, Martell RW: Prolonged remission of severe refractory rheumatoid arthritis following allogenic bone marrow transplantation for drug-induced aplastic anaemia. Bone Marrow Transplantation 1 : 237-239, 1986 McCarty DJ, Carrera GF: Intractable rheumatoid arthritis: treatment with combined cyclophosphamide, azathioprine, and hydroxychloroquine. JAMA 248:1718-1723, 1982 Csuka ME, Carrera GF, McCarty DJ: Treatment of intractable rheumatoid arthritis with combined cyclophosphamide, azathioprine and hydroxychloroquine: a follow-up study. JAMA 255:2315-2319, 1986 Tiliakos NA: Low-dose cytotoxic drug combination therapy in intractable rheumatoid arthritis: two years later (abstract). Arthritis Rheum 29 (suppl 4):S79, 1986 Walters MT, Cawley MID: Combined suppressive drug treatment in severe refractory rheumatoid disease: an analysis of the relative effects of p a r e n t e d methylprednisolone, cyclophosphamide, and sodium aurothiomalate. Ann Rheum Dis 47:92&929, 1988 Biro JA, Segal AM, Mackenzie AH, Mazanec DJ, Wilke WS: The combination of methotrexate and azathioprine for resistant rheumatoid arthritis (abstract). Arthritis Rheum 30 (suppl 4):S18, 1987 Wilke WS, Schemer YR, Clough JD: Combination chemotherapy for severe rheumatoid arthritis. Intern Med Specialist 1059-76, 1989 Brawer AE: The combined use of methotrexate and

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23. 24.

25.

26.

27.

28.

29.

30.

intramuscular gold in rheumatoid arthritis (abstract). Arthritis Rheum 31 (suppl 1):R10, 1988 Sievers K, Hurri L: Combined therapy of rheumatoid arthritis with gold and chloroquine. Acta Rheumatol Scand 9:48-55, 1963 Scott DL, Dawes PT, Tunn E, Fowler PD, Shadforth MF, Fisher J, Clarke S, Collins M, Jones P, Popert AJ, Bacon PA: Combination therapy with gold and hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo-controlled study. Br J Rheumatol 28: 128-133, 1989 Singleton PL, Cervantes AG: Concomitant gold and hydroxychloroquine therapy for second remission of rheumatoid arthritis (abstract), Meeting of the Southeast Asia and Pacific Area League Against Rheumatism. Bangkok, Thailand, 1984 Bunch TW, O’Duffy JD, Tompkins RB, O’Fallon WM: Controlled trial of hydroxychloroquine and D-penicillamine singly and in combination in the treatment of rheumatoid arthritis. Arthritis Rheum 27:267-276, 1984 Gibson T , Emery P, Armstrong RD, Crisp AJ, Panayi GS: Combined D-penicillamine and chloroquine treatment of rheumatoid arthritis: a comparative study. Br J Rheumatol 26:279-284, 1987 McKenna F, Hopkins R, Hinchcl8e KP, Bird HA, Wright V: Gold and penicillamine, alone and in combination in active rheumatoid arthritis (abstract), 16th International Congress of Rheurnatology . Sydney, Australia, May A985 Taggart AJ, Hill J, Asbury C, Dixon JS, Bird HA, Wright V: Sulphasalazine alone or in combination with D-penicillamine in rheumatoid arthritis. Br J Rheumatol 26~32-36, 1987 Farr M, Kitas G, Bacon PA: Sulphasalazine in rheumatoid arthritis: combination therapy with D-penicillamine or sodium aurothiomalate. Clin Rheumatol 7:242-248, 1988