Evaluation of filtration leucocytapheresis for use in the treatment of patients with rheumatoid arthritis

Y. Ueki5, S. Yamasaki, Y. Kanamoto, T. Kawazu, M. Yano, K. Matsumoto, S. Miyake, Y. Tominaga, U. Iwamoto1, J. Suemitsu1, Y. Matsuno1, Y. Sizume2, Y. Takenaka2 and K. Eguchi3

Department of Internal Medicine, Sasebo Chuo Hospital, Sasebo,
1 Asahi Medical Research and Development Laboratory, Oita,
2 Asahi Medical Technical Department, Tokyo and
3 The First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives. To evaluate the efficacy of filtration leucocytapheresis (LCP) for rheumatoid arthritis (RA).

Methods. LCP was carried out three times, with 1 week separating each session, in 25 drug-resistant RA patients.

Results. During each session, 96, 98, 61, 84 and 8% of the granulocytes, monocytes, lymphocytes, platelets and erythrocytes, respectively, that entered the LCP filter were removed. The number of granulocytes, monocytes and lymphocytes in the peripheral blood significantly decreased during each session of LCP. However, there was no significant decrease in the number of circulating blood cells during the study period. On average, 110 x 108 granulocytes, 5.23 x 108 monocytes, and 20.5 x 108 lymphocytes were removed during LCP therapy. Assessment of RA before and after LCP showed a substantial and rapid improvement in the tender joints counts, swollen joint counts, and patient's and physician's assessments. No adverse reactions or complications were noted. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels decreased following LCP, although the change in the latter parameter was statistically insignificant. The concentrations of serum albumin, {gamma}-globulin, IgG, IgM, CH50 and rheumatoid factor titres did not change during or after LCP. Careful analysis indicated that 16 of 25 patients with RA showed >=20% improvement following LCP therapy.

Conclusions. Our results suggest that filtration LCP to remove leucocytes from the peripheral blood exerts an immunomodulatory effect in patients with RA.

KEY WORDS: Leucocytapheresis filter, Leucocytapheresis, Rheumatoid arthritis, Immunomodulation


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a chronic inflammatory disease with multiple articular and systemic manifestations, which are thought to be governed by immunological processes within the synovial tissue [1]. Synovitis of RA is characterized by extensive proliferation of synovial tissues and marked infiltration of chronic inflammatory cells into the joints [2]. Leucocytes migrate into the synovial tissue [3], where they may become involved in cellular interactions, which ultimately lead to the proliferation of synovial tissue, and cartilage destruction [2]. Plasmapheresis was first applied as a treatment for RA in 1963 [4]. Furthermore, depletion of lymphocytes has been used as an alternative to plasmapheresis in the treatment of certain immunological disorders, including RA [59]. The idea that lymphocyte depletion would ameliorate RA stems from early studies using thoracic duct drainage (TDD) [10].

Polyester fibre filters have been safely used during blood transfusions to remove leucocytes from stored blood as a preventive measure against possible side-effects [11]. Because the fine-diameter polyester fibre easily traps leucocytes and platelets, several investigators have employed it in a simple and practical device; a cylindrical leucocytapheresis (LCP) filter with an extracorporeal circulation unit [1214]. Kondoh et al. [12] reported that LCP using a cylindrical LCP filter once or twice weekly produced an immunomodulatory effect. Furthermore, a double-blind, placebo-controlled study by Hidaka et al. [15] has shown that filtration LCP is clinically beneficial in the treatment of RA. A cylindrical LCP filter is an alternative to TDD and LCP using a centrifuge method with the advantages that it can be performed easily and inexpensively. To our knowledge, the relationship between the clinical effectiveness of filtration LCP in RA and the number of leucocytes removed from the circulation has not been investigated previously. The present study was undertaken to investigate whether filtration LCP therapy results in improvement of the clinical condition in RA patients.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects
We studied 25 patients (six men and 19 women; mean age; 57.5 ± 2.6 [ ± standard deviation (S.D.)] yr, range 26–76 yr) who met the RA criteria of the American College of Rheumatology (ACR) [16]. Patients were randomly selected from a cohort of patients with active disease attending an out-patient clinic at the Department of Internal Medicine of Sasebo Chuo Hospital, Sasebo. Patients had to have active disease meeting at least three of four criteria [duration of morning stiffness >=45 min, >=6 swollen joints, >=6 tender joints, erythrocyte sedimentation rate (ESR) >=28 mm/h]. Of the 25 RA patients, all patients were taking non-steroidal anti-inflammatory drugs (NSAIDs), 14 patients prednisolone (2–5 mg/day), eight methotrexate (5–7.5 mg/week), eight bucillamine (100 mg/day), seven D-penicillamine (200 mg/day), six sulphasalazine (1.0 g/day), three auranofin (6 mg/day), and two actarit (300 mg/day). Fourteen patients were taking one disease-modifying anti-rheumatic drug (DMARD), seven were taking two different DMARDs, two were taking three. The number of patients with DMARD failures prior to LCP therapy was 14 and the average duration of stability for the DMARDs taken by the patients was 16 months. Patients continued to receive the DMARDs throughout the study period in the same doses given previously. The medications for each patient were unchanged for at least 3 months prior to the initiation of the study and were maintained without change throughout the study. The characteristics of the patients are summarized in Table 1Go. The course of LCP treatment was selected because all patients we have treated previously with LCP in an uncontrolled fashion have shown a positive response by that time. The study protocol was approved by the Human Ethics Review Committee of Nagasaki University School of Medicine and a signed consent form was obtained from each subject.


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TABLE 1. Characteristics of RA patients

 

Blood samples
Blood samples were withdrawn from the forearm veins before the start of every LCP therapy and 2 and 4 weeks after the end of LCP. To evaluate the removal of blood cells by the LCP filter (CS-100), heparinized peripheral blood samples were collected from the inlet and outlet of the cylindrical case housing the LCP filter, before and after filtration of 0, 750, 1500 and 3000 ml during each session of LCP.

LCP procedure
Treatment was conducted in the out-patient department under aseptic conditions. The LCP filter consists of a porous cylinder with two non-woven sterile polyester fibre fabric filters (CS-100; Asahi Medical Co., Tokyo, Japan; filter average fibre diameter 2.6 µm; profilter average fibre diameter 10–40 µm) spirally wound around the cylinder. Venous blood passes through the profilter and filter layers inside the cylinder (Fig. 1Go), and leucocytes are trapped in the fibre layer. The total extracorporeal blood volume was 200 ml. Blood passes through the fine polyester fibre layer into the cylinder, and leucocytes (including granulocytes, monocytes, and lymphocytes) are trapped by the fibre layer. In each apheresis procedure, a total of 3000 ml of whole blood was filtered and returned to the patient. Access to the circulation for the outlet and return lines was achieved by cannulating the peripheral veins using 18-gauge needles. The cylindrical filter was mounted on the machine for extracorporeal circulation (Plasauto 1000; Asahi Medical Co.) and was perfused with blood at a flow rate of 30–50 ml/min for 60–90 min using a roller pump. Nafamostat mesilate (a protease inhibitor), which inhibits the activity of coagulation factors and platelet aggregation, was continuously infused into the outlet line at a rate of 50 mg/h. In the present study, LCP was carried out three times, once a week, in each patient with a period of 1 week separating each treatment session.



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FIG. 1. Schematic diagram of the LCP filter (CS-100) system used.

 

Number of removed leucocytes and platelets
To estimate the number of removed blood cells, a complete blood cell count, leucocyte differential count, platelet and erythrocyte counts were performed after filtration of 0, 750, 1500 and 3000 ml in each LCP session. The percentage and absolute number of removed blood cells were calculated using the following formulae [12]

where In is the cell count at the inlet before filtration of n ml, and On is the cell count at the outlet after filtration of n ml.

Total number of cells removed during each LCP





where In is the cell count at the inlet before filtration of n ml, and On is the cell count at the outlet after filtration of n ml.

Clinical assessment
The clinical response was assessed according to the ACR core set of outcome measures for RA trials including the duration of morning stiffness (min) [17]. The following definitions of improvement were selected: 20% improvement in tender and swollen joint counts and 20% improvement in three of the five remaining ACR core set measures; patient's and physician's global assessments, pain, disability, and an acute phase reactant (ACR 20% response). Improvements of at least 50% in the continuous variables were also assessed (ACR 50% response). These assessments were carried out before each treatment, 2 and 4 weeks after the end of the last LCP session. All patients were evaluated by the same physician. Neither the examining physician nor the patient was informed of the laboratory findings.

Laboratory examination
In addition to the blood tests described above, the following tests were performed before each session of LCP therapy: ESR, C-reactive protein (CRP), serum albumin, {gamma}-globulin, IgG, IgM, CH50 and IgG type rheumatoid factor (the latex fixation test).

Statistical analysis
Data were expressed as mean ± standard error of the mean (S.E.M). Differences between groups were examined for statistical significance using Student's t-test or the paired t-test. A P value less than 0.05 denoted the presence of a statistically significant difference.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Changes in the percentage of removed peripheral blood cells during LCP therapy
We first examined the percentage of granulocytes, monocytes, lymphocytes, platelets and erythrocytes removed in each of the three sessions of LCP therapy at successive filtration volumes (750, 1500 and 3000 ml). As shown in Fig. 2Go, at 750 ml, 90 ± 3.7% of granulocytes, 100 ± 0.1% of monocytes, and 85 ± 1.8% of lymphocytes that entered the filter were removed in the first LCP. Furthermore, 97 ± 1.3% of platelets and 9 ± 0.9% of erythrocytes that entered the filter were also removed. During the first LCP, the percentage of removed granulocytes and monocytes was the same after filtration of different volumes of blood. However, the percentage of removed lymphocytes and platelets was significantly less at 1500 and 3000 ml (Fig. 2). Similar changes in the percentage of removed blood cells were also observed during the second and third sessions of LCP therapy. In general, the average percentages of removed cells during a single session of LCP were 96% for granulocytes, 98% for monocytes, 61% for lymphocytes, 84% for platelets and 8% for erythrocytes.



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FIG. 2. Changes in the percentage of removed blood cells during each session and course of LCP therapy. Values represent the mean ± S.E.M. of all subjects (n=25). *P < 0.05 vs percentage of cells filtered at 750 ml. 1, 750 ml treatment; 2, 1500 ml treatment; 3, 3000 ml treatment.

 

Changes in the number of circulating blood cells during and after LCP therapy
To examine the effect of LCP therapy on the number of circulating blood cells, we measured the total and differential counts of circulating blood cells by obtaining blood samples from the inlet of the filter during each LCP therapy. As shown in Fig. 3Go, there was a significant granulocytopenia after filtration of 750 ml of blood (P < 0.001). However, the number slightly increased at the end of the first session of LCP therapy. Similar changes in granulocyte count were observed in the second and third sessions of LCP therapy. On the other hand, a significant decrease in the number of circulating monocytes and lymphocytes was noted during the first session of LCP therapy, which remained significantly low at the end. Similar changes in monocytes and lymphocytes were observed during the second and third sessions of LCP therapy. LCP therapy resulted in a significant thrombocytopenia (P < 0.05), but did not change the number of erythrocytes. Furthermore, there were no significant changes in circulating granulocytes, monocytes, lymphocytes and erythrocytes during the study period.



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FIG. 3. Changes in the number of circulating blood cells by LCP therapy. Values represent the mean ± S.E.M. of all subjects (n=25) *P < 0.05 vs cell counts before LCP. 1, before LCP; 2, 750 ml treatment; 3, 1500 ml treatment; 4, 3000 ml treatment; 5, 2 weeks after the end of LCP; 6, 4 weeks after the end of LCP.

 

Changes in the total number of removed leucocytes in LCP therapy
The total number of blood cells filtered per session was calculated based on the percentage of removed cells shown in Fig. 2. As shown in Table 2Go, a higher number of granulocytes was filtered relative to monocytes and lymphocytes during the first session of LCP. Similar results were observed during the other two sessions of LCP. This was also true for the number of platelets and erythrocytes filtered during LCP therapy.


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TABLE 2. Total number of removed blood cells during each session of LCP therapy

 

Clinical improvement (ACR core set) after LCP therapy
To evaluate the clinical effectiveness of LCP therapy in RA, we used the ACR core set and analysed the data at baseline and 4 weeks after the last session of LCP. The clinical responses observed in ACR core sets are shown in Table 3Go. The average score of tender and swollen joints significantly decreased, and almost all patients improved. Furthermore, the patient's and physician's assessment scores also significantly improved in all patients. Based on the data presented in Table 3, 16 of 25 patients with RA achieved an ACR 20% response, showing overall improvement following LCP therapy. ESR significantly decreased following therapy, but CRP did not. Four of 25 LCP-treated patients achieved an ACR 50% response. The duration of ACR 20% improvement following LCP was usually ~8 weeks if additional LCP was not performed (data not shown).


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TABLE 3. Clinical effectiveness of patients with RA who were treated with LCP

 

Changes in serum components following LCP therapy
Several serum components were measured at baseline and 4 weeks after the last session of LCP. No changes were observed in the level of serum albumin and {gamma}-globulin (data not shown). Therefore, no patient required fresh frozen plasma or albumin during or after LCP treatment. Furthermore, the concentration of IgG, IgM, CH50 and the titre of IgG-rheumatoid factor did not change significantly (data not shown).

Side-effects
No worsening of clinical signs or symptoms was noted in any patient during and after LCP therapy. Furthermore, in spite of the fall in white blood cells, no adverse reactions were noted, including the development of infection with cytomegalovirus, herpes zoster, or other viruses during the study period. No abnormal laboratory findings were noted, apart from those reported above.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The use of a simple and practical on-line continuous LCP filter system has been previously described in patients with RA [12]. In Japan, several clinical studies have concluded that filtration LCP is a useful and safe tool for the treatment of RA [1214]. Furthermore, a double-blind, placebo-controlled study by Hidaka et al. [15] has shown that filtration LCP is clinically beneficial in the treatment of RA. However, only a few studies have examined the efficacy of filtration LCP [12]. In the present study, we found that, on average, 96% of granulocytes, 98% of monocytes, and 61% of lymphocytes were filtered in each session of LCP using the CS-100 filter. The calculated percentages of filtered leucocytes in each LCP session in our study were equivalent to those reported by Hidaka et al. Furthermore, the calculated total number of removed leucocytes (per session) was equivalent to that reported using the centrifuge method [5, 8, 18]. The advantages of filtration LCP are that the time required for filtration is relatively short and the procedure can be completed in a third to a quarter of the time required for the centrifuge method. Furthermore, filtration LCP can be performed inexpensively and the method is simple. On the basis of these above findings, it seems likely that our filtration LCP method may be an alternative to TDD and the centrifuge method.

In the present study, a substantial and rapid improvement in the tender joint counts, swollen joint counts, and patient's and physician's assessments was observed following the use of our filtration LCP method. These results are similar to those described in TDD and the centrifuge method. However, we also documented a fall in ESR but no change in other inflammatory parameters [5, 8, 18]. The exact mechanisms which underlie this beneficial effect of filtration LCP are not well understood. Our results also demonstrated that 110 x 108 granulocytes, 5.23 x 108 monocytes, and 20.5 x 108 lymphocytes were removed in each LCP session using the CS-100 filter. Our results are similar to those of Hidaka et al. using the CS-120 filter. Is this removal of any therapeutic benefit?

Granulocytes play a central role in the generation, maintenance, and resolution of inflammation in general and in the degenerative process of rheumatic diseases in particular. An increase in the granulocyte count and in the granulocyte/lymphocyte ratio is well known in patients with RA [19]. The presence of granulocytes in the synovial fluid could damage the synovial membrane and cartilage in RA patients via the release of proteolytic enzymes and oxygen radicals [20, 21]. In the present study, the percentage of removed granulocytes was satisfactorily maintained at almost 100% during the LCP procedure. Furthermore, the circulating granulocytes rapidly decreased during LCP. However, their level slightly increased at the end of each LCP session. Although granulocytes can quickly regenerate, it is possible that redistribution of activated granulocytes from peripheral blood by our filtration LCP may explain, at least in part, the clinical improvement in RA patients.

The rheumatoid synovium is characterized by infiltration of activated macrophages that form a major part of the destructive pannus tissue [22]. Not only tissue macrophages, but also blood monocytes show high activity in RA [23]. Hahn et al. [24] have demonstrated that the use of LCP with the centrifuge method efficiently removes activated monocytes from the blood stream, and that the repopulating cells show reduced activity compared with pre-therapy levels. In the present study, the percentage of removed monocytes was satisfactorily maintained at almost 100% during the LCP procedure. But, we failed to induce a monocytopenia during the study periods. Hahn et al. [24] have demonstrated that the clinical effects of LCP therapy may be via an alteration in the state of activation of macrophages, rather than through an effect on total numbers of circulating monocytes. Although we did not investigate the effects of LCP on serum cytokines and cytokine production from circulating monocytes, it is likely that redistribution of monocytes from peripheral blood by our filtration LCP may explain, at least in part, the clinical improvement in RA patients.

Previous studies have established that T lymphocytes form the majority of synovial inflammatory cells in RA [25]. The involvement of T lymphocytes in RA is also supported by studies indicating that lymphocyte depletion induced pharmacologically [26, 27], or by total lymphoid irradiation [28, 29] or TDD and LCP may result in clinical improvement of patients with RA. In humans, the majority of circulating lymphocytes have a mean life-span of ~4.4 yr [30]. The daily production of circulating lymphocytes is 5.7 x 106, which is much less than the number of lymphocytes removed in one session of LCP (1.99–2.13 x 109) [30]. Sarles et al. [31] have demonstrated that TDD causes peripheral lymphoid tissue depletion in the T cell area. Although we failed to induce a lymphocytopenia during the study periods, LCP used according to the present schedule could potentially exhaust the extravascular pool of lymphocytes. Thus, our results suggest that redistribution of lymphocytes from peripheral blood by our filtration LCP may explain, at least in part, the clinical improvement in RA patients.

Using the controlled filtration LCP, Hidaka et al. showed that the removal of platelets from the circulation played a small role in the improvement of RA. In the present study, on average, 5.2 x 1011 platelets were removed, but the number of circulating platelets did not change significantly during the clinical course. Nafamostat mesilate used as an anti-coagulant within the LCP system inhibits platelet function, but its half-life is only 6–8 min [32], and the extracorporeal circulation time was almost 5 min. Therefore, the activity of nafamostat mesilate at the return line is probably too low to influence platelet function for a significant length of time. No haemorrhagic tendency was observed. Therefore, platelets probably play little or no role in the improvement seen after LCP. On the other hand, various plasma components were not filtered out during this procedure and accordingly their contribution to the observed improvement is negligible.

Our study had a limitation. Admittedly, the improvement noticed in the present uncontrolled study cannot be confirmed to be due to LCP because of placebo effects. A placebo response normally occurs with almost all therapeutic interventions for RA. In Karsh et al.'s randomized placebo-controlled study [8], swollen and active joint counts significantly decreased in the centrifuge LCP group compared with the control group, but there were no significant changes in tender joints and the patient's assessments of pain between the LCP and the control group. But, the number of patients in the LCP and the placebo groups was small and no definite criteria were used to evaluate the clinical improvements. In our study, tender and swollen joints, and patient's and physician's assessment scores significantly decreased in the filtration LCP using the ACR core set. Furthermore, the present study design avoided the possible impact of hospitalization and bed-rest on disease activity by treating all patients on an out-patient basis.

In summary, we have demonstrated that filtration LCP has an immunomodulatory effect by removing leucocytes (granulocytes, monocytes and lymphocytes) from the circulation. Future studies are recommended, after modification of the device, to remove, selectively, activated granulocytes or monocytes and lymphocyte subpopulations, and to optimize the number of filtered leucocytes and the frequency of filtration LCP therapy.


    Acknowledgments
 
The authors are grateful to Miss S. Kuzyuro for the expert technical support in performing blood analyses and Mrs T. Nakao, Mrs T. Iwasa, and Mrs T. Koga for technical assistance in performing LCP procedures. The authors also thank Dr F. G. Issa (Word-Medex, Sydney, Australia) for the careful reading and editing of the manuscript. This work was supported by Asahi Medical Co. Ltd., Tokyo, Japan.


    Notes
 
5 Correspondence to: Y. Ueki, Department of Internal Medicine, Sasebo Chuo Hospital, Yamato-cho 15, Sasebo 857-1195, Japan. Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 23 March 1999; revised version accepted 8 September 1999.



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