Steroid Elimination Research Articles

Is Remission Now an Achievable Goal for More Patients with Systemic Lupus Erythematosus?

More than 3.4 million people worldwide are affected by systemic lupus erythematosus (SLE), a chronic, complex, and unpredictable autoimmune condition that can take years to diagnose. SLE, the most common form of lupus, frequently has a profoundly negative impact on the quality of life for patients, with many reporting chronic fatigue, anxiety, and pain as symptoms. Inadequate disease control, and associated side effects of current treatment for people with SLE, lead to recurrent flares in symptoms and high risk of organ damage. Fifty percent of people with SLE have irreversible organ damage within 5 years of diagnosis due to long-term oral glucocorticoid (GC) use, disease flares, and persistent disease activity. SLE mortality remains unacceptably high and is one of the top 10 causes of death in young women in the USA. Although the speed of innovation has accelerated in recent years, there is still a great need beyond symptom management to tackle the underlying cause of the disease and achieve clinical remission for patients. In 2023, the European Alliance of Associations for Rheumatology (EULAR) updated its recommendations for SLE management, elevating the importance of treating to target remission or low disease activity with elimination of steroids, where possible, to reduce the risk of organ damage and adverse outcomes in patients. EULAR defines remission in SLE, according to the Definition of Remission in SLE (DORIS) criteria, as having no disease activity while receiving treatment, but GC ≤5 mg/day. Two leading SLE experts, Ian Bruce, Queen’s University Belfast, UK, and Julia Weinmann-Menke, Medical Center of the Johannes Gutenberg University, Mainz, Germany, discuss why remission is now a realistic goal in SLE, and how aiming for early and sustained remission can help to improve patient outcomes and address urgent unmet medical needs.

Lowering Expectations: Glucocorticoid Tapering Among Veterans With Rheumatoid Arthritis Achieving Low Disease Activity on Stable Biologic Therapy.

In the Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial, 65% of patients with rheumatoid arthritis (RA) in low disease activity (LDA) on stable biologic therapy successfully tapered glucocorticoids. We aimed to evaluate real-world rates of glucocorticoid tapering among similar patients in the Veterans Affairs Rheumatoid Arthritis registry. Within a multicenter, prospective RA cohort, we used registry data and linked pharmacy claims from 2003 to 2021 to identify chronic prednisone users achieving LDA after initiating a new biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). We defined the index date as first LDA occurring 60 to 180 days after b/tsDMARD initiation. The primary outcome of successful tapering, assessed at day 180 after LDA, required a 30-day averaged prednisone dose both less than or equal to 5mg/day and at least 50% lower than at the index date. The secondary outcome was discontinuation, defined as a prednisone dose of 0 mg/day at days 180 through 210. We used univariate statistics to compare patient characteristics by fulfillment of the primary outcome. We evaluated 100 b/tsDMARD courses among 95 patients. Fifty-four courses resulted in successful tapering; 33 resulted in discontinuation. Positive rheumatoid factor, higher erythrocyte sedimentation rate, more background DMARDs, shorter time from b/tsDMARD initiation to LDA, and higher glucocorticoid dose 30 days before LDA were associated with greater likelihood of successful tapering. In a real-world RA cohort of chronic glucocorticoid users in LDA, half successfully tapered and a third discontinued prednisone within 6 months of initiating a new b/tsDMARD. Claims-based algorithms of glucocorticoid tapering and discontinuation may be useful to evaluate predictors of tapering in administrative data sets.

Pharmacological Management of Steroid-Induced Psychosis: A Review of Patient Cases.

Objective: To review the efficacy and safety of medications used in the management of steroid-induced psychosis. Data Sources: A comprehensive literature search was conducted using PubMed, MEDLINE, ProQuest, and Scopus between May and October 2020 using the following search terminology: "steroid-induced psychosis" OR "corticosteroid-induced psychosis." Study Selection and Data Extraction: Definitive cases, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, were included in this review. Geriatric patients >65 years of age, those with a confounding neurological condition such as a traumatic brain or spinal cord injury, or those with active malignancy were excluded. Data Synthesis: A total of 13 patient cases were included in this review, representing 8 male patients and 5 female patients. The mean age at symptom presentation was 42.5 years. Six patients presented with delusions, 5 presented with hallucinations, and 2 presented with both manifestations; 12 patients were managed with an antipsychotic, with haloperidol being the most commonly prescribed, followed by risperidone. One patient was managed with lithium and clonazepam alone. All patients returned to their psychological baseline upon the discontinuation or decreased dose of steroids in combination with Pharmacological intervention, though the time to resolution of symptoms varied significantly. No notable adverse drug events associated with treatments were reported. Conclusions: Steroid-induced psychosis is a serious adverse effect of corticosteroid therapy; however, management strategies that combine a dose reduction or elimination of steroids, in combination with an antipsychotic medication, are effective in resolving this syndrome.

Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial

Patients with inflammatory diseases, such as rheumatoid arthritis, often receive glucocorticoids, but long-term use can produce adverse effects. Evidence from randomised controlled trials to guide tapering of oral glucocorticoids is scarce. We investigated a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids in patients with rheumatoid arthritis. The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was a double-blind, multicentre, two parallel-arm, randomised controlled trial done at 39 centres from six countries (France, Germany, Italy, Russia, Serbia, and Tunisia). Adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5-15 mg per day for 24 weeks or more were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activaity, confirmed by a Disease Activity Score for 28 joints-erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less 4-6 weeks before and on the day of randomisation. Patients were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16. All patients received tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks) with or without csDMARDs maintained at stable doses during the entire 24-week study. The primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0·6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group. The trial is registered with ClinicalTrials.gov, NCT02573012. Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 (200 [77%] women and 59 [23%] men) were recruited onto the trial. In all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen; the estimated mean change in DAS28-ESR from baseline to week 24 was 0·54 (95% CI 0·35-0·73) with tapered prednisone and -0·08 (-0·27 to 0·12) with continued prednisone (difference 0·61 [0·35-0·88]; p<0·0001), favouring continuing prednisone 5 mg per day for 24 weeks. Treatment was regarded as successful (defined as low disease activity at week 24, plus absence of rheumatoid arthritis flare for 24 weeks and no confirmed adrenal insufficiency) in 99 (77%) patients in the continued-prednisone group versus 85 (65%) patients in the tapered-prednisone group (relative risk 0·83; 95% CI 0·71-0·97). Serious adverse events occurred in seven (5%) patients in the tapered-prednisone group and four (3%) patients in the continued-prednisone group; no patients had symptomatic adrenal insufficiency. In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose. F Hoffmann-La Roche.

Cutaneous Pseudolymphoma: A Brief Review and Report of a Case Treatment Using Rituximab

Cutaneous pseudolymphoma (C-PSL) is characterized by heterogenous lymphoproliferative processes contributing to skin lesions which histologically and clinically mimic malignant cutaneous lymphomas. It is of most importance to diagnose such case precisely and discriminate them from malignant lymphomas since treatment protocols are distinctive. Standard medical approaches for C-PSL includes elimination of causative factors, topical, intralesional and systemic steroids, hydroxychloroquine, and photodynamic therapy. Rituximab as an anti CD20 monoclonal antibody was used in this study to treat a patient with 8 years clinical features of pseudolymphoma with no positive response to routine medications. Follow up of almost more than 18 months revealed a successful treatment without noticeable side effects or disease recurrence.

Combined Effect of Diosgenin Along with Ezetimibe or Atorvastatin on the Fate of Labelled Bile Acid and Cholesterol in Hypercholesterolemic Rats.

We analyzed the effect of diosgenin, administered with atorvastatin or ezetimibe, on the fate of 3H(G)-taurocholic acid or 26-14C-cholesterol in hypercholesterolemic rats. Male Wistar rats received a hypercholesterolemic diet (HD), HD + atorvastatin (HD+ATV), HD + ezetimibe (HD+EZT), HD + diosgenin (HD+DG), HD+ATV+EZT, or HD+ATV+DG for 40 days. We also included a control normal group (ND). The labelled compounds were administered on day 30. The animals were placed in metabolic cages for daily feces collection. At day 40 the rats were sacrificed. Lipid extracts from blood, liver, spinal cord, testicles, kidneys, epididymis, intestine, and feces were analyzed for radioactivity. Cholesterol activity was the highest in the liver in HD rats. DG diminished one half of this activity in HD+DG and HD+ATV+DG groups in comparison with the HD group. HD+ATV rats showed four to almost ten-fold cholesterol activity in the spinal cord compared with the ND or HD rats. Fecal elimination of neutral steroids was approximately two-fold higher in the HD+DG and HD+ATV+DG groups. Taurocholic acid activity was four to ten-fold higher in HD+DG intestine as compared to the other experimental groups. Taurocholic activity in the liver of HD and HD+DG groups was two and a half higher than in ND. Our results show that the combination of DG and ATV induced the highest cholesterol reduction in the liver and other tissues.

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Four Molybdenum-Dependent Steroid C-25 Hydroxylases: Heterologous Overproduction, Role in Steroid Degradation, and Application for 25-Hydroxyvitamin D3 Synthesis.

ABSTRACTSide chain-containing steroids are ubiquitous constituents of biological membranes that are persistent to biodegradation. Aerobic, steroid-degrading bacteria employ oxygenases for isoprenoid side chain and tetracyclic steran ring cleavage. In contrast, a Mo-containing steroid C-25 dehydrogenase (S25DH) of the dimethyl sulfoxide (DMSO) reductase family catalyzes the oxygen-independent hydroxylation of tertiary C-25 in the anaerobic, cholesterol-degrading bacterium Sterolibacterium denitrificans. Its genome contains eight paralogous genes encoding active site α-subunits of putative S25DH-like proteins. The difficult enrichment of labile, oxygen-sensitive S25DH from the wild-type bacteria and the inability of its active heterologous production have largely hampered the study of S25DH-like gene products. Here we established a heterologous expression platform for the three structural genes of S25DH subunits together with an essential chaperone in the denitrifying betaproteobacterium Thauera aromatica K172. Using this system, S25DH1 and three isoenzymes (S25DH2, S25DH3, and S25DH4) were overproduced in a soluble, active form allowing a straightforward purification of nontagged αβγ complexes. All S25DHs contained molybdenum, four [4Fe-4S] clusters, one [3Fe-4S] cluster, and heme B and catalyzed the specific, water-dependent C-25 hydroxylations of various 4-en-3-one forms of phytosterols and zoosterols. Crude extracts from T. aromatica expressing genes encoding S25DH1 catalyzed the hydroxylation of vitamin D3 (VD3) to the clinically relevant 25-OH-VD3 with >95% yield at a rate 6.5-fold higher than that of wild-type bacterial extracts; the specific activity of recombinant S25DH1 was twofold higher than that of wild-type enzyme. These results demonstrate the potential application of the established expression platform for 25-OH-VD3 synthesis and pave the way for the characterization of previously genetically inaccessible S25DH-like Mo enzymes of the DMSO reductase family.

A Single Center 11 Year Experience with 202Pancreas Transplants: Evolving Trends

A single center experience with pancreas transplantation (PTx) over an 11+ year period is reviewed. Methods: We retrospectively studied outcomes in 202 consecutive PTxs in 192 patients at our center. All patients received either rATG or alemtuzumab (Alem) induction with tacrolimus/MMF and tapered steroids or early withdrawal. 179 PTxs (89%) were performed with portal-enteric and 23 with systemic-enteric drainage. Results: From 11/01 to 3/13, we performed 162 simultaneous kidney-PTxs (SKPT), 35 sequential PTxs after kidney (PAK), and 5 PTx alone (PTA; 40 solitary PTxs [SPT]). 186 PTxs (92%) were primary and 16 pancreas retransplants. With a mean follow-up of 5.5 years, overall patient (87% SKPT versus 87.5% SPT), kidney (74% SKPT versus 82.5% SPT) and pancreas graft survival (both 65%) rates were comparable. Causes of PTx loss were also similar between SKPT and SPT; the rates of early thrombosis were 8.6% and 5%, respectively. Acute rejection rates were similar between groups (SKPT 29% versus SPT 26%, p=NS). A randomized trial of Alem versus rATG induction in SKPT demonstrated lower rates of acute rejection and infection in the Alemgroup; consequently, Alem induction has been used exclusively in all PTxs since 2009. Early steroid elimination has been feasible in most patients. Surveillance PTx biopsy-directed immunosuppression has contributed to equivalent long-term outcomes in SKPT and SPT. Good results have been achieved in African-American patients and in patients with a type 2 diabetes phenotype. Conclusions: Excellent 5 year outcomes following PTx can be achieved as >86% of patients are alive, >87% of surviving patients are dialysisfree, 80% of surviving patients remain insulin-free, and 88% of surviving patients have detectable C-peptide levels.

Clinical Predictors of a Poor Response to Anti-TNF Biologic Therapy for Inflammatory Bowel Disease

Introduction: The purpose of this study was to identify baseline characteristics of patients with Crohn’s disease (CD) and ulcerative colitis (UC) which may predict failure of biologic therapy. Methods: This is a retrospective cohort study analyzing a database of 227 patients who had been treated with infliximab, adalimumab, or certolizumab pegol for IBD at the Crohn’s and colitis center at Robert Wood Johnson University Hospital (RWJUH). We evaluated and compared response rates to initial biologic therapy in the presence or absence of multiple clinical parameters to identify their association with biologic failure. Patients with CD and UC were analyzed separately. Clinical response was defined as overall clinical improvement of patients such as restoration of normal bowel function, quality of life, elimination of steroids, and improvement of laboratory markers of inflammation. Data analysis was conducted using chi-square and multivariate regression analysis. Results: In patients with Crohn’s disease, we evaluated baseline characteristics (age of onset, gender, smoking, and family history), disease patterns (disease location, perianal fistulas, enteric fistulas, strictures, surgical resections), extraintestinal manifestations (EIM) including ocular, joint and skin disease, and prior treatment history. There was a statistically significant difference in response rates between males and females (72% vs. 56%; odds ratio [OR] 2.0; p. 04) as well as presence of EIM (51% vs. 68%; OR. 49; p. 05). All other parameters evaluated did not predict failure of biologics in patients with CD. We then analyzed similar parameters in patients with UC who had been treated with biologics. Those with the presence of EIM had a lower response rate to biologics (30% vs. 67%; OR. 21; p. 02). All other parameters failed to show a statistically significant difference. Conclusion: Female gender was associated with failure of biologic therapy in CD while the presence of EIM was associated with poorer response to biologic therapy in both CD and UC. It is interesting to note that baseline characteristics such as younger age of onset, smoking, presence of upper GI disease, stenotic or fistulizing disease was not associated with a lower response rate. The presence of EIM may therefore portend a poorer response rate to anti-TNF therapy compared to previously known markers of aggressive IBD. The trends observed in our study require replication on a larger scale but may serve as clinical predictors to guide anti-TNF therapy in the future.

Long-Term Data On the Use of Everolimus and Low-Dose Ciclosporin A in Children After Kidney Transplantation (Tx).

Background: Actually, only short-term trials using Everolimus in children after Tx have been published. This is the first prospective study to present four-year data using low-dose Ciclosporin A (CsA), Everolimus and steroid elimination. Methods: 35 children (median age: 10.7 ± 5.6 years) received Basiliximab, CsA and Prednisolone after Tx. Everolimus (1.6mg/m2/day) treatment was added two weeks post Tx. In 83% of the patients Prednisolone was withdrawn 8-10 months post Tx. Long-term target trough levels for CsA and Everolimus were 30-50 ng/ml and 2-4 ng/ml. Clinical outcome and side effects were evaluated prospectively. Results: Patient and graft survival were 100% and median eGFR was 62, 61, 58 and 65 ml/min/1.73m2 1-4 years after Tx. Acute rejection (BANFF ≥ Ia) was diagnosed in indication biopsies in in 2/35 (6%) children in the first year after Tx. In the remaining observation time, acute rejection was only diagnosed in one child in year 2 and 4. De novo Donor specific antibodies were found in 4/35 patients in yearly checkups with the histopathological diagnosis of chronic humoral rejection in one patient. In the four years observation time, one child developed EBV associated PTLD that was successfully treated with Rituximab. Two patients developed transient wound healing problems, 17% aphthous stomatitis. No significant albuminuria > 100 mg/mmol creatinine was recognized. Height SDS was -0.73 / -0.74 two and four years after Tx. Despite an elevation of estradiol in 33% of the girls, all sex hormone levels were within the normal range. Conclusions: After ped. kidney Tx, de novo immunosuppression with low-dose CsA, Everolimus, and a withdrawal of Prednisolone is followed by excellent graft survival and function, good growth and only a small number side effects. DISCLOSURE:Pape, L.: Grant/Research Support, Novartis.

A randomized, controlled trial of everolimus‐based dual immunosuppression versus standard of care in de novo kidney transplant recipients

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI-WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.

Pancreas transplantation: The Wake Forest experience in the new millennium.

To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression. A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide. Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a "type 2 diabetes" phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels. In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.

UDP-glucose Dehydrogenase Activity and Optimal Downstream Cellular Function Require Dynamic Reorganization at the Dimer-Dimer Subunit Interfaces

UDP-glucose dehydrogenase (UGDH) provides precursors for steroid elimination, hyaluronan production, and glycosaminoglycan synthesis. The wild-type UGDH enzyme purifies in a hexamer-dimer equilibrium and transiently undergoes dynamic motion that exposes the dimer-dimer interface during catalysis. In the current study we created and characterized point mutations that yielded exclusively dimeric species (obligate dimer, T325D), dimeric species that could be induced to form hexamers in the ternary complex with substrate and cofactor (T325A), and a previously described exclusively hexameric species (UGDHΔ132) to investigate the role of quaternary structure in regulation of the enzyme. Characterization of the purified enzymes revealed a significant decrease in the enzymatic activity of the obligate dimer and hexamer mutants. Kinetic analysis of wild-type UGDH and the inducible hexamer, T325A, showed that upon increasing enzyme concentration, which favors the hexameric species, activity was modestly decreased and exhibited cooperativity. In contrast, cooperative kinetic behavior was not observed in the obligate dimer, T325D. These observations suggest that the regulation of the quaternary assembly of the enzyme is essential for optimal activity and allosteric regulation. Comparison of kinetic and thermal stability parameters revealed structurally dependent properties consistent with a role for controlled assembly and disassembly of the hexamer in the regulation of UGDH. Finally, both T325A and T325D mutants were significantly less efficient in promoting downstream hyaluronan production by HEK293 cells. These data support a model that requires an operational dimer-hexamer equilibrium to function efficiently and preserve regulated activity in the cell.

Impact of Calcineurin-Inhibitor Conversion to mTOR Inhibitor on Renal Allograft Function in a Prednisone-Free Regimen

Traditionally, chronic calcineurin inhibitor (CNI) nephrotoxicity has been considered to be one of the main nonimmune mechanisms causing chronic renal allograft dysfunction. CNI minimization and withdrawal strategies have yielded inconsistent results. Few studies address the feasibility of CNI elimination in a prednisone-free regimen. We report a prospective, randomized trial in 200 patients evaluating the impact on renal function and incidence of acute rejection after conversion from tacrolimus (Tac) to sirolimus (SRL). Patients with recent (<3 months) acute rejection episodes or with >0.5 g/day of proteinuria were excluded. All were induced with alemtuzumab, underwent rapid steroid elimination and were maintained on mycophenolate mofetil and Tac. At 12 months posttransplant, patients were randomized 2:1 to SRL (n = 123) or maintained on Tac (n = 64). Mean follow-up was 41.1 ± 15.8 months in the SRL group and 40.7 ± 14.4 months in the Tac group. Biopsy-proven acute rejection at 24 months postrandomization was similar between the groups. Patient survival, graft survival and estimated GFR were also not statistically different. Our study demonstrates that in a prednisone-free immunosuppressive regimen, conversion from Tac to SRL at 12 months posttransplantation is not associated with increased rates of acute rejection and graft loss. However, despite CNI elimination, renal allograft function is equally maintained in both groups.

Steroid elimination within 24 hours after orthotopic liver transplantation: effectiveness and tolerability

Steroids have been the mainstay of immunosuppressive regimen in liver transplantation. However, the use of steroids is associated with various post-transplant complications. This study evaluated the efficacy and safety of reduced immunosuppressive regimen with steroids (steroid elimination within 24 hours post-transplant) in a cohort of Chinese liver transplant recipients. Seventy-six patients in line with the selection criteria were enrolled in this prospective study. All patients received anti-IL-2 receptor antibody induction and tacrolimus-based maintenance therapy. The recipients were divided into two groups according to the duration of steroid use: 40 transplant in a 3-month withdrawal group and the remaining 36 in a 24-hour elimination group. Recipient survival, post-operative infections, biopsy-proven acute rejection and steroid-resistant acute rejection, non-healing wound, recurrence of hepatitis B virus (HBV) and hepatocellular carcinoma (HCC), de novo diabetes, hyperlipidemia and hypertension were assessed in the two groups. There was no significant difference in patient survival, incidence of acute rejection episodes and hyperlipidemia, and recurrence of HBV and HCC between the two groups. However, the incidence rates of post-transplant infection, non-healing wound, de novo diabetes and hypertension were significantly lower in the 24-hour elimination group than in the 3-month withdrawal group (all P values <0.05). Under anti-IL-2 receptor antibody induction and tacrolimus-based maintainance, steroid elimination within 24 hours post-transplant is associated with reduced steroid-related complications without increasing the risk of rejection.

Certolizumab pegol as treatment for Crohnʼs disease in a community IBD practice

Certolizumab pegol (CZP) is a pegylated-conjugated Fab' agent against tumor necrosis factor, approved for the treatment of moderate to severe Crohn's disease (CD). This single center community practice has retrospectively reviewed 3 years of CZP use as standard of care therapy in patients presenting with moderate to severe CD, both in TNF naive and exposed patients. A retrospective chart review of patients with CD receiving induction and maintenance CZP injections between 7/1/2008 and 6/30/2011 was performed. Demographic and baseline disease characteristics; steroid, narcotic and tobacco use; Harvey Bradshaw Index (HBI), and quality of life scores (SIBDQ) were studied. Steroid elimination and endoscopic endpoints were evaluated when available. Response was defined as a decrease in HBI of 3 points after induction. Remission was defined as a HBI score of < =3. During the review period, a total of 30 CD patients received at least 3 doses of CZP injected at FDA approved dosing for induction and maintenance therapy. Of the 30 evaluated, 60% (n=18) were responders, with 40% (n=12) being non-responders. Fifteen of the 18 responders (50 % of ITT population) achieved clinical remission. The response group included 7 males, 11 females, with average age of 39.4 years and average duration of disease of 7.5 years. Eight responders had prior surgery, 3 were smokers, 4 used narcotics and 17 (94%) were on steroids at the time of CZP initiation. Eleven (61%) of responders were TNF exposed, with a baseline HBI of 8.5 (range 4-14) and SIBDQ of 34 (range 24-42 ). After treatment, the average HBI fell to 1.9 (range 0-5) in the response group with a increase in the average SIBDQ score to 60 (range 47-70). Steroid elimination was successful in 15 responders (83%) with endoscopic healing demonstrated in 10 of 11 patients (5 colonoscopies, 6 wireless capsule endoscopies). All 10 patients in endoscopic remission were also in clinical remission with an average HBI of 1. The non-responder group included 5 males, 7 females, with an average age of 37 years and average disease duration of 9.7 years. Seven non-responders had prior surgery, 4 were smokers, 2 used narcotics and 100% were on steroids at the time of CZP initiation. 83% (n=10) of non-responders had prior TNF exposure. Steroid elimination occurred in one patient (8%) and endoscopic endpoints were not obtained in any of the non-responders. Baseline HBI average for non-responders was 7.9 (range 4-15) with HBI after treatment of 7.6 (range 2-10). The average SIBDQ score for non-responders at baseline was 37 (range 24-64)increasing to 44 (range 25-64) after treatment. In our single center, retrospective study, CZP showed an overall remission rate of 50%, response rate of 60% with successful steroid elimination despite prior biologic exposure (61%). Endoscopic healing and clinical remission was demonstrated in addition to a clear reduction in disease activity and improvement in quality of life.

Pediatric Kidney Transplantation Followed by De Novo Therapy With Everolimus, Low-Dose Cyclosporine A, and Steroid Elimination: 3-Year Data

Acute rejections and infections continue to cause substantial problems for pediatric kidney transplant (KTX) patients because defining an immunosuppressive protocol capable of preventing both has been challenging. Previously, we initiated a prospective trial to evaluate an immunosuppressive regimen designed to achieve this goal. Herein, we present the results of the 3-year follow-up of this trial. After KTX, 20 children (median age 12 years, range 1-17 years) received basiliximab, cyclosporine A (CsA) (trough-level=C0 200-250 ng/mL), and prednisolone. Two weeks post-KTX, everolimus (1.6 mg/m/day) treatment was started (C0 4-6 ng/mL), and the CsA dose was reduced by 50% (C0 75-100 ng/mL, after 6 months: C0 50-75 ng/mL). Prednisolone treatment was gradually withdrawn and was completely stopped at 9 months post-KTX. There was no loss of follow-up and no graft or patient loss during the 3-year period. Indication biopsies showed no acute rejection (Banff ≥IA). One of the patients had signs of chronic humoral rejection. Mean glomerular filtration rate measured at 1 year and 3 years post-KTX was 71±25 and 61±27 mL/min/1.73 m, respectively. In patients transitioned to adult care, mean glomerular filtration rate at 3 years was 49±13 mL/min/1.73 m (P<0.05). No cases of posttransplant lymphoproliferative disorder posttransplant lymphoproliferative disorder or polyoma nephropathy were diagnosed. After 3 years, 17 of 20 patients remained on the original immunosuppressive regimen. A treatment regimen consisting of de novo immunosuppression with basiliximab, CsA, and prednisolone, followed by treatment with everolimus and low-dose CsA combined with steroid withdrawal may be a promising therapy after pediatric KTX.

Randomized Trial of Mycophenolate Mofetil Versus Enteric-Coated Mycophenolate Sodium in Primary Renal Transplantation With Tacrolimus and Steroid Avoidance: Four-Year Analysis

Our single-center, open-labeled randomized trial of 150 adult, primary kidney transplant recipients receiving 2 g mycophenolate mofetil (group A, n=75) versus 1.440 g enteric-coated mycophenolate sodium (group B, n=75), with reduced maintenance tacrolimus dosing, steroid elimination at 1 week, and combined rabbit antithymocyte globulin/daclizumab induction, previously showed at 1 year posttransplant low biopsy-proven acute rejection (BPAR), acceptably high renal function, and no differences in incidence of symptomatic gastrointestinal (GI) side effects between the two groups. This report includes 3 additional years of follow-up with similar endpoints as in the original study. Rates of developing first BPAR, graft failure (death censored and uncensored), death, and adverse events (GI toxicity, infections requiring hospitalization, and new onset diabetes mellitus after transplantation) during the first 48 months posttransplant were compared between the two groups using an intent-to-treat approach. At 48 months posttransplant, patient/graft survival in groups A and B was 97%/90% vs. 96%/86%, respectively (not significant [NS]). Twenty-seven patients experienced BPAR (including borderline), with actuarial 19% (14/75) vs. 18% (13/75) in groups A and B, respectively (NS). Geometric mean*/standard error serum creatinine level and arithmetic mean calculated glomerular filtration rate (±standard error) at 48 months in groups A and B, respectively, were 1.25*/1.06 and 69.2±3.9 vs. 1.20*/1.05 and 71.2±3.2 (NS). Incidence of new onset diabetes mellitus after transplantation (22% vs. 15%), infections requiring hospitalization (31% vs. 39%), and GI side effects (45% vs. 52%) seemed equivalent. This is the first long-term, randomized trial comparing enteric-coated mycophenolate sodium versus mycophenolate mofetil along with reduced maintenance tacrolimus dosing and steroid avoidance, which resulted in similarly low-BPAR rates, acceptably high renal function at 48 months, and an equivalent side effect profile.

Pancreas Transplantation: Lessons Learned From a Decade of Experience at Wake Forest Baptist Medical Center

This article reviews the outcome of pancreas transplantations in diabetic recipients according to risk factors, surgical techniques, and immunosuppression management that evolved over the course of a decade at Wake Forest Baptist Medical Center. A randomized trial of alemtuzumab versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous kidney-pancreas transplantation (SKPT) at our institution demonstrated lower rates of acute rejection and infection in the alemtuzumab group. Consequently, alemtuzumab induction has been used exclusively in all pancreas transplantations since February 2009. Early steroid elimination has been feasible in the majority of patients. Extensive experience with surveillance pancreas biopsies in solitary pancreas transplantation (SPT) is described. Surveillance pancreas biopsy-directed immunosuppression has contributed to equivalent long-term pancreas graft survival rates in SKPT and SPT recipients at our center, in contrast to recent registry reports of persistently higher rates of immunologic pancreas graft loss in SPT. Furthermore, the impact of donor and recipient selection on outcomes is explored. Excellent results have been achieved with older (extended) donors and recipients, in recipients of organs from donation after cardiac death donors managed with extracorporeal support, and in African-American patients. Type 2 diabetics with detectable C-peptide levels have been transplanted successfully with outcomes comparable to those of insulinopenic diabetics. Our experiences are discussed in the light of findings reported in the literature.