The study design is shown in Figure 1. The baseline demographics of patients from the 2 phase III studies were similar (Table 1), although the mean disease duration at the time of entry in MN301 (6.8 years) was greater than that at entry in MN302 (3.7 years), reflecting an increased proportion of patients with longstanding disease (>10 years) in the MN301 patient population. There were no clinically relevant differences between the 2 phase III patient populations with respect to the classification of the severity of RA.
Table 1. Demographics of the patients enrolled in the extension study of leflunomide therapy*
|Characteristic||MN301 (n = 29)||MN302 (n = 185)||Total (n = 214)|
|Sex, no. (%) women||24 (82.8)||136 (73.5)||160 (74.8)|
|Mean age, years (range)||55 (29–79)||57 (31–77)||57 (29–79)|
|No. (%) of patients ≥65 years of age||6 (20.7)||43 (23.2)||49 (22.9)|
|Mean duration of RA, years (range)||6.8 (0.1–26.6)||3.7 (0.3–11.8)||4.1 (0.1–26.6)|
|RA diagnosis at phase III study, % of patients|| || || |
| ≤2 years||38||45||44|
| >2 years but ≤10 years||31||52||49|
| >10 years||31||3||7|
|Steinbrocker class, % of patients|| || || |
| Class I||17.2||23.4||22.5|
| Class II||41.4||49.5||48.4|
| Class III||41.4||27.2||29.1|
|No previous DMARD, % of patients||24||33||32|
|Mean treatment duration, years (range)||4.8 (3.7–5.8)||4.5 (2.8–5.8)||4.6 (2.8–5.8)|
Of the 214 patients (74.8% female) entered into this extension study, 29 were from MN301 and 185 were from MN302. The mean age at the time of enrollment was 57 years (range 29–79 years), and the mean disease duration 4.1 years (range 0.1–26.6 years), with 44% of the patients first being diagnosed <2 years before entry into the MN301 and MN302 trials. The mean duration of leflunomide treatment was 4.6 years (range 2.8–5.8 years); 182 patients continued leflunomide treatment for at least 4 years, with 58 of these patients completing at least 5 years of treatment. In 8 (4%) of the 214 patients, the dosage of leflunomide was decreased from 20 mg/day to 10 mg/day; in 2 of these patients (1%), the 20-mg daily dose was subsequently reinstated. In 2 patients (1%), the dosage of leflunomide was increased from 10 mg/day to 20 mg/day during the course of the study.
Of the 214 patients entering the open-label extension study, 163 (76.2%) received treatment until the study end point. Reasons for withdrawal included adverse events (n = 20; 9.3%), lack of efficacy (n = 9; 4.2%), did not wish to continue (n = 11; 5.1%), lost to followup (n = 4; 1.9%), death (n = 5; 2.3%), unknown (n = 1; 0.5%), and other (n = 1; 0.5%).
The improvements in ACR20, ACR50, and ACR70 response rates observed at year 1 (72.9%, 48.3%, and 14.5%, respectively) were maintained throughout the study until year 4 or the end point (69.2%, 43.0%, and 19.6%, respectively) (Figure 2). Analysis of the individual components of the ACR criteria, including swollen and tender joint counts, investigator's and patient's global assessments, and CRP, showed an improvement from baseline at year 1, which was maintained until the end point of the study (Figure 3). The duration of morning stiffness was reduced at year 1 (mean 24.7 minutes, median 10 minutes) compared with baseline (mean 145.2 minutes, median 120 minutes), and this improvement was maintained until year 4 or the end point (mean 46.4 minutes, median 15 minutes).
Figure 2. American College of Rheumatology 20% (ACR20), ACR50, and ACR70 response rates for leflunomide-treated patients from year 1 until year 4 or the end point.
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Figure 3. Mean scores for tender and swollen joint counts, investigators' and patients' global assessments, C-reactive protein (CRP) levels, and mean Health Assessment Questionnaire (HAQ) scores for leflunomide-treated patients.
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Improvements in the mean CRP level, ESR, and rheumatoid factor level compared with baseline (3.9 mg/dl, 50.3 mm/hour, and 295.1 units/ml, respectively) were observed at year 1 (1.3 mg/dl, 34.3 mm/hour, and 153.4 units/ml, respectively) and were maintained until year 4 or the end point (1.2 mg/dl and 1.4 mg/dl, 33.8 mm/hour and 33.4 mm/hour, and 176.1 units/ml and 176.5 units/ml, respectively).
An improvement in functional ability as measured by HAQ scores was seen at year 1 (mean change −0.6) and was maintained through year 4 or the end point (mean change −0.5 and −0.5, respectively) (Figure 3). A change of −0.22 in functional ability is considered to be clinically meaningful (17). Seventeen patients could not be assessed by HAQ due to the lack of availability of validated language adaptations of the HAQ in Hungary and Slovenia.
The overall mean (±SD) duration of exposure to leflunomide in this followup study was 1.33 ± 0.43 years (range 0.03–1.82 years) for all 214 patients. Of these 214 patients, 183 (85.5%) experienced 1 or more treatment-emergent primary adverse events. The most common primary adverse events were upper respiratory tract infection (23.4%), diarrhea (8.4%), back pain (6.5%), and pain in an extremity (6.5%). Individual treatment-emergent adverse events reported in at least 5% of patients are shown in Table 2.
Table 2. Adverse events and treatment withdrawals*
|All adverse events||183 (85.5)|
|Adverse events occurring in ≥5% of patients|| |
| Upper respiratory tract infection||50 (23.4)|
| Diarrhea||18 (8.4)|
| Back pain||14 (6.5)|
| Pain in extremity||14 (6.5)|
| Bronchitis||13 (6.1)|
| Nausea||13 (6.1)|
| Accidental injury||12 (5.6)|
| Hypertension||11 (5.1)|
|Serious adverse events||75 (35)|
|Treatment-related adverse events||56 (26.2)|
|Withdrawals due to adverse events||20 (9)|
Of the infections reported as being primary adverse events, the most common were upper respiratory tract infection, bronchitis, pharyngitis, and urinary tract infections. Six cases of pneumonia, 1 case of sepsis, and 3 cases of herpes zoster were reported. Of the pneumonia cases, only 2 were considered to be possibly treatment-related; 1 patient recovered, with no further recurrence, and the other patient was withdrawn from the study. Of the other 4 cases of pneumonia, recovery was reported in 3 patients, and 1 patient died. The case of sepsis was mild and was thought not to be related to treatment. Overall, 56 patients (26.2%) experienced primary adverse events that were considered possibly treatment-related, the most frequent of which were diarrhea (5.6%), hypertension (2.8%), abnormal findings on liver function tests (2.8%), rash (2.8%), and eczema (2.3%).
The types of primary adverse events observed in this long-term followup study were very similar to those reported after 2 years of treatment in the 2 phase III studies. The most common adverse events reported in at least 10% of patients at 2 years (upper respiratory tract infection, rash, diarrhea, and alopecia) occurred at lower frequencies during the extension study. In the extension study, only 1 adverse event, upper respiratory tract infection (reported in 23% of patients), was reported in >10% of patients, and no new types of adverse events were observed (Table 3).
Table 3. Adverse events in the present study compared with data from 2 phase III studies*
|Adverse events reported in ≥10% of patients||MN301 (n = 60)||MN302 (n = 292)||Extension study (n = 214)|
|Upper respiratory tract infection||21 (35)||133 (46)||50 (23)|
|Rash||13 (22)||50 (17)||8 (4)|
|Diarrhea||10 (17)||80 (27)||18 (8)|
|Alopecia||8 (13)||57 (20)||4 (2)|
|Bronchitis||8 (13)||51 (18)||13 (6)|
|Dyspepsia||8 (13)||27 (9)||9 (4)|
|Urinary tract infection||8 (13)||23 (8)||7 (3)|
|Increased cough||8 (13)||23 (8)||6 (3)|
|Pruritus||8 (13)||23 (8)||5 (2)|
|Gastrointestinal pain||8 (13)||22 (8)||5 (2)|
|Nausea||7 (12)||35 (12)||13 (6)|
|Maculopapular rash||7 (12)||7 (2)||1 (<1)|
|Tenosynovitis||7 (12)||27 (9)||8 (4)|
|Hypertension||6 (10)||52 (18)||11 (5)|
|Back pain||6 (10)||44 (15)||14 (7)|
|Headache||6 (10)||39 (13)||3 (1)|
|Arthralgia||6 (10)||18 (6)||0 (0)|
Most of the serious adverse events represented hospitalizations (surgery, rehabilitation, and intense physiotherapy) associated with the underlying disease or with surgery in the elderly (e.g., hernia, cataract). Seventy-five patients (35%) experienced serious treatment-emergent adverse events, the most common of which were joint disorder (4.7%), osteoarthritis (1.9%), and pneumonia (1.9%). The number of serious adverse events that were considered to be related to the study medication was low (11 events in 9 patients [4.2%]), with some patients experiencing >1 event.
The frequency of primary adverse events that led to discontinuation of the study medication was low, with 13 such events reported in 12 patients (5.6%). Five deaths occurred during this followup study and were attributable to acute myocardial infarction (MI), MI and subsequent pericardial tamponade, septic shock following surgery, cardiorespiratory insufficiency and suspected coronary embolus, and a car accident with a probable cardiac cause. Only 1 of these deaths (septic shock following surgery) was considered to be possibly treatment-related.
Safety data for laboratory variables.
The mean (±SD) systolic and diastolic blood pressure values at baseline were, respectively, 134.7 ± 19.95 mm Hg and 80.5 ± 9.82 mm Hg. At the study end point, these values had increased slightly to 141.0 ± 19.29 mm Hg and 84.3 ± 10.25 mm Hg, respectively. The extension phase is the first time during which clinically relevant increases in blood pressure occurred (11 patients; 5.1%). Seven patients (3.3%) had changes in systolic blood pressure (<170 mm Hg at baseline and >170 mm Hg at any visit during the study), and 4 patients (1.9%) had changes in diastolic blood pressure (<90 mm Hg at baseline and >90 mm Hg at any visit during the study). In most cases, the clinically relevant values were observed only at isolated visits and normalized during ongoing leflunomide treatment. Blood pressure increases at consecutive visits were observed in 3 patients, none of whom had hypertension reported as an adverse event.
Safety data regarding changes in laboratory values were available for only 182 patients in this study because baseline laboratory values were not available for 32 patients. The majority of patients had normal liver enzyme levels at baseline and at the end point. In study MN301 or MN302, increases from normal at baseline to above the upper limit of normal at the end point of the extension period were seen for serum aspartate transaminase (AST) (12 patients; 6.6%), serum alanine transaminase (ALT) (18 patients; 9.9%), alkaline phosphatase (22 patients; 12.1%), and lactate dehydrogenase (15 patients; 8.2%) (Table 4). During the extension period, clinically noteworthy increases (at least 3-fold the upper limit of normal) in AST occurred in 4 patients, and in 1 of these patients, the ALT level was also at least 3 times the upper limit of normal. Although in 2 of these patients, no adverse event was reported in conjunction with these elevated levels, arrhythmia was reported in the third patient, and diarrhea and abnormal liver function was recorded in the fourth. This patient's leflunomide treatment was interrupted on 2 occasions, and was later discontinued because of surgery for carcinoma.
Table 4. Abnormal findings on liver function tests and discontinuation in 182 patients*
| ||Entire study period||Extension period only|
|Abnormal shift|| |
| Serum alanine transaminase||12 (6.6)||–|
| Serum aspartate transaminase||18 (9.9)||–|
| Alkaline phosphatase||22 (12.1)||–|
| Lactate dehydrogenase||15 (8.2)||–|
|Serum alanine transaminase >3 times the upper limit of normal||–||1 (0.5)|
|Serum aspartate transaminase >3 times the upper limit of normal||–||4 (2.2)|
|Discontinuation due to liver function abnormalities||–||4 (2.2)|
Overall, abnormal findings on liver function tests were reported as a mild or moderate adverse event in 7 patients, including the patient described above. All but 1 of these events were considered by the investigator as being possibly related to the study drug. Four patients withdrew because of these events. Of the 3 patients continuing therapy, 1 recovered, and in the other 2, the abnormal findings on liver function tests did not resolve. However, no dosage adjustments were made in these patients.
Most patients had normal leukocyte counts at baseline and at the end point. High leukocyte counts at baseline were observed in 39 patients (21.4%), but these failed to normalize by the end point in only 11 patients (6.0%). Only 21 patients (11.5%) had a normal leukocyte count at baseline that had changed at the end point. In 11 patients (6.0%), the count changed from normal to high, and in 10 patients (5.5%), it changed from normal to low. In 3 of these 10 patients, leukopenia was reported as a mild primary adverse event. Two of these events reversed during the study, and 2 were considered related to leflunomide. The majority of patients had normal platelet counts at both baseline and the end point. Seventy-three patients (40.1%) had a high platelet count at baseline, which normalized by the end point in 56 patients (30.8%). Only 1 patient had a low value at the end point.