Steroid-sparing Strategies Research Articles

Inflammatory Bowel Disease Patients Hospitalized for Flares Are at Risk for Chronic Steroid Use Due to Lack of Clear Instructions at Discharge: A 15-Month Retrospective Study at a Private, Not-For-Profit Academic Hospital

Patients with inflammatory bowel disease (IBD) who are hospitalized with an IBD flare can be managed acutely with short-term (4-6 weeks) high dose glucocorticoid taper. Corticosteroid use beyond 3-4 months can cause serious and significant side effects. Thus, it is imperative for patients to be discharged with a prednisone tapering plan and steroid-sparing treatment strategy. This quality assessment project examines the rate at which IBD patients remain on high dose steroids 3 months after hospital discharge.

Omega‐3 Fatty Acid and Glucocorticoid Additively Suppress Pro‐inflammatory/ Interferon‐Regulated Gene Responses and Inflammasome Activation in Novel Alveolar Macrophage Model

Glucocorticoids (GCs, a.k.a. steroids) are a widely used treatment in chronic inflammatory and autoimmune diseases, but have many injurious side effects. Dietary omega‐3 fatty acids (O3FA) are effective anti‐inflammatory agents with potentially distinct and overlapping mechanisms of action with GCs. However, the potential for combining these anti‐inflammatory agents as a steroid‐sparing strategy is understudied. The goal of this study was to assess the interactive effects of the O3FA docosahexaenoic acid (DHA) and GC dexamethasone (DEX) in modulating inflammasome activation and interferon‐regulated gene (IRG) response in Max Planck Institute (MPI) cells, a novel murine alveolar macrophage model derived from fetal liver. MPI cells were pre‐treated with 0, 5, 10 or 20 μM DHA‐BSA conjugate for 24 hr, followed by 0, 0.01, 0.1, or 1 μM DEX for 1 hr. This was followed by stimulation with 20 ng/mL lipopolysaccharide (LPS) for 2 or 4 hr. At this point, cells were either i) directly harvested and analyzed for pro‐inflammatory and IRG gene expression by qRT‐PCR, or ii) incubated with 5 μM nigericin for 45 min to achieve inflammasome activation, as measured by IL‐1β in the supernatant. LPS treatment significantly induced both pro‐inflammatory and IRG responses in this cell line, and was also required for nigericin‐induced IL‐1β release. Singular treatment with either DHA or DEX alone both exhibited concentration‐dependent reduced inflammatory gene expression and inflammasome activation. When combined, DHA and DEX suppressed these responses in an additive manner. Taken together, this model offers a tool to identify interrelated mechanisms of action of O3FAs and GCs with the long‐term goal of implementing this combination in new steroid‐sparing therapies against inflammatory and autoimmune diseases.Support or Funding InformationResearch funded in part by the Dr. Robert and Carol Deibel Family Endowment fund

Targeting IL-17A/glucocorticoid synergy to CSF3 expression in neutrophilic airway diseases.

IL-17A plays a critical role in the pathogenesis of steroid-resistant neutrophilic airway inflammation, which is a hallmark of severe asthma and chronic obstructive pulmonary disease (COPD). Through RNA sequencing analysis of transcriptomes of human airway smooth muscle cells treated with IL-17A, dexamethasone (DEX, a synthetic glucocorticoid drug), alone or in combination, we identified a group of genes that are synergistically induced by IL-17A and DEX, including the neutrophil-promoting cytokine CSF3. In type-17 (Th17/IL-17Ahi) preclinical models of neutrophilic severe asthma (acute and chronic) and COPD, although DEX treatment was able to reduce the expression of neutrophil-mobilizing CXCL1 and CXCL2 in lung tissue, CSF3 expression was upregulated by DEX treatment. We found that DEX treatment alone failed to alleviate neutrophilic airway inflammation and pathology, and even exacerbated the disease phenotype when CSF3 was highly induced. Disruption of the IL-17A/DEX synergy by IL-17A inhibition with anti-IL-17A mAb or cyanidin-3-glucoside (C3G, a small-molecule IL-17A blocker) or depletion of CSF3 effectively rendered DEX sensitivity in type-17 preclinical models of neutrophilic airway diseases. Our study elucidates what we believe is a novel mechanism of steroid resistance in type-17 neutrophilic airway inflammation and offers an effective steroid-sparing therapeutic strategy (combined low-dose DEX and C3G) for treating neutrophilic airway diseases.

Lupus Nephritis in Children: 21-Year Experience of a Single Center in Belarus

The article presents a historical and prospective analysis of the clinical and paraclinical data of a cohort of children suffering from systemic lupus erythematosus (SLE) with kidney damage, observed in a single center for 21 year. The case histories of 62 patients (51 girls and 11 boys) with a diagnosis of SLE and lupus nephritis (LN) who were monitored and treated at the Byelorussian Center for Pediatric Nephrology and Renal Replacement Therapy of the 2nd Children's Clinical Hospital in Minsk in the period from 1998 to 2019 yrs. We evaluated the initial manifestations of the disease, age of the onset, time of diagnosis (from the first symptom to the diagnosis), clinical manifestations at the time of diagnosis, the duration of SLE and treatment at the time of kidneys biopsy, as well as the activity of the disease. During the observation period (from 3 months up to 12 years) the frequency of extrarenal and renal exacerbations was analyzed, and the activity, treatment and outcome were evaluated. Male gender and early debut are factors worsening the prognosis of the disease (55% of boys showed progression of CRF). In children, the disease proceeds with a high degree of activity, rapid multi-organ involvement, requires more aggressive therapy with prescription of several immunosuppressive agents, which increases the risk of infection. Nephritis is an unfavorable prognostic criterion and is crucial in determining the volume of therapy for SLE. Noncompliance in therapy, social status were factors of an unfavorable outcome in children. Timely diagnosis and aggressive intervention to suppress the activity of the disease should be used to prevent chronic irreversible damage. Children with SLE and kidney damage are at high risk for early development of cardiovascular disorders. Steroid-sparing strategies must be actively implemented in clinical practice in order to prevent severe side effects.

Longitudinal disease- and steroid-related damage among adults with childhood-onset systemic lupus erythematosus

ObjectivesDetermine whether adults with childhood-onset systemic lupus erythematosus (cSLE) are at increased risk for disease- and steroid-related damage as compared to individuals with adult-onset SLE (aSLE), and whether they continue to accumulate disease damage in adulthood. MethodsData derive from the 2007–2015 cycles of the Lupus Outcomes Study, a longitudinal cohort of adults with confirmed SLE. The Brief Index of Lupus Damage (BILD), a validated, patient-reported measure, was used to assess SLE-associated damage. Participants with baseline BILD were included (N = 1035). Diagnosis at age < 18 years was defined as cSLE (N = 113). Outcome variables included BILD score at baseline and follow-up, clinically significant change in BILD score over follow-up period, and presence of steroid-related damage (cataracts, osteoporosis-related fracture, avascular necrosis or diabetes mellitus). ResultsMean time between baseline and follow up BILD assessment was 6.3 ± 1.7 years. In adjusted analyses, participants with cSLE and aSLE had similar levels of disease-related damage, and accumulated damage at similar rates. Participants with cSLE were more likely to report steroid-related damage (OR 1.7, 95% CI 1.1–2.8) in the adjusted analysis as compared to those with aSLE. Likelihood of steroid-related damage increased with disease duration for both groups, but was consistently higher among cSLE participants. ConclusionIn this longitudinal cohort of adults with SLE, participants continued to accumulate damage at similar rates over time, regardless of age at onset or disease duration. Childhood-onset predicted increased risk of steroid-related damage. Aggressive use of steroid-sparing treatment strategies during childhood may be important to prevent steroid-related damage in adulthood.

Abstract B154: Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses— Implications for the management of irAEs

Abstract Background: Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high doses of corticosteroids or, in refractory cases, with tumor necrosis factor (TNF) antagonists, are the mainstay of treatment for irAEs. It is currently unknown what is the impact of corticosteroids and anti-TNF on the activity of antitumor T-cells. Methods: The influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10 to 125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing capacity of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Results: Overall, dexamethasone at low or intermediate/high dose impaired the activation (respectively -46% and -62% in n=8) and tumor-killing ability (respectively -48% and -53% in n=6) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T-cell activation and tumor killing (respectively -20% in n=8 and -10% in n=6). A brief resting following exposure to dexamethasone was sufficient to rescue the in vitro activity of TILs. Conclusions: Clinically relevant doses of infliximab only influenced to a lesser extent the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. These data support steroid-sparing strategies and early initiation of anti-TNF for the treatment of irAEs in immuno-oncology. Citation Format: Marco Donia, Troels H. Borch, Haja D. Radic, Christopher Chamberlain, Aishwarya Gokuldass, Inge Marie Stentoft Svane, Arianna Draghi. Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses— Implications for the management of irAEs [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B154.

Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses: implications for the management of irAEs.

Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high dose corticosteroids, or tumor necrosis factor (TNF) antagonists in refractory cases, is the mainstay of treatment for irAEs. It is currently unknown what impact corticosteroids and anti-TNF have on the activity of antitumor T cells. In our study, the influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10-125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing ability of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high doses impaired the activation (-46 and -62%, respectively) and tumor-killing ability (-48 and -53%, respectively) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (-20%) and tumor killing (-10%). A 72-hr resting period after withdrawal of dexamethasone was sufficient to rescue the in vitro activity of TILs, while a short withdrawal did not result in a full rescue. In conclusion, clinically relevant doses of infliximab only had a minor influence on the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. However, the activity of TILs could be restored after withdrawal of steroids. These data indirectly support steroid-sparing strategies and early initiation of anti-TNF therapy for the treatment of irAEs in immuno-oncology.

52P - Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses: Implications for the management of irAEs

Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high dose corticosteroids, or tumor necrosis factor (TNF) antagonists in refractory cases, is the mainstay of treatment for irAEs. It is currently unknown what impact corticosteroids and anti-TNF have on the activity of antitumor T cells. In our study, the influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10-125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing ability of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high doses impaired the activation (-46 and -62%, respectively) and tumor-killing ability (-48 and -53%, respectively) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (-20%) and tumor killing (-10%). A 72-hr resting period after withdrawal of dexamethasone was sufficient to rescue the in vitro activity of TILs, while a short withdrawal did not result in a full rescue. In conclusion, clinically relevant doses of infliximab only had a minor influence on the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. However, the activity of TILs could be restored after withdrawal of steroids. These data indirectly support steroid-sparing strategies and early initiation of anti-TNF therapy for the treatment of irAEs in immuno-oncology.

Biochemical efficacy of tioguanine in autoimmune hepatitis: a retrospective review of practice in the Netherlands.

SummaryBackgroundAzathioprine (AZA) and mercaptopurine (MP) are the cornerstone of steroid‐sparing strategies in autoimmune hepatitis (AIH). Up to 20% of patients do not tolerate or respond to these regimens.AimTo evaluate retrospectively the tolerability and efficacy of tioguanine (thioguanine) (TG) therapy in selected patients with AIH and AIH variant syndromes.MethodsRecords of 52 patients who received TG therapy were retrieved from nine hospitals in the Netherlands. Indications for TG treatment were intolerable side effects on AZA or MP (n = 38), insufficient response (n = 11) or first‐line treatment (n = 3). Treatment efficacy was defined as normalisation of serum aminotransferases and serum immunoglobulin G.ResultsNo serious adverse events occurred in patients treated with TG during a median follow‐up of 18 months (range 1‐194). Treatment was well tolerated in 41 patients (79%), whereas four had tolerable (8%) and seven (13%) intolerable side effects. Thirty‐eight patients were treated with TG after intolerable side effects on AZA or MP; 29 patients continued TG therapy of whom 24 (83%) achieved complete biochemical remission, four (14%) had incomplete and one (3%) had no response; nine discontinued treatment. Seven of 11 patients with insufficient response to AZA or MP were responsive to TG, three with complete and four with incomplete biochemical remission; four discontinued due to intolerance (n = 2) and non‐response (n = 2). TG was effective in all AIH patients as first‐line maintenance treatment.ConclusionIn our retrospective review of TG therapy in selected patients with AIH or AIH variants who previously failed on AZA or MP, TG appeared tolerable with biochemical efficacy.

Conversion From Steroid to Everolimus in Maintenance Kidney Transplant Recipients With Posttransplant Diabetes Mellitus.

Although steroid withdrawal has been attempted to ameliorate various complications in kidney transplant recipients, a steroid-sparing strategy has more frequently led to acute rejection. We investigated the use of everolimus to safely overcome steroid withdrawal in kidney transplant recipients with posttransplant diabetes mellitus under maintenance immunosuppressive therapy. A total of 75 de novo consecutive kidney transplant recipients received conventional immunosuppressive therapy comprising tacrolimus (trough level of 5 ng/mL), mycophenolate mofetil (1000 mg), and methylprednisolone (4 mg). Patients with posttransplant diabetes mellitus underwent simultaneous everolimus administration (trough level of 3-5 ng/mL) and steroid withdrawal at 1 to 15 months after transplant. Graft outcomes were compared between the everolimus and steroid groups. In the everolimus group, renal function and hemoglobin A1c levels at 12 months after administration were compared with values before everolimus administration. The mean posttransplant follow-up period in the everolimus (n = 25) and steroid (n = 50) groups was 672 and 747 days, respectively. All grafts survived in both groups, and biopsy-proven acute rejection rates did not significantly differ between the groups (16% vs 12%; P = .72). Furthermore, no acute rejection occurred after everolimus administration. In the everolimus group, hemoglobin A1c significantly declined at 9 months after everolimus administration (6.94% vs 6.53%; P = .047). In addition, both serum creatinine levels and estimated glomerular filtration rates in the everolimus group were stable for 12 months after everolimus administration. Steroid withdrawal using everolimus as maintenance immunosuppressive therapy for kidney transplant recipients may safely ameliorate posttransplant diabetes mellitus, achieve better glycemic control, and maintain stable renal function.

Pediatric Systemic Lupus Erythematosus: Learning From Longer Follow Up to Adulthood.

Background: Pediatric systemic lupus erythematosus (pSLE) is a rare condition, representing approximately 10% of SLE cases. The aim of this study was to identify variables to improve the diagnostic awareness and management of pSLE patients.Methods: This retrospective study included 25 patients diagnosed with pSLE and followed at the University of Pisa. We collected data about clinical profile at disease onset and during a long-term follow-up, including disease activity, organ damage development, and treatments received.Results: The mean patient age at disease onset was 14.6 ± 1.6 years, and the mean follow-up period was 14.17 ± 8.04 years. The most common initial manifestations were arthritis, malar rash, and cytopenias. The median time to diagnosis since the first symptoms was 6 months, and was significantly longer in patients with hematological onset (54 months). During follow-up, the number of patients with renal involvement showed a significant increase, from 36% at diagnosis to 72.2% after 10 years of disease evolution. Patients who developed chronic organ damage maintained a higher time-averaged disease activity during follow-up and received a significantly higher dose of corticosteroids.Conclusion: Patients with immune cytopenia represent a group deserving strict clinical follow-up for the risk of evolution to SLE. Intense surveillance of renal function, early treatment and steroid-sparing strategies should be strongly considered in the management of pSLE patients.

Improved Medical Treatment and Surgical Surveillance of Children and Adolescents with Ulcerative Colitis in the United Kingdom.

Pediatric ulcerative colitis (UC) presents at an earlier age and increasing prevalence. Our aim was to examine morbidity, steroid sparing strategies, and surgical outcome in children with active UC. A national prospective audit was conducted for the inpatient period of all children with UC for medical or surgical treatment in the United Kingdom (UK) over 1 year. Thirty-two participating centers recruited 224 children in 298 admissions, comparisons over 6 years were made with previous audits. Over 6 years, recording of Paediatric Ulcerative Colitis Activity Index (PUCAI) score (median 65)(23% to 55%, P < 0.001), guidelines for acute severe colitis (43% to 77%, P < 0.04), and ileal pouch surgery registration (4% to 56%, P < 0.001) have increased. Corticosteroids were given in 183/298 episodes (61%) with 61/183 (33%) not responding and requiring second line therapy or surgery. Of those treated with anti-TNFalpha (16/61, 26%), 3/16 (18.8%) failed to respond and required colectomy. Prescription of rescue therapy (26% to 49%, P = 0.04) and proportion of anti-TNFalpha (20% to 53%, P = 0.03) had increased, colectomy rate (23.7% to 15%) was not significantly reduced (P = 0.5). Subtotal colectomy was the most common surgery performed (n = 40), and surgical complications from all procedures occurred in 33%. In 215/224 (96%) iron deficiency anemia was detected and in 51% treated, orally (50.2%) or intravenously (49.8%). A third of children were not responsive to steroids, and a quarter of these were treated with anti-TNFalpha. Colectomy was required in 41/298 (13.7%) of all admissions. Our national audit program indicates effectiveness of actions taken to reduce steroid dependency, surgery, and iron deficiency. 10.1093/ibd/izy042_video1izy042.video15769503407001.

The cost of systemic corticosteroid-induced morbidity in severe asthma: a health economic analysis

BackgroundTreatment of severe asthma may include high dose systemic-steroid therapy which is associated with substantial additional morbidity. This study estimates the additional healthcare costs associated with steroid-induced morbidity by comparing three patients groups: those with severe asthma, moderate asthma and no asthma.MethodsPatients with severe asthma (n = 808, GINA step 5 treatment) were matched by age and gender with patients with mild/moderate asthma (n = 3,975, GINA step 2 and 3 treatment) and a non-asthma control cohort (with a diagnosis of rhinitis; n = 2,412) from the Optimum Patient Care Research Database (OPCRD), a nationally representative primary care database. Prescribed drugs and publicly funded healthcare activity were monetised and annual costs per patient estimated. Regression analyses were used to estimate the additional healthcare cost associated with steroid-induced morbidity.ResultsAverage healthcare costs per person per year range from £2603 - £4533 for the severe asthma cohort, to £978 - £2072 for the mild/moderate asthma cohort, to £560 - £1324 for the non-asthma control cohort, depending on the costing scenario. Differences in induced morbidity costs were evident between patients with asthma differentiated by steroid exposure. In relation to prescription drugs used to treat steroid-induced co-morbidities, females with severe asthma and high steroid exposure cost approximately £789 more per year than a corresponding female with no asthma, while males cost approximately £744 more than their counterparts with no asthma. Estimates were extrapolated to all healthcare costs.ConclusionsThis study provides the first robust estimates of the additional cost of healthcare related to steroid-induced morbidity relative to patients with no steroid exposure. The study will help inform use of steroid-sparing strategies in this patient group.

Measures to reduce maintenance therapy with oral corticosteroid in adults with severe asthma.

Maintenance therapy with oral corticosteroid (OCS) is used, although not based on evidence, for patients with severe asthma, but OCS is associated with serious adverse effects; therefore, management strategies aimed at steroid sparing are important. To provide an update on the evidence for OCS-sparing strategies in adults with severe asthma. A systematic literature review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 21 studies (which comprised 3060 subjects) were included. Of the nonbiologic oral steroidsparing strategies (n = 5), the following lowered the OCS dose: Internet-based tapering strategy (44% reduction in OCS dose), inhaled corticosteroids (mometasone furoate [mean daily OCS dose reduction of 39% and 31% in patients treated with 800 mcg/day and 1600 mcg/day, respectively] and ciclesonide [OCS dose reduction of 47% and 63% in patients treated with 640 mcg/day and 1.280 mcg/day, respectively]), and methotrexate (OCS dose reduction of 55%). Of the biologic oral steroidtapering strategies (16 studies) the following agents lowered the OCS dose: cyclosporin A (62% reduction in OCS dose), masitinib (78% reduction in OCS dose), mepolizumab (50%83% reduction in OCS dose), and omalizumab (30%64% of enrolled patients achieved a reduction in OCS dose, and one study reported a dose reduction of 45%). In adults with severe asthma, several corticosteroid-sparing interventions were shown to be effective in reducing systemic steroid exposure, not least in studies of add-on biologic therapy. However, based on the available studies, ciclesonide, based on the low potential for systemic effect, especially seems to be a good candidate for reducing steroid exposure in these patients before possible initiation of biologic therapy.

Steroid avoidance or withdrawal for kidney transplant recipients.

Steroid-sparing strategies have been attempted in recent decades to avoid morbidity from long-term steroid intake among kidney transplant recipients. Previous systematic reviews of steroid withdrawal after kidney transplantation have shown a significant increase in acute rejection. There are various protocols to withdraw steroids after kidney transplantation and their possible benefits or harms are subject to systematic review. This is an update of a review first published in 2009. To evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. We searched the Cochrane Kidney and Transplant Specialised Register to 15 February 2016 through contact with the Information Specialist using search terms relevant to this review. All randomised and quasi-randomised controlled trials (RCTs) in which steroids were avoided or withdrawn at any time point after kidney transplantation were included. Assessment of risk of bias and data extraction was performed by two authors independently and disagreement resolved by discussion. Statistical analyses were performed using the random-effects model and dichotomous outcomes were reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals. We included 48 studies (224 reports) that involved 7803 randomised participants. Of these, three studies were conducted in children (346 participants). The 2009 review included 30 studies (94 reports, 5949 participants). Risk of bias was assessed as low for sequence generation in 19 studies and allocation concealment in 14 studies. Incomplete outcome data were adequately addressed in 22 studies and 37 were free of selective reporting.The 48 included studies evaluated three different comparisons: steroid avoidance or withdrawal compared with steroid maintenance, and steroid avoidance compared with steroid withdrawal. For the adult studies there was no significant difference in patient mortality either in studies comparing steroid withdrawal versus steroid maintenance (10 studies, 1913 participants, death at one year post transplantation: RR 0.68, 95% CI 0.36 to 1.30) or in studies comparing steroid avoidance versus steroid maintenance (10 studies, 1462 participants, death at one year after transplantation: RR 0.96, 95% CI 0.52 to 1.80). Similarly no significant difference in graft loss was found comparing steroid withdrawal versus steroid maintenance (8 studies, 1817 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.17, 95% CI 0.72 to 1.92) and comparing steroid avoidance versus steroid maintenance (7 studies, 1211 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.09, 95% CI 0.64 to 1.86). The risk of acute rejection significantly increased in patients treated with steroids for less than 14 days after transplantation (7 studies, 835 participants: RR 1.58, 95% CI 1.08 to 2.30) and in patients who were withdrawn from steroids at a later time point after transplantation (10 studies, 1913 participants, RR 1.77, 95% CI 1.20 to 2.61). There was no evidence to suggest a difference in harmful events, such as infection and malignancy, in adult kidney transplant recipients. The effect of steroid withdrawal in children is unclear. This updated review increases the evidence that steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. There was no evidence to suggest a difference in patient mortality or graft loss up to five year after transplantation, but long-term consequences of steroid avoidance and withdrawal remain unclear until today, because prospective long-term studies have not been conducted.

Lenalidomide as a Steroid Sparing Agent in a Myelodysplastic Syndrome Patient with Refractory Sweet Syndrome

Malignancy associated Sweet syndrome (acute febrile neutrophilic dermatosis) accounts for approximately 20% of all cases of Sweet syndrome and is characterized by painful, erythematous inflammatory papules and nodules that can precede, coincide or follow malignancies with predilection for hematologic malignancies (mainly acute myeloid leukemia and myelodysplastic syndrome). Corticosteroids are the cornerstone of treatment with exquisite response which has made many clinicians to include steroid responsiveness as one of the diagnostic criteria. However, recurrence can occur with tapering of steroids often needing a suppressive prophylaxis with unacceptably high dose of steroid for longer term. In addition, recurrence following tapering of steroids is a unique feature of malignancy associated Sweet syndrome occurring in two-third of patients. There is a paucity of effective steroid sparing strategy in the treatment of this disorder. Here we report a patient with myelodysplasia and refractory sweet syndrome successfully treated with low dose lenalidomide with resolution of skin lesions, improvement in hemoglobin level, allowing rapid and successful tapering of steroid and improvement in hyperglycemia. Immunomodulatory agents such as lenalidomide may have activity against sweet syndrome associated with myelodysplastic syndrome and therefore deserve further clinical investigation.

Steroid avoidance or withdrawal for pancreas and pancreas with kidney transplant recipients.

Pancreas or kidney-pancreas transplantation improves survival and quality of life for people with type 1 diabetes mellitus and kidney failure. Immunosuppression after transplantation is associated with complications. Steroids have adverse effects on cardiovascular risk factors such as hypertension, hyperglycaemia or hyperlipidaemia, increase risk of infection, obesity, cataracts, myopathy, bone metabolism alterations, dermatologic problems and cushingoid appearance. Whether avoiding steroids changes outcomes is unclear. We aimed to assess the safety and efficacy of steroid early withdrawal (treatment for less than 14 days after transplantation), late withdrawal (after 14 days after transplantation) or steroid avoidance in patients receiving a pancreas (including a vascularized organ) alone (PTA), simultaneous with a kidney (SPK) or after kidney transplantation (PAK). We searched the Cochrane Renal Group's Specialised Register (to 18 June 2014) through contact with the Trials' Search Co-ordinator. We handsearched: reference lists of nephrology textbooks, relevant studies, recent publications and clinical practice guidelines; abstracts from international transplantation society scientific meetings; and sent emails and letters seeking information about unpublished or incomplete studies to known investigators. We included randomised controlled trials (RCTs) or cohort studies of steroid avoidance (including early withdrawal) versus steroid maintenance or versus late withdrawal in pancreas or pancreas with kidney transplant recipients. We defined steroid avoidance as complete avoidance of steroid immunosuppression, early steroid withdrawal as steroid treatment for less than 14 days after transplantation and late withdrawal as steroid withdrawal after 14 days after transplantation. Two authors independently assessed the retrieved titles and abstracts, and where necessary the full text reports to determine which studies satisfied the inclusion criteria. Authors of included studies were contacted to obtain missing information. Statistical analyses were performed using random effects models and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). Cohort studies were not meta-analysed, but their findings summarised descriptively. Three RCTs enrolling 144 participants met our inclusion criteria. Two compared steroid avoidance versus late steroid withdrawal and one compared late steroid withdrawal versus steroid maintenance. All studies included SPK and only one also included PTA. All studies had an overall moderate risk of bias and presented only short-term results (six to 12 months). Two studies (89 participants) compared steroid avoidance or early steroid withdrawal versus late steroid withdrawal. There was no clear evidence of an impact on mortality (2 studies, 89 participants: RR 1.64, 95% CI 0.21 to 12.75), risk of kidney loss censored for death (2 studies, 89 participants: RR 0.35, 95% CI 0.04 to 3.09), risk of pancreas loss censored for death (2 studies, 89 participants: RR 1.05, 95% CI 0.36 to 3.04), or acute kidney rejection (1 study, 49 participants: RR 2.08, 95% CI 0.20 to 21.50), however results were uncertain and consistent with no difference or important benefit or harm of steroid avoidance/early steroid withdrawal. The study that compared late steroid withdrawal versus steroid maintenance observed no deaths, no graft loss or acute kidney rejection at six months in either group and reported uncertain effects on acute pancreas rejection (RR 0.88, 95% CI 0.06 to 13.35). Of the possible adverse effects only infection was reported by one study. There were significantly more UTIs reported in the late withdrawal group compared to the steroid avoidance group (1 study, 25 patients: RR 0.41, 95% CI 0.26 to 0.66).We also identified 13 cohort studies and one RCT which randomised tacrolimus versus cyclosporin. These studies in general showed that steroid-sparing and withdrawal strategies had benefits in lowering HbAc1 and risk of infections (BK virus and CMV disease) and improved blood pressure control without increasing the risk of rejection. However, two studies found an increased incidence of acute pancreas rejection (HR 2.8, 95% CI 0.89 to 8.81, P = 0.066 in one study and 43.3% in the steroid withdrawal group versus 9.3% in the steroid maintenance, P < 0.05 at three years in the other) and one study found an increased incidence of acute kidney rejection (18.7% in the steroid withdrawal group versus 2.8% in the steroid maintenance, P < 0.05) at three years. There is currently insufficient evidence for the benefits and harms of steroid withdrawal in pancreas transplantation in the three RCTs (144 patients) identified. The results showed uncertain results for short-term risk of rejection, mortality, or graft survival in steroid-sparing strategies in a very small number of patients over a short period of follow-up. Overall the data was sparse, so no firm conclusions are possible. Moreover, the 13 observational studies findings generally concur with the evidence found in the RCTs.

Inflammatory Arthritis in Patients With Myelodysplastic Syndromes

We describe the characteristics and outcome of inflammatory arthritis in patients with myelodysplastic syndrome (MDS) in a French multicenter retrospective study. Twenty-two patients with MDS (median age, 77.5 yr [interquartile range, 69-81]; 10 women) were included. Inflammatory arthritis presented as polyarthritis in 17 cases (77%) and with symmetric involvement in 15 cases (68%). At diagnosis, the median disease activity score 28 based on C-reactive protein (DAS28-CRP) was 4.5 [2-6.5]. Two patients had anti-citrullinated protein antibodies (ACPAs), and 1 had radiologic erosions. The median time between the diagnoses of arthritis and MDS was 10 months [6-42], with a median articular symptom duration of 3 months [2-8]. The diagnosis of both diseases was concomitant in 6 cases (27%); arthritis preceded MDS in 12 cases (55%), and occurred after MDS in 4 (18%). While the number of swollen and tender joints significantly decreased during follow-up, as did the median DAS28-CRP (from 4.3 [3.8-4.6] at baseline to 2.9 [1.75-3.3]; p < 0.05), CRP remained elevated (CRP >20 mg/L) in 8 patients (42%). Nevertheless, radiographic progression and new ACPA positivity were not observed during a median follow-up of 29 months [9-76]. While most of the patients were treated with steroids (n = 16) for arthritis, additional treatment was administered in only 4 patients (hydroxychloroquine, n = 2; sulfasalazine [Salazopyrin] and etanercept, n = 1, respectively). Eleven patients died during follow-up from acute myeloid leukemia (n = 5); infections (n = 3); or cerebral bleeding, cardiorespiratory failure, or undetermined cause (n = 1, respectively). Inflammatory arthritis associated with MDS can have various presentations and is often seronegative and nonerosive. Steroids alone are the most common treatment in MDS-associated arthritis, but that treatment is insufficient to control arthritis. Steroid-sparing strategies need to be identified.

Differences in the management of pediatric and adult onset ulcerative colitis — lessons from the joint ECCO and ESPGHAN consensus guidelines for the management of pediatric ulcerative colitis

An expert panel of the European Crohn's and Colitis Organisation (ECCO) and European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) initiated a consensus process to produce the first pediatric specific ulcerative colitis (UC) guidelines based on a systematic literature review. Treatment strategies must reflect that pediatric-onset UC has a slightly different phenotype than adult-onset disease with more often extensive (pancolitis) and more aggressive disease course. Other pediatric-specific aspects include growth, puberty, bone density accrual and emotional development and body image acquisition. These differences and others influenced the development of pediatric treatment algorithms. It is recommended that virtually all children with UC must be treated with some maintenance therapy and 5-ASA requirement and dosing are often higher in children. A larger number of children are at risk for steroid-dependency, and this should not be tolerated; steroid sparing strategies with early use of immunosuppressors are recommended in high-risk patients. On the other hand, the safety profile of immunosuppressive therapy in children includes the rare forms of lymphomas and many future treatment years. Colectomy and pouch formation should be balanced in the treatment algorithms against the higher rate of future infertility in girls. The acute and on-going management of pediatric UC should be guided by evidence- and consensus-based balanced decisions, reflecting a vision of long-term treatment goals.

The consequences of pediatric renal transplantation on bone metabolism and growth

During childhood, growth retardation, decreased final height and renal osteodystrophy are common complications of chronic kidney disease (CKD). These problems remain present in patients undergoing renal transplantation, even though steroid-sparing strategies are more widely used. In this context, achieving normal height and growth in children after transplantation is a crucial issue for both quality of life and self-esteem. The aim of this review is to provide an overview of pathophysiology of CKD-mineral bone disorder (MBD) in children undergoing renal transplantation and to propose keypoints for its daily management. In adults, calcimimetics are effective for posttransplant hyperparathyroidism, but data are missing in the pediatric population. Fibroblast growth factor 23 levels are associated with increased risk of rejection, but the underlying mechanisms remain unclear. A recent meta-analysis also demonstrated the effectiveness of rhGH therapy in short transplanted children. In 2013, the daily clinical management of CKD-MBD in transplanted children should still focus on simple objectives: to optimize renal function, to develop and promote steroid-sparing strategies, to provide optimal nutritional support to maximize final height and avoid bone deformations, to equilibrate calcium/phosphate metabolism so as to provide acceptable bone quality and cardiovascular status, to correct all metabolic and clinical abnormalities that can worsen both bone and growth (mainly metabolic acidosis, anemia and malnutrition), promote good lifestyle habits (adequate calcium intake, regular physical activity, no sodas consumption, no tobacco exposure) and eventually to correct native vitamin D deficiency (target of 25-vitamin D >75 nmol/l).