Rituximab in Patients With Rheumatoid Arthritis
Rituximab in Patients With Rheumatoid Arthritis
Patient demographics are summarized in Table 1, and the patient distribution during the study is presented in Figure 1. Patients were predominantly female (75%) and seropositive (89%). Patient was considered to be seropositive if he/she had rheumatoid factor and/or anti–cyclic citrullinated peptide antibodies. Median disease duration was 15 years (range, 0–47 years), and the average number of previously used DMARDs was 6 (range, 1–12). Almost every patient (93%) had used traditional DMARDs also in combinations. A combination of MTX, sulfasalazine, hydroxychloroquine, and small-dose prednisolone (FIN-RACo combination therapy) had been used by 56 patients (37%). The most common previously or concomitantly used drug was MTX (97% of the patients), followed by hydroxychloroquine/chloroquine (95%), sulfasalazine (91%), aurothiomalate (74%) and leflunomide (69%). During RTX treatment, 20% of the patients received MTX, 33% received MTX together with other DMARDs, 39% used other DMARDs than MTX, whereas 8% of the patients did not use any concomitant DMARD therapy.
The median number of biologics was 1 (range, 0–4) before RTX initiation. The majority of the patients had been treated at least by 1 TNF-α blocking agent; adalimumab (n = 75), etanercept (n = 74), or infliximab (n = 49). A subset of patients (n = 26, 17%) had received 3 or more TNF-α blockers prior to the first RTX treatment course.
A considerable proportion of patients (n = 42) had never used biologics prior to RTX treatment onset (Table 1). The reasons to use RTX as the first biologic drug included (an individual patient may have had >1 reason) increased frequency of infections (n = 13), preceding malignancies (n = 5, including lymphoma in 2), economical reasons (n = 6), active/latent tuberculosis (n = 7), the presence of antinuclear and/or anti-DNA antibodies in high titers (n = 1), and concomitant multiple sclerosis (n = 1).
For all 151 RA patients, the BL median serum CRP and ESR values were 24 mg/L (range, 1–174 mg/L) and 34 mm/h (range, 2–114 mm/h), respectively (Table 2). After the first RTX treatment course, the median change of these values was as follows: CRP -19.7 mg/L (range, -164 to 111 mg/L) and ESR -9.0mm/h (range, -93 to 48 mm/h).
Values (at least 1) of DAS28 were available for 150 of 151 RA patients either at BL or during follow-up. However, for 125 patients, both BL and at least 1 follow-up value at any time point were available. Median DAS28 at BL was 5.4 (range, 0.5–8.6) for these 125 patients (Table 2, Fig. 2A). After the first treatment course, the value decreased to 3.3 (range, 0.6–6.6; n = 113), and after the second treatment course to 3.1 (range, 0.1–6.5; n = 105). The decreases in DAS28 were statistically significant both after the first and the second treatment courses (P < 0.001 for both). The responses after the first and the second treatment courses were similar in patients who had received 0 or only 1 prior TNF-α inhibitor versus patients with 2 or more prior TNF-α inhibitors (Table 2). The improvements in DAS28 during the first and second cycles were similar in patients who had had 0 to 2 previous TNF-α inhibitors compared with patients with more than 2 previous TNF-α inhibitors (data not shown). In the seronegative RA patients, the median DAS28 was 6.1 (range, 2.9–6.8; n = 12) at BL and declined to 4.9 (range, 3.2–5.9; n = 7; P = 0.156) after the first treatment course. In the seropositive RA patients, the BL DAS28 decreased from median 5.3 (range, 0.5–8.6; n = 111) to 3.1 (range, 0.6–6.6; n = 104; P < 0.0001). The improvement in DAS28 was significantly better in seropositive patients compared with seronegative patients (P < 0.01). The higher disease activity at BL in the seronegative patients is probably due to the fact that they had a more refractory disease. The median number of previous biologicals in the seronegative group was 3 compared with 1 in the seropositive patients (data not shown).
(Enlarge Image)
Figure 2.
The DAS28 score changes and disease activity after RTX treatment courses. A, The DAS28 values, (B) disease activity rates. C, The DAS28 scores of only the patients who have both a pretreatment and posttreatment values available regarding each respective treatment course.
Of the 113 RA patients with DAS28 data available at BL and after the first treatment course, 54 (48%) achieved low disease activity, including 36 (32%) with remission. The results of the first course and the subsequent courses are presented in Figure 2B; DAS28 appeared to return close to the BL value before each subsequent course, but RTX treatment improved DAS28 even in these cases (Fig. 2C). The median precourse BL DAS28 before the second, third, and fourth courses were 4.6 (range, 1.7–7.8; n = 77), 4.24 (range, 1.7–7.2; n = 50), and 3.97 (range, 2.1–6.2; n = 24), respectively. The mean time to retreatment after the first course of RTX was 11 months and varied between 11 and 13 months after the second, third, and fourth courses. Two patents achieved long-term remission with DAS28 of less than 2.6 at every consecutive visit for at least 2 years without need for retreatment: one patient after the second retreatment and the other after the fourth retreatment.
Responses were similar during the first 2 RTX treatment courses irrespective of whether given with or without concomitant MTX. The median BL DAS28 score of patients treated with RTX + MTX (either with or without concomitant other DMARDs) was 5.2 (range, 0.5–7.4; n = 63). Median changes in DAS28 were -1.7 (n = 52), -2.4 (n = 50), and -2.7 (n = 24) after the first, second and the third courses, respectively. The corresponding values with patients treated with RTX + DMARDs other than MTX was 5.8 (range, 3.2–8.6; n = 48) at BL with median changes of -2.3 (n = 38), -2.9 (n = 31), and -2.7 (n = 23) after the first, second, and third courses, respectively. The differences in the DAS28 score improvements between patients using or not using concomitant MTX were not statistically significant at any time point.
European League Against Rheumatism response criteria good, moderate, or no responses after the first treatment course were seen in 38%, 44%, and 18% of the patients, respectively. Results of this and the subsequent courses are presented in Figure 3A. A separate analysis was performed of those 46 patients with European League Against Rheumatism response data available regarding both the first and the second courses. For this analysis, the second treatment response was evaluated based on the change of the pretreatment value of the corresponding course. Altogether 79% of the patients maintained or improved their status of moderate or good response after the second treatment course. Furthermore, 38% of the initial nonresponders achieved either a moderate or good response after the second treatment course. This means that only 5 patients (11%) did not respond to either of the treatment courses (Fig. 3B). European League Against Rheumatism response for seronegative RA patients (n = 7) was moderate in 43% and none in 57% of the cases. Instead, in seropositive RA patients (n = 88), 41% showed a good and 44% a moderate response, whereas only 15% of the seropositive cases showed no response to RTX therapy.
(Enlarge Image)
Figure 3.
European League Against Rheumatism response rates after the RTX treatment courses (A). European League Against Rheumatism response rates after the first and the second courses in the patients having both values available (B). Gray bars indicate the number of patients responding to first treatment course. Black, hatched, and white bars indicate the number of patients responding to the second treatment course within the same patient group, that is, 10 of 15 patients had a good response both after the first and second treatment courses.
In total, 31 RA patients (21%) discontinued treatment because of lack of efficacy. Among these, 15 (45%) discontinued after the first treatment course and 12 (42%) after the second course. Four RA patients (13%) received 3 courses of RTX but discontinued thereafter (Fig. 1). European League Against Rheumatism response data were available for only 10 of these patients, showing moderate response in 5 and no response in the other 5 patients.
The average number of biologics prior to the first RTX course was higher among the patients who discontinued RTX therapy because of inefficacy than in the ones who responded to the therapy (1.96 vs 1.41). Of these 31 RA patients dropping out from RTX therapy because of inefficacy, 7 (23%) continued with conventional DMARDs. Their lowest DAS28 value after RTX therapy was 3.3 (range, 1.8–5.4), whereas the corresponding score for the patients who changed to biologicals was slightly higher: 4.1 (range, 2.9–4.9). The most commonly used options after RTX were abatacept (n = 12), tocilizumab (n = 10), and infliximab (n = 4). In general, the RA patients responded to the subsequent therapies.
In total, 82 serious AEs (SAEs) (12 related and 70 unrelated) and 196 AEs (64 related and 132 unrelated) were recorded. There were 2 related fatalities during the study, 1 case of small cell lung carcinoma and 1 case of acute leukemia in conjunction with pyelonephritis. The reporting investigator, however, assessed the latter fatal event probably unrelated to RTX therapy, but because of the uncertainty of the relation, this event had to be recorded as related. The other SAEs were anaphylactic reaction, Mycoplasma pneumonia, agranulocytosis, suspected pulmonary fibrosis (atypical) or suspected pulmonary sarcoidosis, neutropenia, a Fallopian cancer residual (malignancy present before RTX initiation), an unhealed wound from surgical procedure, and pyelonephritis in 1 patient each. One case of interstitial pulmonary reaction and another of worsening of CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome occurred in patients with these manifestations already present before the initiation of RTX but reported as related SAEs.
There were 11 discontinuations due to AEs, sometimes in combination with lack of efficacy. The events were leukopenia, large granular lymphocytic leukemia, anaphylaxia, pneumonitis, and an RTX-induced lung reaction (all serious). Nonserious events leading to discontinuation were mild insomnia, pulmonary infiltration, polyneuropathy, herpes simplex rash, elevated blood pressure during infusion and rash, and lower limb numbness and pain.
Results
Demographics
Patient demographics are summarized in Table 1, and the patient distribution during the study is presented in Figure 1. Patients were predominantly female (75%) and seropositive (89%). Patient was considered to be seropositive if he/she had rheumatoid factor and/or anti–cyclic citrullinated peptide antibodies. Median disease duration was 15 years (range, 0–47 years), and the average number of previously used DMARDs was 6 (range, 1–12). Almost every patient (93%) had used traditional DMARDs also in combinations. A combination of MTX, sulfasalazine, hydroxychloroquine, and small-dose prednisolone (FIN-RACo combination therapy) had been used by 56 patients (37%). The most common previously or concomitantly used drug was MTX (97% of the patients), followed by hydroxychloroquine/chloroquine (95%), sulfasalazine (91%), aurothiomalate (74%) and leflunomide (69%). During RTX treatment, 20% of the patients received MTX, 33% received MTX together with other DMARDs, 39% used other DMARDs than MTX, whereas 8% of the patients did not use any concomitant DMARD therapy.
The median number of biologics was 1 (range, 0–4) before RTX initiation. The majority of the patients had been treated at least by 1 TNF-α blocking agent; adalimumab (n = 75), etanercept (n = 74), or infliximab (n = 49). A subset of patients (n = 26, 17%) had received 3 or more TNF-α blockers prior to the first RTX treatment course.
A considerable proportion of patients (n = 42) had never used biologics prior to RTX treatment onset (Table 1). The reasons to use RTX as the first biologic drug included (an individual patient may have had >1 reason) increased frequency of infections (n = 13), preceding malignancies (n = 5, including lymphoma in 2), economical reasons (n = 6), active/latent tuberculosis (n = 7), the presence of antinuclear and/or anti-DNA antibodies in high titers (n = 1), and concomitant multiple sclerosis (n = 1).
Efficacy
For all 151 RA patients, the BL median serum CRP and ESR values were 24 mg/L (range, 1–174 mg/L) and 34 mm/h (range, 2–114 mm/h), respectively (Table 2). After the first RTX treatment course, the median change of these values was as follows: CRP -19.7 mg/L (range, -164 to 111 mg/L) and ESR -9.0mm/h (range, -93 to 48 mm/h).
Values (at least 1) of DAS28 were available for 150 of 151 RA patients either at BL or during follow-up. However, for 125 patients, both BL and at least 1 follow-up value at any time point were available. Median DAS28 at BL was 5.4 (range, 0.5–8.6) for these 125 patients (Table 2, Fig. 2A). After the first treatment course, the value decreased to 3.3 (range, 0.6–6.6; n = 113), and after the second treatment course to 3.1 (range, 0.1–6.5; n = 105). The decreases in DAS28 were statistically significant both after the first and the second treatment courses (P < 0.001 for both). The responses after the first and the second treatment courses were similar in patients who had received 0 or only 1 prior TNF-α inhibitor versus patients with 2 or more prior TNF-α inhibitors (Table 2). The improvements in DAS28 during the first and second cycles were similar in patients who had had 0 to 2 previous TNF-α inhibitors compared with patients with more than 2 previous TNF-α inhibitors (data not shown). In the seronegative RA patients, the median DAS28 was 6.1 (range, 2.9–6.8; n = 12) at BL and declined to 4.9 (range, 3.2–5.9; n = 7; P = 0.156) after the first treatment course. In the seropositive RA patients, the BL DAS28 decreased from median 5.3 (range, 0.5–8.6; n = 111) to 3.1 (range, 0.6–6.6; n = 104; P < 0.0001). The improvement in DAS28 was significantly better in seropositive patients compared with seronegative patients (P < 0.01). The higher disease activity at BL in the seronegative patients is probably due to the fact that they had a more refractory disease. The median number of previous biologicals in the seronegative group was 3 compared with 1 in the seropositive patients (data not shown).
(Enlarge Image)
Figure 2.
The DAS28 score changes and disease activity after RTX treatment courses. A, The DAS28 values, (B) disease activity rates. C, The DAS28 scores of only the patients who have both a pretreatment and posttreatment values available regarding each respective treatment course.
Of the 113 RA patients with DAS28 data available at BL and after the first treatment course, 54 (48%) achieved low disease activity, including 36 (32%) with remission. The results of the first course and the subsequent courses are presented in Figure 2B; DAS28 appeared to return close to the BL value before each subsequent course, but RTX treatment improved DAS28 even in these cases (Fig. 2C). The median precourse BL DAS28 before the second, third, and fourth courses were 4.6 (range, 1.7–7.8; n = 77), 4.24 (range, 1.7–7.2; n = 50), and 3.97 (range, 2.1–6.2; n = 24), respectively. The mean time to retreatment after the first course of RTX was 11 months and varied between 11 and 13 months after the second, third, and fourth courses. Two patents achieved long-term remission with DAS28 of less than 2.6 at every consecutive visit for at least 2 years without need for retreatment: one patient after the second retreatment and the other after the fourth retreatment.
Responses were similar during the first 2 RTX treatment courses irrespective of whether given with or without concomitant MTX. The median BL DAS28 score of patients treated with RTX + MTX (either with or without concomitant other DMARDs) was 5.2 (range, 0.5–7.4; n = 63). Median changes in DAS28 were -1.7 (n = 52), -2.4 (n = 50), and -2.7 (n = 24) after the first, second and the third courses, respectively. The corresponding values with patients treated with RTX + DMARDs other than MTX was 5.8 (range, 3.2–8.6; n = 48) at BL with median changes of -2.3 (n = 38), -2.9 (n = 31), and -2.7 (n = 23) after the first, second, and third courses, respectively. The differences in the DAS28 score improvements between patients using or not using concomitant MTX were not statistically significant at any time point.
European League Against Rheumatism response criteria good, moderate, or no responses after the first treatment course were seen in 38%, 44%, and 18% of the patients, respectively. Results of this and the subsequent courses are presented in Figure 3A. A separate analysis was performed of those 46 patients with European League Against Rheumatism response data available regarding both the first and the second courses. For this analysis, the second treatment response was evaluated based on the change of the pretreatment value of the corresponding course. Altogether 79% of the patients maintained or improved their status of moderate or good response after the second treatment course. Furthermore, 38% of the initial nonresponders achieved either a moderate or good response after the second treatment course. This means that only 5 patients (11%) did not respond to either of the treatment courses (Fig. 3B). European League Against Rheumatism response for seronegative RA patients (n = 7) was moderate in 43% and none in 57% of the cases. Instead, in seropositive RA patients (n = 88), 41% showed a good and 44% a moderate response, whereas only 15% of the seropositive cases showed no response to RTX therapy.
(Enlarge Image)
Figure 3.
European League Against Rheumatism response rates after the RTX treatment courses (A). European League Against Rheumatism response rates after the first and the second courses in the patients having both values available (B). Gray bars indicate the number of patients responding to first treatment course. Black, hatched, and white bars indicate the number of patients responding to the second treatment course within the same patient group, that is, 10 of 15 patients had a good response both after the first and second treatment courses.
In total, 31 RA patients (21%) discontinued treatment because of lack of efficacy. Among these, 15 (45%) discontinued after the first treatment course and 12 (42%) after the second course. Four RA patients (13%) received 3 courses of RTX but discontinued thereafter (Fig. 1). European League Against Rheumatism response data were available for only 10 of these patients, showing moderate response in 5 and no response in the other 5 patients.
The average number of biologics prior to the first RTX course was higher among the patients who discontinued RTX therapy because of inefficacy than in the ones who responded to the therapy (1.96 vs 1.41). Of these 31 RA patients dropping out from RTX therapy because of inefficacy, 7 (23%) continued with conventional DMARDs. Their lowest DAS28 value after RTX therapy was 3.3 (range, 1.8–5.4), whereas the corresponding score for the patients who changed to biologicals was slightly higher: 4.1 (range, 2.9–4.9). The most commonly used options after RTX were abatacept (n = 12), tocilizumab (n = 10), and infliximab (n = 4). In general, the RA patients responded to the subsequent therapies.
Safety
In total, 82 serious AEs (SAEs) (12 related and 70 unrelated) and 196 AEs (64 related and 132 unrelated) were recorded. There were 2 related fatalities during the study, 1 case of small cell lung carcinoma and 1 case of acute leukemia in conjunction with pyelonephritis. The reporting investigator, however, assessed the latter fatal event probably unrelated to RTX therapy, but because of the uncertainty of the relation, this event had to be recorded as related. The other SAEs were anaphylactic reaction, Mycoplasma pneumonia, agranulocytosis, suspected pulmonary fibrosis (atypical) or suspected pulmonary sarcoidosis, neutropenia, a Fallopian cancer residual (malignancy present before RTX initiation), an unhealed wound from surgical procedure, and pyelonephritis in 1 patient each. One case of interstitial pulmonary reaction and another of worsening of CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome occurred in patients with these manifestations already present before the initiation of RTX but reported as related SAEs.
There were 11 discontinuations due to AEs, sometimes in combination with lack of efficacy. The events were leukopenia, large granular lymphocytic leukemia, anaphylaxia, pneumonitis, and an RTX-induced lung reaction (all serious). Nonserious events leading to discontinuation were mild insomnia, pulmonary infiltration, polyneuropathy, herpes simplex rash, elevated blood pressure during infusion and rash, and lower limb numbness and pain.
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