Intravenous Cyclosporine Research Articles

Irradiation of Donor Mononuclear Cells for Treatment of Chemorefractory Metastatic Solid Cancers: A Community-Based Immune Transplant Pilot Study

PurposeChemotherapy has demonstrated ability to generate tumor antigens secondary to induction of apoptosis, against which human leukocyte antigen-compatible, irradiated, related donor mononuclear cells may be administered with immune stimulation to activate antigen presenting and cytotoxic T cells, while minimizing risk of graft-versus-host disease (GVHD). The present study endeavours to describe feasibility and efficacy of this treatment, specifically in the community setting.Materials and MethodsEligible patients had rapidly progressive, chemorefractory metastatic solid tumors. Treatment consisted of intravenous etoposide and cyclosporine for three days followed by granulocyte-macrophage colony-stimulating factor for 5 days. The following week, 5×107 haploidentical or more closely matched irradiated donor mononuclear cells were given weekly for 10 weeks along with interleukin-2.ResultsThree patients were enrolled, and the regimen was well-tolerated, with no GVHD observed. All patients had clinical response, despite advanced and heavily pretreated disease.ConclusionThe above-outlined protocol demonstrates favorable tolerability and efficacy, and appears to be feasible in the community setting. While the optimal chemotherapy, immunostimulation, and irradiation regimens may be further optimized, future investigation appears warranted, and may include community oncology programs.

Surgery is a real alternative to rescue therapy in patients with steroid-refractory ulcerative colitis

Dear Editor: The life-time risk of a fulminant flare of ulcerative colitis, which is a potentially life-threatening condition, is approximately 15–20 %. The mainstay of conventional therapy is intravenous corticosteroids of 1 mg/bwkg, however approximately one third of the patients fail to respond to a 3to 5-day intensive intravenous regimen, which sets up an interdisciplinary challenge for the surgeon and internist alike. The three options to be considered are intravenous cyclosporin (CsA) therapy, infliximab (IFX) treatment or total proctocolectomy. With the introduction of CsA in the early 1990, the rate of urgent colectomies decreased, since 76 % to 86 % of the patients will initially respond to CsA rescue medication, thus avoiding colectomy in the short run. However, 88 % of patients initially responding to CsA rescue therapy will require colectomy upon 7 years of follow-up and CsA use is still restricted by potential serious adverse events. Colectomy and receiving even a temporary stoma are of the most fearful complications for patients with inflammatory bowel disease. The recommended surgical procedure is restorative proctocolectomy with ileal pouch anal anastomosis (IPAA), which is considered to be a cure for ulcerative colitis; however, reports on functional outcome and postoperative quality of life are contradictory and a variety of complications can occur after surgery. In steroid-refractory ulcerative colitis our therapeutic decision between medical rescue and colectomy remains theoretical in the lack of comparative data. The aim of our study was to evaluate and compare long-term disease outcome in patients with steroid-refractory colitis who either responded to CsA rescue therapy or had to be operated on due to failure of rescue medication. Data of 90 patients with steroid-refractory severe ulcerative colitis were analyzed, of whom 44 patients responded to CsA rescue therapy (CsA responders) and 46 patients underwent colectomy due to early or late failure of rescue therapy (colectomy group). Clinical disease severity was assessed by the Lichtiger score. CsA was introduced intravenously, 4 mg/bwkg initially, which was changed to oral administration after 1 week and maintained for 6–12 months (earlier discontinuation of the therapy was either due to side effects or loss of therapeutic effect); the dosing was continuously monitored by drug serum level. Twenty-six patients received corticosteroids and 17 patients were on immunomodulator therapy at the time of the initiation of CsA rescue. The indication of colectomy was severe disease activity with early failure of the rescue medication or relapse after rescue medication. The mean disease duration was 10 years at the time of surgery. Twenty-five patients K. Gecse :K. Farkas : Z. Szepes : F. Nagy : T. Wittmann : T. Molnar (*) First Department of Internal Medicine, University of Szeged, H-6720, Koranyi fasor 8, Szeged, Hungary e-mail: molnar.tamas@med.u-szeged.hu

Successful treatment of cepacia syndrome with a combination of intravenous cyclosporin, antibiotics and oral corticosteroids

Burkholderia cepacia complex (BCC) is a group of 17 closely related bacterial species that can cause pulmonary infection in patients with cystic fibrosis (CF). The clinical manifestations of BCC infection are varied but can include cepacia syndrome, which is a rapidly progressing necrotising pneumonia with an almost universally fatal outcome. We report the case of a 38year old man, known to have chronic infection with the ET12 strain of Burkholderia cenocepacia who developed cepacia syndrome 26years after initial infection. Aggressive treatment with a combination of 4 intravenous antibiotics, oral corticosteroids and cyclosporin brought about clinical, radiological and biochemical resolution of his cepacia syndrome. This case highlights the possible role of cyclosporin in the treatment of cepacia syndrome.

Sa1893 Predictive Factors of Response to Intravenous Cyclosporine in Severe Ulcerative Colitis: Development of a Novel Calculation Formula for Earlier Clinical Decision-Making

Sa1893 Predictive Factors of Response to Intravenous Cyclosporine in Severe Ulcerative Colitis: Development of a Novel Calculation Formula for Earlier Clinical Decision-Making

Facial Ulceration in a Patient With Crohn's Disease

Question: A 55-year-old woman with longstanding ileocolonic Crohn's disease presented with a facial lesion. She had previously undergone a total proctocolectomy and end-ileostomy for disease that was refractory to prednisone, 6-mercaptopurine, infliximab, and adalimumab. In 2010, she developed an ulcerating lesion on her face, between the left naris and left upper lip. A biopsy showed dermal neutrophilic infiltration (Figure A), and wound cultures did not demonstrate infection. The lesion worsened despite treatment with certolizumab pegol, topical tacrolimus, and intralesional steroids. The patient was admitted for severe facial pain associated with worsening of the ulcerating lesion. She had no gastrointestinal symptoms. On physical examination, there was a 2 × 2-cm ulcer superior to the left upper lip with a full-thickness defect, through which a tooth could be seen (Figure B). The borders of the ulcer had a raised, violaceous edge overhanging the ulcer bed. What is the diagnosis? Look on page 1258 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Pyoderma gangrenosum (PG) typically involves the lower extremities, but infrequently affects other areas including the face.1Wittekindt C. Luers J.C. Klussmann J.P. et al.Pyoderma gangrenosum in the head and neck.Arch Otolaryngol Head Neck Surg. 2007; 133: 83-85Crossref PubMed Scopus (10) Google Scholar Others have reported improvement with various immunosuppressive agents, anti-tumor necrosis factor (TNF) therapy, and intravenous immunoglobulin (IVIg).2Lachapelle J.M. Marot L. Jablonska S. Superficial granulomatous pyoderma gangrenosum of the face, successfully treated by ciclosporine: a long-term follow-up.Dermatology. 2001; 202: 155-157Crossref PubMed Scopus (36) Google Scholar PG classically exhibits pathergy with any trauma, including surgical manipulation.3Davis J.C. Landeen J.M. Levine R.A. Pyoderma gangrenosum: skin grafting after preparation with hyperbaric oxygen.Plast Reconstr Surg. 1987; 79: 200-207Crossref PubMed Scopus (78) Google Scholar Although biopsy results alone cannot be used to diagnose PG, the histopathology of lesions usually shows significant dermal neutrophilic infiltration with occasional cases showing leukocytoclastic vasculitis (Figure A).2Lachapelle J.M. Marot L. Jablonska S. Superficial granulomatous pyoderma gangrenosum of the face, successfully treated by ciclosporine: a long-term follow-up.Dermatology. 2001; 202: 155-157Crossref PubMed Scopus (36) Google Scholar Our patient presented with full-thickness penetration of the lip secondary to PG that progressed despite treatment with an anti-TNF drug and topical tacrolimus. She was started on a continuous infusion of intravenous cyclosporine in conjunction with corticosteroids. One week after starting cyclosporine, the lesion had partially improved. However, she experienced septic complications necessitating discontinuation of cyclosporine and was thus given 2 doses of IVIg.4Gupta A.K. Shear N.H. Sauder D.N. Efficacy of human intravenous immune globulin in pyoderma gangrenosum.J Am Acad Dermatol. 1995; 32: 140-142Abstract Full Text PDF PubMed Scopus (82) Google Scholar Broad-spectrum antibiotics were also initiated. In addition, she underwent hyperbaric oxygen therapy in preparation for wound closure, to minimize infection and promote angiogenesis.3Davis J.C. Landeen J.M. Levine R.A. Pyoderma gangrenosum: skin grafting after preparation with hyperbaric oxygen.Plast Reconstr Surg. 1987; 79: 200-207Crossref PubMed Scopus (78) Google Scholar Three sutures were used to close the full-thickness defect (Figure C). She improved on these treatment modalities and was discharged on certolizumab pegol, oral corticosteroids, and topical tacrolimus. Four months after presentation, the lesion had completely healed (Figure D). Although most literature cautions against surgical manipulation of PG owing to pathergy, this situation required wound closure to allow the patient to eat, and prevent potential wound seeding from oropharyngeal organisms while on significant immunosuppression. This case of complicated facial PG failing anti-TNF therapy was thus successfully treated using intravenous cyclosporine, IVIg, and hyperbaric oxygen in conjunction with surgical wound closure.

Infliximab or cyclosporine for acute severe ulcerative colitis: A retrospective analysis

Medical treatment of steroid-refractory ulcerative colitis (UC) is limited to either cyclosporine or infliximab. Studies comparing cyclosporine with either placebo or intravenous methylprednisone showed promise for cyclosporine, but associated it with significant toxicity. There is conflicting, but increasingly positive evidence for using infliximab. There are no studies directly comparing these two treatments. Our aim was to compare the outcomes of patients with steroid-refractory UC treated with either intravenous cyclosporine or infliximab. We carried out a retrospective review of inpatients with steroid-refractory UC, treated with either intravenous cyclosporine or infliximab, at Waitemata District Health Board, between January 2001 and February 2010. The primary end-points were time to colectomy, and colectomy rates at 3 and 12 months. Secondary end-points were time to discharge from initiation of treatment, steroid dependence at 12 months, and reported adverse events. The total study population was 38, with 19 in the infliximab group. Follow up to 12 months was complete in all patients. At 3 months, the colectomy rate was 63% for cyclosporine, compared to 21% (P = 0.0094). By 12 months the rate was 68% and 37% for cyclosporine and infliximab, respectively (P = 0.06). Patients in the cyclosporine group required an additional 5 days in hospital (P = 0.0086). Steroid dependence at 12 months was 50% for cyclosporine versus 25% for infliximab (P = 0.36). Cyclosporine caused more adverse events (P = 0.17). Infliximab improved clinical outcomes compared to the previous use of intravenous cyclosporine in patients admitted with steroid-refractory acute severe UC.

Neonatal herpes simplex type II virus infection complicated with meningitis and virus-associated hemophagocytic syndrome

A 14-day-old neonate was transferred to our university hospital because of respiratory distress and mild disturbance of consciousness. He had no history of abnormal pregnancy or delivery, but had developed apnea at 6 days old. Thereafter, respiratory distress progressed and his condition deteriorated. On admission to our hospital, several vesicles were found on the left upper arm, and moderate hepatomegaly was also present. Herpes simplex virus (HSV) type II genome was detected from serum, spinal fluid, and bone marrow. Laboratory examinations revealed typical abnormalities of disseminated intravascular coagulation, increased levels of serum ferritin, aspartate aminotransferase, and lactate dehydrogenase. Bone marrow aspiration demonstrated activated macrophages and hemophagocytosis. Spinal tap revealed numerous mononuclear cells. Meningitis and virus-associated hemophagocytic syndrome (VAHS) due to systemic HSV type II infection were thus diagnosed. Acyclovir (60 mg/kg/day) and vidarabine were promptly administered. Dexamethasone palmitate and intravenous cyclosporine were also administered for systemic inflammation due to VAHS. Finally, these aggressive therapies rescued the patient without any sequelae. In general, neonatal systemic HSV infection is life-threatening and results in poor intact survival. Our case report suggests that not only antiviral treatment for HSV, but also anti-inflammatory treatment including steroid and cyclosporine should be considered from the early phase of neonatal systemic HSV infection.

Chronic Recalcitrant Stevens-Johnson Syndrome

We describe a girl presented with chronic mucositis and palmoplantar ulcerative lesions. The diagnosis of chronic Stevens-Johnson syndrome (SJS) was made based on the clinical manifestations and histopathology findings and exclusion of other diagnosis. She had unusual chronic disease course; not responding to low dose corticosteroid treatment. The institution of intensive intravenous pulse corticosteroid, cyclosporine and hyperbaric oxygen therapy induced a complete remission. This report is intended to widen the range of clinical course of SJS and treatment options.

Etanercept for the treatment of intractable hemophagocytic syndrome with systemic lupus erythematosus

A 41-year-old woman presented with continuous fever, and her laboratory data suggested the recrudescence of systemic lupus erythematosus. She was treated with 60 mg/day prednisolone. With a dose reduction of prednisolone, high fever and pancytopenia were observed again. A bone marrow biopsy revealed hemophagocytosis. The effects of steroid pulse therapy, high-dose intravenous immunoglobulin, cyclosporine A, and methotrexate were insufficient. However, after four injections of etanercept (25 mg, twice a week) subcutaneously, her symptoms had completely resolved. In such cases, therapy with etanercept may be effective.

Adult-onset Still’s disease in pregnancy

We report a case of adult-onset Still’s disease (AOSD) in a pregnant patient that was successfully treated using intravenous methylprednisolone, cyclosporine, and plasma exchange, allowing safe delivery. Pregnancy appears to be one risk factor for AOSD, and we summarize the relationship between AOSD and pregnancy. A 28-year-old Japanese woman, in the 21st week of her first pregnancy, had suffered from low-grade fever and sore throat for 2 weeks. She was referred to us for a high spiking fever, cervical lymph node enlargement, non-pruritic diffuse rash with typical Kobner’s sign, and painful polyarthritis with palpable synovitis affecting the wrists, knees, and ankle joints bilaterally. She was referred to our department and admitted in September 2010. Chest radiography revealed bilateral pleural effusion, which was suggestive of pleuritis. Laboratory studies showed high levels of C-reactive protein (115 mg/L) and ferritin (24,883 ng/mL, normal \120 ng/mL), anemia (hemoglobin 10.5 g/dL), and an elevated white blood cell count (25,100/lL with 96.5% peripheral neutrocytes). Liver dysfunction was identified (aspartate transaminase 123 IU/ L, normal \39 IU/L; alanine aminotransferase 94 IU/L, normal \40 IU/L). Negative results were obtained for serum rheumatoid factor and antinuclear antibody. Blood cultures and exhaustive serological investigation for bacterial and viral etiologies of AOSD-like syndromes repeatedly yielded negative results. Her serum interleukin (IL)-18 level was significantly elevated (128,000 pg/mL), but IL-12 was not detectable. A diagnosis of AOSD was therefore made, according to the criteria described by Yamaguchi et al. [1]. Her symptoms worsened despite the initiation of prednisolone at 60 mg/day (treatment conducted in consultation with the obstetrician). As hemophagocytic syndrome developed as a complication after a few days, she received two courses of intravenous methylprednisolone pulse therapy, and plasma exchange, performed 15 times. Because the short-term effect of the pulse therapy was insufficient, we consulted her obstetrician again, and together with the obstetrician, we judged that maternal survival was the priority. We obtained informed consent for the use of cyclosporine in pregnancy from the patient and her family. Cyclosporine and liposomal dexamethasone palmitate were added after the pulse therapy, leading to improvement in the patient’s condition. During the clinical course, the patient suffered from severe oral ulcers induced by cytomegalovirus. Ganciclovir was prescribed because of concerns that congenital cytomegalovirus infection could develop in the fetus. At gestational week 33, she underwent urgent Cesarean section because the fetus showed intrauterine growth restriction, and she gave birth to a 1.3-kg healthy girl with no apparent abnormalities. After 1 month, with no clinical or biological signs of AOSD recurrence, she was discharged with her baby. M. Yamamoto (&) T. Tabeya C. Suzuki Y. Naishiro H. Yajima Y. Shimizu M. Obara H. Yamamoto T. Sugaya H. Takahashi Y. Shinomura First Department of Internal Medicine, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan e-mail: mocha@cocoa.plala.or.jp

“Tac”kling a Difficult Problem

“Tac”kling a Difficult Problem

Decreased cyclosporin A absorption after treatment with GoLytely lavage solution in rats.

Recently we observed a case in which the cyclosporin A absorption decreased after treatment with GoLytely lavage solution in a kidney transplant patient. In this study, we confirmed the decrease of the blood concentration of cyclosporin A after oral administration by GoLytely (Macrogol 3350) based on experiments with rats. The peak blood cyclosporin A concentration, and the area under the blood drug concentration-time curve from 0 to 24 h in the GoLytely-administered group were significantly lower than the control group. In the case of gastrointestinal dysfunction such as diarrhoea, or in treatment with laxatives such as GoLytely lavage solution, whole blood cyclosporin levels must be carefully monitored, and intravenous cyclosporin A may be more suitable for providing adequate immunosuppression.

Severe immunosuppression in inflammatory bowel disease: opening the floodgates to opportunists?

Dear editor: Ulcerative colitis is a primarily non-infectious, chronic inflammatory bowel disease that typically affects the rectum and may involve the whole colon in an uninterrupted pattern. The disease has a high impact on the patients' health-related quality of life and is prone to repetitive hospitalisation. Therapeutic options primarily include lifestyle alterations, medical management and surgical interventions. Medical as well as surgical therapy may be associated with lifethreatening complications, which may require intensive care unit (ICU) admission. Here, we report on a female patient suffering from ulcerative colitis, whose medical therapy was complicated by toxic megacolon, and later on pulmonary aspergillosis and disseminated herpes zoster. A 55-year old woman with ulcerative colitis suffered from purulent haemorrhagic diarrhoea and weight loss of 9 kg within 2 weeks and was treated in a community general hospital for 6 weeks. Azathioprine (2.5 mg kg d p.o.) was administered for a total of 15 days and had been discontinued due to severe leukopenia. At that time, the patient had a high erythrocyte thiopurine methyl thiopurine methyltransferase (TPMT) activity (38 nmol h− gHb−; normal >23, intermediate 10–23, low <10 nmol h− gHb−), which represents the detoxifyfing enzyme for azathioprine. In addition, TPMT genotyping was performed and confirmed the absence of clinically relevant enzyme polymorphisms. Furthermore, toxic 6-thioguanine nucleotides (6-TGN) were undetectable in the patient's blood. Persistent bowel inflammation was treated with high doses of topical and systemic corticosteroids (prednisolone up to 2 mg kg− per day) and intravenous cyclosporine (3 mg kg− as continuous infusion over 24 h) in combination with antimicrobial therapy. Cyclosporine was discontinued after 6 days as leukopenia deteriorated, and subsequent immunomodulatory therapy consisted of mesalazine and regressive doses of prednisolone. At transferal to our university hospital, the patient presented the full clinical picture of toxic megacolon, which required emergency subtotal colectomy, blind closure of the rectum and percutaneous ileostomy. Following surgery, the patient was transferred to the intermediate care unit and treated with antimicrobial therapy (cefuroxime and metronidazole) and moderate doses of corticosteroids (prednisolone 1 mg kg per day). On postoperative day 3, she developed acute cholecystitis, which required urgent cholecystectomy and escalation of antimicrobial therapy (meropenem and vancomycin). Throughout the early clinical course, the patient remained leukopenic with white blood cell counts between 950 and 2,840 cells per microliter. Fractional lymphocyte count persisted below 10%. Filgrastim treatment (recombinant-methionyl human granulocyte colony-stimulating factor; r-metHuG-CSF; Christian Ertmer and Wolf A. Mardin equally contributed to this work.

The use of traditional and newer calcineurin inhibitors in inflammatory bowel disease

Intravenous cyclosporine A (CsA) is an effective treatment for patients with severe, steroid-refractory ulcerative colitis (UC). Like the response to CsA, clinical trials have shown that two-thirds of patients with refractory UC respond to tacrolimus therapy. However, it is unclear how/when this agent should be used for patients with active UC. We reviewed the results of previous studies regarding calcineurin inhibitors in UC patients. We examined the best way to use tacrolimus to obtain maximum efficacy by comparing the results from clinical trials with those from a recent survey in Japan. Calcineurin inhibitors are useful to induce remission in patients with refractory UC; however, the long-term prognosis has not been shown to be improved by CsA. Early intervention with CsA/tacrolimus may improve the long-term prognosis of UC patients just as infliximab does for Crohn's disease patients. Recent studies have indicated that a fasting state and administration of a higher dosage of tacrolimus at the beginning of therapy are critical in ensuring that the target trough concentration of the agent is reached. The use of higher initial doses of tacrolimus ensured that patients achieved their target levels. Further studies will be needed to elucidate the efficacy of top-down therapy with tacrolimus in patients with UC. Physicians must know how to use calcineurin inhibitors to obtain maximum efficacy.

The use of Cyclosporin A in acute steroid-refractory ulcerative colitis: Long term outcomes

Background and aimsApproximately 15% of patients with ulcerative colitis will have a severe flare requiring hospitalisation at some stage. For those who fail to respond to intravenous steroids Cyclosporin A (CyA) therapy is one option. We have evaluated the management of such patients in our centre and present the long term colectomy avoidance rates. Methods38 consecutive patients receiving CyA for an acute, steroid-refractory flare of colitis were retrieved from our database. Records were unavailable for 2 patients and 2 received therapy twice, hence 38 episodes were analysed. Results24/36 patients were male; median age 37years. On admission 20 patients were taking oral steroids; 8 were taking a thiopurine and 7 patients were on no treatment. CyA was started a median of 8days after admission (range 1–28) and most patients (32/38) received this orally at doses of 4.5–8.3mg/kg. 15 patients have undergone colectomy, 11 of these during the same admission for lack of response to CyA. Of the patients who were discharged without surgery, 84% have still not required colectomy after a median follow-up of 3.8years. Adverse effects were mostly minor, though two patients developed neutropenia on dual immunosuppression. ConclusionsCyA can be administered orally with good tolerability. We use it as a bridging therapy to Azathioprine. In our population, 84% of those who responded to CyA have not required surgery.

Acute renal failure early after heart transplantation: risk factors and clinical consequences

Limited information exists about acute renal failure (ARF) early after heart transplantation (HTx). We correlated pre-, per-, and post-operative patient and donor parameters to the risk of developing ARF. We also analyzed the consequences of ARF on kidney function after HTx, risk of later need for chronic dialysis or kidney transplantation, and mortality. In a retrospective study from 1983 to 2007, 145 (25%) of 585 HTx recipients developed ARF, defined as ≥ 26.4 micromol/L or ≥ 50% increase in serum creatinine from pre-operatively to the seventh day post-HTx and/or the need of early post-operative dialysis. Independent risk factors for ARF were intravenous cyclosporine immediately post-operatively (odds ratio [OR] 2.16, 95% CI 1.34-3.50, p = 0.02), donor age (OR 1.02, 95% CI 1.00-1.04, p = 0.02), and pre-operative cardiac output (OR 1.38, 95% CI 1.12-1.71, p = 0.003). The development of ARF was a predictor for short-term survival (≤ 3 months) ranging from 98% for patients who improved their creatinine after HTx vs. 79% for those in need of dialysis (p < 0.001). However, ARF did not predict subsequent end stage renal disease in need of dialysis or renal transplantation. ARF is a common complication post-HTx. As ARF is associated with short-term survival, post-operative strategies of preserving renal function have the potential of reducing mortality. Of avoidable risk factors, the use of intravenous CsA should be discouraged.

Rapid resolution of pyoderma gangrenosum after treatment with intravenous cyclosporine

Rapid resolution of pyoderma gangrenosum after treatment with intravenous cyclosporine

DELAYED SPONTANEOUS REMISSION IN A CHILD WITH PRIMARY ACQUIRED CHRONIC PURE RED CELL APLASIA

The acquired form of pure red cell aplasia (PRCA) presents either as an acute self-limited disease, predominantly seen in children, or as a chronic illness more frequently seen in adults with rare spontaneous remissions. A 14-year-old boy presented with pallor, without hepatosplenomegaly, jaundice, lymphadenopathy, petechiae, or any other apparent abnormalities. Isolated anemia in the presence of normal white cell and platelet counts with a marrow of normal cellularity and absence of erythroblasts but normal myeloid cells and megakaryocytes revealed the diagnosis of PRCA. All possible investigations excluded secondary causes of PRCA. The patient required packed red cell transfusions every 2 to 3 weeks. He failed therapy with intravenous immunoglobulin, corticosteroids, cyclosporine A plus corticosteroids, antithymocyte globulin, anti-CD 20 (rituximab), and erythropoietin (EPO). He showed a severe, resistant, and transfusion-dependent PRCA. Spontaneous remission with normal hemoglobin and reticulocyte levels was dramatic 6.5 years after the diagnosis of PRCA and 3.6 years after his last treatment.

Rapid endoscopic improvement is important for 1-year avoidance of colectomy but not for the long-term prognosis in cyclosporine A treatment for ulcerative colitis

Intravenous (IV) cyclosporine A (CSA) is one of the treatments of choice for patients with steroid-refractory severe ulcerative colitis (UC). In this study, we evaluated the overall experience with CSA treatment in UC patients, from their initial response to long-term prognosis. The medical records of 72 patients admitted to our hospital with a severe UC flare-up and treated with IV CSA between November 1996 and October 2008 were reviewed retrospectively. The initial response to CSA was assessed using a clinical activity index, and colectomy was assigned as the endpoint for the long-term prognosis. Overall, 53 of 72 (73.6%) patients responded initially to CSA. We could not determine any specific parameters that predicted an initial response. A life-table analysis for all patients revealed that 54.4% of patients required a colectomy within 11years. The long-term risk of surgery was associated with a shorter disease duration, history of adverse reactions against medications and lack of immunomodulator use. In addition, endoscopic improvement at day 14 was associated with colectomy at 1year, but not with the long-term prognosis. Although CSA can exert high initial efficacy for severe attacks of UC, >50% of patients who relapse require a colectomy. Specifically, mucosal healing evaluated by endoscopy was associated with the 1-year colectomy rate. In contrast, a history of adverse drug reactions was correlated with the long-term colectomy rate. Therefore, we propose that treatment of severe UC with CSA requires consideration of both initial remission and long-term maintenance as management goals.

Prediction of Intravenous Cyclosporine Area Under the Concentration–Time Curve After Allogeneic Stem Cell Transplantation

Currently, routine monitoring of cyclosporine in patients undergoing allogeneic stem cell transplantation is based on analysis of trough, or C0, predose concentrations. However, recent studies in solid organ transplant recipients have demonstrated that monitoring cyclosporine exposure by analyzing 2-hour postdose concentrations (C2) or area under the concentration-time curve (AUC) may improve clinical outcome. This study investigated the ability of single samples to predict exposure to intravenous cyclosporine in eight patients undergoing allogeneic stem cell transplantation. Patients received cyclosporine at a starting dose of 2.5 mg/kg 12-hourly by intravenous infusion over 4 hours. Blood samples were taken at 0, 1, 2, 3, 4, 4.17, 4.33, 4.67, 5, 6, 8, and 12 hours after the start of the infusion. Linear regression was undertaken to investigate the relationship between AUC and concentrations measured at individual time points; bias and precision were also examined. Cyclosporine doses ranged from 250 mg to 430 mg/day, AUC from 3.85 to 8.39 mg.h/L, clearance from 19.1 to 48.1 L/h, and elimination half-life from 3.7 to 15.5 hours. Although Cmax and the concentration measured at 3 hours (C3) provided the best prediction of AUC (r = 0.90 and r = 0.87, respectively), the infusion protocol made the time of Cmax difficult to predict. Concentrations measured at the end of the infusion (Cend) and 12 hours postdose (C12) gave similar results (r = 0.87 and 0.77, respectively). These data suggest that C12 concentrations provide an acceptable marker of total exposure to intravenous cyclosporine in patients undergoing allogeneic stem cell transplantation.