Ken Yamaji

Immunoadsorption plasmapheresis using a phenylalanine column as an effective treatment for lupus nephritis.

Abstract:  Immunoadsorption plasmapheresis (IAPP) is effective for eliminating pathogenic molecules such as anti‐DNA antibody (anti‐DNA Ab) and immune complexes from the serum of patients with systemic autoimmune diseases. The purpose of this study was to assess patients with lupus nephritis (LN) treated by IAPP using a phenylalanine column and determine its efficacy with respect to conventional therapies. Six patients (M = 1, F = 5) with histologically proven LN associated with proteinuria and abnormal sedimentation on urinalysis were the subjects for this study. All were treated with oral corticosteroid (prednisolone 1 mg/kg/day) and IAPP (Immusorba PH – 350; 2 L of plasma twice weekly for 2 weeks). Serum anti‐DNA Ab and complement, urinary protein, and creatinine clearance were measured over 6 weeks (pretreatment, before and after each of 2 IAPP sessions, and 1 and 4 weeks after the second IAPP session). Clinical efficacy of IAPP was compared with conventional pharmacotherapy regimes by conducting a retrospective review of 23 LN patients treated at our hospital using corticosteroid pulse therapy (CSPT, N = 7, intravenous methylprednisolone 500 mg/day for 3 days), intravenous cyclophosphamide pulse therapy (IVCY, N = 7), or corticosteroid monotherapy (CSMT, N = 9, oral prednisone 1 mg/kg body weight daily, for 4 weeks). Immunosuppressants and anticoagulants were not used. With IAPP, mean urinary protein excretion decreased from 2.2 ± 1.7 g/day pretreatment to 0.4 ± 0.6 g/day post‐treatment (P < 0.001). Mean serum anti‐DNA Ab also decreased from 84.0 ± 88.1 U/mL pretreatment to 5.8 ± 5.5 U/mL post‐treatment (P < 0.05). In combination with corticosteroid therapy, IAPP would appear to be an effective and safe treatment for LN.

Long-term clinical outcomes of synchronized therapy with plasmapheresis and intravenous cyclophosphamide pulse therapy in the treatment of steroid-resistant lupus nephritis.

Abstract:  In recent years, the vital prognosis of the patients with lupus nephritis (LN) has improved dramatically as a result of steroid therapy and the administration of immunosuppressants including cyclophosphamide, but recurrent cases and complications associated with these therapies are a concern. In this study, a long‐term retrospective evaluation was performed over a period of five years concerning the clinical characteristics, remission rate and relapse rate by dividing 38 patients with LN into three groups receiving either plasmapheresis (PP), intravenous cyclophosphamide pulse therapy (IVCY), or both PP and IVCY (synchronized PP–IVCY) as the treatments added to steroid therapy. The complete remission rates of PP, IVCY and PP–IVCY were 5/9 (55.6%), 8/16 (50.0%) and 9/13 (69.2%), respectively. The relapsing rates of PP, IVCY and PP–IVCY were 3/9 (33.3%), 3/16 (18.8%) and 1/13 (7.7%), respectively. Synchronized PP–IVCY therapy might be superior to PP or IVCY in achieving complete remission of LN, and in minimizing the risk of relapse of impaired renal function.

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. 

Fluctuations in peripheral blood leukocyte and platelet counts and leukocyte recruitment with large volume leukocytapheresis in healthy volunteers.

Abstract:  Based on sporadic reports indicating that the effectiveness of leukocytapheresis (LCAP) is proportional to the number of leukocytes removed, it is anticipated that increasing the volume of blood treated, and thus the number of leukocytes removed, will improve the effectiveness of therapy. In advance of its clinical application, the possible clinical usefulness of large volumes of LCAP (pulse LCAP), which treats 5000 mL of blood rather than the usual volume of 3000 mL, was investigated in healthy subjects. As compared with conventional LCAP, pulse LCAP provided comparable safety and enabled the removal of approximately 4.7 times more neutrophils, 1.2 times more lymphocytes, and 1.6 times more monocytes. It also resulted in a more pronounced overshoot phenomenon, as well as lymphocyte and monocyte overshoot, which are not seen with conventional LCAP. The neutrophil overshoot resulted from the recruitment of leukocytes from the bone marrow neutrophil pool as well as from the circulating neutrophil pool and marginal neutrophil pool. Recruitment from the bone marrow pool involved not only recruitment of mature neutrophils but also recruitment from all stages of differentiation and proliferation, including the pluripotent stem cell (CFU‐GEMM) fraction; granulocyte‐monocyte precursor cell (CFU‐GM) fraction; and the fraction of juvenile granulocyte precursors cells capable of cell division, from myeloblasts to myelocytes. Based on the lymphocyte and monocyte overshoot, it was inferred that cells were recruited from mucosal lymphatic tissue, in addition to the lymph nodes, spleen, thymus, and bone marrow. These phenomena might play an important role in the mechanism that underlies the effectiveness of LCAP and the increased effectiveness of pulse LCAP, and it will be necessary to work to elucidate them. Moreover, it appears that investigating the clinical efficacy of pulse LCAP in patients who do not respond to conventional LCAP would be of major significance.

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.

Involvement of Mucosal-associated Invariant T cells in Ankylosing Spondylitis

Objective. Ankylosing spondylitis (AS) is characterized by chronic inflammation of the axial and peripheral joints and ligamentous attachments. Gut immunity is thought to be involved in AS, because a prominent coexistence of gut and joint inflammation has been observed in patients with AS. Mucosal-associated invariant T (MAIT) cells are preferentially located in the gut lamina propria and produce inflammatory cytokines such as interleukin 17 (IL-17) and tumor necrosis factor-α (TNF-α), which are therapeutic targets for AS. This study aimed to investigate the involvement of MAIT cells in AS. Methods. The frequency of MAIT cells and their cytokine production were determined in patients with AS and healthy controls (HC). The expression of a MAIT cell activation marker (CD69) was analyzed in patients with AS by using flow cytometry. Results. The frequency of MAIT cells in the peripheral blood was lower in patients with AS compared with HC. The levels of IL-17 produced by MAIT cells after activation were higher in patients with AS than in the HC. CD69 expression on MAIT cells correlated with the Ankylosing Spondylitis Disease Activity Score in patients with AS. Conclusion. These results suggest the involvement of MAIT cells in the pathogenesis of AS.

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.

Activation status of mucosal-associated invariant T cells reflects disease activity and pathology of systemic lupus erythematosus

BackgroundMucosal-associated invariant T (MAIT) cells are innate-like lymphocytes constituting a large proportion of peripheral blood T cells expressing αβ T-cell receptor in humans. In this study, we aimed to investigate their involvement in systemic lupus erythematosus (SLE).MethodsPeripheral blood MAIT cells from patients with SLE were assessed for their frequency, activation markers, and cell death by flow cytometry. The correlation between plasma cytokine levels and CD69 expression on MAIT cells was analyzed. The major histocompatibility complex class I-related protein MR1-restricted antigen-presenting capacity of antigen-presenting cells was investigated. Cytokine-mediated activation of MAIT cells in the absence of exogenous antigens was also examined.ResultsThe frequency of MAIT cells was markedly reduced in SLE. The reduced number of MAIT cells was not attributable to the downregulation of surface markers, but it was partially due to the enhanced cell death of MAIT cells, possibly by activation-induced cell death. The CD69 expression levels on MAIT cells in SLE correlated with disease activity. Moreover, monocytes from patients with SLE exhibited increased ability to induce MAIT cell activation. The plasma concentration of interleukin (IL)-6, IL-18, and interferon (IFN)-α positively correlated with the expression levels of CD69 on MAIT cells in SLE. MAIT cells were activated by cytokines, including IFN-α, IL-15, and IL-12 plus IL-18, in the absence of exogenous antigens.ConclusionsThese results suggest that MAIT cells reflect the pathological condition of SLE and that their activated status correlates with presence of disease.

Clinical characteristics and change in the antibody titres of patients with anti-MDA5 antibody–positive inflammatory myositis

Objective The aim of this study was to evaluate the clinical characteristics of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive inflammatory myositis, and the change in anti-MDA5 antibody titres before and after onset. Method For 105 PM/DM patients, newly diagnosed in our hospital within the period 2008-2016, serum anti-MDA5 antibody levels were measured at diagnosis and after treatment by ELISA using the MESACUP anti-MDA5 test. The relationships between anti-MDA5 antibody levels and clinical manifestations, laboratory data, and mortality were examined. Result Compared with patients who were anti-MDA5 antibody negative, those who were antibody positive demonstrated more frequent dermatitis, clinically amyopathic DM, interstitial lung disease and rapid-progressive interstitial lung disease, as well as significantly higher serum ferritin, significantly lower creatine kinase and aldolase, and significantly less frequent ANA (⩾1:160) and anti-cytoplasmic pattern of ANA staining positivity. Anti-MDA5 antibody titres were examined before disease onset in two patients; one showed antibody positivity with low titres 2 years earlier, while both exhibited increased titres at onset. Anti-MDA5 antibody titres declined significantly less in survivors than in non-survivors after treatment; however, there was no significant difference between the two groups when the rate was compared at 2 months after treatment. Conclusion An initial decrease in anti-MDA5 antibody titre after commencement of treatment was observed in most of the patients, including in fatal cases, suggesting that this may not necessarily be a useful marker for treatment of patients with DM.

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.