11
Combination therapy in rheumatoid arthritis A . C. S C H W A R Z E R M. H. A R N O L D P. M. B R O O K S
Combinations of slow-acting antirheumatic drugs (SAARDs) have been used increasingly in the past decade for the treatment of rheumatoid arthritis (RA). Heightened awareness of the poor long-term prognosis in RA and the need to treat this disease more aggressively have led to the re-evaluation of this therapeutic strategy. Despite the frequent use of SAARDs, RA continues to cause both significant morbidity and mortality. Scott et al (1987) studied 112 RA patients treated for 20 years with gold, D-penicillamine (DPA), chloroquine or cytotoxic drugs. Despite demonstrating a favourable result at 10 years, by 20 years 54% of patients were either dead (35%) or severely disabled (19%). Other authors have also demonstrated the decreased survival in RA (Rasker and Cosh, 1981; Mitchell et al, 1986; Vollertsen et al, 1986). In a carefully conducted prospective study of 805 patients over 12 years, Mitchell et al (1986) demonstrated that survival of patients with RA from the time of diagnosis was approximately 50% less than population controls. Furthermore, treatment with gold and prednisone was not associated with either decreased or increased mortality except for a clustering of deaths of patients with vasculitis within the prednisone group. RA is also associated with significant mocbidity. In a study by Pincus et al (1984), 75 patients with RA were reviewed 9 years after an initial evaluation. Severe morbidity was seen in the 55 survivors, with 92% suffering significantly lower overall functional capacity. Work disability occurred in 85 % of patients under 65 years who had been working full-time at disease onset. There were 27 patients aged less than 55 in 1973, or younger than 64 in 1982, who were working full-time at disease onset. Only 11 (41%) were working full-time in 1973 and 4 (15%) were working full-time by 1982. Increased mortality was noted in this group of patients, with 20 (27 %) dying during the 9-year period. The expected number, obtained from standard mortality tables, was 15. At entry these patients had significantly reduced functional capacity compared with the survivors. The available SAARDs used to treat RA are effective in the short term but are frequently stopped because of inefficacy or side-effects. Situnayake Bailli~re's Clinical Rheumatology--
Vol. 4, No. 3, December1990 ISBN0-7020-1484-2
663 Copyright9 1990,byBailli6reTindall Allrightsofreproductionin anyformreserved
664
A. C. S C H W A R Z E R ET A L
et al (1987) found that fewer than 20% of patients who started gold, DPA or sulphasalazine (SAS) were still taking these drugs 5 years later. After 2 years of treatment 60-70% were no longer taking these drugs. There is some evidence that the withdrawal rate of patients on methotrexate (MTX), however, may be lower, with 62% remaining on the drug at 3 years in one study (Weinblatt et al, 1988) and 50% 5 years after commencement in another (Alarc6n et al, 1989). This has not been a universal finding, with one study demonstrating that only 25% remain on MTX 72 weeks after commencement (Arnold et al, 1990). Thompson et al (1985), in a retrospective study of 247 case notes using life-table analysis, found that response rates to first and second SAARDs were each approximately 60%, whereas the response rate to the third drug was as low as 30%. Further, success with one course of a SAARD does not ensure that the patient will respond a second time to the same agent. In one study only 36% of those who had a good initial response to gold achieved complete remission with the second course (Evers and Sundstrom, 1983). Another study demonstrated that patients who had previously failed gold therapy responded less favourably to treatment with levamisole, DPA and azathioprine (AZA) (Bentzon et al, 1986). One measure by which the effectiveness of a particular treatment is evaluated is the reduction in the number of new erosions or healing of old erosions, However, although there is some evidence that we can influence the development of erosions in the short term with gold (Sigler et al, 1974; Luukainen et al, 1977), sulphasalazine (SAS) (Van der Heijde et al, 1989), cyclophosphamide (CYCLO) (Co-operating Clinics of the North American Rheumatism Association, 1970) and MTX (Kremer and Lee, 1988; Weinblatt et al, 1988) it is unlikely that this is sustained. Several authors suggest that SAARDs fail to have any significant effect on radiological progression (Scott et al, 1983; Pullar et al, 1984; Spector and Scott, 1988). Importantly, it would seem that the earlier the treatment with a SAARD the better the chances of stopping erosions (Luukkainen et al, 1977). Unfortunately, despite the widespread and accepted use of radiography in the assessment of drug efficacy, there are a number of variables, especially technical and associated with interpretation (Brower, 1990), that make it a less than perfect technique. In view of the poor results with existing therapy it is necessary to rethink the approach to the treatment of RA. RA should no longer be considered a 'benign' disease. The rheumatoid pannus is more akin to a locally invasive neoplasm (Ehrlich, 1982; Hamilton, 1983; Sebaldt, 1988) and therefore more aggressive and earlier treatment is required. Consequently, a number of new strategies have evolved. One is the very early treatment of disease with SAARDs. This may be critical because joint destruction occurs early. Brook and Corbett (1977) found that as many as 90% of those patients with erosive rheumatoid disease demonstrated erosions radiographically in the first 2 years. The poor long-term results in most studies may reflect delayed treatment initiated after this crucial period. Another approach is to use two or more SAARDs simultaneously or cyclically in a similar fashion to the use of immunosuppressive agents in the treatment of some malignancies. A
COMBINATION THERAPY IN RHEUMATOID ARTHRITIS
665
modification of this approach is to commence with one agent and then add a further agent if the first does not induce a remission. Many rheumatologists have now abandoned the traditional 'therapeutic pyramid' and some even propose reversing this with a 'step-down bridge' approach of combined medications (Healey and Wilske, 1989) that are stopped sequentially as the disease is controlled. The aim of combination therapy is to improve efficacy while minimizing side-effects. By combining drugs with different modes of action it is hoped that additive or synergistic effects may be achieved. However, deciding on appropriate combinations is difficult because of our lack of understanding of precisely how these drugs work in RA. Further, pathogenic mechanisms are poorly understood. R A may represent a cluster of diseases with diverse aetiologies whose major manifestation is chronic polyarthritis (Kushner, 1989).
STUDIES INVOLVING COMBINATIOINS OF SAARDs
Several factors have retarded our progress in the search for successful combinations of SAARDs. One of these has been toxicity, especially myelotoxicity, which occurs with these agents. The concern about severe toxicity in a seemingly non-fatal disease has blunted much of the earlier enthusiasm for this form of treatment. Secondly, 'aggressive' treatment has been reserved for patients with severe disease who have failed numerous SAARDs taken individually. It is possible that this approach selects a subset of patients who are unlikely to respond to any SAARD we can offer (Scott et al, 1983). Such study subjects are more often found in Tertiary Referral Centres and therefore the results of trials may not reflect the type of responses that may be obtained in the wider population of patients with RA. One dilemma has been how to define the precise target population to receive combination therapy. Should we be aiming our treatment at a particular subgroup or should this approach be directed at all patients with R A ? If we are to target a particular group then we are left with the difficulty of accurately selecting those patients who are less likely to do well from conventional approaches and who may benefit from this form of aggressive treatment. In order to make rational decisions regarding the treatment of patients with severe R A one must carefully analyse the existing literature. In the evaluation of therapies, the nature of the trial and details of documentation of demographic data and responses should be considered. The design given the most credibility in the evaluation of treatments is the prospective randomized controlled trial (Kirwan and Currey, 1983; Rosenbloom et al, 1985; Felson et al, 1990; Ratain and Hochberg, 1990). This is often preceded by an open trial in which there are no comparative or control groups. Favourable results in this latter type of study would prompt the more expensive and time-consuming study. The judgement of the efficacy of a modality of treatment should not rely solely on the results of the open trial.
666
A.C.
S C H W A R Z E R ET A L
Guidelines for the conduct of clinical trials have been set out by Kirwan and Currey (1983) and more recently by Ratain and Hochberg (1990). A number of recommendations serve to highlight many inadequacies inherent in the studies on combination therapy. Particularly important are randomization and blinding, which reduce the potential for bias. Additionally, there should be useful outcome endpoints that include subjective as well as objective measurements. Short-term outcome measures are no substitute for long-term measures (Kirwan and Currey, 1983). Adequacy of sample size is stressed and the trial needs to be of adequate duration. P values should be adjusted to allow for multiple comparisons. It is important to do an 'intent to treat' analysis, as ignoring the group who have withdrawn from the study will introduce a bias in favour of the new treatment (Ratain and Hochberg, 1990). One of the major problems faced when comparing results of trials in RA, in particular those involving combination therapy, is the lack of standardization of measures (Felson et al, 1990; Kirwan and Currey, 1983). Different trials use diverse outcome measures with differences in their sensitivity to change. Also, the multiplicity of often interdependent outcome measures in clinical trials raises the chances of obtaining a spuriously significant result. The use of fewer measures reduces the number of false-positive results or Type I errors. Examination of several comparative trials by Felson et al (1990) showed that conclusions were often made on tenuous statistical evidence. For example, conclusions of improvement were made when the differences were not statistically significant. A number of studies have demonstrated the efficacy of combination therapy in RA. However, many of these studies are open, uncontrolled or retrospective and of short duration with inadequate patient numbers. In all there have been 31 reports on the use of combination therapy in the treatment of rheumatoid arthritis of which three were randomized doubleblind studies (Bunch et al, 1984; McKenna et al, 1985; Scott et al, 1989) at the time of this review. To gain perspective, an analysis of clinical trials of combinations of various agents follows.
Studies involving anti-malarials Eleven studies report the use of antimalarials in combination. The popularity of the antimalarials, especially hydroxychloroquine (HCQ), stems from the fact that they are relatively safe and well tolerated by patients. These drugs have been used in association with CYCLO (McCarty and Carrera, 1982; Butler and Tiliakos, 1985; Csuka et al, 1986), A Z A (McCarty and Carrera, 1982; Csuka et al, 1986; Langevitz et al, 1989), gold (Sievers and Hurri, 1963; Langevitz et al, 1989; Scott et al, 1989), DPA (Martin et al, 1982; Bunch et al, 1984; Gibson et al, 1987), MTX (Butler and Tiliakos, 1985; Langevitz et al, 1989; Schwarzer et al, 1990) and SAS (Schwarzer et al, 1990).
Cyclophosphamide and azathioprine in combination with hydroxychloroquine The use of combinations of cytotoxic agents was first reported by McCarty
C O M B I N A T I O N T H E R A P Y IN R H E U M A T O I D ARTHRITIS
667
and Carrera (1982), who rekindled the earlier interest of Sievers and Hurri in the use of combined drug therapy. This aggressive approach attempted to induce a prolonged remission that would then enable the eventual withdrawal of all drugs. From 1974, 17 patients with severe refractory disease were treated with a combination of CYCLO, AZA and HCQ. The mean disease duration at the commencement of therapy was 9.3 years and all but one patient had previously been treated with gold compounds together with HCQ. These patients had ceased gold because of toxicity or escape from control. No patient had received gold within the past 3 months. The response, after a mean follow-up of 27 months, was excellent, with 5 patients achieving complete remission (no joint swelling or tenderness), 2 left with activity in a single joint and 7 with partial disease suppression. Radiographs of 9 patients demonstrated recortication of erosive lesions. Two patients were able to cease the drugs and maintain remission. Evidence of vasculitis (nailfold thrombi) resolved in all 6 patients with this problem. Ten patients had been taking prednisone at the start of therapy. This was discontinued in 5 patients at the time of final evaluation and the daily dose was lowered in 4 of the remaining 5 patients. Unfortunately, side-effects were common and only 5 patients did not experience adverse reactions that could be attributable to one or more of the drugs used. Of concern was the presence of symptomatic cystitis in 5 patients although it was overt in only one case, responding to cessation of CYCLO. The doses of both CYCLO and AZA were significantly lower than the doses generally recommended in RA with the mean daily dose of CYCLO being 38.5 mg and of AZA 55 rag. In an additional 4 patients treatment was ceased because of complications of infected leg ulcers (1), an infected hip-joint prosthesis (1), haemorrhagic cystitis (1), and oral ulceration accompanying severe reversible leukopenia (1). The same group presented follow-up data in 1986 (Csuka et al, 1986). After a mean of 43 months of treatment, 16 out of 31 patients achieved complete remission, with 7 achieving near remission (residual swelling and tenderness of a single joint) and 7 partial disease suppression. Rheumatoid nodules disappeared in 7 patients and one patient developed new nodules. Prednisone was discontinued in 8 of 13 patients and the dose was lowered in 2 others. Mean maintenance doses were 30 mg daily of CYCLO and 74 mg per day of AZA, again less than is often advocated in the treatment of RA. These excellent results were balanced by the significant toxicity, with 4 patients developing neoplasia during treatment and only 6 patients reporting no adverse events. All patients eventually relapsed after cessation of therapy. Disease recurred in 10 patients 2-6 months after cessation of CYCLO and in 6 patients 2-36 months after the other therapy had been ceased. It would appear that these and similar combinations, although effective, need to be continued indefinitely if the benefit is to be sustained. The long-term risks, especially of malignancies, would therefore be increased. In young patients this is a serious consideration. The main fault in these studies, as acknowledged by the authors, is the absence of controls. However, it would appear that combinations of cytotoxics may have merit in
668
A.C.
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SCHWARZER ET AL
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Combination therapy in rheumatoid arthritis A . C. S C H W A R Z E R M. H. A R N O L D P. M. B R O O K S
Combinations of slow-acting antirheumatic drugs (SAARDs) have been used increasingly in the past decade for the treatment of rheumatoid arthritis (RA). Heightened awareness of the poor long-term prognosis in RA and the need to treat this disease more aggressively have led to the re-evaluation of this therapeutic strategy. Despite the frequent use of SAARDs, RA continues to cause both significant morbidity and mortality. Scott et al (1987) studied 112 RA patients treated for 20 years with gold, D-penicillamine (DPA), chloroquine or cytotoxic drugs. Despite demonstrating a favourable result at 10 years, by 20 years 54% of patients were either dead (35%) or severely disabled (19%). Other authors have also demonstrated the decreased survival in RA (Rasker and Cosh, 1981; Mitchell et al, 1986; Vollertsen et al, 1986). In a carefully conducted prospective study of 805 patients over 12 years, Mitchell et al (1986) demonstrated that survival of patients with RA from the time of diagnosis was approximately 50% less than population controls. Furthermore, treatment with gold and prednisone was not associated with either decreased or increased mortality except for a clustering of deaths of patients with vasculitis within the prednisone group. RA is also associated with significant mocbidity. In a study by Pincus et al (1984), 75 patients with RA were reviewed 9 years after an initial evaluation. Severe morbidity was seen in the 55 survivors, with 92% suffering significantly lower overall functional capacity. Work disability occurred in 85 % of patients under 65 years who had been working full-time at disease onset. There were 27 patients aged less than 55 in 1973, or younger than 64 in 1982, who were working full-time at disease onset. Only 11 (41%) were working full-time in 1973 and 4 (15%) were working full-time by 1982. Increased mortality was noted in this group of patients, with 20 (27 %) dying during the 9-year period. The expected number, obtained from standard mortality tables, was 15. At entry these patients had significantly reduced functional capacity compared with the survivors. The available SAARDs used to treat RA are effective in the short term but are frequently stopped because of inefficacy or side-effects. Situnayake Bailli~re's Clinical Rheumatology--
Vol. 4, No. 3, December1990 ISBN0-7020-1484-2
663 Copyright9 1990,byBailli6reTindall Allrightsofreproductionin anyformreserved
664
A. C. S C H W A R Z E R ET A L
et al (1987) found that fewer than 20% of patients who started gold, DPA or sulphasalazine (SAS) were still taking these drugs 5 years later. After 2 years of treatment 60-70% were no longer taking these drugs. There is some evidence that the withdrawal rate of patients on methotrexate (MTX), however, may be lower, with 62% remaining on the drug at 3 years in one study (Weinblatt et al, 1988) and 50% 5 years after commencement in another (Alarc6n et al, 1989). This has not been a universal finding, with one study demonstrating that only 25% remain on MTX 72 weeks after commencement (Arnold et al, 1990). Thompson et al (1985), in a retrospective study of 247 case notes using life-table analysis, found that response rates to first and second SAARDs were each approximately 60%, whereas the response rate to the third drug was as low as 30%. Further, success with one course of a SAARD does not ensure that the patient will respond a second time to the same agent. In one study only 36% of those who had a good initial response to gold achieved complete remission with the second course (Evers and Sundstrom, 1983). Another study demonstrated that patients who had previously failed gold therapy responded less favourably to treatment with levamisole, DPA and azathioprine (AZA) (Bentzon et al, 1986). One measure by which the effectiveness of a particular treatment is evaluated is the reduction in the number of new erosions or healing of old erosions, However, although there is some evidence that we can influence the development of erosions in the short term with gold (Sigler et al, 1974; Luukainen et al, 1977), sulphasalazine (SAS) (Van der Heijde et al, 1989), cyclophosphamide (CYCLO) (Co-operating Clinics of the North American Rheumatism Association, 1970) and MTX (Kremer and Lee, 1988; Weinblatt et al, 1988) it is unlikely that this is sustained. Several authors suggest that SAARDs fail to have any significant effect on radiological progression (Scott et al, 1983; Pullar et al, 1984; Spector and Scott, 1988). Importantly, it would seem that the earlier the treatment with a SAARD the better the chances of stopping erosions (Luukkainen et al, 1977). Unfortunately, despite the widespread and accepted use of radiography in the assessment of drug efficacy, there are a number of variables, especially technical and associated with interpretation (Brower, 1990), that make it a less than perfect technique. In view of the poor results with existing therapy it is necessary to rethink the approach to the treatment of RA. RA should no longer be considered a 'benign' disease. The rheumatoid pannus is more akin to a locally invasive neoplasm (Ehrlich, 1982; Hamilton, 1983; Sebaldt, 1988) and therefore more aggressive and earlier treatment is required. Consequently, a number of new strategies have evolved. One is the very early treatment of disease with SAARDs. This may be critical because joint destruction occurs early. Brook and Corbett (1977) found that as many as 90% of those patients with erosive rheumatoid disease demonstrated erosions radiographically in the first 2 years. The poor long-term results in most studies may reflect delayed treatment initiated after this crucial period. Another approach is to use two or more SAARDs simultaneously or cyclically in a similar fashion to the use of immunosuppressive agents in the treatment of some malignancies. A
COMBINATION THERAPY IN RHEUMATOID ARTHRITIS
665
modification of this approach is to commence with one agent and then add a further agent if the first does not induce a remission. Many rheumatologists have now abandoned the traditional 'therapeutic pyramid' and some even propose reversing this with a 'step-down bridge' approach of combined medications (Healey and Wilske, 1989) that are stopped sequentially as the disease is controlled. The aim of combination therapy is to improve efficacy while minimizing side-effects. By combining drugs with different modes of action it is hoped that additive or synergistic effects may be achieved. However, deciding on appropriate combinations is difficult because of our lack of understanding of precisely how these drugs work in RA. Further, pathogenic mechanisms are poorly understood. R A may represent a cluster of diseases with diverse aetiologies whose major manifestation is chronic polyarthritis (Kushner, 1989).
STUDIES INVOLVING COMBINATIOINS OF SAARDs
Several factors have retarded our progress in the search for successful combinations of SAARDs. One of these has been toxicity, especially myelotoxicity, which occurs with these agents. The concern about severe toxicity in a seemingly non-fatal disease has blunted much of the earlier enthusiasm for this form of treatment. Secondly, 'aggressive' treatment has been reserved for patients with severe disease who have failed numerous SAARDs taken individually. It is possible that this approach selects a subset of patients who are unlikely to respond to any SAARD we can offer (Scott et al, 1983). Such study subjects are more often found in Tertiary Referral Centres and therefore the results of trials may not reflect the type of responses that may be obtained in the wider population of patients with RA. One dilemma has been how to define the precise target population to receive combination therapy. Should we be aiming our treatment at a particular subgroup or should this approach be directed at all patients with R A ? If we are to target a particular group then we are left with the difficulty of accurately selecting those patients who are less likely to do well from conventional approaches and who may benefit from this form of aggressive treatment. In order to make rational decisions regarding the treatment of patients with severe R A one must carefully analyse the existing literature. In the evaluation of therapies, the nature of the trial and details of documentation of demographic data and responses should be considered. The design given the most credibility in the evaluation of treatments is the prospective randomized controlled trial (Kirwan and Currey, 1983; Rosenbloom et al, 1985; Felson et al, 1990; Ratain and Hochberg, 1990). This is often preceded by an open trial in which there are no comparative or control groups. Favourable results in this latter type of study would prompt the more expensive and time-consuming study. The judgement of the efficacy of a modality of treatment should not rely solely on the results of the open trial.
666
A.C.
S C H W A R Z E R ET A L
Guidelines for the conduct of clinical trials have been set out by Kirwan and Currey (1983) and more recently by Ratain and Hochberg (1990). A number of recommendations serve to highlight many inadequacies inherent in the studies on combination therapy. Particularly important are randomization and blinding, which reduce the potential for bias. Additionally, there should be useful outcome endpoints that include subjective as well as objective measurements. Short-term outcome measures are no substitute for long-term measures (Kirwan and Currey, 1983). Adequacy of sample size is stressed and the trial needs to be of adequate duration. P values should be adjusted to allow for multiple comparisons. It is important to do an 'intent to treat' analysis, as ignoring the group who have withdrawn from the study will introduce a bias in favour of the new treatment (Ratain and Hochberg, 1990). One of the major problems faced when comparing results of trials in RA, in particular those involving combination therapy, is the lack of standardization of measures (Felson et al, 1990; Kirwan and Currey, 1983). Different trials use diverse outcome measures with differences in their sensitivity to change. Also, the multiplicity of often interdependent outcome measures in clinical trials raises the chances of obtaining a spuriously significant result. The use of fewer measures reduces the number of false-positive results or Type I errors. Examination of several comparative trials by Felson et al (1990) showed that conclusions were often made on tenuous statistical evidence. For example, conclusions of improvement were made when the differences were not statistically significant. A number of studies have demonstrated the efficacy of combination therapy in RA. However, many of these studies are open, uncontrolled or retrospective and of short duration with inadequate patient numbers. In all there have been 31 reports on the use of combination therapy in the treatment of rheumatoid arthritis of which three were randomized doubleblind studies (Bunch et al, 1984; McKenna et al, 1985; Scott et al, 1989) at the time of this review. To gain perspective, an analysis of clinical trials of combinations of various agents follows.
Studies involving anti-malarials Eleven studies report the use of antimalarials in combination. The popularity of the antimalarials, especially hydroxychloroquine (HCQ), stems from the fact that they are relatively safe and well tolerated by patients. These drugs have been used in association with CYCLO (McCarty and Carrera, 1982; Butler and Tiliakos, 1985; Csuka et al, 1986), A Z A (McCarty and Carrera, 1982; Csuka et al, 1986; Langevitz et al, 1989), gold (Sievers and Hurri, 1963; Langevitz et al, 1989; Scott et al, 1989), DPA (Martin et al, 1982; Bunch et al, 1984; Gibson et al, 1987), MTX (Butler and Tiliakos, 1985; Langevitz et al, 1989; Schwarzer et al, 1990) and SAS (Schwarzer et al, 1990).
Cyclophosphamide and azathioprine in combination with hydroxychloroquine The use of combinations of cytotoxic agents was first reported by McCarty
C O M B I N A T I O N T H E R A P Y IN R H E U M A T O I D ARTHRITIS
667
and Carrera (1982), who rekindled the earlier interest of Sievers and Hurri in the use of combined drug therapy. This aggressive approach attempted to induce a prolonged remission that would then enable the eventual withdrawal of all drugs. From 1974, 17 patients with severe refractory disease were treated with a combination of CYCLO, AZA and HCQ. The mean disease duration at the commencement of therapy was 9.3 years and all but one patient had previously been treated with gold compounds together with HCQ. These patients had ceased gold because of toxicity or escape from control. No patient had received gold within the past 3 months. The response, after a mean follow-up of 27 months, was excellent, with 5 patients achieving complete remission (no joint swelling or tenderness), 2 left with activity in a single joint and 7 with partial disease suppression. Radiographs of 9 patients demonstrated recortication of erosive lesions. Two patients were able to cease the drugs and maintain remission. Evidence of vasculitis (nailfold thrombi) resolved in all 6 patients with this problem. Ten patients had been taking prednisone at the start of therapy. This was discontinued in 5 patients at the time of final evaluation and the daily dose was lowered in 4 of the remaining 5 patients. Unfortunately, side-effects were common and only 5 patients did not experience adverse reactions that could be attributable to one or more of the drugs used. Of concern was the presence of symptomatic cystitis in 5 patients although it was overt in only one case, responding to cessation of CYCLO. The doses of both CYCLO and AZA were significantly lower than the doses generally recommended in RA with the mean daily dose of CYCLO being 38.5 mg and of AZA 55 rag. In an additional 4 patients treatment was ceased because of complications of infected leg ulcers (1), an infected hip-joint prosthesis (1), haemorrhagic cystitis (1), and oral ulceration accompanying severe reversible leukopenia (1). The same group presented follow-up data in 1986 (Csuka et al, 1986). After a mean of 43 months of treatment, 16 out of 31 patients achieved complete remission, with 7 achieving near remission (residual swelling and tenderness of a single joint) and 7 partial disease suppression. Rheumatoid nodules disappeared in 7 patients and one patient developed new nodules. Prednisone was discontinued in 8 of 13 patients and the dose was lowered in 2 others. Mean maintenance doses were 30 mg daily of CYCLO and 74 mg per day of AZA, again less than is often advocated in the treatment of RA. These excellent results were balanced by the significant toxicity, with 4 patients developing neoplasia during treatment and only 6 patients reporting no adverse events. All patients eventually relapsed after cessation of therapy. Disease recurred in 10 patients 2-6 months after cessation of CYCLO and in 6 patients 2-36 months after the other therapy had been ceased. It would appear that these and similar combinations, although effective, need to be continued indefinitely if the benefit is to be sustained. The long-term risks, especially of malignancies, would therefore be increased. In young patients this is a serious consideration. The main fault in these studies, as acknowledged by the authors, is the absence of controls. However, it would appear that combinations of cytotoxics may have merit in
668
A.C.
u
SCHWARZER ET AL
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