Kunio Ohnishi

Leukocytapheresis therapy, performed with leukocyte removal filter, for inflammatory bowel disease

Leukocytapheresis (LCAP), performed with a leukocyte removal filter, was administered five times, at 1-week intervals, for 5 weeks of intensive therapy and five times, at approximately 1-month intervals, for approximately 5 months of maintenance therapy, to 13 patients with inflammatory bowel disease (IBD) diagnosed as ulcerative colitis (UC) in 8 and Crohns disease (CD) in 5. Clinical and blood examinations showed no side effects in any of the patients. During the intensive therapy, excellent or moderate clinical response was recognized in 11 of the 13 patients (84.6%), of whom 6 had a dramatic response; the excellent or moderate clinical response continued throughout the maintenance therapy in 8 of the patients (61.5%). Flow cytometry showed that the patients who had improved generally had high values for percentages of HLADR+, HLADR+CD3+, and HLADR+CD8+ cells before the first LCAP, and that these values and the C-reactive protein levels and erythrocyte sedimentation rates had decreased to the normal range by the end of both intensive and maintenance therapy. In the patients who showed poor response, in contrast, all the above values had been at or near normal before the initial LCAP administration. The clinical improvement in the absence of any additional medical treatment suggests that LCAP has the capacity to influence the causal mechanism(s) of IBD and that IBD is strongly associated with the cell-mediated immune response.

Association between IL-18 gene promoter polymorphisms and inflammatory bowel disease in a Japanese population

Background: Interleukin‐18 (IL‐18) is a pleiotropic cytokine that induces the production of interferon (IFN)‐&ggr; and also to regulate Th2 cytokines. Recently, association studies between IL‐18 gene promoter polymorphisms and several Th1‐ or Th2‐mediated inflammatory diseases were reported. In inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohns disease (CD), recent evidence suggests that IL‐18 is involved in the pathogenesis. Methods: Using DNA direct sequencing, we investigated IL‐18 gene promoter polymorphisms at −607C/A and −137G/C. Allele, genotype, and haplotype frequencies were determined in 210 Japanese patients with UC, 205 patients with CD, and 212 controls. Results: In UC, the −137C allele frequency was significantly higher in the proctitis‐type patients than in controls (Pc = 0.0068). The −137 genotype frequency was also significantly different in the proctitis‐type patients than in controls (Pc = 0.032). No other allele and genotype frequencies were significantly associated with UC after Bonferroni correction. Furthermore, the frequency of haplotype 2 (−607A, −137C), which had a lower promoter activity and IFN‐&ggr; mRNA level than the other haplotypes as previously reported, was significantly higher in the proctitis‐type patients than in controls (Pc = 0.01). In CD, we could not find any significant differences. Conclusions: IL‐18 gene promoter polymorphisms may not be associated with disease susceptibility but related to the extent of disease in UC.

Multivariate Analysis for Factors Predicting Rapid Response of Leukocytapheresis in Patients With Steroid-resistant Ulcerative Colitis: A Multicenter Prospective Open-label Study

Leukocytapheresis (LCAP) has been advocated as a treatment for moderate to severe active ulcerative colitis (UC) in Japan. To clarify the predictive factors for a rapid response to LCAP treatment, we conducted a multicenter prospective open‐label study. A total of 105 patients with UC were analyzed. LCAP was performed using a Cellsorba EX column once a week for 5–10 sessions. The response was evaluated by the clinical activity index (CAI). When the CAI score decreased to less than half the pretreatment value or to less than 5 points within 3 weeks, the patient was considered to be a rapid responder. The average CAI significantly decreased from 11.7 to 4.2 (P < 0.01). Seventy‐four percent of the patients responded to the therapy, and 53% of these patients were rapid responders. The following significant factors correlated with the rapid LCAP response: (i) steroid resistance (P < 0.05), (ii) severe disease indicated by a CAI score greater than 11 (P = 0.05), (iii) disease duration of less than 1 year (P < 0.05), and (iv) C‐reactive protein levels before treatment (P < 0.01). These results suggest that the early initiation of LCAP is beneficial in patients with steroid‐resistant UC.

Activated platelets as a possible early marker to predict clinical efficacy of leukocytapheresis in severe ulcerative colitis patients

BackgroundLeukocytapheresis (LCAP) is an effective adjunct for patients with active ulcerative colitis (UC). Because LCAP may have the potential to remove and modulate not only leukocytes but also platelets, we evaluated the correlation between activated platelets and the therapeutic response to LCAP.MethodsFourteen patients with severe UC received weekly LCAP for 5 consecutive weeks. Their average clinical activity index (CAI) and endoscopic index (EI) were 9.6 ± 3.4 and 10.9 ± 1.0, respectively. Their peripheral blood was sampled before and after every LCAP and stained with fluorescent antibodies to the activation-dependent surface antigens of platelets (CD63, CD62-P) prior to flow cytometry. Endoscopic evaluations were performed after the last LCAP.ResultsClinical remission (CAI < 4) was induced in 50% of the patients (7/14) after 5 weeks, and there were no significant differences observed in clinical background between the responder group (RG) and the nonresponder group (NG). In the RG, the populations of CD63+ (P < 0.03) and CD62-P+ (P < 0.05) platelets were significantly decreased after the first LCAP, and their reduction ratio decreased gradually with repeated LCAP. A significant improvement of the EI score, especially mucosal damage, was achieved in RG (P < 0.04) but not in NG.ConclusionsThese results indicate that the therapeutic responses to LCAP were reflected in modulations of population and/or platelet functions, especially after the first session. The decrease of such activated platelets immediately after the first LCAP may be an early marker for predicting the response in patients with severe UC.

Detection of Specific IgE Antibodies to Nafamostat Mesilate as an Indication of Possible Adverse Effects of Leukocytapheresis using Nafamostat Mesilate as Anticoagulant

Abstract: The aim was to determine whether adverse effects of leukocytapheresis (LCAP) are related to nafamostat mesilate (NM) as an anticoagulant. Anti‐NM IgE were detected in inflammatory bowel disease (IBD) patients who were administrated LCAP in our institute. Forty‐nine patients (ulcerative colitis (UC)/Crohns disease (CD): 30/19) were evaluated. Anti‐NM IgE was measured by the ELISA method. Total IgE level and eosinophil count was tested concurrently. We retrospectively checked the presence of allergic symptoms and medications used concurrently with LCAP. Anti‐NM IgE were present in six symptomatic patients (6/49; 12.2%) whose adverse effects were highly suspected to be from NM. However, 21 patients showed anti NM IgE‐negative, in spite of the fact that their adverse effects were also highly suspected to be from NM. Through the detection of anti‐NM IgE alone we could not estimate the relevance of NM  as  an  anticoagulant  to  the  adverse  effects  of  LCAP.

Exacerbated autoimmune hepatitis successfully treated with leukocytapheresis and bilirubin adsorption therapy.

A 58-year-old man with subacute fulminant onset of autoimmune hepatitis (AIH) was treated by leukocytapheresis (LCAP) and bilirubin adsorption therapy (BAT), rather than by administration of highdose corticosteroids as he had mild glucose intolerance, and a definitive diagnosis of AIH was not obtained on admission; further, there was a risk of viral infection. After initiation of the therapies, serum transaminases and bilirubin, immunoglobulins, anti-nuclear antibodies, and rheumatoid factor decreased rapidly, as did the initially high levels of activated cells and several pro-inflammatory cytokines. Liver inflammation observed on liver biopsy settled during the course of the therapies, with no adverse side effects. A pause in the therapies was associated with deterioration; however, restoration of apheresis was followed by normalization. Remission was sustained throughout the period monitored, except for a recurrence 14 months after discharge, which was successfully resolved by two additional LCAP sessions. These results suggest that LCAP influences the causal mechanism(s) of exacerbation of AIH.

A new treatment for HCV-ulcerative colitis comorbidity intolerant to INF-α

companied by signs of Albright osteodystrophy, but recessive and multifactorial inheritance are also described. Albright syndrome type I leads to the clinical picture of hypoparathyroidism with severely impaired enteral calcium absorption because of decreased 1hydroxylation of vitamin D3. Absence of the respective gene mutation of protein G (Gs ) in our patient as demonstrated by sequencing of exons 7–13 of the gene encoding Gs (GNAS-1) is still compatible with presence of subtype Ia, as most, but not all patients with the more common form, type Ia, have detectable mutation in the GNAS-1 (2–4). Hypoparathyroidism is considered a comparably rare cause of diarrhea in which correction of hypocalcemia may lead to normalized stool frequency. However, the exact pathophysiological mechanisms remain to be elucidated. Apart from impaired secretion of enteropancreatic peptides after a caloric stimulus (5), an increased permeability of the intestinal epithelium because of cytosceletal alterations has been suggested (6). After establishing the diagnosis, the patient received i.v. calcium (20 ml/10% thrice weekly) in addition to the oral calcium supplementation. Additionally, we switched the previously insufficient vitamin D supplementation from calcitriol to alfacalcidol (3 g/day in divided doses). This therapy resulted in prompt cessation of the diarrhea within a few days. Meanwhile, the treatment was switched to oral calcium supplementation (1 g/day). Currently, the patient reports three formed stools a day, and the muscle cramps have subsided. Most interestingly, in our patient, the diagnosis of pseudohypoparathyroidism was already suggested in 1977, which turned out after the patient showed his former medical record that he had stored away at home. Probably because of the reduced intelligence, this information was lost for more than 25 years.

A Suppository Chinese Medicine (Xilei-san) for Refractory Ulcerative Proctitis: A Pilot Clinical Trial

posed as a possible indication of peroral XS. We have hypothesized that XS might be a useful therapeutic option for active UP patients refractory to conventional topical therapies if it would be applied in suppository form. A prospective open-labeled clinical trial was held from April 1, 2005 to December 31, 2006 to evaluate the efficacy of SXS for active refractory UP patients. Mean ( 8 SD) age and duration of UP of the enrolled patients were 36.2 8 9.1 years and 56.3 8 47.4 months, respectively. All patients had an episode of treatment with a combination of either peroral 5Dear Sir, Six patients with active ulcerative proctitis (UP) (male/female = 2/4) were treated with an originally developed suppository Xilei-san (SXS), a traditional Chinese medicine, which is composed of watermelon frost, calcite, cow gallstone, peal powder, borax, borneol, indigo, and ammonium chloride. This mixed traditional medicine has a long history in China and it has been accepted as a medicine for erosions and ulcerations of the tongue, pharynx and oral cavity. The therapeutic mechanism of XS has never been fully understood, but some domestic reports inform that ulcerative colitis (UC) has been proPublished online: August 3, 2007

Poorly controlled ulcerative colitis treated by colectomy during remission induced by extracorporeal leukocyte removal therapy

Both monocyte-granulocytapheresis (M-GCAP) and leukocytapheresis (LCAP) are categorized as extracorporeal leukocyte removal therapies (ECCTs). These therapies have been recognized as efficient adjuncts for patients of steroid-resistant ulcerative colitis (UC). This study aimed to consider the adaptation and the limitation of these new therapies from the clinical standpoint based on a case of UC showing strong resistance to high-dose continuous steroid injection therapy. The patient successfully underwent a scheduled colectomy while maintaining remission after applying M-GCAP and LCAP independently. Surgical therapy was chosen because of a deep ulcer in the patients sigmoid colon, which was assumed to constitute a future risk for perforation. This case suggests that combining ECCT with steroid therapy can maintain such poorly controlled and high-risk UC patients safely for the scheduled colectomy while improving the prognosis by reducing the dosage of steroid efficiently prior to operation.

Extracorporeal Monocyte Granulocytapheresis was Effective for a Patient of Erythema Nodosum Concomitant withUlcerative Colitis

Abstract:  We report an erythema nodosum (EN) patient whose condition becameapparent during the clinical course of ulcerative colitis (UC).The patient relapsed frequently in spite of taking a high dose adrenocorticalsteroid during his morbidity period of UC. Monocyte‐granulocytapheresis(M‐GCAP) was combined with 5‐aminosalicylic acid 2250 mg/dayperoral and once a day of steroid enema. Monocyte‐granulocytapheresiswas performed once a week for 5 weeks, and succeeded in inducingclinical remission for both UC and EN. The immunological and clinical connectionsbetween UC and EN have never been fully elucidated. In this case,because the symptoms of UC and EN revealed parallel improvementafter his inflammatory reaction had been brought under control by combining M‐GCAP therapy, we hypothesize that theonset of EN appeared as a result of the patients long‐term,treatment‐resistant immuno‐disturbance, which first appeared as symptomsof UC. Immunomodulative effects induced by M‐GCAP might help tocontrol other chronic non‐specific inflammations not concerned withtargeted organ(s).