Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years

G. F. Ferraccioli, E. Gremese, P. Tomietto, G. Favret, R. Damato and E. Di Poi

Division of Rheumatology, Department of Internal Medicine, School of Medicine, DPMSC, University of Udine, 33100 Udine, Italy


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To evaluate two monotherapies followed by step-up combination therapy with two or three complementary drugs in active rheumatoid arthritis (RA) in comparison with sulphasalazine (SSZ) alone.

Methods. One hundred and twenty-six consecutive patients with early active RA were enrolled in this open controlled clinical trial. The primary end-point was 50% improvement according to the ACR criteria (ACR50) at 6, 12 or 18 months. The secondary end-points were a full response (Magnusson criteria) and/or remission (ACR criteria) at 3 yr. Methotrexate (MTX) (group 1), cyclosporin A (CsA) (group 2) or SSZ (group 3) was used first. After 6 months, a combination of two drugs (CsA and MTX) was employed in groups 1 and 2. SSZ was added after 12 months if improvement was less than ACR50 with the combination. Group 3 continued with SSZ alone.

Results. After 6 months, 57% of patients in group 1, 31% of group 2 (MTX vs CsA, P=0.002) and 33% of group 3 (MTX vs SSZ, P=0.01) had reached ACR50 improvement according to intention-to-treat analysis. At month 12 after starting a drug combination, 67% of group 1 and 76% of group 2 had reached ACR50 compared with 24% of group 3. At the 18-month follow-up, 90% of group 1 and 88% of group 2 but only 24% of group 3 had reached ACR50. After 18 months, 62% of group 1, 60% of group 2 and 48% of group 3 showed side-effects and three, five and eight patients in the three groups respectively had dropped out of the study. At the 3-yr follow-up, 9% of the patients in groups 1 and 2 and 7% of group 3 were in remission according to the ACR criteria; according to the Magnusson criteria, 40% showed a full response in groups 1 and 2 but only 21% did so in group 3.

Conclusion. MTX appears to be the fastest-acting agent. A step-up approach with MTX plus CsA plus SSZ led to a 50% improvement according to the ACR criteria in most patients. After 3 yr, 40% of patients receiving combination therapy and 21% of patients receiving monotherapy showed a full response, while 9 and 7% respectively attained remission.

KEY WORDS: Combination therapy, Monotherapy, Methotrexate, Cyclosporin A, Sulphasalazine.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis, joint damage and progressive disability in a high percentage of patients [1]. An aggressive approach with the aim of stopping inflammation, thus reducing cartilage damage, subchondral bone erosions and disability [24] is now advocated in the early phases of the disease, especially in patients with a poor prognosis.

In clinical practice, rheumatoid patients who show a poor response to one or more conventional disease-modifying anti-rheumatic drugs (DMARDs) are given combination therapy [5]. However, the best strategy for these patients has not yet been defined. Clinicians must frequently choose between a step-up therapeutic schedule, consisting of a first DMARD followed by the addition of a second if there is no adequate response, or a step-down approach in which initial combination therapy is followed by a reduction of the dose or the abandonment of one of the DMARDs, leaving only the anchor drug as a maintenance treatment [68]. We do not know whether it is better to use step-up or step-down treatment, and in particular whether there is a DMARD that may be used preferentially as an anchor drug. In this study, we investigated this problem in patients with early RA. We used a step-up schedule because this made it easier to control the possible appearance of toxicity.

We report the results of a 3-yr prospective study in 126 patients, with the aim of obtaining 50% improvement, and possibly a full clinical response, by using monotherapy or combination therapy with two or three drugs selected from those showing possible additive biological effects but no additive toxic effects [9]. We sought to answer the following questions. (i) Which induction schedule—methotrexate (MTX), cyclosporin A (CsA) or sulphasalazine (SSZ)—allows the fastest 50% improvement according to the American College of Rheumatology (ACR) criteria? (ii) Will a combination of the three drugs in sequence rescue poor responders and will monotherapy work as well? (iii) How many patients will show a significant clinical response or remission with the two approaches? (iv) Will the toxicity be acceptable even in the groups receiving combination therapy?


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
One hundred and twenty-six patients attending the Rheumatology Unit of the University of Udine entered the study. All patients met the ACR criteria for RA [6] and all patients had already received at least a 4-month course of antimalarials. Most were receiving prednisone 5 mg/day as a previous DMARD [10]. Biochemical, immunological and immunogenetic typing was performed for all patients at entry to the study. All patients had at least one erosion on X-rays of their hands or feet. Inclusion criteria for active disease were: (i) erythrocyte sedimentation rate (ESR) >30 mm/1st h or C-reactive protein (CRP) concentration >20 mg/l; (ii) more than six swollen joints (66-joint count, SJC) or more than nine tender joints (68-joint count, TJC); (iii) moderate or severe pain rated on a verbal scale as none, mild, moderate or severe; (iv) receiving prednisone at 5 mg/day. At least three of these criteria had to be present for at least 3 months before the study baseline. Exclusion criteria were: (i) age <17 or >70 yr; (ii) comorbidities that might preclude any of the therapeutic approaches; (iii) previous treatment with immune suppressants; (iv) possible pregnancy or breast-feeding; (v) psychiatric or neurological disease. Patients with hypertension under treatment were excluded. Before starting the study we calculated that, with a power of 80% and a significance level of 5%, 43 patients per arm would have been necessary to demonstrate a 25% increase in success in attaining 50% improvement according to the ACR criteria (ACR50) [11] given that monotherapy would allow a 20% rate of success, the combination would allow a 45% rate of success (25% or more). All patients gave informed consent to participation in the study. The full response was defined according to the criteria provided by Magnusson (see below) [12]. The local Ethics Committee approved the study protocol.

Treatment
Forty-two patients were enrolled in each arm between June 1993 and June 1995. Patients were divided into three groups at entry: patients in group 1 were given MTX 10 mg/week plus folic acid 5 mg 24 h later. After 8 weeks the dose was increased monthly by 5 mg, up to 20 mg/week, as initial monotherapy [13]. Group 2 received CsA 3 mg/kg per day with a possible increase after 12 weeks, up to 5 mg/kg/day, according to the clinical response and to internationally accepted guidelines [14]. Group 3 received only SSZ; the dose started at 1 g/day and increased by 500 mg each week for 5 weeks to reach 3 g/day. Patients were allocated randomly to one of the three groups for the first 6 months and were then managed in an open fashion. Patients in groups 1 and 2 who had not shown ACR50 improvement after 6 months were given the combination therapy (CsA plus MTX). After 12 months, patients in groups 1 and 2 who had not reached ACR50 were given SSZ, starting at 500 mg/day and increasing weekly up to 3 g/day according to safety and tolerability. When adding a new DMARD, the trough blood level of CsA was checked and the daily dose was adjusted as necessary.

Patients were asked to report any skin rash, diarrhoea, nausea, vomiting, epigastric pain, mouth ulcers and any other adverse effects. Laboratory assessment included complete blood cell and platelet counts at each clinic visit, liver chemistry and creatinine and blood urea values. When major toxicity occurred (haematological, renal, hepatic or neurological, as judged by the attending physician), the drug likely to have been responsible was withdrawn. If there was minor toxicity (nausea, dyspepsia, mild or moderate hypertension, decrease of glomerular filtration rate <30% of the basal level) patients were given anti-nausea, prokinetic or anti-hypertensive treatment (perdipine) or CsA was reduced by 25 or 50 mg/day. Attempts to decrease or stop the daily prednisone dose were performed throughout the study period. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) were allowed concurrently. Discontinuation of any treatment because of persistent, unremitting disease activity was done only when the patient and the attending physician judged it strictly necessary.

Primary and secondary end-points
The primary end-point was ACR50 at 6, 12 or 18 months. We then followed the patients up to the third year, and the secondary end-points were a full response for at least 3 months according to the Magnusson criteria (no steroids plus fulfilment of four of the following six criteria: morning stiffness <30 min; no fatigue; no joint pain; no joint tenderness or pain on motion; no soft tissue swelling in joints or tendon sheaths; and ESR <30 mm/h in females and <20 mm/h in males while on DMARDs) [11] and/or full remission according to the ACR criteria [15]. The patient's global assessment (PGA) used the following scale: perfect health=0, mild impairment=1, moderate impairment=2, severe impairment=3, very severe impairment=4, handicapped=5. Pain and the physician's global assessment (PhGA) were expressed on a visual analogue scale of 10 cm. Patients were assessed by a physician every month for 6 months and every 3 months thereafter, unless an assessment was needed urgently. The assessing physicians were always the same (RD, EDP) but were unaware of the treatment schedule, which was defined by the principal investigator (GFF).

Analysis of clinical results and toxicity
The intention-to-treat principle and valid completers analysis were used for the clinical assessment and the last observation that was performed was used to assess toxicity.

Statistical analysis
Statistical analysis was performed with the Systat program for the Macintosh (Evanston, IL, USA). Confidence intervals were calculated for all clinical variables and acute-phase reactants. Continuous and non-continuous variables were compared with parametric (Student's t-test) or non-parametric (Mann–Whitney U-test) tests, while proportions were assessed by means of the {chi}2 test with Yates’ correction.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Clinical, demographic and serological data are reported in Table 1Go. The three groups were homogeneous for age, sex, rheumatoid factor positivity and HLA DR1/DR4 positivity (Table 2Go). All Gowere erosive at baseline and had received antimalarials. After the first 6 months, 24 patients (57%) in group 1, 13 patients (31%) in group 2 and 14 patients (33%) in group 3 showed ACR50 improvement. When only the valid completers were considered, the percentages were 57, 32 and 37 respectively. The difference was in favour of MTX ({chi}2 test; vs CsA, P=0.01; vs SSZ, P=0.02). After combining the two induction drugs in patients who had improvement of less than ACR50, four more patients (67%) reached the main outcome in group 1 and 19 patients reached ACR50 (76%) in group 2 compared with 10 patients (24%) in group 3. In the valid completers analysis the percentages were 68, 78 and 27 respectively. Patients who had not shown ACR50 improvement after 12 months were given SSZ. After 18 months ACR50 improvement was reached by 10 more patients (90%) in group 1, five more patients (88%) in group 2 but only by 24% of patients (ten patients) in group 3 (Table 3Go). When only the valid completers were considered the percentages were 95, 92 and 25 respectively. When taking into account the clinical variables, we found no differences between group 1 and group 2, whereas there were statistically significant differences in several parameters between groups 1 and 3 (SJC, TJC, PGA, PhGA, ESR and CRP) and between groups 2 and 3 (TJC, PGA, PhGA and pain). This shows that for most of the variables the step-up therapy provides clear improvement (Table 4Go). This made it possible to decrease and then stop prednisone in several patients when ACR50 was reached and was stable. After 36 months, no further changes were observed (Table 5Go).


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TABLE 1.  Demographic, clinical and immunological characteristics of the patients receiving one of the three DMARDs (mean±S.D.)

 

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TABLE 2.  HLA DR characteristics of the three groups entered in the prospective study (number of patients)

 

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TABLE 3.  Analysis of the response after 18 months of step-up therapy [mean {Delta} (95% confidence interval)]

 

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TABLE 4.  Analysis of the response during the follow-up from the 18th to the 36th month of therapy [mean {Delta} (95% confidence interval)]

 

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TABLE 5.  Type of side-effects shown by the patients during the four phases of the study

 
HLA typing and clinical response
We analysed whether the initial response (6-month assessment) to the therapeutic schedule might be linked to DR alleles. We observed no statistically significant difference between the groups: ACR50 improvement was seen in 4/14 DR4- or DR1-positive patients in group 1, 12/23 of DR4- or DR1-positive patients in group 2 and 9/22 of DR4- or DR1-positive patients in group 3 ({chi}2 test; no significant difference between groups). On the other hand, among the DR4/1-negative patients, 20/25 in group 1, 1/17 in group 2 and 5/18 in group 3 reached ACR50 improvement ({chi}2 test, group 1 vs group 2, DR-negative patients, P<0.0001; {chi}2 test, group 1 vs group 3, DR-negative patients, P<0.002) (Table 6Go).


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TABLE 6.  Relationship between DR4/DR1 positivity vs negativity and response to treatments

 

Follow-up
After the first 18 months, 6/30 patients in group 1, 5/28 in group 2 and 10/32 in group 3 were still taking prednisone, and these patients continued prednisone afterwards. Patients on the combination of MTX plus CsA continued the predefined doses, while the addition of SSZ led, in four patients per group, to adjustment of the CsA dose (increased dose) in order to maintain a trough blood level between 100 and 200 pg/ml.

After 3 yr the patients were assessed for persistence of the Magnusson criteria for at least 3 months or for remission according to the ACR criteria for at least 2 months, after stopping any treatment except NSAIDs. In both groups, 40% of patients in groups 1 and 2 met the full response criteria, while only 21% did so in group 3 ({chi}2 test; group 1 vs group 2 and group 2 vs group 3, P=0.009). On the other hand, 9% satisfied the criteria for full remission in groups 1 and 2 while 7% achieved full remission in group 3. All patients who reached a full response or remission were steroid-free when the outcome was assessed.

Side-effects and toxicity
The side-effects increased over time, and eventually 26/42 (62%) patients in group 1 and 25/42 (60%) in group 2 had side-effects compared with 48% in group 3 (statistically not significant) (Table 5Go). Among the patients receiving triple therapy (21 patients), only five could tolerate the maximum dose of 3 g/day while the remaining patients continued with a dose ranging between 1 and 2.5 g/day. Gastrointestinal side-effects (dyspepsia, nausea) was the main reason for remaining on lower doses. There were fewer premature withdrawals due to toxicity or to lack of efficacy in the combination therapy schedule (7% in group 1, 12% in group 2 and 48% in group 3, P=0.0001). There were no drop-outs in group 1, two in group 2 and five in group 3 in the first 6 months. Five patients were lost to follow-up in group 3. In group 2, one patient dropped out but none was lost to follow-up. By 12 months, one patient was lost to follow-up and two patients had dropped out of the study in groups 1 and 2, while five patients were lost to follow-up in group 3. At 18 months, three, five and ten patients had dropped out in groups 1, 2 and 3 respectively, and two, two and ten respectively were lost to follow-up. No further changes were seen at 36 months.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In recent years aggressive therapeutic approaches to RA have become fairly common in many rheumatological centres. This is due to the availability of new combinations of DMARDs that show additive biological effects and clinical benefits without increasing toxicity [24]. In all the most recent studies, no major toxicities were observed even after prolonged periods. These results have prompted the adoption of schedules with drugs that have demonstrated clinical efficacy in monotherapy and effectiveness against erosions [1618]. As a possible combination, we selected as DMARDs the three drugs with the greatest clinical efficacy, without additive toxicity, and the highest chance of controlling the rate of disease progression at the joint level [1922]. When using MTX, CsA or SSZ, we observed, as expected, that the fastest-acting DMARD was indeed MTX. MTX was the only drug that led to more than 50% of the patients in monotherapy reaching ACR50 improvement in the first 6 months after baseline. This result appears statistically better than that obtained with CsA or SSZ.

More surprisingly, in Mediterranean patients we confirmed recent data by O'Dell et al. [23] showing that MTX gives poorer results in DR4/DR1-positive patients, and we present data suggesting that CsA monotherapy is efficacious in this subset of patients in the first 6 months; SSZ falls in between. We did not genotype our patients for 0401, 0404, etc., and therefore our data must be confirmed in other cohorts.

The slow effects of CsA support recent findings showing that CsA requires more than 6 months to give the best clinical and biological results [24]. When using combinations of MTX plus CsA (or CsA plus MTX) plus SSZ, we obtained 50% improvement in the great majority of the patients after 18 months. We deem this one of the major findings of our study. We do not know whether this result depended on our use of SSZ as a final rescue drug or the fact that the patients we enrolled had the mildest type of rheumatoid disease. We tried to answer this by comparing the basal values of clinical parameters with those presented in other studies. The average number of swollen joints in our patient population was undoubtedly lower than in the studies of Tugwell et al. [2], Boers et al. [4] and O'Dell et al. [3], in which it was 15, 16, and 31 respectively. Our results might have been achieved because our patients had a milder type of rheumatoid disease. The same type of therapeutic strategy should be assessed in patients with a higher number of swollen joints and with more severe disease. Certainly, in long-term treatment programmes the safety issue must receive considerable attention. Yocum et al. [25] have recently observed that patients receiving MTX plus CsA had an increased drop-out rate after 18 months of treatment due to an increased creatinine concentration.

The debate about which is the best therapeutic approach with multiple drugs now appears to be crucial. Two methods may be employed: the step-down and the step-up approach. According to our data we prefer the second option because, with an anchor drug like MTX, more than 50% of the patients can be placed under adequate control. The poor responders can then be offered further possible alternatives within a few months, even earlier than in our study. All our patients who responded to treatment had shown evidence of response by the fourth month. Therefore, within 8 months it is possible to establish the long-term therapeutic schedule for any patient [26]. So far no data are available in the literature to support the contention that patients who show poor prognostic factors at disease onset, such as a high number of swollen joints, a high erosion score plus rheumatoid factor positivity and positivity for DR4/DR1, should start immediately on the full combination of drugs. More data are needed in order to define this issue prospectively, in order to identify at the start the patients who need combination therapy and those who do not. In this study we present evidence that a step-up approach with MTX, CsA or SSZ can be used effectively in rheumatoid patients to obtain an important clinical response, as defined by Magnusson, in about 40% of patients compared with 21% of patients receiving monotherapy with SSZ. We do not know what was the role played by the 5 mg of prednisone at entry into our study. None of the patients who had a full response or were in remission were still taking prednisone.

Our results also confirm that combining three drugs is not only clinically useful but is also feasible in terms of toxicity. In the first 18 months of the trial the number of patients experiencing side-effects was slightly higher in the combination therapy groups, but because of side-effects or lack of efficacy the number of drop-outs was clearly in favour of the combination therapy schedules.

Although overall the data were favourable, we must recognize that a surprisingly low rate of remissions was seen. Therefore our data thoroughly support the common belief that, when adopting a more aggressive approach, we can change the clinical behaviour but not the overall course of the disease, which remains incurable with the available DMARDs. It is unknown whether other types of combination therapy that include biological response modifiers will allow different outcomes. Combinations of anti-TNF (or TNF-receptor fusion protein) plus MTX or CsA appear promising [27, 28].


    Acknowledgments
 
This work was supported by the University of Udine.


    Notes
 
This work was presented in abstract form at the 1997 ACR meeting (abstract no. 1129).

Correspondence to: G. F. Ferraccioli. Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 9 November 2001; Accepted 28 February 2002





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