Corticosteroid Reduction Research Articles

Infliximab (Remicade?) in uveitis: a review

AbstractTumor necrosis factor (TNF)‐α has been implicated as an important mediator in autoimmune ocular inflammatory disease pathogenesis as shown by animal studies and its detection in the ocular fluids of patients with uveitis. Blockade of TNF‐α has emerged as one of the most promising therapies in autoimmune diseases including uveitis. Currently, there are three TNF‐α antagonists: two monoclonal antibodies (infliximab and adalimumab) and a soluble receptor that binds soluble TNF‐α (etanercept). Infliximab is a chimeric monoclonal antibody directed against TNF‐α. It binds with high affinity to both the soluble and the membrane‐bound TNF‐α and inhibits a broad range of biologic activities of TNF‐α. Binding to membrane TNF‐α can mediate programmed cell death. Several studies reported that infliximab therapy was rapidly effective and safe treatment for refractory noninfectious uveitis including childhood uveitis and is indicated as rescue therapy for relapses of ocular inflammation or as maintenance therapy when conventional immunosuppression fails. It also allowed a reduction of corticosteroids and immunosuppressive drugs required to control the disease. However, repeated infusions are required to maintain long‐term remission. Moreover, infliximab administration is costly and requires hospital admission. Adalimumab, fully humanized monoclonal anti‐ TNF‐α antibody, was also found to be effective and safe therapy for the management of refractory noninfectious uveitis. Several studies reported that infliximab was more effective than etanercept in the treatment of refractory uveitis. Perhaps infliximab’s ability to target membrane‐bound TNF‐α in addition to the soluble form may contribute to its increased efficacy in comparison with etanercept for uveitis.

Levalbuterol versus albuterol

Albuterol has been used for more than 40 years to treat acute asthma exacerbations as a racemic mixture of isomers: the active form, (R)-albuterol, or levalbuterol, and (S)-albuterol, classically considered inert. The single-isomer formulation, levalbuterol, has been synthesized recently and used therapeutically when the racemate is deemed less desirable. Basic investigations indicate that racemic albuterol and levalbuterol can produce effects that favor asthma remediation, including corticosteroid amplification and reduction of inflammatory mediators; in contrast, (S)-albuterol produces opposite effects. With inhalation of racemic albuterol, circulating (S)-albuterol persists 12 times longer than levalbuterol, suggesting potential for paradoxical effects observed clinically. Although mainly consistent with basic findings, clinical studies suggest no overwhelming superiority of levalbuterol over racemic albuterol; however, levalbuterol's effects may be greatest in moderate to severe asthma patients, especially with racemic albuterol overuse. Recent adoption of the hydrofluoroalkane formulation has narrowed the cost gap between levalbuterol and racemic albuterol metered-dose inhalers, but it remains for the nebulized formulations. Thus, physician selection of these drugs has remained dependent on experience, pharmaceutical knowledge, and established prescribing habits combined with cost factors, formulary structures, and availability, such that racemic albuterol is still used significantly compared with levalbuterol to treat acute asthma exacerbations.

Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids

Lupus nephritis is a life-threatening complication of SLE. Treatment regimes include steroids and cyclophosphamide, both associated with significant morbidity. Newer regimes include mycophenolate mofetil (MMF). We report our outcomes in a prospectively monitored cohort of patients receiving our new standard treatment protocol, comprising rituximab induction therapy and MMF maintenance in patients already taking maintenance immunosuppression for SLE who developed lupus nephritis. We then attempted steroid reduction/withdrawal. Patients with class III/IV/V lupus nephritis were included. All patients were on steroids prior to the development of lupus nephritis. Eighteen patients have reached at least 1 year follow-up. These patients received rituximab induction therapy and MMF maintenance therapy. Steroid reduction/withdrawal was guided by clinical response. Fourteen of 18 (78%) patients achieved complete or partial remission with a sustained response of 12/18 (67%) at 1 year, with 2 patients having a relapse of proteinuria. Four patients did not respond. There was a significant decrease in proteinuria from a mean protein:creatinine ratio (PCR) of 325 mg/mmol at presentation to 132 mg/mmol at 1 year (P = 0.004). Serum albumin significantly increased from a mean of 29 g/L at presentation to 34 g/L at 1 year (P = 0.001). The complication rate was low with no severe infections. Following treatment with rituximab, 6 patients stopped prednisolone, 6 patients reduced their maintenance dose and 6 patients remained on the same dose (maximum 10 mg). This data demonstrates the efficacy of a rituximab and MMF based regime in the treatment of lupus nephritis, allowing a reduction or total withdrawal of corticosteroids.

Masitinib, a c‐kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid‐dependent asthmatics

Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c-kit) and platelet-derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c-kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma. The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints. A 16-week randomized, dose-ranging (3, 4.5, and 6 mg/kg/day), placebo-controlled study was undertaken in 44 patients with severe corticosteroid-dependent asthma who remained poorly controlled despite optimal asthma management. At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of -78% and -57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 (P < 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema. Masitinib, a c-kit and PDGF-receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid-dependent asthma. These preliminary results warrant further long-term clinical studies in severe asthma

Mometasone furoate in the management of asthma: a review

Inhaled corticosteroids (ICS) have proven to be the most effective and essential therapy for the treatment of bronchial asthma. The 2007 National Asthma Education and Prevention Program guidelines recommend ICS as preferred therapy for patients with mild to severe persistent asthma. Mometasone furoate (MF) is a relatively new ICS agent with high affinity for the glucocorticoid receptor. It is approved in the US for maintenance treatment of asthma for patients 4 years of age and older. It has been shown to be well tolerated with no significant adverse side effects observed in clinical trials and post-marketing surveillance. The efficacy of mometasone furoate has been established in large, well-designed studies. In patients with persistent asthma previously treated either with short-acting beta-agonists alone or twice-daily maintenance therapy with ICS, once-daily MF has been shown to be superior to placebo in improving lung function, symptom control, and quality of life; and has shown comparable efficacy compared with budesonide, beclomethasone, and fluticasone. Twice-daily dosing with MF has been demonstrated to successfully allow for reduction or elimination of oral corticosteroids in severe asthmatics.

The role of TNF‐alpha blockers in uveitis therapy

AbstractTumor necrosis factor (TNF)‐α has been implicated as an important mediator in autoimmune ocular inflammatory disease pathogenesis as shown by animal studies and its detection in the ocular fluids of patients with uveitis. Blockade of TNF‐α has emerged as one of the most promising therapies in autoimmune diseases including uveitis. Currently, there are three TNF‐α antagonists: two monoclonal antibodies (infliximab and adalimumab) and a soluble receptor that binds soluble TNF‐α (etanercept). Infliximab is a chimeric monoclonal antibody directed against TNF‐α. It binds with high affinity to both the soluble and the membrane‐bound TNF‐α and inhibits a broad range of biologic activities of TNF‐α. Several studies reported that infliximab therapy was rapidly effective and safe treatment for refractory noninfectious uveitis including childhood uveitis and is indicated as rescue therapy for relapses of ocular inflammation or as maintenance therapy when conventional immunosuppression fails. It also allowed a reduction of corticosteroids and immunosuppressive drugs required to control the disease. However, repeated infusions are required to maintain long‐term remission. Moreover, infliximab administration is costly and requires hospital admission. Recently, adalimumab, fully humanized monoclonal anti‐ TNF‐α antibody, was also found to be effective and safe therapy for the management of refractory noninfectious uveitis. Several studies reported that infliximab was more effective than etanercept in the treatment of refractory uveitis. Perhaps infliximab’s ability to target membrane‐bound TNF‐α in addition to the soluble form may contribute to its increased efficacy in comparison with etanercept for uveitis.

Corticosteroid Reduction With Tacrolimus (CORRETA) TRIAL: A Prospective Brazilian Multicenter, Randomized Trial of Early Corticosteroid Reduction Versus Regular Corticosteroid Dosage Maintenance on a Tacrolimus (Prograf) and Mycophenolate Mofetil (Cellcept) Immunosuppression Regimen in Kidney Transplant Recipients: Interim Analysis

Corticosteroids are a cornerstone of immunosuppressive therapy in renal transplantation despite their side effects and morbidity. Newer immunosuppressive agents may be more effective to allow corticosteroid sparing. An interim analysis of 60 completed out of 100 planned primary kidney transplant recipients is presented. All patients on tacrolimus (Prograf) and MMF (Cellcept) were randomized into two groups following a 1:1 distribution for early steroid reduction at posttransplant day 7 (G1; n = 31) versus to long-term maintenance steroids (G2; n = 29). Primary efficacy endpoints were composite endpoint of death, graft loss, or severe acute rejection at 6 and 12 months follow-up. Safety evaluation included severity and frequency of diabetes mellitus, hypertension, hyperlipidemia, leukopenia, infection, malignancy, and severe adverse events. Mean age was 39.1 years, with 45.0% males and 66.7% Caucasians. African-Americans were 25.8% in G1 and 27.6% in G2. One death occurred in each group, as well as one case of severe (Banff III) rejection in G1 ( P = 1.00). The incidence of rejection episodes between groups was not significant, namely, 41.9% in G1 and 20.7% in G2 ( P = .077). There were no differences between groups concerning mean, systolic and diastolic blood pressure, HbA1c, or creatinine at 12 months. This interim analysis showed no evidence of an increased risk of poorer performance among the early steroid reduction or safety differences in kidney transplant recipients versus a regular dosage steroid group of patients. Further analysis of the complete study data is underway.

Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America

Thomas J. Walsh, Elias J. Anaissie, David W. Denning, Raoul Herbrecht, Dimitrios P. Kontoyiannis, Kieren A. Marr, Vicki A. Morrison, Brahm H Segal, William J. Steinbach, David A. Stevens, Jo-Anne van Burik, John R. Wingard, and Thomas F. Patterson Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland; University of Arkansas for Medical Sciences, Little Rock; The University of Texas M. D. Anderson Cancer Center, Houston, and The University of Texas Health Science Center at San Antonio, San Antonio; Oregon Health and Sciences University, Portland; Veterans Affairs Medical Center and University of Minnesota, Minneapolis, Minnesota; Roswell Park Cancer Institute, Buffalo, New York; Duke University Medical Center, Durham, North Carolina; Santa Clara Valley Medical Center, San Jose, and Stanford University, Palo Alto, California; University of Florida, College of Medicine, Gainesville, Florida; University of Manchester, Manchester, United Kingdom; and University Hospital of Strasbourg, Strasbourg, France

201: Extracorporeal Photopheresis (ECP) is an Effective Therapy for the Treatment of Children with Steroid Refractory (SR) Chronic Graft vs Host Disease (cGVHD)

ECP is an immune modulatory therapy that works by causing donor lymphocyte apoptosis and tolerance. We hypothesize that ECP is an effective therapy in treating SR cGVHD and allows for reduction in corticosteroids. We performed a retrospective study at Children's Memorial Hospital to evaluate the effectiveness of ECP in SR cGVHD in children.

Anti‐TNF‐α Therapy in Seven Patients with Behçet's Uveitis

Behcet's disease (BD) is a chronic, relapsing, multisystem disease. In some patients, ocular involvement can lead to severe vision impairment despite immunosuppressive therapy. Since high levels of circulating TNF-alpha have been found both in peripheral blood and aqueous humor of patients with active BD, we evaluated the efficacy of anti-TNF-alpha therapy in seven patients with severe ocular involvement resistant to previous treatment. Seven patients with sight-threatening relapsing uveitis refractory to immunosuppressive regimens received intravenously infliximab, at a dose of 3-5 mg/kg, on week 0-2-4 and then every 6-8 weeks, in combination with low-dose prednisone and methotrexate or azathioprine. Efficacy was assessed in terms of number and severity of relapses of posterior uveitis, visual acuity, and reduction of corticosteroids and immunosuppressive drugs. After a mean follow-up period of 23 months, the total number of relapses dropped to 6, compared to the 21 observed in an equivalent period of time before treatment. The visual acuity improved in 4 eyes, while it remained stable in 9. Therapy with infliximab considerably reduced the required daily dose of both corticosteroids and immunosuppressive drugs. In our experience infliximab proved to be safe and effective in controlling both the number and intensity of cases of posterior uveitis and the extraocular manifestations of BD. It also allowed a reduction of corticosteroids and immunosuppressive drugs required to control the disease. However, ocular and systemic manifestations tended to recur after drug withdrawal or when the interval between infliximab courses was longer than 8 weeks. Moreover, infliximab administration is costly and requires hospital admission.

Airway cell and cytokine changes in early asthma deterioration after inhaled corticosteroid reduction

Back-titration of inhaled corticosteroid (ICS) dose in well-controlled asthma patients is emphasized in clinical guidelines, but there are few published data on the airway cell and cytokine changes in relation to ICS reduction. In our study, 20 mild-to-moderate persistent (inspite of low-moderate dose ICS treatment) asthmatic subjects prospectively rendered largely asymptomatic by high-dose ICS were assessed again by clinical, physiological, and airway inflammatory indices after 4-8 weeks of reduced ICS treatment. We aimed at assessing the underlying pathological changes in relation to clinical deterioration. Patients recorded daily symptom scores and peak expiratory flows (PEF). Spirometry and airways hyperreactivity (AHR) were measured and bronchoscopy was performed with assessment of airway biopsies (mast cells, eosinophils, neutrophils, and T lymphocytes), bronchoalveolar lavage (BAL) IL-5 and eotaxin levels and cellular profiles at the end of high-dose ICS therapy and again after ICS dose reduction. Baseline data were compared with symptomatic steroid-free asthmatics (n=42) and non-asthmatic controls (n=28). After ICS reduction, subjects experienced a variable but overall significant increase in symptoms and reductions in PEF and forced expiratory volume in 1 s. There were no corresponding changes in AHR or airways eosinophilia. The most relevant pathogenic changes were increased CD4(+)/CD8(+) T cell ratio, and decreased sICAM-1 and CD18 macrophage staining (potentially indicating ligand binding). However, there was no relationship between the spectrum of clinical deterioration and the changes in cellular profiles or BAL cytokines. These data suggest that clinical markers remain the most sensitive measures of early deterioration in asthma during back-titration of ICS, occurring at a time when AHR and conventional indices of asthmatic airway inflammation appear unchanged. These findings have major relevance to management and to how back-titration of ICS therapy is monitored.

Adrenalectomy promotes a permanent decrease of plasma corticoid levels and a transient increase of apoptosis and the expression of Transforming Growth Factor beta1 (TGF-beta1) in hippocampus: effect of a TGF-beta1 oligo-antisense.

BackgroundCorticosterone reduction produced by adrenalectomy (ADX) induces apoptosis in dentate gyrus (DG) of the hippocampus, an effect related to an increase in the expression of the pro-apoptotic gene bax. However it has been reported that there is also an increase of the anti-apoptotic gene bcl-2, suggesting the promotion of a neuroprotective phenomenon, perhaps related to the expression of transforming growth factor β1 (TGF-β1). Thus, we have investigated whether TGF-β1 levels are induced by ADX, and whether apoptosis is increased by blocking the expression of TGF-β1 with an antisense oligonucleotide (ASO) administered intracerebrally in corticosterone depleted rats.ResultsIt was observed an increase of apoptosis in DG, 2 and 5 days after ADX, in agreement with a reduction of corticosterone levels. However, the effect of ADX on the number of apoptotic positive cells in DG was decreased 5 days after the lesion. In CA1–CA3 regions, the effect was only observed 2 days after ADX. TGF-β1 mRNA levels were increased 2 days after ADX. The sustained intracerebro-ventricular administration of a TGF-β1 ASO via an osmotic mini pump increased apoptosis levels in CA and DG regions 5 days after ADX as well as sham-operated control animals. No significant effect was observed following a scrambled-oligodeoxynucleotide treatment.ConclusionThe changes in both the pattern and the magnitude of apoptotic-cell morphology observed 2 and 5 days after ADX suggest that, as a consequence of the reduction of corticosteroids, some trophic mechanisms restricting cell death to a particular time window are elicited. Sustained intracerebral administration of TGF-β1 ASO increased the apoptosis promoted by ADX, suggesting that TGF-β1 plays an anti-apoptotic role in vivo in hippocampus.

Predictors of Loss of Asthma Control Induced by Corticosteroid Withdrawal

Asthma guidelines recommend reducing the dose of inhaled corticosteroids after establishing control. To identify predictors of loss of control and the kinetics of symptoms, and inflammatory and physiological measurements when inhaled corticosteroids are reduced in patients with stable asthma. In a single-blind study, the daily dose of inhaled corticosteroid was reduced by one-half at intervals of 20+/-2 days in 17 adults with controlled asthma until loss of asthma control occurred or until the corticosteroid was replaced with placebo for 20 days. The patients recorded symptoms and peak expiratory flow each day, and forced expiratory volume in 1 s (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), exhaled nitric oxide, and eosinophils in sputum and blood were measured every 10 days. A loss of asthma control was defined as a worsening of the symptoms score of at least 20%, and either a decrease in FEV1 of at least 15% or a decrease in PC20 of at least fourfold. Two patients had a respiratory infection and were withdrawn from the study. In eight patients, asthma became uncontrolled after a mean of 33 days (range 13 to 48 days). This was accurately reflected by a worsening of all parameters. The first parameter to change was the sputum eosinophil percentage (20 days before the loss of asthma control). Significant changes in exhaled nitric oxide, FEV1 and methacholine PC20 were observed only when the symptoms became uncontrolled. A high blood eosinophil count at baseline (risk ratio of 2.5, 95% CI 1.0 to 6.5) and an increase in sputum eosinophil count after the reduction of corticosteroids were predictors of loss of asthma control. In patients whose asthma is controlled on inhaled corticosteroid, it is prudent not to reduce the dose further if the blood eosinophils are increased or if the sputum eosinophils increase by as little as 1% after the reduction of corticosteroids.

OP12. DISEASE ACTIVITY ASSESSMENT IN POLYMYALGIA RHEUMATICA (PMR) AND GIANT CELL ARTERITIS (GCA)

Polymyalgia rheumatica (PMR) constitutes a common rheumatic disorder in the elderly population, affecting from 0.1 to 0.5% of people older than 50 years. The diagnosis is based upon a clinical syndrome, consisting of pain and stiffness in the shoulder and pelvic girdle, muscle tenderness of the upper and lower limbs, non-specific somatic complaints, frequently occurring fever, weight loss and fatigue. Moreover the acute phase response measured by Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) is highly elevated, despite the fact that PMR may also exist without elevated acute phase reactants [1–3]. Although PMR and Giant Cell Arteritis (GCA) are commonly regarded as two clinical variations of the same disease, their clinical picture is quite different. Whilst in PMR the musculoskeletal symptoms predominate, arterial inflammation and its consequences constitute the major features of GCA [1]. Giant-cell arteritis is less frequent than polymyalgia rheumatica. The American College of Rheumatology-criteria include an erythrocyte sedimentation rate of at least 50 mm per hour as one of the five criteria found to be useful in the classification of giant-cell arteritis [4]. It is well known and overall consensus that corticosteroid therapy in PMR and GCA usually leads to a rapid and dramatic improvement. Usually higher starting doses are administered in GCA patients. [1]. The EULAR response criteria for PMR and the PMR-disease activity score (PMR-AS) [5, 6] were developed on the basis of corticosteroid treatment. Along with the reduction of corticosteroids almost all parameters of disease activity, showed significant improvement indicating decrease of inflammatory activity, reduction of pain, and amelioration of functional status of the patients. The EULAR response criteria for PMR comprise a core set of markers of disease activity for monitoring therapeutic responses in PMR, namely ESR or CRP, representing the acute phase response, and the VAS of patient's pain, Physician's global assessment (PhGA), morning stiffness (MST) and the ability to elevate the upper limbs, representing the clinical situation [5]. In view of the crucial role pain plays during the course of the disease, it was decided to insist on the presence of a change of pain intensity, whereas out of the other four parameters only three have to change to indicate improvement or deterioration [5]. In order to express PMR-activity as an absolute number a PMR disease activity score, the PMR-AS, was developed on the basis of the EULAR response criteria. The PMR-AS is to be calculated as: CRP (mg/dl) + VAS p (0 – 10) + VAS ph (0 – 10) + [MST (min)*0,1] + EUL (3 – 0) [6]. Cronbach's alpha for the composite score amounted to 0.914 and 0.881 in two patient cohorts, indicating high internal consistency. Factor analysis revealed that each single item contributes significantly to the total score. PMR-AS values below 7 can be regarded as indicating low disease activity, between 7 and 17 medium disease activity, and greater than 17 high PMR-activity. In a third control cohort the PMR-AS was proven to be highly correlated to patient's global assessment, patient satisfaction and ESR (p<0.001) [6]. In GCA the onset of symptoms may occur subacutely, but also abruptly. An elevated ESR as well as elevated CRP-levels and elevated Interleukin-6-levels (IL-6) are considered as diagnostic features and as markers for disease activity [1]. Imaging techniques, such as magnetic resonance imaging and PET-scans play an important role as diagnostic, but also as monitoring tools during the course of GCA and its treatment respectively [7, 8]. Up to now the gold standard of monitoring GCA- patients comprises ESR or CRP, which is thought to provide higher specificity, in addition the control of symptoms as well as patient's global assessment. Anticardiolipin antibody levels may be helpful to predict flares and relapses in GCA patients; additionally IL-6 levels were recently described not only as markers for disease activity assessment, but also as prognostic markers. An elevated Il-6 production was seen to be related to a lower incidence of disease related ischemic events in GCA-patients [9, 10]. It may be anticipated that a better knowledge of disease activity processes, an exact monitoring of disease activity and treatment responses, as well as an increased risk-estimation of treatment schedules, e.g. corticosteroids, in PMR and GCA will result in improved clinical decision–making and ultimately in improved patient care.

Corticosteroid sparing effects of vitamin C and magnesium in asthma: a randomised trial

The study aims to assess the a priori hypothesis that regular supplementation with vitamin C or magnesium will permit a reduction in the corticosteroid dose required to maintain asthma control in adults. We invited all participants recruited from primary care centres who completed a parallel-group, randomised, placebo-controlled, 16-week supplementation trial of 1g/day vitamin C or 450 mg/day magnesium to continue and participate in a structured corticosteroid reduction protocol over 10 weeks. A total of 92 participants (29 vitamin C, 31 magnesium and 32 placebo) entered the study. Assuming no reduction in corticosteroid dose in the 10 who subsequently withdrew, the geometric mean reductions in inhaled corticosteroid dose achieved with vitamin C, magnesium and placebo were 49, 13 and 11 microg, respectively. Relative to placebo, the unadjusted effect of vitamin C was significant, and remained at borderline significance after adjustment for baseline corticosteroid dose (relative reduction ratio=4.03, 95% CI 0.95 to 17.1, P=0.06). We conclude that while vitamin C supplements may have modest corticosteroid sparing effects and hence the potential to reduce exposure to their side effects, magnesium supplements have no effect on the inhaled corticosteroid dose required to maintain asthma control.

Successful Treatment for Recurrent Painful Hashimoto's Thyroiditis by Total Thyroidectomy

Painful Hashimoto's thyroiditis is an atypical variant of Hashimoto's thyroiditis characterized by thyroid pain and fever. In patients with this condition, anti-inflammatory agents are not always effective as in those with subacute thyroiditis. Therefore, long-term pain management is an important issue. We report herein four cases of painful Hashimoto's thyroiditis requiring total thyroidectomy to relieve thyroid pain and histologic findings of the thyroid gland. All patients had high titers of anti-thyroperoxidase (TPO) and thyroglobulin antibodies. Three were hypothyroid, and the other was euthyroid. During the first visit, four patients had fever and/or thyroid pain with elevated C-reactive protein or erythrocyte sedimentation rate, and they were treated with oral corticosteroids given continuously or intermittently for 9 to 48 months. Because a reduction or discontinuation of corticosteroids caused recurrent painful attacks, the decision was made to perform surgery. After total thyroidectomy, their symptoms disappeared. The histopathologic characteristics of these hypothyroid cases were advanced fibrosis and destructive thyroid architecture. One euthyroid case showed a mild fibrous change and the presence of foreign body type giant cells. In conclusion, total thyroidectomy is the effective and reliable treatment for patients with recurrent painful Hashimoto's thyroiditis. Pathologic characteristics include advanced fibrosis and destructive thyroid architecture.

CORTICOSTEROID USE IN PATIENTS WITH CLOSTRIDIUM DIFFICILE INFECTION

Purpose: Corticosteroids are commonly used to treat ulcerative colitis and Crohn's colitis; however, their effects on patients with Clostridium difficile colitis may be detrimental. The aim of this study was to determine if corticosteroids are associated with an increased risk of developing severe outcomes leading to surgery and/or death. Methods: A case control study based on review of charts and our hospital's information system of 181 patients aged 18 years or older who were confirmed to have C difficile infection from May 1, 2001 to May 31, 2003, at St. Vincent Charity Hospital, Cleveland, OH. The main outcome measures were the number of patients who had severe outcomes, leading to colectomy and/or death, comparing patients who received corticosteroids to those who did not. Results: Of the 181 confirmed case of C difficile infection, 126 patients did not receive corticosteroids, whereas 55 patients received them for treatment of other medical problems. Patients who developed severe outcomes in both groups were generally older. Serum albumin levels were lower in patients who required a colectomy and/or expired, however there was no significant difference whether they had received corticosteroids or not, p = .777. Out of 126 patients who did not receive corticosteroids (control group), there were 20 deaths (15.87%), compared to 22 out of 55 deaths (40%), in the corticosteroid group [odds ratio (OR) = 4.752; 95% confidence interval [CI]: 2.329 to 9.695;p <.001]. In the control group there were 4 out of 126 patients (3.17%) who required a colectomy compared to 9 out of 5 5 patients (16.36%) in the corticosteroid group [OR = 5.967; CI: 1.752 to 20.328; p <.004]. In the control group, 1 out of 4 patients who had a colectomy expired after surgery (25%), compared to 6 out of 9 patients (66.66%) in the corticosteroid group [OR = 6; CI: 0.422 to 85.252]. Conclusions: Our study shows that when corticosteroids are used for treatment of other medical conditions in patients with C difficile colitis there is increased risk for the development of severe outcomes leading to colectomy and/or death. Further studies would be warranted to test the validity of these findings and to determine whether corticosteroid reduction or IV immunoglobulin administration would be helpful in severe cases of C difficile colitis.

Fallberichte

High-dose immunoglobulins (IVIG) are important agents in the treatment of numerous autoimmune disorders. In the field of dermatology, increasing numbers of patients with bullous autoimmune disorders and mixed connective tissue diseases have been treated. We successfully treated a patient with pemphigus vulgaris with IVIG, after he had developed osteonecrosis of his right femoral head while on azathioprine and corticosteroids. After reduction of oral corticosteroids, his disease flared dramatically. The addition of a high dose immunosuppressive regimen including azathioprine and dapsone failed to help. Thus high dose IVIG (2 mg/kg, 4 weeks interval) therapy was initiated and induced complete healing of the skin lesions. The clinical improvement and the titer of the relevant autoantibodies against desmoglein 3 and desmoglein 1 showed correlation.

Visceral leishmaniasis in immunocompromised patients with and without AIDS: a comparison of clinical features and prognosis

Visceral leishmaniasis is basically a disease of healthy infants and adults. However, in the last decade an increasing number of cases of kala azar in immunocompromised patients have been reported with emphasis on atypical manifestations of the disease. During a period of 11 years, 20 immunocompromised patients with AIDS (12 patient), haematological neoplasia (3 patients), corticosteroid therapy (3 patients) or renal transplantation (2 patients) were studied by one or more of the authors. We did not find differences in the presentation of leishmaniasis between patient with or without AIDS and most patients had fever, enlargement of the liver and spleen, blood cytopenias and biochemical abnormalities. Serology was more frequently positive in HIV-negative than in HIV-positive patients (100% versus 63.6%; P=0.13). Bone marrow biopsy was diagnostic in 66% and 87% of patients with and without AIDS, respectively. Failure of anti-leishmanial therapy occurred in 6 of 19 patients treated (31.5%), and 3 patients with AIDS and another 3 without AIDS died during the first episode of leishmaniasis. Of 12 survivors, relapses occurred in five (41.6%). Only patients in whom immunosuppression was ameliorated by means of antiretroviral therapy or by reduction of corticosteroid and other immunosuppressive drugs did not relapse. Treatment of kala azar in immunocompromised host is in satisfactory and new drugs or strategies are urgently needed.

Inhibitors of purine and pyrimidine synthesis: mycophenolate, azathioprine, and leflunomide

The major goal in the treatment of autoimmune blistering diseases has changed from simply keeping the patient alive to suppressing disease while maintaining quality of life and minimizing drug side effects. Researchers and clinicians are constantly seeking steroid-sparing agents that would allow a dose reduction in corticosteroids with no loss of benefit. Purine and pyrimidine base inhibitors are commonly used for this purpose. These drugs act by inhibiting cell division and inducing cell death. The pharmacologic and clinical aspects of azathioprine, mycophenolate mofetil, and leflunomide are discussed in this review.