Adsorptive granulocyte/monocyte apheresis for the treatment of refractory rheumatoid arthritis: an open pilot multicentre trial

R. Sanmartí1, S. Marsal2, J. Valverde3, E. Casado4, R. Lafuente5, N. Kashiwagi6, J.-R. Rodriguez-Cros1, A. Erra2, D. Reina3 and J. Gratacós4

1 Hospital Clínic, IDIBAPS, Rheumatology, 2 Hospital General i Universitari Vall d'Hebrón, Rheumatology, 3 Hospital Universitari de Bellvitge, Rheumatology, L'Hospitalet de Llobregat, 4 Corporació Parc Taulí, Rheumatology, Sabadell, 5 Otsuka Pharmaceutical SA, Barcelona, Spain and 6 Otsuka Frankfurt Research Institute GmbH, Frankfurt, Germany.

Correspondence to: R. Sanmartí. E-mail: sanmarti{at}clinic.ub.es


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To assess the efficacy and safety of adsorptive granulocyte and monocyte apheresis (GCAP) in patients with refractory rheumatoid arthritis (RA).

Methods. Patients with active and refractory RA were treated with weekly GCAP sessions using a column filled with acetate beads (Adacolumn®) over five consecutive weeks. Clinical assessments and response to therapy were analysed at weeks 5, 7, 12 and 20 in an open multicentre trial. The primary outcome measure of clinical response was 20% improvement in the American College of Rheumatology criteria (ACR20) at week 20. EULAR (European League Against Rheumatism) response criteria, based on the disease activity score for 28 joints (DAS28) and disability using the Health Assessment Questionnaire (HAQ), were also assessed.

Results. Of 27 patients, 81.5% were women with mean disease duration of 14.4 yr. The mean number of previous disease-modifying antirheumatic drugs (DMARDs) was 3.7, and 48.1% of patients had previously failed on biologicals. On an intention-to-treat basis, 40.7% of patients achieved an ACR20 and 44.4% a therapeutic EULAR response at week 20. These percentages were 50 and 54.5% in 22 patients who completed the trial. In the 10 completers who had previously failed on biologicals, an ACR response was achieved in four patients (ACR20, two; ACR50, one; ACR70, one). A significant decrease was recorded in different ACR response components, including the tender joint and swollen joint counts, pain score and patient and physician global disease assessments, as well as the DAS28 index; most of them improved after week 5. ESR and CRP, but not the HAQ score, had decreased significantly at week 20. The treatment was well tolerated and only one serious adverse event related to the study procedure was documented (sepsis due to a catheter infection).

Conclusions. GCAP treatment led to significant clinical improvement in a subset of patients with RA who had failed to respond to DMARDs or biologicals. Further large, placebo-controlled studies are warranted to fully assess the therapeutic value of GCAP for refractory RA.

KEY WORDS: Rheumatoid arthritis, Apheresis


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is characterized by symmetrical erosive synovitis that may result in progressive joint destruction and significant disability [1]. Several disease-modifying anti-rheumatic drugs (DMARDs) are available for controlling disease activity, but these medications rarely induce stable clinical remission [2]. Moreover, adverse events or loss of efficacy do not permit DMARD treatment for a long period in a significant proportion of patients [3]. In recent years, biological therapy, especially the TNF-{alpha} antagonists (infliximab, etanercept, adalimumab), has demonstrated significant efficacy in RA refractory to DMARDs, but concerns about costs and safety in the long term limits their use [4, 5]. Further, up to 30% of RA patients treated with TNF blocking agents discontinue this therapy after 1 yr, due to inefficacy or adverse events [6]. Therefore, the search for more effective treatments for patients who do not respond to DMARDs or biologicals is warranted.

The Adacolumn® is a selective granulocyte, monocyte/macrophage (GCAP) apheresis medical device containing cellulose acetate beads as adsorptive leucocytapheresis carriers. GCAP has shown significant efficacy in patients with inflammatory bowel diseases, such as ulcerative colitis [7, 8]. Likewise, open studies in Japan reported that GCAP improved clinical symptoms in patients with RA [9, 10]. Since no studies have been performed so far in Caucasian RA populations and using standard measures of response to therapy, we undertook this 20-week open multicentre pilot trial of GCAP in active refractory RA at four centres in Spain.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Patients with a diagnosis of adult RA, as defined by the American College of Rheumatology (ACR) [11] were included. Patients had to be at least 18 years old and were required to have an active disease, defined by ≥4 tender and swollen joints (of 28), and an elevation of C-reactive reactive protein (CRP) >20 mg/l or erythrocyte sedimentation rate (ESR) >30 mm/h. Additionally, patients were required to have failed on one or more DMARDs. DMARD treatment was kept stable for at least 6 weeks before entry and throughout the study. NSAIDs and prednisone (at a dose of up to 10 mg/day) were allowed; the dose was kept stable for at least 4 weeks before entry. Patients who had received biological therapy (infliximab, etanercept, adalimumab or anakinra) during the previous 2 months were excluded. Similarly, patients with serious cardiac and/or cerebral disease in the 6 months prior to the study entry or with a systemic infection were excluded. Absolute granulocyte count <2000/µl, haemoglobin <8 g/dl or platelets <50 000/µl were also reasons for exclusion.

Clinical and laboratory assessments
Clinical assessments were performed at entry and at weeks 5, 7, 12 and 20. The following clinical parameters were analysed: tender and swollen joint counts (28 joints) [12], global assessment of disease activity by physician (PhGA) and patient (PGA), pain using a 10 cm visual analogue scale, and disability using the Health Assessment Questionnaire (HAQ) [13]. Laboratory analysis, including ESR, CRP, complete blood cell count and blood chemistry with coagulation profiles, was performed at weeks 0, 1, 3, 5, 7, 12 and 20.

Measurement of clinical response
The primary efficacy end-point was the percentage of patients achieving the ACR criteria for 20% improvement in RA (ACR20) [14] at week 20. The proportion of patients with ACR50 (50% improvement) and ACR70 (70% improvement) was also determined. The European League Against Rheumatism (EULAR) response criteria, using the DAS28 score (details at www.das-score.nl), was also assessed. Adverse events were recorded at each visit.

Ethics
The study protocol was reviewed and approved by the institutional review board for ethics of clinical studies involving humans at each participating centre. Furthermore, prior to GCAP, informed consent was obtained from all patients verbally and in writing after they had been informed of the purpose of the study and the nature of the procedures involved. Patients were advised that they were free to withdraw from the study at any time without jeopardizing their subsequent care and treatment.

Apheresis procedure
Adacolumn® is a direct haemoperfusion type of leucocytapheresis device manufactured by Japan Immunoresearch Laboratories (Takasaki, Japan). The device column is a single-use (disposable) polycarbonate column with a capacity of about 335 ml, filled with 220 g cellulose acetate beads of 2 mm in diameter bathed in physiological saline as the column leucocytapheresis carriers. The carriers selectively adsorb granulocytes and monocytes/macrophages from the blood in the column [15, 16]. The beads have been reported [10] to adsorb up to 67% of granulocytes, 57% of monocytes and about 2% of lymphocytes from the peripheral blood passing through the column (Fc-gamma-R and complement receptor-bearing leucocytes). The GCAP course consisted a set of five sessions over 5 consecutive weeks. Duration of each session was 60 min, at a flow rate of 30 ml/min. Blood inlet and outlet were via suitable veins in the left and the right arms. Central venous catheterization was considered in selected cases. An anticoagulant needed to be added as continuous infusion during the apheresis.

Statistical analysis
Efficacy was evaluated using both intention-to-treat (ITT) and completer analysis. The ITT analysis included all patients who received at least one GCAP session. Patients who did not complete the intended five sessions prior to the primary efficacy time-point (week 20), irrespective of the reason, were considered as non-responders, even if they had responded. The completer analysis evaluated efficacy in those patients who completed all five GCAP sessions and the follow-up visits. Data for baseline vs subsequent time-points are compared for each assessment using the Wilcoxon signed rank test. Rate differences between groups were analysed with Fisher's exact test, while comparison between groups was done with the Mann–Whitney U-test. A P value <0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The demographic and clinical characteristics of 27 patients included in this study are presented in Table 1. Most patients had very advanced RA and had received multiple DMARDs. All but one patient had received two or more DMARDs, including methotrexate. Thirteen patients (48.1%) had received one or several biological drugs (infliximab, 9; etanercept, 8; adalimumab, 4; anakinra, 2), which were stopped due to adverse events or poor efficacy. At entry, the disease was very active, with a mean number of tender and swollen joints of 13.7±7.6 and 10.1±4.5 (of 28), respectively. A total of 24 patients had severe active disease (DAS28>5.1) and 22 had significant disability (HAQ score>1.5). Twenty-two of 27 patients completed the trial. Three patients were withdrawn due to insufficient control of arthritis symptoms; one patient due to problems with venous access and catheter infection, and one patient due to protocol violation at week 12.


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TABLE 1. Demographic and clinical characteristics of the 27 patients at study entry

 
The course of different clinical and biological parameters of the disease activity is shown in Fig. 1 at different time points up to week 20. Most of the disease activity parameters improved significantly. This improvement was seen at week 5 (last GCAP session) and was maintained during the 20 weeks of follow-up. Mean reductions in the number of tender and swollen joints of 49.9 and 47.7%, respectively, were observed at week 20 compared with baseline values. The reductions for ESR and CRP were 13.7 and 9.7%, respectively. The percentage of patients with severe disease activity (DAS28>5.1) declined from 88.8% at study entry to 47.6% at week 20. The mean DAS28–ESR score was 6.68±0.88 at entry and 5.21±1.22 at week 20 (P<0.0001). Similar results were obtained for DAS28–CRP (6.15±0.84 vs 4.69±1.17, P<0.0001). The values for pain assessment, PhGA and PGA, also improved significantly during the study period. A reduction in the HAQ was observed, but it did not reach statistical significance.



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FIG. 1. Evolution of clinical and biological disease activity parameters. (A) Changes in tender and swollen joint count. (B) Changes in patient's and physician's global assessment of disease activity. (C) Changes in DAS 28-4 ESR and DAS 28-4 CRP. (D) Changes in C-reactive protein. (E) Changes in erythrocyte sedimentation rate. (F) Changes in health assessment questionnaire score. Change from baseline (week 0) by Wilcoxon signed rank test (*P<0.05; **P<0.01; ***P<0.001). Data are median values.

 
A total of 11 patients achieved the primary efficacy objective (ACR20 at week 20), 40.8% in an ITT analysis and 50% in patients who completed the study. These percentages were 30.8 and 40%, respectively, in the subgroup of patients who had previously been treated with biologicals (Table 2). At weeks 5 and 12, the percentages of patients achieving an ACR20 response were 36 and 39%, respectively. In four of 10 patients who completed the trial and previously had failed on biologicals, an ACR response was achieved at week 20 (ACR20, two patients; ACR50, one patient; ACR70, one patient). The DAS28–EULAR response at week 20 was 44.4 (by ITT) and 54.5% (per protocol); the response was classified as moderate in all cases.


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TABLE 2. ACR20 responses at week 20 in the whole group and in patients previously treated with biologicals

 
When assessing the clinical response according to different baseline subgroups, 70% of patients with high serum CRP values (>40 mg/l) at baseline showed an ACR20 improvement at week 20 compared with 33.3% in patients with lower CRP values. Also, the percentage of ACR20 responders was higher in patients with lower disability (HAQ<1.8) at entry (75 vs 35.7%). However, the differences did not reach statistical significance. No differences were observed in the percentage of ACR20 responses when these were analysed in accordance with the other baseline parameters analysed. The treatment was well tolerated and only one serious adverse event related to the GCAP procedure was observed: a case of sepsis due to the central venous catheter manipulation. The patient was withdrawn from the study after the fourth GCAP session and was treated with antibiotics, with complete recovery. Two other serious events were reported (one cardiovascular event and one acute pyelonephritis) that were judged not to be related to the study treatment. Laboratory examinations showed no significant changes in haematological parameters, renal function or liver function after the treatment.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This is the first open study of GCAP with acetate beads in Caucasian RA patients and using standard measures of response to therapy. The results of the present study suggest that GCAP is effective in the treatment of RA that is refractory to conventional DMARDs or biologicals. The disease activity parameters improved significantly after the GCAP treatment. This improvement was observed after five sessions (week 5) and was sustained until the end of the follow-up (week 20). The improvements were observed in both the clinical parameters of disease activity and the acute-phase reactants, although it was less pronounced in the latter and the mean DAS 28 score was still high at the end of the study (5.21±1.22). However, the percentage of patients with severe disease activity (DAS28>5.1) had decreased by 41% at week 20. A significant percentage of patients (40.7% in the ITT analysis) achieved an ACR20 response at week 20 and a similar percentage (44.4%) showed a therapeutic response according to the DAS28–EULAR criteria.

It is important to emphasize that the patients included in this study had very active RA that was refractory to multiple DMARDs (mean of about 4), the disease being advanced and disabling. Moreover, almost half of the patients had previously been treated with one or multiple TNF-{alpha} antagonists. Such patients are expected to show a poor therapeutic response [17]. Nonetheless, our results suggest a clinical benefit from GCAP in RA. This efficacy has been previously documented in open studies in a Japanese population using non-standardized methods to measure the clinical response [9, 10].

Other forms of apheresis have been proved to be effective in RA. In a double-blind sham-controlled study using the Prosorba column, 31.9% of patients with refractory RA achieved an ACR20 response compared with 11.4% of the placebo group [18]. Similarly, the Cellsorba column, which removes not only granulocytes and monocytes but also lymphocytes, has been proved to be effective in RA in a small placebo-controlled trial [19]. Obviously, one of the main limitations of our study is that it was an open study with a small sample size and a short follow-up period. Nevertheless, taking into account the severity of the patient population included, the rate of response seems unlikely to be explained by a placebo effect. An encouraging observation was that some of the patients who were previously treated with biologicals, but had failed, showed a clinical response to GCAP. When analysing possible baseline predictive factors of response, those patients with high CRP values and those with low HAQ showed a good trend in therapeutic response. These findings suggest that patients in whom the true synovial inflammation, rather than residual joint damage, plays a major role in arthritis symptoms are more likely to benefit from GCAP.

The exact mechanism of action of GCAP is not well understood yet. In an animal model of arthritis, this procedure demonstrated a significant reduction in the infiltration of leucocytes into the arthritic joints [20]. Ramlow et al. [21] reported that GCAP down-modulated the TNF-{alpha} and IL-1ß production capacities of leucocytes in a sham-controlled study in healthy subjects. Suppression of leucocyte production of several proinflammatory cytokines, including TNF-{alpha}, IL-1, IL-6 and IL-8, has also been described in ulcerative colitis after GCAP [7]. Similarly, the release of IL-1 receptor antagonist in the column outflow has been documented during the GCAP procedure [16].

Apheresis treatment was well tolerated and only one serious adverse event related to the study treatment was observed, in a patient treated via a central vein catheter. This was a sepsis, after which the therapy was stopped and the patient was treated with antibiotics; the patient recovered without lasting harm.

In summary, this open multicentre study suggests that adsorptive granulocyte and monocyte apheresis is effective in the treatment of a subgroup patients with RA that is refractory to DMARDs or biologicals. Since this therapy is safe and well tolerated, it could be an alternative treatment for patients with RA. However, long-term follow-up is required to determine the duration of the clinical response in order to maximize the best maintenance therapeutic strategy. Also, studies on the cost-efficacy of this therapeutic apheresis procedure are required. However, we concede that randomized controlled trials are necessary to fully assess the efficacy of GCAP in the treatment of RA.


    Acknowledgments
 
The authors thank Natalia Oudovenko of Otsuka Frankfurt Research Institute GmbH, Frankfurt for her excellent support as a study coordinator.

N.K. is a Senior Scientific Advisor of Otsuka Frankfurt Research Institute GmbH, Frankfurt, Germany.

Supplementary data

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    Supplementary data are available at Rheumatology Online.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 28 February 2005; revised version accepted 4 May 2005.



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