Double filtration plasmapheresis combined with rituximab for donor-specific antibody desensitization in haploidentical haematopoietic stem cell transplantation

Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical haematopoietic stem cell transplantation (Haplo-HSCT). Double filtration plasmapheresis (DFPP) avoids the unnecessary loss of plasma proteins and increases the efficiency of purification. To investigate the effectiveness of the desensitization protocol including DFPP and rituximab, we conducted a nested case–control study. Thirty-three patients who had positive DSA were desensitized by the protocol and 99 patients with negative DSA were randomly matched as control. The median DSA mean fluorescence intensity values before and after DFPP treatment were 7505.88 ± 4424.38 versus 2013.29 ± 4067.22 (p < 0.001). All patients in DSA group achieved haematopoietic reconstitution and the median neutrophils and platelets engraftment times were 13 (10–21) and 13 (10–29) days respectively. Although the cumulative incidence of II–IV aGVHD (41.4% vs. 28.1%) and 3-year moderate to severe cGVHD (16.8% vs. 7.2%) were higher in DSA cohort than in the control, no statistical significance was observed. The 3-year non-relapse mortality and the overall survival were 6.39% and 72.0%, respectively, in the DSA cohort, which were comparable to the negative control. In conclusion, DFPP and rituximab could be effectively used for desensitization and overcome the negative effects of DSA in Haplo-HSCT.     

Microalbuminuria: A marker of severe disease activity in rheumatoid arthritis

ObjectiveMicroalbuminuria is associated with increased risk for renal and cardiovascular mortality and morbidity in diabetes mellitus, hypertension, patients with acute myocardial infarction and elderly patients but the significance of microalbuminuria in rheumatoid arthritis and its correlation with disease activity is not well studied. The present study is therefore aimed to determine the microalbuminuria in rheumatoid arthritis patients and to correlate it with indicators of disease activity like CRP and ESR.MethodsHundred confirmed cases of Rheumatoid arthritis (2010 ACR-EULAR criteria) and hundred age and sex matched controls were taken. Those suffering from hypertension, diabetes mellitus and renal disease were excluded. Microalbumin was assessed by immunoturbidimetric method on Delta nephelometer. Disease activity was assessed by CRP and ESR.ResultsThe relative frequency of microalbuminuria in patients with rheumatoid arthritis was 26% as compared to 4% in controls. The median level of microalbuminuria in rheumatoid arthritis patients was significantly greater than in the controls (17 vs. 3.29, p < 0.01). Microalbuminuria significantly correlated with CRP (p < 0.001, r = 0.457) and ESR (p < 0.001, r = 0.361). A significant correlation was found with duration of disease (p < 0.05, r = 0.231) and number of joints involved (p < 0.05, r = 0.240).ConclusionsWe found increased prevalence of microalbuminuria in rheumatoid arthritis patients and it correlated with acute phase reactants.     

Virological effects and safety of combined double filtration plasmapheresis (DFPP) and interferon therapy in patients with chronic hepatitis C: A preliminary study.

PURPOSE: In patients with chronic genotype 1b hepatitis C and a high viral load, the viral load was reduced by double filtration plasmapheresis (DFPP), followed by combined interferon and ribavirin therapy. The safety and virological effects of this treatment method were preliminarily investigated. METHODS: In nine patients with chronic hepatitis C, DFPP was performed three times on days 1, 2, and 4, and the administration of interferon and ribavirin was initiated immediately after DFPP on day 1. RESULT: The HCV RNA was undetectable in all patients after the plasma was passed through a plasma fractionator (second filter) in the DFPP circuit. After 2 weeks, the HCV RNA tended to decrease in the DFPP group more than in the control group (-2.45+/-1.12 versus -1.57+/-0.95, P=0.073). However, this decrease was not attributable to a sustained virological response (SVR) (22.2% versus 18.2%, P=0.822). Most of the adverse events were caused by the interferon and ribavirin combination therapy. CONCLUSION: DFPP can be safely performed concomitantly with interferon and ribavirin combination therapy in chronic hepatitis C patients. The combination may contribute to an early virological response. The effect of DFPP on the SVR and its significance remain to be clarified.     

MRI appearance of retrocalcaneal bursitis and rheumatoid nodule in a patient with rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disorder of unknown etiology characterized by symmetric, erosive synovitis and sometimes multisystem involvement. Rheumatoid nodules have been reported in as many as 20–30% of patients with rheumatoid arthritis; however, they are not commonly seen in the feet. We present magnetic resonance (MR) findings of a rarely seen case of rheumatoid bursitis in the retrocalcaneal bursa associated with a subcutaneous rheumatoid nodule inferior to the calcaneus which histologically confirmed the rheumatoid arthritis. To the best of our knowledge, this is the first case that rheumatoid bursitis in the retrocalcaneal bursa associated with the rheumatoid nodule in the foot was revealed by MR imaging.     

More Selective Removal of Myeloperoxidase‐Anti‐Neutrophil Cytoplasmic Antibody From the Circulation of Patients With Vasculitides Using a Novel Double‐Filtration Plasmapheresis Therapy

Our aim was to investigate the removal of myeloperoxidase‐anti‐neutrophil cytoplasmic antibody (MPO‐ANCA) from the circulation of patients with vasculitides by double‐filtration plasmapheresis (DFPP) using various primary separator and secondary separator combinations. Nineteen patients diagnosed with vasculitides positive for serum MPO‐ANCA were enrolled and received 56 sessions of DFPP. One patient received three sessions of DFPP using MPS07 (the primary filter)/EC50W (the secondary filter), nine patients received 27 sessions of DFPP using MPS07/EC20W, and the other nine patients received 26 sessions of DFPP using EC50W/EC20W. The sieving coefficients (SC) of albumin, immunoglobulin (Ig)A, IgG and IgM were measured, as well as the reduction ratio in plasma protein concentrations and MPO‐ANCA titer after a single session of DFPP. The MPS07 filter was well permeable for all the above‐mentioned plasma proteins; the EC50W and EC20W filters were permeable for albumin and IgG, less for IgA and IgM. During DFPP using MPS07/EC50W, the reduction ratio of IgG was much lower than IgM and IgA (30.5 ± 9.0% vs. 89.7 ± 5.4% and 61.7 ± 14.8%). During DFPP using MPS07/EC20W, the decline in IgM, IgA, and IgG was 94.2 ± 3.1%, 96.2 ± 2.3%, and 64.7 ± 21.0%, respectively. During DFPP using EC50W/EC20W, the decline in IgM, IgA, and IgG was 2.8 ± 12.9%, 90.9 ± 4.4%, and 43.5 ± 13.8%, respectively. The percentage reduction in MPO‐ANCA titer after a single session of DFPP using EC50W/EC20W was 34.6 ± 14.3%. DFPP using EC50W/EC20W filters may be more selective for the removal of pathogens such as IgG, with subsequently effective reduction of serum ANCA titer.     

Successful treatment by double filtrate plasmapheresis in a pregnant woman with the rare P blood group and a history of multiple early miscarriages

Individuals of P type, a rare blood group, have anti-PP(1)P(k) antibody in their serum, which causes spontaneous abortion in the early stages. We report a patient of p type suffering from multiple spontaneous abortions. We also review previously reported cases from published work. A 36-year-old woman (gravida 2, para 0) was referred to our hospital because of habitual abortion. At the third pregnancy, we started double filtration plasmapheresis (DFPP) from 7 weeks 3 days to remove the antibody. We attained rapid decline in the titer and normal fetal growth. Gradual tapering of the DFPP frequency caused neither a rebound of the titer nor growth retardation. During the course, she experienced only one episode of catheter infection as an adverse effect. At 37 weeks 3 days, after 57 DFPP repetitions, a 2496 g girl was delivered by cesarean section. The infant suffered neither from anemia nor from severe jaundice. A review of previous reports indicates that the titer of the pathogenic antibody should be kept as low as possible from the early gestational stage in P-incompatible habitual abortion cases, otherwise the case typically comes to an unfavorable outcome. Plasma exchanges with fresh plasma potentially induce contamination by either known or unknown pathogens. Such risks are reduced using DFPP because the volume of albumin solution that replaces fresh plasma is less than that by plasma exchange. The present case, along with previous reports, shows that DFPP is an effective therapy for treating P-incompatible pregnancy.     

Status of plasmapheresis for the treatment of toxic epidermal necrolysis in Japan

This study describes the efficacy of plasmapheresis for the treatment of toxic epidermal necrolysis (TEN), as reported in Japan. TEN patients treated with plasmapheresis were collected from Japanese literature. The type of plasmapheresis, number of sessions, efficacy of plasmapheresis, and present outcome were examined. Forty-seven TEN patients treated with plasmapheresis have been reported in the literature: 19 men and 28 women with ages ranging from 1 to 96 years (mean 50.3 years). Twenty-five of these treatments included simple plasma exchange (PE), 13 included double filtration plasmapheresis (DFPP), and one included PE and DFPP. The number of plasmapheresis sessions ranged from 1 to 6 and the mean number of sessions was 3.1. The efficacy of plasmapheresis for the treatment of TEN was as follows: excellent, 30 cases; good, 8 cases; fair, 3 cases; no effect, 5 cases; and unknown, 1 case. The rate of effectiveness was 80.9%; eleven patients died; and the mortality rate was 23.4%. In summary, plasmapheresis, including both PE and DFPP, were found to be effective treatments for Japanese patients with TEN, who had been unresponsive to corticosteroids, and for those who show severe clinical manifestations.     

Statin treatment for rheumatoid arthritis: a promising novel indication

The results of several cross-sectional trials suggest that patients with rheumatoid arthritis (RA) have increased vascular risk and cardiovascular mortality. It was demonstrated that inflammation plays a pivotal role in the pathogenesis of both RA and atherosclerosis. This association may explain the high incidence of cardiovascular disease in RA patients. A number of recent studies show that routine statin use in patients with RA offers considerable advantages. Statin treatment has been supported to exert a beneficial effect on disease activity, swollen joint count, endothelial dysfunction, and arterial stiffness in RA patients. These improvements are coupled with a mild to moderate improvement in plasma markers of inflammation, such as C-reactive protein and erythrocyte sedimentation rate. Statins have a satisfactory safety profile with relatively few adverse effects. In the absence of side effects and contraindications, it may be reasonable to consider statin use in selected cases, particularly in patients with a long history of active RA who are at increased cardiovascular risk.     

Use of etanercept in a patient with rheumatoid arthritis on hemodialysis

Abstract

Disease-modifying anti-rheumatic drugs (DMARDs) are typically used for the therapy of rheumatoid arthritis (RA), but most have some nephrotoxicity. In several clinical studies, etanercept had fewer adverse effects on renal function than other DMARDs. We report the case of a 64-year-old woman with RA and renal insufficiency on hemodialysis treated using etanercept therapy. This case suggests that etanercept therapy might be effective in the short term for such patients.     

Use of etanercept in a patient with rheumatoid arthritis on hemodialysis

Disease-modifying anti-rheumatic drugs (DMARDs) are typically used for the therapy of rheumatoid arthritis (RA), but most have some nephrotoxicity. In several clinical studies, etanercept had fewer adverse effects on renal function than other DMARDs. We report the case of a 64-year-old woman with RA and renal insufficiency on hemodialysis treated using etanercept therapy. This case suggests that etanercept therapy might be effective in the short term for such patients.     

Double filtration plasmapheresis and interferon combination therapy for chronic hepatitis C patients with genotype 1 and high viral load

Aim: The efficacy and safety of double filtration plasmapheresis (DFPP) plus interferon (IFN) combination therapy were compared with those of IFN therapy alone in 193 chronic hepatitis C patients having a high hepatitis C virus ribonucleic acid load of difficult-to-treat genotype 1b. Methods: All patients received either interferon alpha-2b (IFN-alpha-2b) monotherapy or combination therapies with ribavirin and IFN-alpha-2b or pegylated interferon alpha-2b (PEG-IFN-alpha-2b). Each patient individually decided whether to receive concomitant DFPP. DFPP was immediately followed by IFN treatment, and up to five sessions were given during the first week. Results: Sixty patients decided to receive DFPP. In the DFPP plus PEG-IFN-alpha-2b therapy group (n = 30), viral load reduction at 4 weeks after the start of treatment was greater than innon-DFPP (n = 74) (2.47 vs 1.52, log, P = 0.010), and the sustained virus response was also higher (77.8% vs 50.0%), even in cases of re-treated patients (relapsers or non-responders to previous IFN therapies). Adverse events, mild and transient, were observed in 38.3% of all DFPP-treated patients. Conclusion: DFPP plus IFN combination therapy produced a great reduction of viral load during the early stage of treatment and achieved a high sustained virus response, suggesting that this combination therapy may be a new modality for chronic hepatitis C patients at difficult-to-treat states.     

Manifestation of rheumatoid arthritis in a patient with hereditary haemochromatosis

Articular symptoms are frequent manifestations of hereditary haemochromatosis. The clinical signs of the arthropathy of haemochromatosis are not specific and difficult to identify in case of co-incidence of haemochromatosis with Heberden’s and Bouchard’s osteoarthritis or rheumatoid arthritis (RA). Here the manifestation of RA in a patient is reported who was successfully treated for haemochromatosis. Six months after terminating phlebotomy, the patient presented again suffering from impressive swelling of all MCP joints, showing strong synovitis in ultrasound, and from morning stiffness longer than 1 h. ESR, CRP, IgM rheumatoid factor, and anti-cyclic citrullinated peptide antibodies were markedly elevated. Based on these findings the diagnosis of RA was made. Therefore, the high prevalence of RA and haemochromatosis in the general population underlines the usefulness of a screening for HFE gene mutations in RA patients with an atypical course of the disease as well as in patients with undifferentiated arthritis.     

Successful treatment of protein-losing enteropathy due to AA amyloidosis with octreotide in a patient with rheumatoid arthritis

Protein-losing enteropathy (PLE) is a rare syndrome of gastrointestinal protein loss that may complicate a variety of diseases. This excessive protein loss across the gut epithelium can be explained by several mechanisms, such as augmentation of the intestinal mucosal capillary permeability, mucosal disruption, intestinal or mesenteric vasculitis, and lymphangiectasia. However, these pathophysiologic alterations of the gut are closely linked to the underlying cause, and primary treatment for PLE should be directed at the underlying condition. Here, we report a female patient with rheumatoid arthritis who developed severe PLE due to AA amyloidosis and was successfully treated with octreotide. She had been suffered from rheumatoid arthritis for 18 years, and her arthritic symptoms at the time of presentation were not definite but manifested as severe diarrhea and general edema with hypoalbuminemia. PLE due to gastrointestinal amyloidosis was confirmed by increased fecal α₁-antitrypsin clearance and a colonoscopic biopsy that was positive for amyloid deposits. The diarrhea dissipated with conventional treatment, but the general edema resolved only after introducing a long-acting somatostatin analog (octreotide), along with a gradual recovery of the serum albumin level. This case teaches us that in the case of PLE due to AA amyloidosis that is refractory to conventional treatment, the administration of octreotide should be considered.     

Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis

Objectives

The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks.

Methods

One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels.

Results

Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks.

Conclusions

Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.     

抗Sa抗体、抗环瓜氨酸肽抗体、葡萄糖6-磷酸异构酶抗原和类风湿因子联合检测对类风湿关节炎的诊断意义

目的 探讨抗Sa抗体、抗环瓜氨酸肽(CCP)抗体、葡萄糖6-磷酸异构酶(GPI)抗原及类风湿因子(RF)联合检测对类风湿关节炎(RA)诊断的意义.方法 采用酶联免疫吸附试验(ELISA)检测抗Sa抗体、抗CCP抗体及RF亚型RF-IgA、RF-IgG、RF-IgM,免疫比浊法检测RF.结果 抗Sa抗体、抗CCP抗体、GPI抗原、RF对RA诊断的特异性和敏感性分别为95.69％和59.79％、98.28％和90.72％、76.14％和78.35％、67.24％和91.75％.RF-IgA、RF-IgG、RF-IgM对于RA诊断的特异性和敏感性分别为89.66％和58.76％、90.52％和68.04％、79.31％和79.38％.两项指标联合检测对RA诊断的特异性和敏感性为92.24％ ～ 100.00％和47.42％～86.60％;3项指标联合检测对RA诊断的特异性和敏感性为99.14％～100％和46.39％～71.13％;4项指标联合检测对RA诊断的特异性和敏感性为100.00％和46.39％.抗Sa抗体阳性组患者C反应蛋白水平高于阴性组(P＜0.05).结论 两项及两项以上指标联合检测可以显著提高RA诊断的特异性,有利于RA的早期诊断及治疗.     

Epstein-Barr virus-associated B-cell type non-Hodgkin's lymphoma with concurrent p53 protein expression in a rheumatoid arthritis patient treated with methotrexate

A Japanese male patient received various medications for his long-standing rheumatoid arthritis (stage IV, class II). He developed a mass on the right anterior chest wall after being treated with methotrexate (MTX) for 4 months. A biopsy of the mass showed it to be Epstein Barr virus (EBV)-associated lymphoma of B-cell phenotype stage IE (bulky mass), with positive EBV-encoded small RNAs (EBERs) in situ hybridization, EBV latent membrane protein-1 (LMP-1) negative, EB nuclear antigen-2 (ERNA-2) negative, CD20/L26 (+), CD45RO/UCHL-1 (-). A single band of the joined termini of the EBV genome was demonstrated in DNA extracted from the mass, suggesting a clonal disorder of the mass. Immunostaining of the mass with p53 antibody was also positive. With discontinuation of MTX and administration of chemotherapy, the tumor disappeared but recurred after 3 months. This case suggests that concordant p53 expression and latent EBV infection may play an important role in the pathogenesis of lymphomas arising in patients with rheumatoid arthritis who are immunosuppressed with MTX.     

Successful treatment of rheumatoid arthritis is associated with a reduction in serum sE-selectin and thrombomodulin level

The aim of this study was to investigate the changes in serum levels of endothelial cell injury markers, soluble (s) E-selectin and thrombomodulin (TM), in patients with rheumatoid arthritis (RA) before and after antirheumatic drug treatment and to assess the relationship between these changes and clinical responses to the drug treatment. Eleven patients with RA having active arthritis and 12 healthy volunteers were enrolled in the study. They were monitored by clinical and laboratory parameters while receiving a combination of methotrexate, hydroxychloroquine and sulphasalazine. Pre- and post-treatment clinical and laboratory parameters, including sE-selectin and sTM levels, were measured. The ages of the patients were comparable with those of the control groups. Significant improvements were detected in erythrocyte sedimentation rate, C-reactive protein, hemoglobin, morning stiffness, patients global assessment, physicians global assessment, number of tender joints and number of swollen joints improved at the end of the therapy (for each parameter p<0.05). Significant improvements were detected in clinical and laboratory parameters. In the patient group there were significant decreases in the levels of sTM and sE-selectin after treatment (p<0.05). The patient group had significantly higher sTM and sE-selectin levels than the control group at the beginning of the study (p<0.01), but the difference returned to normal after the treatment (p>0.05). The sE-selectin and sTM levels significantly correlated with each other, and also with clinical and laboratory findings. Combination treatment successfully treated RA patients. sE-selectin and sTM levels probably reflect disease activity and can be helpful in monitoring disease status and response to therapy.Abbreviations ARDS Adult respiratory distress syndrome - ALT Alanine aminotransferase - ALP Alkaline phosphates - AST Aspartate - CRP C-reactive protein - CBC Complete blood count - DIC Disseminated intravascular coagulation - DMARD Disease-modifying antirheumatic drugs - ESR Erythrocyte sedimentation rate - GGT -glutamyl transpeptidase - HCQ Hydroxychloroquine - MTX Methotrexate - NSAID Non-steroidal anti-inflammatory drugs - PMN Polymorphonuclear - RA Rheumatoid arthritis - SSZ Sulphasalazine - TM Thrombomodulin     

Infectious myositis involving the piriformis in a patient with rheumatoid arthritis

A 49-year-old Japanese woman treated with oral corticosteroids, methotrexate, and infliximab for malignant rheumatoid arthritis was admitted because of fever and low back pain. The white blood cell count and C-reactive protein concentration were elevated. Lumbar and pelvic computed tomography showed enlargement of the piriformis muscle including a hypodense area consistent with gas formation. The patient was treated successfully for infectious myositis with intravenous antibiotics.     

A case of malignant fibrous histiocytoma on the knee joint in a patient with rheumatoid arthritis

An elderly woman with rheumatoid arthritis and receiving nonsteroidal anti-inflammatory drugs (NSAIDs) treatment was diagnosed with a malignant fibrous histiocytoma in her left knee joint. However, no metastatic lesion caused by the malignant fibrous histiocytoma was found, probably owing to the NSAIDs therapy. Her general condition worsened, and eventually led to renal failure and death from progressive respiratory failure caused by pulmonary effusion. This is the first known report of a malignant fibrous histiocytoma originating in the left knee joint that was complicated by rheumatoid arthritis. Received: September 18, 2000 / Accepted: March 8, 2001