ORIGINAL ARTICLE
Long-Term Real-Life Experience With Rituximab in Adult Finnish Patients With Rheumatoid Arthritis Refractory or With Contraindication to Anti–Tumor Necrosis Factor Drugs Heikki Valleala, MD, PhD,* Markku Korpela, MD, PhD,† Tuija Hienonen-Kempas, MSc, PhD,‡ Kai Immonen, MD, PhD,§ Jukka Lähteenmäki, MD,§ Tea Uusitalo, MD,║ Riitta Komulainen, MD,¶ Timo Möttönen, MD, PhD,# and Pekka Hannonen, MD, PhD** Objective: The objective of this study was to evaluate the long-term safety and efficacy of repeated rituximab (RTX) infusions in the treatment of rheumatoid arthritis in daily clinical practice in Finland. Methods: Data were collected from the medical records of a total of 151 patients with rheumatoid arthritis treated with RTX and followed up for at least 12 months after the treatment onset. Change in the 28-joint Disease Activity Score (DAS28), European League Against Rheumatism response criteria and proportions of patients reaching disease remission (DAS28 < 2.6) or low disease activity (DAS28 < 3.2) were used to assess the clinical response. Results: Of the 151 patients 128 received 2 courses, 76 received 3 courses, and 42 received 4 courses of RTX. The mean time to retreatment for the first 4 courses varied between 11 and 13 months. Median DAS28 decreased from 5.4 (0.5–8.6) to 3.3 (0.6–6.6) after the first course. After the second treatment course, the DAS28 was 3.1 (range, 0.1–6.5). The From the *Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki; †Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Tampere; ‡Roche Finland, Espoo; §Department of Medicine, North Karelia Central Hospital, Joensuu; ║Department of Internal Medicine, Kanta-Häme Central Hospital, Hämeenlinna Regional Hospital, Hämeenlinna; ¶Department of Internal Medicine, Kanta-Häme Central Hospital, Riihimäki Regional Hospital, Riihimäki; #Department of Medicine, Division of Rheumatology, Turku University Hospital, Turku; and **Department of Medicine, Jyväskylä Central Hospital, Jyväskylä, Finland. This study was sponsored by Roche Finland. H.V. has received payment form Roche for collecting study data, is a paid consultant and advisory board member for Roche, and has received payment for lectures and meeting expenses from Roche. M.K. is a paid consultant and advisory board member for BMS, GSK, MSD, Roche, UCB Pharma; has received payment for fees for participation in review activities and for travel expenses from Roche and has received payment for lectures from Abbott, GSK, MSD, Pfizer, and Roche and for meeting expenses from Abbott, GSK, Jansen, MSD, and Pfizer. T.H.-K. is a Roche employee, participates to a monthly Roche stock purchase program, and has received payment for a lecture from Pharma Industry Finland. T.M. has received payment for participation in review activities from Roche; is a paid consultant for Roche, MSD, and Pfizer; has received payment for lectures from Abbvie, Amgen, BMS, GSK, MSD, Pfizer, Roche, and UCB; has received payment for development of educational presentations from Pfizer, Abbvie, and AstraZeneca; and is a paid advisory board member for Abbot, Amgen, Lilly, MSD, Pfizer, Roche, UCB, and AstraZeneca, Servier. P.H. is a paid advisory board member for Roche and a paid consultant for Roche, MSD, and Pfizer; has received support for travel to meetings from Roche and payment for expert testimony from Roche and MSD; has received payment for lectures form Roche, MSD, Pfizer, Abbvie, and AstraZeneca; has received payment for development of educational presentations from MSD; Pfizer, Abbvie, and AstraZeneca; and has received payment for meeting expenses from several companies including Roche, Abbvie, Actelion, MSD, Pfizer, BMS, and UCB. K.I. is a paid advisory board member for Roche and has received support for travel to meetings and grant support from Roche. J.L. has received grant support from Roche. T.U. and R.K. have nothing to declare. Correspondence: Heikki Valleala, MD, PhD, Helsinki University Central Hospital, PO Box 372, FIN-00029, HUS, Helsinki, Finland. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1076-1608/15/2101–0024 DOI: 10.1097/RHU.0000000000000166
24
www.jclinrheum.com
median precourse baseline DAS28 before the second and third courses were 4.6 (range, 1.7–7.8) and 4.24 (range, 1.7–7.2), respectively. The number of previously failed tumor necrosis factor inhibitors did not predict response to RTX in this patient cohort with extensive use of previous disease-modifying antirheumatic drugs (median = 6). Conclusions: The treatment as-needed regimen used in this study cohort led to delayed RTX retreatment and disease flare in a significant proportion of patients. A regular retreatment every 6 months, at least, after the first 2 treatment courses in patients who are not in remission could allow better control of disease activity. Key Words: rituximab, rheumatoid arthritis, observational, long-term, effectiveness (J Clin Rheumatol 2015;21: 24–30)
R
ituximab (RTX) in combination with methotrexate (MTX) is approved in Finland for the treatment of severe active rheumatoid arthritis (RA) in patients who have not responded to conventional disease-modifying antirheumatic drugs (DMARDs) and to at least 1 anti–tumor necrosis factor α (anti–TNF-α) therapy or are intolerant to anti–TNF-α’s. The need for treatment beyond TNF-α inhibitors is evident because 25% of patients treated with TNF-α inhibitors either do not achieve adequate clinical response or are unable to tolerate them during the first year,1 and the 5-year cumulative drug survival for TNF-α inhibitors is approximately 50%.2 Rituximab has a unique mode of action and long dosing interval. The standard course of RTX is two 1000-mg intravenous infusions with interval of 2 weeks between each dose. The optimal treatment paradigm for RTX has not been definitely determined. However, there is increasing evidence that retreatment after 24 weeks in RA patients with residual disease activity leads to improved efficacy and tighter control of disease activity compared with retreating patients after they have experienced an obvious disease flare.3–5 The aim of the present study was to evaluate the long-term safety and efficacy of repeated RTX treatments in daily clinical practice.
MATERIALS AND METHODS This observational study aimed to follow up adult patients with RA treated with RTX in a routine clinical setting in Finland from April 2005 to December 2011. The patients included in these analyses had been treated according to local standard of care, and, for example, visit intervals were not fixed. Data were collected from medical records of a total of 151 patients fulfilling the American College of Rheumatology criteria for RA6 and treated with RTX. Our data partially extend the earlier report by Valleala et al7 with longer follow-up times on some patients (cohort 1, n = 56, 37%), but include also data of new patients (cohort 2, n = 95, 63%). Patient distribution during the study course is presented in Figure 1. The shortest follow-up period was set to at least 1 year from the initiation of RTX therapy. Patient's written informed
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
Long-Term Experience With Rituximab in RA
FIGURE 1. Flowchart of patient distribution during the study.
consent was obtained before data collection was initiated. Patients were coded, and the collected data were anonymous. Approval for the study was obtained from the ethical review board of the Hospital District of Helsinki and Uusimaa and by the ethical committees of all 7 participating hospitals. The information collected included the previous usage of conventional DMARDs and biologics. In addition, concomitant chronic diseases or other factors affecting the choice of RTX therapy were documented. At the onset of RTX therapy and at subsequent follow-up and retreatment visits, data on erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), number of tender and swollen joints, Health Assessment Questionnaire score, and visual analog scale (0–100 mm) scores for patient’s assessment of pain and general health status, as well as physician’s assessment of disease activity, were collected. Follow-up information after discontinuation of RTX therapy was also obtained. All data were observational and collected when available from the hospital case records. Rituximab was administered on days 1 and 15 as 1000-mg intravenous infusions with intravenous methylprednisolone premedication. Upon a disease flare, a retreatment course of RTX was administered. For a small proportion of patients (n = 17), RTX therapy was initiated with 500 mg of RTX 2 weeks apart. Subsequently, the majority of these patients received retreatment with the 1000-mg dose of RTX. Treatment response after RTX therapy was defined according to European League Against Rheumatism response criteria8,9 at 3 months at the earliest. As the timing of the follow-up visits varied, we chose to use the lowest 28-joint Disease Activity Score (DAS28) value after each RTX course for efficacy analysis. Responses were calculated from the patients’ original baseline (BL) values to the indicated time point. Good response was defined as a DAS28 of less than 3.2 and DAS28 score improvement from BL of greater than 1.2. Moderate response was defined as 3.2 ≤ DAS28 ≤ 5.1 and improvement of 0.6 to 1.2, or DAS28 of greater than 5.1 and improvement of
greater than 1.2. Low disease activity was defined as DAS28 of less than 3.2 and remission as DAS28 of less than 2.6. In our previous study,7 adverse reactions with causality to RTX were collected. During this study, all adverse events (AEs) were collected for the whole follow-up period including the time after RTX discontinuation, because of update in reporting guidelines. Physicians were asked to assess seriousness of the event (nonserious/serious) as well as the causality of the event to RTX. Descriptive statistics, such as medians and ranges, were used to describe patient demographics and treatment responses. Treatment responses were also evaluated using Wilcoxon signed rank (within group), Wilcoxon rank sum (between group comparisons), and χ2 tests when appropriate.
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)10 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
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jclinrheum.com
25
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
Valleala et al
TABLE 1. Patient Demographics at Treatment Onset
Patients Disease duration: median (range), y Age, median (range), y Gender female/male (%) Seropostitive/seronegative (%) No. prior DMARDs: median (range) DMARD combination: yes/no FIN-RACo combination: yes/no No. prior biologics: median (range) 0 1 2 3–4
All
Cohort 1
Cohort 2
151 14.5 (0–47) 59 (24–84) 75/25 (%) (75%/25%) 89/11 (%) (89%/11%) 6 (1–12) 140/10a 56/47a 1 (0–4) 42 (28%) 37 (24%) 40 (26%) 32 (21%)
56 14 (2–47) 57 (24–84) 80/20 (%) 88/12 (%) 7 (1–12) 48/8 7/5a 2 (0–4) 14 (25%) 13 (23%) 9 (16%) 20 (36%)
95 15 (0–45) 60 (25–81) 72/28 (%) 91/9 (%) 5 (1–10) 92/2a 49/42a 1 (0–4) 28 (29%) 24 (25%) 31 (33%) 12 (13%)
a
For remaining patients information was missing.
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)
TABLE 2. Disease Status at Baseline and After the First and Second RTX Treatment Coursesa After Treatment Course BL Patients DAS28 0 Prior biologics (n = 36/35/23) 1 Prior biologics (n = 36/35/23) >1 Prior biologics (n = 62/54/44) Patient's global assessment Physician’s assessment of disease activity Patient’s assessment of pain (visual analog scale 0–100) Health Assessment Questionnaire score ESR, mm/h CRP, mg/L Swollen joint count 28 Swollen joint count 54 Tender joint count 28 Tender joint count 53
125 5.4 5.2 5.3 5.7 60.5 47 60 1.25 34 24 7 9 6 10
(0.5–8.6) (2.2–7.3) (2.6–7.3) (0.5–8.6) (0–100) (5–89) (4–100) (0–2.75) (2–114) (1–174) (0–24) (0–35) (0–26) (0–35)
1st 113 3.5 3.1 3.2 3.5 30 18 30 1 14 5.9 1 2 1 2
(0.6–6.6) (0.6–6.0) (1.4–4.4) (0.7–6.6) (0–100) (0–66) (0–100) (0–2.63) (2–74) (0.3–97) (0–18) (0–19) (0–17) (0–25)
2nd 105 3.1 2.7 2.8 3.0 26 18 25 1 10 4.4 0 1 1 1
(0.1–6.5) (1.3–5.4) (0.8–4.5) (0.1–6.5) (0–100) (0–55) (0–100) (0–2.9) (1–57) (0–48) (0–11) (0–14) (0–25) (0–35)
Values are median (range). a Analysis includes all patients with DAS28 values available at a given time point. For posttreatment analysis, the lowest DAS28 value before the next treatment was used. Parameters other than DAS28 were analyzed if information on more than 95% of the patients was available.
26
www.jclinrheum.com
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
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
Long-Term Experience With Rituximab in RA
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). 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
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.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jclinrheum.com
27
Valleala et al
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
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. 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
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.
28
www.jclinrheum.com
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
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.
DISCUSSION We report an observational study of 151 RA patients refractory to or with contraindications to multiple DMARDs and biological therapies who were treated with RTX according to local standard of care. In our cohort, the number of previous DMARDs was high compared with a previously reported large observational cohort form 10 European registries (6 vs 2.6).11 The high number of failed traditional DMARDs is attributable to the widely used treatment strategy in Finland to combine several DMARDs in early disease. Also, the number of previous biological agents was somewhat higher than in the report based on the CERRERA database.11 In Finland, only biological agents administered subcutaneously are reimbursed by National Insurance Institute, whereas hospitals have to pay for biological agents administered intravenously. This economical channeling may explain why the treating physician may in some instances switch to a second or even third TNF-blocking agent when the previous drug(s) with this mode of action have already failed. Consistent with observations made in other patient populations,11–13 seropositive RA patients achieved significantly greater reductions in the DAS28 score after the first RTX course
Long-Term Experience With Rituximab in RA
than seronegative patients. In the small subset of RA patients who were both rheumatoid factor and cyclic citrullinated peptide antibodies negative, the treatment response was modest and did not reach statistical significance. Similar to our previous study,7 concomitant treatment with DMARDs other than MTX yielded equally good response to RTX compared with comedication with MTX. In most cases, RA patients who had responded to the first treatment course continued to respond well to subsequent courses of RTX. In recently published observational studies, lower number of previously failed anti–TNF-α agents was associated with a better response to RTX. Reportedly, the lack of response to 2 or more anti–TNF-α agents indicates resistance to treatment in general.11,12 In contrast, the number of failed TNF-α inhibitors did not predict the DAS28 change in response to RTX in the present study cohort. However, most RA patients in this cohort can be judged as refractory to treatment irrespective of the number of previously failed anti-TNFs because the median number of failed DMARDs in this study was high (6). The treatment intervals were somewhat longer than reported in a recent open-label study or in a long-term extension study (8.5 to 9 vs 11–13 months in this study).14,15 The Finnish guideline for RTX therapy in RA advises consideration of retreatment after 6 months in initial responders who have considerable residual disease activity (DAS28 > 3.2). However, in the present cohort, this approach led to delayed RTX retreatment and disease flare in a significant proportion of patients. Recent evidence shows that the more aggressive “treat to target” approach for RTX treatment leads to more effective disease management without compromised safety profile compared with treatment as-needed (PRN) strategy.3–5,16 Thus, a fixed retreatment at 6 months, at least, after the first and second courses in patients who are not in remission (DAS28 > 2.6) would probably give a better long-term outcome. In line with previous experience, RTX was generally well tolerated over multiple treatment courses. No new safety signals were observed. Only 11 patients (7.2%) discontinued RTX because of AEs, and 2 serious infections with causality to RTX were reported. Moreover, the most frequently reported reason to choose RTX as a biological therapy was the increased risk of infections (in 28% of cases). This figure was even higher in the patients who received RTX as their first biological therapy. Our study has some limitations. At the time of this study, immunoglobulin G was not routinely monitored before each RTX retreatment. The lack of immunoglobulin G data is a drawback when evaluating the long-term safety of RTX. Similar to all observational studies, this study may suffer from expectation bias. Moreover, we used the lowest recorded posttreatment DAS28 value in each cycle for response evaluation as the timing of the follow-up visit varied. These factors together may lead into an overestimation of response rates after RTX therapy. Missing data are another concern in observational studies. All parameters needed to calculate the DAS28 score were available for approximately 70% of the patients in each RTX course. The missing values were, however, considered to have occurred at random, which should reduce the potential bias caused by exclusion of patients without calculable DAS28 scores from analyses. In line with observations from the extension of controlled trials and other open-label cohorts, repeated courses of RTX were generally well tolerated and produced sustained efficacy in RA patients who had responded to the first treatment course. However, the PRN approach used in this study cohort led to delayed RTX retreatment and disease flare in a significant proportion of patients. Thus, a regular retreatment every 6 months, at least, after the first 2 treatment courses in patients who are not in remission could allow better control of disease activity. Our results strengthen prior observations that seropositive RA patients
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jclinrheum.com
29
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
Valleala et al
demonstrate a more robust response to RTX compared with the seronegative cases. ACKNOWLEDGMENT The authors thank the study site personnel who contributed to this study. Data management, statistical analysis, and first draft of the materials and methods as well as results section were done at the direction and under the supervision of the authors by 4Pharma personnel Teppo Huttunen, Elina Tenhunen, and Christian Rummey. Their contribution for the manuscript is greatly appreciated. REFERENCES 1. Hochberg MC, Lebwohl MG, Plevy SE, et al. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum. 2005;34:819–836. 2. Kievit W, Fransen J, Adang EM, et al. Long-term effectiveness and safety of TNF-blocking agents in daily clinical practice: results from the Dutch Rheumatoid Arthritis Monitoring register. Rheumatology. 2011;50: 196–203. 3. Mease PJ, Cohen S, Gaylis NB, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE Trial. J Rheumatol. 2010;37:917–927. 4. Vander Cryssen B, Durez P, Westhovens R, et al. The Belgian MIRA (MabThera In Rheumatoid Arthritis) registry: clues for the optimization of rituximab treatment strategies. Arthritis Res Ther. 2010;12:R169. 5. Emery P, Mease PJ, Rubbert-Roth A, et al. Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis. Rheumatology. 2011;50:2223–2232. 6. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324. 7. Valleala H, Korpela M, Möttönen T, et al. Rituximab therapy in patients with rheumatoid arthritis refractory or with contraindication to anti-tumour
30
www.jclinrheum.com
necrosis factor drugs: real-life experience in Finnish patients. Scand J Rheumatol. 2009;38;323–327. 8. Prevoo ML, Van’t Hof MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:44–48. 9. Van Gestel AM, Prevoo ML, Van’t Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organisation/International League Against Rheumatism criteria. Arthritis Rheum. 1996;39:34–40. 10. Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet. 1999;353:1568–1573. 11. Chatzidionysiou K, Lie E, Nasonov E, et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann Rheum Dis. 2011;70:1575–1580. 12. Narvaez J, Díaz-Torné C, Ruiz JM, et al. Predictors of response to rituximab in patients with active rheumatoid arthritis and inadequate response to anti-TNF agents or traditional DMARDs. Clin Exp Rheumatol. 2011;29:991–997. 13. Soliman MM, Hyrich KL, Lunt M, et al. British Society for Rheumatology Biologics Register. Effectiveness of rituximab in patients with rheumatoid arthritis: observational study from the British Society for Rheumatology Biologics Register. J Rheumatol. 2012;39:240–246. 14. Haraoui B, Bokarewa M, Kallmeyer , et al. RESET Investigators. Safety and effectiveness of rituximab in patients with rheumatoid arthritis following an inadequate response to 1 prior tumor necrosis factor Inhibitor: the RESET Trial. J Rheumatol. 2011;38:2548–2556. 15. Keystone E, Fleischmann R, Emery P, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis. An open-label extension analysis. Arthritis Rheum. 2007;56:3896–3908. 16. Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:909–920.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Long-Term Real-Life Experience With Rituximab in Adult Finnish Patients With Rheumatoid Arthritis Refractory or With Contraindication to Anti–Tumor Necrosis Factor Drugs Heikki Valleala, MD, PhD,* Markku Korpela, MD, PhD,† Tuija Hienonen-Kempas, MSc, PhD,‡ Kai Immonen, MD, PhD,§ Jukka Lähteenmäki, MD,§ Tea Uusitalo, MD,║ Riitta Komulainen, MD,¶ Timo Möttönen, MD, PhD,# and Pekka Hannonen, MD, PhD** Objective: The objective of this study was to evaluate the long-term safety and efficacy of repeated rituximab (RTX) infusions in the treatment of rheumatoid arthritis in daily clinical practice in Finland. Methods: Data were collected from the medical records of a total of 151 patients with rheumatoid arthritis treated with RTX and followed up for at least 12 months after the treatment onset. Change in the 28-joint Disease Activity Score (DAS28), European League Against Rheumatism response criteria and proportions of patients reaching disease remission (DAS28 < 2.6) or low disease activity (DAS28 < 3.2) were used to assess the clinical response. Results: Of the 151 patients 128 received 2 courses, 76 received 3 courses, and 42 received 4 courses of RTX. The mean time to retreatment for the first 4 courses varied between 11 and 13 months. Median DAS28 decreased from 5.4 (0.5–8.6) to 3.3 (0.6–6.6) after the first course. After the second treatment course, the DAS28 was 3.1 (range, 0.1–6.5). The From the *Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki; †Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Tampere; ‡Roche Finland, Espoo; §Department of Medicine, North Karelia Central Hospital, Joensuu; ║Department of Internal Medicine, Kanta-Häme Central Hospital, Hämeenlinna Regional Hospital, Hämeenlinna; ¶Department of Internal Medicine, Kanta-Häme Central Hospital, Riihimäki Regional Hospital, Riihimäki; #Department of Medicine, Division of Rheumatology, Turku University Hospital, Turku; and **Department of Medicine, Jyväskylä Central Hospital, Jyväskylä, Finland. This study was sponsored by Roche Finland. H.V. has received payment form Roche for collecting study data, is a paid consultant and advisory board member for Roche, and has received payment for lectures and meeting expenses from Roche. M.K. is a paid consultant and advisory board member for BMS, GSK, MSD, Roche, UCB Pharma; has received payment for fees for participation in review activities and for travel expenses from Roche and has received payment for lectures from Abbott, GSK, MSD, Pfizer, and Roche and for meeting expenses from Abbott, GSK, Jansen, MSD, and Pfizer. T.H.-K. is a Roche employee, participates to a monthly Roche stock purchase program, and has received payment for a lecture from Pharma Industry Finland. T.M. has received payment for participation in review activities from Roche; is a paid consultant for Roche, MSD, and Pfizer; has received payment for lectures from Abbvie, Amgen, BMS, GSK, MSD, Pfizer, Roche, and UCB; has received payment for development of educational presentations from Pfizer, Abbvie, and AstraZeneca; and is a paid advisory board member for Abbot, Amgen, Lilly, MSD, Pfizer, Roche, UCB, and AstraZeneca, Servier. P.H. is a paid advisory board member for Roche and a paid consultant for Roche, MSD, and Pfizer; has received support for travel to meetings from Roche and payment for expert testimony from Roche and MSD; has received payment for lectures form Roche, MSD, Pfizer, Abbvie, and AstraZeneca; has received payment for development of educational presentations from MSD; Pfizer, Abbvie, and AstraZeneca; and has received payment for meeting expenses from several companies including Roche, Abbvie, Actelion, MSD, Pfizer, BMS, and UCB. K.I. is a paid advisory board member for Roche and has received support for travel to meetings and grant support from Roche. J.L. has received grant support from Roche. T.U. and R.K. have nothing to declare. Correspondence: Heikki Valleala, MD, PhD, Helsinki University Central Hospital, PO Box 372, FIN-00029, HUS, Helsinki, Finland. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1076-1608/15/2101–0024 DOI: 10.1097/RHU.0000000000000166
24
www.jclinrheum.com
median precourse baseline DAS28 before the second and third courses were 4.6 (range, 1.7–7.8) and 4.24 (range, 1.7–7.2), respectively. The number of previously failed tumor necrosis factor inhibitors did not predict response to RTX in this patient cohort with extensive use of previous disease-modifying antirheumatic drugs (median = 6). Conclusions: The treatment as-needed regimen used in this study cohort led to delayed RTX retreatment and disease flare in a significant proportion of patients. A regular retreatment every 6 months, at least, after the first 2 treatment courses in patients who are not in remission could allow better control of disease activity. Key Words: rituximab, rheumatoid arthritis, observational, long-term, effectiveness (J Clin Rheumatol 2015;21: 24–30)
R
ituximab (RTX) in combination with methotrexate (MTX) is approved in Finland for the treatment of severe active rheumatoid arthritis (RA) in patients who have not responded to conventional disease-modifying antirheumatic drugs (DMARDs) and to at least 1 anti–tumor necrosis factor α (anti–TNF-α) therapy or are intolerant to anti–TNF-α’s. The need for treatment beyond TNF-α inhibitors is evident because 25% of patients treated with TNF-α inhibitors either do not achieve adequate clinical response or are unable to tolerate them during the first year,1 and the 5-year cumulative drug survival for TNF-α inhibitors is approximately 50%.2 Rituximab has a unique mode of action and long dosing interval. The standard course of RTX is two 1000-mg intravenous infusions with interval of 2 weeks between each dose. The optimal treatment paradigm for RTX has not been definitely determined. However, there is increasing evidence that retreatment after 24 weeks in RA patients with residual disease activity leads to improved efficacy and tighter control of disease activity compared with retreating patients after they have experienced an obvious disease flare.3–5 The aim of the present study was to evaluate the long-term safety and efficacy of repeated RTX treatments in daily clinical practice.
MATERIALS AND METHODS This observational study aimed to follow up adult patients with RA treated with RTX in a routine clinical setting in Finland from April 2005 to December 2011. The patients included in these analyses had been treated according to local standard of care, and, for example, visit intervals were not fixed. Data were collected from medical records of a total of 151 patients fulfilling the American College of Rheumatology criteria for RA6 and treated with RTX. Our data partially extend the earlier report by Valleala et al7 with longer follow-up times on some patients (cohort 1, n = 56, 37%), but include also data of new patients (cohort 2, n = 95, 63%). Patient distribution during the study course is presented in Figure 1. The shortest follow-up period was set to at least 1 year from the initiation of RTX therapy. Patient's written informed
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
Long-Term Experience With Rituximab in RA
FIGURE 1. Flowchart of patient distribution during the study.
consent was obtained before data collection was initiated. Patients were coded, and the collected data were anonymous. Approval for the study was obtained from the ethical review board of the Hospital District of Helsinki and Uusimaa and by the ethical committees of all 7 participating hospitals. The information collected included the previous usage of conventional DMARDs and biologics. In addition, concomitant chronic diseases or other factors affecting the choice of RTX therapy were documented. At the onset of RTX therapy and at subsequent follow-up and retreatment visits, data on erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), number of tender and swollen joints, Health Assessment Questionnaire score, and visual analog scale (0–100 mm) scores for patient’s assessment of pain and general health status, as well as physician’s assessment of disease activity, were collected. Follow-up information after discontinuation of RTX therapy was also obtained. All data were observational and collected when available from the hospital case records. Rituximab was administered on days 1 and 15 as 1000-mg intravenous infusions with intravenous methylprednisolone premedication. Upon a disease flare, a retreatment course of RTX was administered. For a small proportion of patients (n = 17), RTX therapy was initiated with 500 mg of RTX 2 weeks apart. Subsequently, the majority of these patients received retreatment with the 1000-mg dose of RTX. Treatment response after RTX therapy was defined according to European League Against Rheumatism response criteria8,9 at 3 months at the earliest. As the timing of the follow-up visits varied, we chose to use the lowest 28-joint Disease Activity Score (DAS28) value after each RTX course for efficacy analysis. Responses were calculated from the patients’ original baseline (BL) values to the indicated time point. Good response was defined as a DAS28 of less than 3.2 and DAS28 score improvement from BL of greater than 1.2. Moderate response was defined as 3.2 ≤ DAS28 ≤ 5.1 and improvement of 0.6 to 1.2, or DAS28 of greater than 5.1 and improvement of
greater than 1.2. Low disease activity was defined as DAS28 of less than 3.2 and remission as DAS28 of less than 2.6. In our previous study,7 adverse reactions with causality to RTX were collected. During this study, all adverse events (AEs) were collected for the whole follow-up period including the time after RTX discontinuation, because of update in reporting guidelines. Physicians were asked to assess seriousness of the event (nonserious/serious) as well as the causality of the event to RTX. Descriptive statistics, such as medians and ranges, were used to describe patient demographics and treatment responses. Treatment responses were also evaluated using Wilcoxon signed rank (within group), Wilcoxon rank sum (between group comparisons), and χ2 tests when appropriate.
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)10 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
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jclinrheum.com
25
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
Valleala et al
TABLE 1. Patient Demographics at Treatment Onset
Patients Disease duration: median (range), y Age, median (range), y Gender female/male (%) Seropostitive/seronegative (%) No. prior DMARDs: median (range) DMARD combination: yes/no FIN-RACo combination: yes/no No. prior biologics: median (range) 0 1 2 3–4
All
Cohort 1
Cohort 2
151 14.5 (0–47) 59 (24–84) 75/25 (%) (75%/25%) 89/11 (%) (89%/11%) 6 (1–12) 140/10a 56/47a 1 (0–4) 42 (28%) 37 (24%) 40 (26%) 32 (21%)
56 14 (2–47) 57 (24–84) 80/20 (%) 88/12 (%) 7 (1–12) 48/8 7/5a 2 (0–4) 14 (25%) 13 (23%) 9 (16%) 20 (36%)
95 15 (0–45) 60 (25–81) 72/28 (%) 91/9 (%) 5 (1–10) 92/2a 49/42a 1 (0–4) 28 (29%) 24 (25%) 31 (33%) 12 (13%)
a
For remaining patients information was missing.
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)
TABLE 2. Disease Status at Baseline and After the First and Second RTX Treatment Coursesa After Treatment Course BL Patients DAS28 0 Prior biologics (n = 36/35/23) 1 Prior biologics (n = 36/35/23) >1 Prior biologics (n = 62/54/44) Patient's global assessment Physician’s assessment of disease activity Patient’s assessment of pain (visual analog scale 0–100) Health Assessment Questionnaire score ESR, mm/h CRP, mg/L Swollen joint count 28 Swollen joint count 54 Tender joint count 28 Tender joint count 53
125 5.4 5.2 5.3 5.7 60.5 47 60 1.25 34 24 7 9 6 10
(0.5–8.6) (2.2–7.3) (2.6–7.3) (0.5–8.6) (0–100) (5–89) (4–100) (0–2.75) (2–114) (1–174) (0–24) (0–35) (0–26) (0–35)
1st 113 3.5 3.1 3.2 3.5 30 18 30 1 14 5.9 1 2 1 2
(0.6–6.6) (0.6–6.0) (1.4–4.4) (0.7–6.6) (0–100) (0–66) (0–100) (0–2.63) (2–74) (0.3–97) (0–18) (0–19) (0–17) (0–25)
2nd 105 3.1 2.7 2.8 3.0 26 18 25 1 10 4.4 0 1 1 1
(0.1–6.5) (1.3–5.4) (0.8–4.5) (0.1–6.5) (0–100) (0–55) (0–100) (0–2.9) (1–57) (0–48) (0–11) (0–14) (0–25) (0–35)
Values are median (range). a Analysis includes all patients with DAS28 values available at a given time point. For posttreatment analysis, the lowest DAS28 value before the next treatment was used. Parameters other than DAS28 were analyzed if information on more than 95% of the patients was available.
26
www.jclinrheum.com
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
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
Long-Term Experience With Rituximab in RA
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). 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
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.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jclinrheum.com
27
Valleala et al
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
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. 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
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.
28
www.jclinrheum.com
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
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.
DISCUSSION We report an observational study of 151 RA patients refractory to or with contraindications to multiple DMARDs and biological therapies who were treated with RTX according to local standard of care. In our cohort, the number of previous DMARDs was high compared with a previously reported large observational cohort form 10 European registries (6 vs 2.6).11 The high number of failed traditional DMARDs is attributable to the widely used treatment strategy in Finland to combine several DMARDs in early disease. Also, the number of previous biological agents was somewhat higher than in the report based on the CERRERA database.11 In Finland, only biological agents administered subcutaneously are reimbursed by National Insurance Institute, whereas hospitals have to pay for biological agents administered intravenously. This economical channeling may explain why the treating physician may in some instances switch to a second or even third TNF-blocking agent when the previous drug(s) with this mode of action have already failed. Consistent with observations made in other patient populations,11–13 seropositive RA patients achieved significantly greater reductions in the DAS28 score after the first RTX course
Long-Term Experience With Rituximab in RA
than seronegative patients. In the small subset of RA patients who were both rheumatoid factor and cyclic citrullinated peptide antibodies negative, the treatment response was modest and did not reach statistical significance. Similar to our previous study,7 concomitant treatment with DMARDs other than MTX yielded equally good response to RTX compared with comedication with MTX. In most cases, RA patients who had responded to the first treatment course continued to respond well to subsequent courses of RTX. In recently published observational studies, lower number of previously failed anti–TNF-α agents was associated with a better response to RTX. Reportedly, the lack of response to 2 or more anti–TNF-α agents indicates resistance to treatment in general.11,12 In contrast, the number of failed TNF-α inhibitors did not predict the DAS28 change in response to RTX in the present study cohort. However, most RA patients in this cohort can be judged as refractory to treatment irrespective of the number of previously failed anti-TNFs because the median number of failed DMARDs in this study was high (6). The treatment intervals were somewhat longer than reported in a recent open-label study or in a long-term extension study (8.5 to 9 vs 11–13 months in this study).14,15 The Finnish guideline for RTX therapy in RA advises consideration of retreatment after 6 months in initial responders who have considerable residual disease activity (DAS28 > 3.2). However, in the present cohort, this approach led to delayed RTX retreatment and disease flare in a significant proportion of patients. Recent evidence shows that the more aggressive “treat to target” approach for RTX treatment leads to more effective disease management without compromised safety profile compared with treatment as-needed (PRN) strategy.3–5,16 Thus, a fixed retreatment at 6 months, at least, after the first and second courses in patients who are not in remission (DAS28 > 2.6) would probably give a better long-term outcome. In line with previous experience, RTX was generally well tolerated over multiple treatment courses. No new safety signals were observed. Only 11 patients (7.2%) discontinued RTX because of AEs, and 2 serious infections with causality to RTX were reported. Moreover, the most frequently reported reason to choose RTX as a biological therapy was the increased risk of infections (in 28% of cases). This figure was even higher in the patients who received RTX as their first biological therapy. Our study has some limitations. At the time of this study, immunoglobulin G was not routinely monitored before each RTX retreatment. The lack of immunoglobulin G data is a drawback when evaluating the long-term safety of RTX. Similar to all observational studies, this study may suffer from expectation bias. Moreover, we used the lowest recorded posttreatment DAS28 value in each cycle for response evaluation as the timing of the follow-up visit varied. These factors together may lead into an overestimation of response rates after RTX therapy. Missing data are another concern in observational studies. All parameters needed to calculate the DAS28 score were available for approximately 70% of the patients in each RTX course. The missing values were, however, considered to have occurred at random, which should reduce the potential bias caused by exclusion of patients without calculable DAS28 scores from analyses. In line with observations from the extension of controlled trials and other open-label cohorts, repeated courses of RTX were generally well tolerated and produced sustained efficacy in RA patients who had responded to the first treatment course. However, the PRN approach used in this study cohort led to delayed RTX retreatment and disease flare in a significant proportion of patients. Thus, a regular retreatment every 6 months, at least, after the first 2 treatment courses in patients who are not in remission could allow better control of disease activity. Our results strengthen prior observations that seropositive RA patients
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jclinrheum.com
29
JCR: Journal of Clinical Rheumatology • Volume 21, Number 1, January 2015
Valleala et al
demonstrate a more robust response to RTX compared with the seronegative cases. ACKNOWLEDGMENT The authors thank the study site personnel who contributed to this study. Data management, statistical analysis, and first draft of the materials and methods as well as results section were done at the direction and under the supervision of the authors by 4Pharma personnel Teppo Huttunen, Elina Tenhunen, and Christian Rummey. Their contribution for the manuscript is greatly appreciated. REFERENCES 1. Hochberg MC, Lebwohl MG, Plevy SE, et al. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum. 2005;34:819–836. 2. Kievit W, Fransen J, Adang EM, et al. Long-term effectiveness and safety of TNF-blocking agents in daily clinical practice: results from the Dutch Rheumatoid Arthritis Monitoring register. Rheumatology. 2011;50: 196–203. 3. Mease PJ, Cohen S, Gaylis NB, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE Trial. J Rheumatol. 2010;37:917–927. 4. Vander Cryssen B, Durez P, Westhovens R, et al. The Belgian MIRA (MabThera In Rheumatoid Arthritis) registry: clues for the optimization of rituximab treatment strategies. Arthritis Res Ther. 2010;12:R169. 5. Emery P, Mease PJ, Rubbert-Roth A, et al. Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis. Rheumatology. 2011;50:2223–2232. 6. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324. 7. Valleala H, Korpela M, Möttönen T, et al. Rituximab therapy in patients with rheumatoid arthritis refractory or with contraindication to anti-tumour
30
www.jclinrheum.com
necrosis factor drugs: real-life experience in Finnish patients. Scand J Rheumatol. 2009;38;323–327. 8. Prevoo ML, Van’t Hof MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:44–48. 9. Van Gestel AM, Prevoo ML, Van’t Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organisation/International League Against Rheumatism criteria. Arthritis Rheum. 1996;39:34–40. 10. Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet. 1999;353:1568–1573. 11. Chatzidionysiou K, Lie E, Nasonov E, et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann Rheum Dis. 2011;70:1575–1580. 12. Narvaez J, Díaz-Torné C, Ruiz JM, et al. Predictors of response to rituximab in patients with active rheumatoid arthritis and inadequate response to anti-TNF agents or traditional DMARDs. Clin Exp Rheumatol. 2011;29:991–997. 13. Soliman MM, Hyrich KL, Lunt M, et al. British Society for Rheumatology Biologics Register. Effectiveness of rituximab in patients with rheumatoid arthritis: observational study from the British Society for Rheumatology Biologics Register. J Rheumatol. 2012;39:240–246. 14. Haraoui B, Bokarewa M, Kallmeyer , et al. RESET Investigators. Safety and effectiveness of rituximab in patients with rheumatoid arthritis following an inadequate response to 1 prior tumor necrosis factor Inhibitor: the RESET Trial. J Rheumatol. 2011;38:2548–2556. 15. Keystone E, Fleischmann R, Emery P, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis. An open-label extension analysis. Arthritis Rheum. 2007;56:3896–3908. 16. Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:909–920.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
