Steroid-dependent Patients Research Articles

Leucocytapheresis for ulcerative colitis

1 d 0 patients with active ulcerative colitis (UC) treated with up o 10 apheresis sessions using an adsorptive column containng cellulose acetate beads. Fifty patients improved, of which 4 went into remission, and the courses of treatment allowed eduction in steroid intake by the steroid-dependent patients. hese data resemble those published by several other authors 2–4]. In this commentary, we discuss the theory behind using eucocytapheresis to treat IBD, its different forms, the way in hich these remove leucocytes, and the indications, efficacy, afety, and possible future role of leucocytapheresis. One of the key pathogenic processes in IBD is the loss f the gut’s normal tolerance to luminal bacteria, resulting n an inflammatory response with influx into the mucosa of arge numbers of neutrophils and monocytes. Removal of ctivated circulating leucocytes, and their replacement with leucocytes, either by passing venous blood through an adsorptive system, or by centrifugation. Of the two commonly used adsorptive systems, one contains cellulose acetate beads (Adacolumn, Japan Immunoresearch Laboratories, Takasaki, Japan) and the other, a polyester fibre filter (Cellsorba, Asahi Medical Company, Tokyo, Japan). The mechanisms and consequences of leucocyte removal differ between the systems. Interaction between blood and cellulose acetate beads causes complement activation and the production of active fragments such as C3a and C5a, which are potent neutrophil activators. These fragments, along with immunoglobulin, bind to the beads causing leucocytes expressing Fc R or complement receptors to be adsorbed [9]; the system removes about 65% of neutrophils, 55% of monocytes and 2% of lymphocytes. The polyester fibre filter system not only removes leucocytes by adsorption but also mechanically filters blood cells. This one marrow-derived unactivated leucocytes is, therefore, a herapeutically attractive principle. Apheresis appears to acomplish this goal; although the overall number of circulatng leucocytes may not be decreased by leucocytapheresis, he proportion of neutrophils with an immature phenotype results in the removal of almost 100% of neutrophils and monocytes, and 20–60% of lymphocytes [10]. Centrifugation is at least as effective at removing leucocytes as adsorptive columns [4] and has been claimed to be more effective in the treatment of UC [11].

Primary and secondary osteoporosis' incidence of subsequent vertebral compression fractures after kyphoplasty.

Retrospective review of prospective database. Define the incidence of adjacent and remote fractures after kyphoplasty vertebral augmentation, and identify vulnerable subpopulations at increased risks. Painful osteoporotic compression fractures can be effectively treated with methyl methacrylate vertebral augmentation, but the effect of intervention on the generation of future remote and adjacent fractures has not been identified. No paper has analyzed the association of long-term steroid use to subsequent compression fractures. A total of 175 patients were treated for compression fractures, from October 1999 to November 2001, 60 patients were excluded due to insufficient follow-up (less than 3 months) or malignancy related fracture. The remaining 115 patients' charts and radiographs were then individually analyzed. New fractures were identified based on changes from baseline imaging studies (). Demographic information, vertebral levels treated, adjacent fractures, and remote fractures underwent statistical analyzed (P < 0.05). A total of 225 vertebral bodies were treated in 115 patients using the kyphoplasty technique; of those, 26 patients developed 34 subsequent compression fractures. The mean follow-up was 11 months (range, 3-33 months). The incidence of subsequent fracture per procedure per kyphoplasty was 15.1% (34 of 225), overall incidence per patient was 22.6% (26 of 115). There were 80 patients with primary osteoporosis and 35 patients with secondary steroid-induced osteoporosis. These populations were similar in terms of demographics, single or multiple sites, along with two or three adjacent levels treated. Seventeen of the 26 (65%) patients with subsequent fracture had secondary steroid-induced osteoporosis, while only 9 of the 26 (35%) patients had primary osteoporosis. Therefore, the incidence of post-kyphoplasty VCF in the primary osteoporotic patient was 11.25% (9 of 80) and the incidence in the steroid-induced osteoporotic patient was 48.6% (17 of 35). This increased fracture rate in the steroid-dependent patients was significant (P < 0.0001), along with adjacent fractures (12 of 19 on steroids, P = 0.0009), and remote fractures (7 of 9 on steroids, P = 0.027). Steroid-induced compression fractures appear to have an increased incidence of subsequent fractures after the kyphoplasty procedure. The kyphoplasty protocol with concurrent medical osteoporotic regimen does not appear to increase, and may serve to reduce, the incidence of remote and adjacent fractures for primary osteoporotic fractures.

MYCOPHENOLATE MOFETIL (CELLCEPT®) ASSOCIATED ENTEROCOLITIS

Mycophenolate mofetil (Cellcept®) inhibits purine synthesis and is a commonly used agent in immunosuppression regimens for patients after solid organ transplantation. In addition mycophenolate mofetil (MMF) has also been used experimentally in steroid resistant or steroid dependent inflammatory bowel disease patients. Gastrointestinal side effects are the most common adverse reaction with diarrhea affecting as many as 31 % to 51 % of patients taking MMF. We describe a renal transplant recipient who developed ileocolitis related to MMF. A 28 year old man presented to the emergency room 19 months after under-going a living-related renal transplant with malaise, nausea, and two weeks of diarrhea which became bloody several days prior to admission. Medications included prednisone, tacrolimus, mycophenolate mofetil, gemfibrozil, clonidine, quetiapine, pioglitazone and buproprion. Pertinent admission labs: WBC 3.9 with 33% poly s and 11 % bands, Hct 25.8, platelets 320K, creatinine 3.4, and BUN 60. Stool samples were negative for clostridium difficile toxin and enteric pathogens. An empiric course of levofloxacin did not improve his symptoms. The patient developed progressive hematochezia, nausea, vomiting, and abdominal pain. Colonoscopy demonstrated diffuse areas of ulceration involving the terminal ileum, cecum, ascending colon and transverse colon. There was sparing of the left colon and rectum. Pathology of the terminal ileum demonstrated severe atrophy, reparative changes, mucus depletion, edema, inflammation and prominent apoptosis. Colonic biopsies demonstrated cryptitis, crypt distortion, atrophy and prominent apoptosis. No viral inclusions were seen and immunostains for CMV were negative. A diagnosis of erosive enterocolitis associated with MMF was made. The MMF dose was reduced and his symptoms resolved. He remains well 12 months later without recurrent diarrhea. Clinicians caring for patients on mycophenolate mofetil must be aware of the commonly encountered gastrointestinal side effects. The frequency of gastrointestinal side effects appear to be dose related and may first present months after initiation of therapy. Dose reduction may result in symptom resolution. The histology of MMF related erosive enterocolitis has features similar to graft-versus-host disease predominantly demonstrating apoptosis. Gastrointestinal side effects of mycophenolate mofetil may limit its use as an immunosuppressive agent in patients with inflammatory bowel disease.

Adsorptive Granulocyte and Monocyte Apheresis versus Prednisolone in Patients with Corticosteroid-Dependent Moderately Severe Ulcerative Colitis

Background/Aim: Active ulcerative colitis (UC) is often associated with increased peripheral granulocytes and monocytes/macrophages which show activation behavior and prolonged survival time. Further, mucosal granulocyte level parallels intestinal inflammation and can predict UC relapse. Accordingly, our aim was to see if adsorptive granulocyte/monocyte apheresis (GMA) can promote remission and spare steroid in patients with steroid-dependent (SD) UC. Methods: 69 SD patients, at the time of relapse, were randomly assigned to groups I (n = 46) and II (n = 23). The mean dose of prednisolone (PSL) was 12 mg/day/patient, CAI (clinical activity index) 9.2 in both groups. Group I patients were given up to 11 GMA sessions over 10 weeks with Adacolumn; in group II, the mean dose of PSL was increased to 30 mg/day/patient. Results: At week 12, 83% of group I and 65% of group II patients were in remission, CAI in group I was 1.7 (p < 0.001) and in group II, 2.5 (p < 0.001). Further, during the 12 weeks of treatment, the cumulative amount of PSL received per patient was 1,157 mg in group I and 1,938 mg in group II (p = 0.001). Conclusions: GMA appeared to be an effective adjunct to standard drug therapy of moderately severe UC by promoting remission and sparing steroids.

Efficacy of intravenous immunoglobulin in chronic idiopathic pericarditis: report of four cases

Human intravenous immunoglobulins (hIVIgs) are used in two broad categories of diseases: immunodeficiency and autoimmunity. Among the immune-mediated diseases hIVIgs are of benefit in idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and dermatomyositis. Chronic idiopathic pericarditis (CIP) is a chronic disease of unknown origin characterized by recurrent episodes of pericardial inflammation. The cause of the recurrence is unknown, although in some cases it may be traced to a viral infection and to the presence of antimyocardial antibodies. Since a viral infection can induce an autoimmune process through a mechanism of molecular mimicry, and since the optimal therapy for prevention of the recurrences has not been established, we reasoned that treatment with hIVIgs could be beneficial in our patients unresponsive to previous immunosuppressive therapies. We describe four patients affected by CIP treated with monthly high-dose hIVIgs (0.4 g/kg daily for 5 consecutive days) for five times followed by administration every 2 months. Three of the four patients could permanently discontinue steroid therapy and are still in remission after years of follow-up. Our experience suggests that hIVIgs therapy may be a useful and safe treatment for CIP in steroid-dependent patients.

Efficacy and safety of thiopurinic immunomodulators (azathioprine and mercaptopurine) in steroid-dependent ulcerative colitis.

The efficacy of azathioprine in the management of steroid-dependent ulcerative colitis is taken for granted. However, study populations frequently include together steroid-dependent and refractory patients. To assess the efficacy and safety of thiopurinic immunomodulators in strictly defined steroid-dependent ulcerative colitis. Survey of 34 patients with steroid-dependent ulcerative colitis, treated with azathioprine according to protocol. Therapeutical success: glucocorticoid withdrawal within 12 months, without steroid requirements during another year. Mean age was 39.1 +/- 17 years. Pancolitis and extensive colitis accounted for 50% of cases. Therapeutic success of immunomodulator treatment reached 70.6%, intention to treat analysis (confidence interval 95%: 52-84%) and 72.7%, as per protocol (confidence interval 95%: 54-86%). Mean time to steroid withdrawal was 4.6 months. In therapy successes, mean corpuscular volume and total serum bilirubin increased with treatment time (P = 0.0001). Fifteen adverse effects were observed in 13 patients (38%). Azathioprine was withdrawn in seven cases (20.6%); in four of them (with liver toxicity), treatment with mercaptopurine was indicated. Therapy with thiopurinic immunomodulators (azathioprine) represents the first option in the management of steroid-dependent ulcerative colitis. Its efficacy (70%) and its acceptable safety support this view. Increasing mean corpuscular volume and serum bilirubin values may be a surrogate marker of a beneficial effect.

P0680 LEUKOCITE ADSORPTIVE APHERESIS IN PAEDIATRIC INFLAMMATORY BOWEL DISEASE: SAFETY, TOLERANCE AND PRELIMINARY DATA OF EFFICACY

Introduction: Granulocytapheresis has proved its efficacy in adult IBD(1).Granulocytemonocyte(GM) apheresis is carried out with a column filled with cellulose diacetate beads (Adacolumn, Japan Immunoreseach Laboratories, Takasaki, Japan) that adsorb circulating GM. Reduction of activated GM and its immunomodulatory effect(2) results in alleviation of inflammation and promotes remission. No severe side-effects have been reported. Methods: These are the preliminary data of a multicenter pilot study on efficacy, safety and tolerance of Granulocytapheresis in paediatric IBD. Steroid-refractory and steroid-dependent ulcerative colitis patients and Crohn’s disease patients unresponsive to conventional treatments, aged 12–18 years (weigth >30kgs), are eligible. Granulocytapheresis is performed as previously described (1). Results: Patient 1: 15 year-old boy, with active ileocolic Crohn’s disease and perianal fistula for two years. Previous treatments: enteral nutrition,5-ASA,azathioprine, antibiotics,infliximab. PCDAI before apheresis: 35. Sessions were well tolerated. No complications nor side effects owing to apheresis. 3 weeks after last session, he is in remission(PCDAI:5). No gastrointestinal symptoms, mild perianal disease and decreased inflammation markers. He has gained 4.8 kgs in two months. Patient 2: 14 year-old girl. Stricturing ileo-colic Crohn’s disease since 9 years of age without response to enteral nutrition,5-ASA, azathioprine, infliximab. PCDAI before apheresis: 52’5. Sessions well tolerated, no complications nor side-effects. No remission of her moderate flare-up (PCDAI30), no changes in inflammatory markers. Due to persistence of her symptoms, methrotexate treatment was begun. Conclusion: Granulocytapheresis is a safe and well tolerated treatment in paediatric IBD. We have not seen any complication nor side-effect due to the technique in our two patients. We hope to reach conclusions on its efficacy once our study is finished.

Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients

Most chronic inflammatory diseases are well controlled by glucocorticoids. However, a minority of patients fails to respond adequately to this treatment. We wished to determine whether glucocorticoid insensitivity in a group of steroid-resistant (SR) and steroid-dependent (SD) asthmatic subjects resulted from an inability of the glucocorticoid receptor (GR) to translocate into the nucleus. Glucocorticoid receptor nuclear translocation was determined in PBMCs by immunocytochemistry and GR function measured by suppression of TNF-alpha-induced GM-CSF release and effects of dexamethasone on histone acetylation. Glucocorticoid repression of TNF-alpha-induced GM-CSF release was reduced in PBMCs from SD and SR patients. This inhibition correlated with a failure of GR to translocate into the nucleus and induce histone acetylation in response to dexamethasone. In addition, dexamethasone failed to inhibit TNF-alpha-induced histone acetyltransferase activity, which predominantly targeted histone residues lysine (K)8 and K12. However, in a subset of patients, even high levels of GR nuclear translocation failed to produce histone acetylation in response to dexamethasone. Histone H4 K5 acetylation, a marker of dexamethasone transactivation, was specifically reduced in this group. However, cells from this subset of steroid-insensitive subjects were still capable of inhibiting TNF-alpha-induced histone acetylation. We have identified a novel mechanism of glucocorticoid insensitivity in a group of SR and SD subjects. These data suggest that most patients respond to glucocorticoids according to the degree of GR nuclear translocation occurring, but some subjects with steroid resistance have a reduced response because of a failure of steroids to transactivate, rather than transrepress.

Single-dose daily administration of cyclosporin A for relapsing nephrotic syndrome.

Cyclosporin A (CsA) has been reported to be effective as a steroid-sparing agent in frequently relapsing nephrotic syndrome (FRNS). However, low efficacy has sometimes been observed in selected patients with steroid-dependent FRNS. We speculated that a low peak level of CsA in the blood might be the cause, and conducted a prospective pilot study on such steroid-dependent FRNS patients to examine whether single-dose daily administration of CsA would yield a sufficient peak blood level, and therefore a satisfactory steroid-sparing effect. Five children with steroid-dependent FRNS, aged 7-16 years, were enrolled in the study. All had been treated with prednisolone combined with twice daily CsA ( T), which was subsequently replaced with the single-dose daily administration protocol ( S), because of a poor steroid-sparing effect. Although the mean daily CsA dosage with the S protocol was significantly lower than with the T protocol ( S 2.4+/-1.1 mg/kg per day vs. T 3.6+/-0.8 mg/kg per day, P<0.05), the mean peak blood level tended to be higher with the S protocol than the T protocol ( S 764+/-122 ng/ml vs. T 358+/-250 ng/ml, P=0.1797) without mean trough blood level elevation. As a result, the minimum dose of prednisolone required for maintenance of clinical remission tended to be lower with the S than the T protocol ( S 0.4+/-0.2 mg/kg on alternate days vs. T 0.6+/-0.4 mg/kg on alternate days, P=0.0656). No evidence of CsA nephrotoxicity was observed in a repeat renal biopsy performed 9 months after commencement of the S protocol in one patient. These clinical observations, although on a small number of patients and preliminary, suggest that single-dose daily administration of CsA might be an attractive protocol in selected patients with steroid-dependent FRNS in whom CsA administration by the conventional protocol is associated with a poor steroid-sparing effect.

Efficacy and Effective Endoscopic Findings of Granulocyte and Monocyte Absorption Apheresis (GCAP) and Leukocytapheresis (LCAP) Therapy in Patients with Refractory Active Ulcerative Colitis (UC)

Background: UC is a chronic inflammatory bowel disease of unknown etiology. Frequent relapse often results in long-term medication and impaired quality of life of the patients. Recently it has been proved that GCAP and LCAP are effective and safe for patients with moderate to severe UC. Aim: The aim of the present study is to prove efficacy and endoscopic findings of GCAP and LCAP in active UC patients, especially in refractory and steroid-dependent cases. Subjects and methods: Active UC patients (Mean age 39.8; Duration of the disease 5.6 years; 19 male, 9 female; 24 total colitis, 4 left-sided colitis; 18 refractory to conventional therapy and 7 steroid dependent) were treated with GCAP (n=18) or LCAP (n=10). The patients received one or two GCAP/LCAP session per week for 5 consecutive weeks. And the patients received colonoscopy before and after GCAP/LCAP session. Results: About 68 % of the patients achieved clinical response, and no severe adverse-effects were observed. Most of steroid-dependent patients or patients who had side-effect due to steroid (6 osteoporosis, 3 diabetes, 1 compression fracture of lumbar vertebra, 1 femoral bone necrosis, 1 schizophrenia, 1 erythema nodosum) were successfully controlled. Seven patients underwent scheduled colectomy for future exacerbation of the disease in remission stage and one patient with semi-emergent operation. Endoscopically, 12/14 cases with shallow ulcers and erosion throughout the colon and 7/12 with deep ulcerations responded to the treatment, however, 2 with massive ulceration of whole mucosa did not respond. Conclusion: GCAP/LCAP were valuable therapies for refractory or steroid-dependent patients, and endoscopic findings are helpful in expecting clinical effectiveness.

Leflunomide treatment of Crohn's disease patients intolerant to standard immunomodulator therapy.

Immunomodulator therapy with the purine analogs azathioprine and 6-mercaptopurine (6-MP), is efficacious in the treatment of moderate to severe Crohn's disease (CD), but is not tolerated by a significant minority of patients. The pyrimidine analog, leflunomide, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) patients. Because established RA immunomodulator agents may demonstrate success in the treatment of CD, we reviewed our clinical open-label experience with leflunomide in a refractory CD population. GOALS Assess the effect of leflunomide 20 mg daily, on disease activity, steroid requirement and serologic measures of inflammatory activity in our series of CD patients intolerant to azathioprine/6-MP. CD patients intolerant of azathioprine/6-MP were offered leflunomide treatment. The Harvey-Bradshaw (H-B) disease activity index, global assessment, serologic parameters and ability to taper corticosteroids of those who accepted were retrospectively assessed. Leflunomide was well tolerated and resulted in a significant reduction in the H-B score, global assessment and serologic parameters in 8/12 patients. Average follow-up was 38 weeks and a majority of steroid-dependent patients were able to successfully taper following leflunomide initiation. Our case series demonstrates that the pyrimidine analog leflunomide may be effective for treating moderate to severe CD patients intolerant to standard immunomodulator therapy and warrants further investigation in a randomized controlled trial.

Colchicine as an oral corticosteroid sparing agent for asthma.

Oral corticosteroids are used as a treatment for asthma, but they are often associated with serious side effects. Colchicine is an anti-inflammatory, immuno modulating agent, which could potentially have a beneficial effect in the treatment of asthma as well as act as a steroid-sparing agent. To determine the effectiveness of colchicine as an oral corticosteroid sparing agent for in the treatment of chronic asthma. We searched the Cochrane Airways Group trials register (November 2002), SIGLE (1980 to 2001) and reference lists of potential articles. We also contacted researchers in the field. Randomised controlled trials investigating the addition of colchicine compared to placebo in stable steroid dependent asthmatics. No trials were found that met the inclusion criteria. We were unable to perform any meta-analyses. Two small studies have assessed the efficacy of colchicine subsequent to inhaled steroid withdrawal and as a tapering agent in inhaled steroids. Both studies failed to detect a significant difference between colchicine and placebo. No relevant trials have been published, so there is no evidence to indicate that colchicine is beneficial or otherwise in the management of steroid-dependent asthmatic patients. There is a need for well designed randomised controlled trials to be performed.

Human Alloreactive CTL Interactions with Gliomas and with Those Having Upregulated HLA Expression from Exogenous IFN-γ or IFN-γ Gene Modification

By flow cytometry, a panel of 18 primary glioma cell explants exhibited high expression of class I HLA-A, B, C, but class II HLA-DR expression was absent. Freshly isolated normal brain cells displayed little or no HLA antigens. Alloreactive cytotoxic T lymphocytes (aCTL), sensitized to the HLA of the patient, were generated in a one-way mixed lymphocyte response (MLR). The specificity of aCTL was confirmed to be to target cells (patient glioma cells or lymphoblasts) expressing the relevant HLA antigens. However, nontumor patient-specific aCTL did not lyse normal brain cells. Titration of antibodies to HLA class I into cytotoxicity assays blocked lysis of gliomas by aCTL, confirming aCTL T cell receptor (TCR) interactions with the class I antigen on gliomas. Furthermore, aCTL interactions with glioma cells caused their apoptosis. Coincubations of aCTL with gliomas resulted in upregulated cytokine secretion. Importantly, dexamethasone, an immunosuppressive steroid used for brain edema, did not affect aCTL lytic function against tumor, indicating that steroid-dependent patients may benefit from the immunotherapy. We also explored the use of interferon-gamma (IFN-gamma) to increase aCTL tumor recognition. Coincubation of gliomas with exogenous IFN-gamma (500 U/ml, 48 h) caused a 3-fold upregulation of HLA class I and a slight induction of class II antigen expression. Gene-modified glioma cells producing IFN-gamma similarly displayed upregulated HLA expression. Glioma cells incubated with exogenous IFN-gamma or IFN-gamma-transduced glioma cells were more susceptible to lysis by aCTL than their parental counterparts, thus supporting the concept of combining IFN-gamma cytokine gene therapy with adoptive aCTL immunotherapy for brain tumor treatment.

Remission maintenance by tioguanine in chronic active Crohn's disease.

Tioguanine may offer an alternative for immunosuppression in chronic active Crohn's disease. Recently, we have shown that tioguanine is effective in inducing rapid remission. To evaluate the role of tioguanine in the maintenance of remission in chronic active Crohn's disease. A follow-up study was performed to investigate the long-term efficacy and safety of and tolerance to tioguanine in chronic active Crohn's disease. Sixteen patients who had successfully received 6-tioguanine for remission induction were enrolled. The reasons for immunosuppressive therapy were steroid dependence (n = 10), steroid refractoriness (n = 6) and intolerance (n = 6) or refractoriness (n = 1) to azathioprine. After remission induction therapy for 6 months, patients were treated for another 6 months with a daily dose of 20-40 mg tioguanine. Primary outcomes were remission (Crohn's disease activity index < 150) and complete steroid reduction in steroid-dependent patients at 12 months. Laboratory controls of white blood count and liver enzymes, as well as erythrocyte tioguanine nucleotide levels, were performed regularly. After 12 months of treatment, 14 of 16 (88%) patients were in remission, and 12 of these were completely free of systemic steroids. Adverse events during maintenance therapy included photosensitivity (one patient), minor viral infections (one), headache (four) and mild alopecia (one). One patient developed elevated liver enzymes, splenomegaly and thrombocytopenia, indicative of nodular regenerative hyperplasia of the liver. In responders to tioguanine, the drug appears to be very effective in maintaining remission of chronic active Crohn's disease. Unfortunately, long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction. Therefore, to date, tioguanine cannot be recommended for general use outside clinical trials.

Mycophenolate mofetil in refractory inflammatory bowel disease.

Mycophenolate mofetil has been claimed to be effective and well tolerated in refractory inflammatory bowel disease although there is little information regarding its use in clinical practice. To review our experience in achieving and maintaining remission in refractory inflammatory bowel disease and to document tolerability, major toxicity and efficacy. A retrospective audit was performed of the records of all patients with inflammatory bowel disease treated with mycophenolate mofetil (1-2 g/day) over a 3-year period. Thirty-nine patients were identified. Almost all had been intolerant of, or had not responded to azathioprine, and 38 were steroid-dependent. mycophenolate mofetil was discontinued in 22 patients, 11 due to intolerance and 10 because of lack of efficacy. Of the 17 on treatment at the end of the study period 16 were in remission and off all steroid therapy, but one needed infliximab to maintain remission. No major toxicity was noted and there was no major sepsis. Approximately 40% of patients with severe refractory inflammatory bowel disease achieved remission and complete steroid withdrawal on mycophenolate mofetil therapy, almost 30% could not tolerate the drug, and a further 30% did not respond. Mycophenolate mofetil therapy may have a role for steroid-dependent patients refractory to azathioprine.

Cytokine and anti-cytokine therapies for inflammatory bowel disease.

Although the pathogenesis of inflammatory bowel disease (IBD) remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Current disease management guidelines have therefore focused on the use of anti-inflammatory agents, aminosalicylates and corticosteroids. These conventional therapies continue to be a first choice in the management of IBD. Immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate or cyclosporin, are demonstrating increasing importance against steroid-resistant and steroid-dependent patients. However, some patients are still refractory to these therapies. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Other immunosuppressive agents including FK506 and thalidomide have expanded the choice of medical therapies available for certain subgroups of patients. Furthermore, biological therapies have begun to assume a prominent role. Studies with chimeric monoclonal anti-TNF-alpha antibody treatment have been reported with dramatic successes. However, observations in larger numbers of treated patients are needed to explicate fully the safety of or risks posed by this agent such as developing lymphoma, or other malignancies. Another anti-inflammatory cytokine-therapy includes anti anti-IL-6R, anti-IL-12 or toxin-conjugated anti IL-7R, recombinant cytokines (IL-10 or IL-11). Given the diversity of proinflammatory products under its control, NF-kappaB may be viewed as a master switch in lymphocytes and macrophages, regulating inflammation and immunity. Although some of them still need more confirmatory studies, those immune therapies will provide new insights into cell-based and gene-based treatment against IBD in near future.

Management of Crohn's disease (CD) of the ileoanal pouch with infixinab

Background: 6-Thioguamne (6-TG) may offer an ahernative in immunosuppression for chronic active Crohn's disease (CD) Recently, we showed 6-TG to be rapidly effective in remi~ion induction therapy (Herr/inger etal . , AP&fff in press). To evaluate its role in remission maintenance we conducted a tbilc~w-up study to investigate the long-term efficacy, safety and tolerance of 6-TG in chi'nnic active CD. Patients and Methods: 16 patients who had succes~sb.llly recmved 6-thiognanine tor remission induction were enrolled. Reasons [br immunosuppressiw therapy were steroid-dependency (n = 10), steroid-reti'act oriness (n = 6), and/or intoleance (n = 6) or ret}actoriness (n = 1 ) to azathioprine (Aza), respectively. After the remission induction therapy of six months patients were treated for another st',: months with a &fly dose of 20 to 40rag 6-TG. Primary outcomes were clinical remission (CDAI< 150) and complete steroid-reduction in steroid-dependent patients at month 12. Laboratory controls of white blood count and liver enzymes as well as measurement of erythmcyte 6thioguanine nucleotides (TGN) were performed regulanly Results: Afier 12 months of treatmer~t 14/16 patients were in clinical remission. All but three patients were completely weaned from systemic steroids. At month 12 four of 16 patients were successfnlly switched to ~.a, one patient received methotrexate and relapsed. Three patients refused further treatment and two of them relapsed four months later. Eight patients are still on 6-thiognanine with a daily dose of 10 to 20mg and in remission. Adverse events during maintenance therapy included photosensitivity (n:l), minor viral infections (1), headache (4) and mild alopecia (1) One patient developed elevated liver enzymes, splenomegaly and thrombocytopenia. This patient recovered within 24 weeks after stopping 6-thinguanine. Conclusimrs: 6-Thingnamne appears to be very effective in remission maintanance therapy in chronic active Cmhn's disease Unfortunately', long-term bepatotoxlciy seems to be an unpredictable and potentially severe prohlem Tberetore, fi'om our point of view to date 6-TG can not be recommended tbr general use outside controlled trials.

Extracorporeal photopheresis therapy in the management of steroid-refractory or steroid-dependent cutaneous chronic graft-versus-host disease after allogeneic stem cell transplantation: feasibility and results.

We conducted a retrospective analysis of all allogeneic stem cell transplantation (ASCT) patients started on extracorporeal photopheresis (ECP) for the management of steroid-dependent (SD) or steroid-refractory (SR) cutaneous chronic graft-versus-host disease (cGVHD) following ASCT during a 36-month period (9/98-8/01). Only SD or SR patients who were treated by ECP after day 100 and who received at least 4 weeks of ECP were considered evaluable for this analysis. Out of 64 ASCT patients reviewed, 32 patients met the inclusion criteria. All 32 patients had been previously treated with systemic corticosteroids with 11 (34%) being SR and 21 (66%) SD. Cutaneous cGVHD was extensive in 28 patients (88%) and was accompanied by visceral (hepatic, gastrointestinal) cGVHD in 23 patients (72%). The 32 evaluated patients had received a median of three prior therapies before ECP, most commonly systemic corticosteroids, tacrolimus, and mycophenolate mofetil. Patients received a median of 36 ECP sessions (range 12-98) over a median of 5.3 months (range 1-28), with a median of six sessions per month. The complete response (CR) rate was 22% (n=7) and the partial response rate was 34% (n=11). In all, 28 patients were on systemic corticosteroid therapy at ECP initiation and 18 patients achieved 50% dose reduction while on ECP, yielding a 64% steroid-sparing response rate. Of seven CRs, five are ongoing. A total of 11 (34%) patients have died after ECP, with all cases due to visceral cGVHD or cGVHD-related infectious complications. All 21 surviving patients remain on at least some immunosuppressive cGVHD therapy (including ECP in eight). Overall, ECP displays a substantial response rate and, in particular, steroid-sparing activity in SR/SD extensive cutaneous cGVHD. However, most patients continue to require at least some chronic therapy and cGVHD-related morbidity and mortality remain high.

Comparison of the efficacy and safety of high doses of beclometasone dipropionate suspension for nebulization and beclometasone dipropionate via a metered-dose inhaler in steroid-dependent adults with moderate to severe asthma

Nebulization for the administration of high doses of inhaled corticosteroids can benefit steroid-dependent asthmatics. The objective of this double-blind, double-dummy, multicentre, randomized, prallel-group study was to compare the efficacy and safety of high-dose corticosteroids given by nebulization or metered-dose inhalation in adult patients with asthma. Following a 2-week run-in period, 124 patients, aged 18–70 years, with moderate to severe asthma treated with high-dose inhaled steroids were randomized to one of two treatment groups for 12 weeks: beclometasone dipropionate (BDP) suspension for nebulization 3000–4000 μg day −1 b.i.d. given via a nebulizer ( n=63), or BDP spray 1500–2000 μg day −1 b.i.d. given via a metered-dose inhaler (MDI) plus spacer (BDP MDI) ( n=61). Comparable improvements over baseline, which were statistically significant in most cases, were reported at study end for the two treatment groups in the various efficacy parameters evaluated (pulmonary function tests, clinical symptoms scores, and the use of rescue salbutamol). The primary efficacy endpoint was morning pulmonary expiratory flow rate (PEFR). For the intent-to-treat population, in the BDP nebulization group mean morning PEFR increased statistically significantly from 308.7 ± 107.81 min −1 to 319.2 ± 104.01 min −1, while in the BDP MDI group the increase was from 301.5 ± 94.71 min −1 to 309.3 ± 86.71 min −1. The two treatments were equally well tolerated. A total of 19 patients in each group reported adverse events during the treatment period, and these were generally mild-moderate in severity. In conclusion, the results of this study demonstrate that BDP suspension for nebulization 3000–4000 μg day −1 given via a nebulizer and BDP spray 1500–2000 μg day −1 given van an MDI plus spacer are equally effective, with an acceptable safety and tolerability profile, when used in steroid-dependent adult patients with moderate to severe asthma.

Open-Label Trial of High-Dose Intravenous Immunoglobulin in Patients with Severe Asthma

Anti-inflammatory corticosteroid therapy is highly effective, however, the long term adverse effects may be devastating for patients with severe asthma. Intravenous immunoglobulin (IVIG) is known to have immunomodulatory effects, and in a few clinical trials has been shown to have potential benefit as a steroid-sparing agent in asthma patients requiring high doses of corticosteroids. This study assessed the efficacy of high-dose IVIG in reducing the steroid requirement and subsequently improving the pulmonary function, symptomatology, and quality of life in patients with severe steroid-dependent asthma. Six immunocompetent, steroid-dependent patients were enrolled in an open-label trial of IVIG given as six monthly infusions of 2 g/kg per dose. Five patients completed the study. Of these, four showed a significant reduction in oral corticosteroid requirement while being treated with IVIG. The mean reduction was 10.1 mg/d (p = 0.02), which was an almost 50% decrease in corticosteroid requirement. Two patie...