Kazuo Kempe

Filtration Leukocytapheresis Therapy in the Treatment of Rheumatoid Arthritis Patients Resistant To or Failed with Methotrexate

Abstract:  Filtration leukocytapheresis (LCP) is a treatment for abnormal autoimmune states, which removes responsible leukocytes from the peripheral blood. To examine the efficacy of LCP therapy in the treatment of rheumatoid arthritis (RA), nine patients were selected, who were either resistant to methotrexate, or failed with methotrexate due to drug ineffectiveness or adverse side effects. For these patients, LCP therapy was performed once a week for five weeks. After five LCP treatments, the patients were observed for 12 weeks, to test the efficacy of the treatment. The definition of improvement given by the American College of Rheumatology (ACR core set) was used for efficacy evaluation of LCP therapy. As the result, 77.8% of the patients showed an ACR 20% response and 44.4% of the patients showed an ACR 50% response. With improvement of joint symptoms, IL‐6 was significantly decreased at 8 weeks and 12 weeks after the treatment. The expression of adhesion molecules CD11a, CD11b, and CD18 on granulocytes decreased directly after the LCP treatment. No adverse side effect was monitored during the study period. These results indicates that LCP treatment is a useful treatment for RA patients who were resistant to methotrexate, or failed with methotrexate due to  ineffectiveness  or  side effects  of  the  drug. 

Investigation of the clinical effect of large volume leukocytapheresis on methotrexate-resistant rheumatoid arthritis.

Abstract:  Leukocytapheresis (LCAP) is already being used in a clinical setting for the treatment of autoimmune diseases such as inflammatory bowel disease and rheumatoid arthritis, and it has been reported to be effective. However, it is totally or partially ineffective in some patients, which has forced clinicians to rethink therapeutic strategies and concurrent treatment. With the aim of enhancing the therapeutic effect, we carried out large volume leukocytapheresis, with a throughput of 5000 mL instead of the 3000‐mL throughput of conventional leukocytapheresis in nine patients with rheumatoid arthritis resistant to methotrexate treatment. Using Cellsorba, the column filled with the unwoven fabric made of the polyethylene phthalate, a leukocyte removal filter, large volume leukocytapheresis was carried out once a week for a total of five sessions. The observation period was the 12‐week period following completion of treatment. The American College of Rheumatology (ACR) core set was used for assessment of efficacy. Eight weeks after completion of treatment, a 20% improvement in ACR was observed in 77.8% (7/9) of subjects, a 50% improvement in ACR was seen in 55.6% (5/9) of subjects, and a 70% improvement in ACR was observed in 22.2% (2/9) of subjects. C‐reactive protein decreased gradually as treatment progressed, and a significant decrease was observed 4 weeks after completion of treatment. The fact that some subjects had an ACR70 response, few reports of which are observed in the case of conventional leukocytapheresis, and the fact that the effect continued up to 12 weeks after completion of treatment suggests that the degree and duration of the effect of large volume leukocytapheresis might be longer than those of conventional leukocytapheresis.

Autofeedback from ultrasound images provides rapid improvement in palpation skills for identifying joint swelling in rheumatoid arthritis.

Objective. Joint swelling, an important factor in the classification criteria and disease activity assessment in rheumatoid arthritis (RA), renders joint palpation a necessary skill for physicians. Ultrasound (US) examination that visualizes soft tissue abnormalities is now used to assess musculoskeletal disease. We assessed the usefulness of US assessments in enhancing physical joint examination skills. Methods. We examined 1944 joints (bilateral shoulder, elbow, wrist, metacarpophalangeal joints 1–5, and knee joints) in 108 patients with RA during April–July 2011. We first physically examined and confirmed joint swelling; subsequently, the same rheumatologist conducted US examinations and multiple assessors graded the joint swelling. When the 2 results differed, we received autofeedback from the US results to improve the physical examination skills. Results. The sensitivities and specificities of physical examination for US-detected swollen joint, the correlation coefficient (CC) of the swollen joint counts, and the concordance rate in each patient for joint swelling sites and power Doppler (PD)-positive sites with the κ coefficients between the physical and US examinations were compared over time. We found that the sensitivity of physical examination increased by 42 percentage points (pp), while the specificity decreased by 18 pp. The average CC in June–July was greater than that in April–May. The percentage of κ coefficients > 0.8 increased from 8.8% to 17% for joint swelling and from 8.3% to 14% for PD-positive sites. Conclusion. Our results suggest that autofeedback from US assessment provides quick improvement in palpation skills for identifying joint swelling in patients with RA.

Observational cross-sectional study revealing less aggressive treatment in Japanese elderly than nonelderly patients with rheumatoid arthritis.

Background:Elderly patients with rheumatoid arthritis (RA) have more aging-related complications than nonelderly patients with RA. Objectives:The objective of the study was to investigate the treatment status of elderly patients with RA. Methods:Between January and March 2008, 969 patients with RA were enrolled in this observational cross-sectional study. Prescription of disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and laboratory data related to RA, including matrix metalloproteinase 3, rheumatoid factor, and anti-cyclic citrullinated peptide antibody levels, were compared between the elderly and the nonelderly patients. Results:Fewer DMARDs were prescribed to the elderly patients (1.40 [SD, 0.57] vs. 1.51 [SD, 0.61]; P = 0.029). Furthermore, a lower percentage of patients received methotrexate (MTX) (47.2% vs. 56.9%; P = 0.0001), a lower average dosage of MTX was administered (5.46 [SD, 1.66] mg/wk vs. 5.96 [SD, 1.77] mg/wk; P = 0.0001), and fewer biologic DMARDs were used (1.46% vs. 5.59% for infliximab, P = 0.0008; 0.58% vs. 3.19% for etanercept, P = 0.0038) in the elderly group. The laboratory data suggested that the disease status was uncontrolled to a greater extent, and complications were more common in the elderly group. Conclusion:Elderly patients with RA receive less aggressive treatment than nonelderly patients with RA, despite laboratory evidence for poorly controlled disease status among the elderly. The use of a less aggressive regimen could be attributed to the higher prevalence of complications and problems. Therefore, the elderly with RA should be considered a different patient population from the viewpoint of treatment and be administered specialized medical care.

Effect of various anticoagulant agents on large-volume leukocytapheresis using new Cellsorba CS-180S Filter.

We conducted a study to evaluate the effect of various anticoagulant agents on large‐volume leukocytapheresis using the new Cellsorba CS‐180S Filter filled with a changed solution of sodium pyrosulfite and sodium carbonate. We conducted the study on a total of 12 cases of rheumatoid arthritis. As the anticoagulant agents we used sodium citrate, nafamostat mesilate and low molecular weight heparin. The new Cellsorba CS‐180S was safely used with the various blood anticoagulant agents. Also, through adjustment of the sodium citrate percentage to the blood flow volume, it is hypothesized that it is possible to increase the neutrophil removal rate.

Separation of Circulating MicroRNAs Using Apheresis in Patients With Systemic Lupus Erythematosus.

MicroRNAs (miRNAs), which are important inhibitors of mRNA translation, participate in differentiation, migration, cell proliferation, and cell death. The pathology of miRNAs results in alterations in protein expression. Recently, miRNAs circulating in peripheral blood have been shown to control the synthesis and translation of proteins at distal sites after intake into local cells. A number of studies are currently being conducted to investigate how to use miRNAs in disease treatment, but no studies have attempted to alleviate disease by directly eliminating miRNAs from blood. Therefore, we examined whether the removal or reduction of circulating miRNAs with apheresis improved pathologies caused by miRNAs.

Reduction in bradykinin generation during leukocytapheresis using novel cellsorbaTM CS‐180S: Effects of changing the filling solution

We evaluated the bradykinin generation level during leukocytapheresis (LCAP) using novel CellsorbaTM CS‐180S, which has sodium pyrosulfite and sodium carbonate as a filling solution. Subjects of this study were 14 rheumatoid arthritis patients. Regardless of the type of anticoagulant used, bradykinin levels were lower with the novel CS‐180S than with the conventional CS‐180S (28.7 ± 53.3 vs. 8.0 ± 2.7 as the mean ± standard deviation). When anticoagulants other than nafamostat mesilate were used with the conventional CS‐180S, bradykinin levels increased at the column outlet compared with the column inlet, and adverse effects of bradykinin were seen in several cases. In contrast, bradykinin levels remained low and no bradykinin‐associated adverse events were observed with the novel CS‐180S. We recommend using the novel column instead of the conventional column in the treatment of LCAP. J. Clin. Apheresis 29:90–96, 2014.

Changes in the Expression of Circulating microRNAs in Systemic Lupus Erythematosus Patient Blood Plasma After Passing Through a Plasma Adsorption Membrane: Expression Changes of miRNAs in Apheresis

MicroRNAs (miRNAs, miRs) are small non‐coding RNAs that mainly function in the post‐transcriptional regulation of genes. miRNA that is secreted outside of cells, and which circulates in the peripheral blood, is called circulating microRNA. Systemic lupus erythematosus (SLE) is a typical autoimmune connective tissue disease and is mainly treated with immunosuppressive drugs. Therapeutic apheresis is often used to eliminate autoantibodies and cytokines. We have previously shown that circulating miRNAs in the blood of patients with SLE can be separated and removed from the blood using a plasma separation membrane. In the present study, we further separated circulating miRNA from three SLE patients blood plasma by passing it through a plasma adsorption membrane, and then measured changes in miRNA levels using miRNAs microarray chip. Although the levels of many miRNAs were unaffected after passage through the plasma adsorption membrane, expression of some miRNAs, including miR‐1246, miR‐4732‐5p, and miR‐6088 are declined.