Alternate-day Prednisolone Research Articles

Levamisole in childhood idiopathic nephrotic syndrome: new promises, and advocacy for global access

In the current issue of Kidney International, Sinha etal. present data from an open-label, noninferior, randomized controlled trial comparing 12-months of alternate-day prednisolone, given daily during infection, versus levamisole, in children with frequently relapsing or steroid-dependent nephrotic syndrome. This study suggests that both of these strategies are efficacious and safe. Results of this study should redefine the role of levamisole in future guidelines, and a call for global availability of levamisole should be advocated.

An open label non-inferiority randomized controlled trial evaluated alternate day prednisolone given daily during infections vs. levamisole in frequently relapsing nephrotic syndrome

Initial therapies for children with frequently relapsing nephrotic syndrome include alternate-day prednisolone that is given daily during infections, or levamisole. In this open label, non-inferiority trial, 160 patients, 2 to 18-years-old with frequent relapses, were randomly assigned to receive either prednisolone (0.5-0.7 mg/kg/alternate-day, given daily during infections), or levamisole (2-2.5 mg/kg/alternate-days) for one-year. Patients with relapses on alternate day prednisolone at over 1 mg/kg, prior use of potent steroid-sparing therapies, eGFR under 60 ml/min/1.73 m2 and significant steroid toxicity were excluded. Primary outcome was the proportion of patients with frequent relapses, defined as three-relapses in one-year, or two-relapses within six-months if associated with significant steroid toxicity or loss to follow up. Eighty patients each were randomized to receive prednisolone and levamisole. Baseline features showed preponderance of young patients presenting within two-years of disease onset. On intention-to-treat analysis, frequent relapses were more common in patients administered prednisolone (40% versus 22.5%; risk difference 17.5%; 95% confidence interval 3.4-31.6%). Prednisolone was not non-inferior to levamisole in preventing frequent relapses. However, the two groups showed similar proportions of patients in sustained remission, comparable frequency of relapses, and low frequency of adverse events. The decline in steroid requirement from baseline was higher in the levamisole group. Per-protocol analysis showed similar results. These results have implications for choice of therapy for frequently relapsing nephrotic syndrome. Although therapy with alternate-day prednisolone was not non-inferior to levamisole in preventing frequent relapses, both therapies were effective in other outcome measures. Thus, levamisole was relatively steroid-sparing and may be preferred in patients at risk of steroid toxicity.

Short Course of Daily Prednisolone During Upper Respiratory Tract Infection for Children With Relapsing Steroid Sensitive Nephrotic Syndrome

PREDNOS 2 was a double blind placebo controlled trial done to investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection—related relapses. It evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. At the beginning of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. The primary outcome was the incidence of first upper respi-ratory tract infection-related relapse. The modified intention-to-treat analysis population comprised 271 children (mean (SD) age, 7.6 (3.5) years; 64.2% male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) in the predniso-lone arm and 58 (44.3%) in the placebo arm (adjusted risk difference, 0.02; 95% CI, 0.14 to 0.10; P =0.70). No evidence was found that the treatment effect differed according to background immuno-suppressive treatment. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40–1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81–1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P=0.09). The authors concluded that, results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK and further work is needed to study the inter-ethnic differences in the study response.

Evaluation of Daily Low-Dose Prednisolone During Upper Respiratory Tract Infection to Prevent Relapse in Children With Relapsing Steroid-Sensitive Nephrotic Syndrome

In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population. To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection-related relapses. This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020. At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. The primary outcome was the incidence of first upper respiratory tract infection-related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, -0.02; 95% CI, -0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response. isrctn.org Identifier: ISRCTN10900733; EudraCT 2012-003476-39.

Optimizing the corticosteroid dose in steroid-sensitive nephrotic syndrome.

The use of corticosteroids in the treatment of steroid-sensitive nephrotic (SSNS) syndrome in children has evolved surprisingly slowly since the ISKDC consensus over 50 years ago. From a move towards longer courses of corticosteroid to treat the first episode in the 1990s and 2000s, more recent large, well-designed randomized controlled trials (RCTs) have unequivocally shown no benefit from an extended course, although doubt remains whether this applies across all age groups. With regard to prevention of relapses, daily ultra-low-dose prednisolone has recently been shown to be more effective than low-dose alternate-day prednisolone. Daily low-dose prednisolone for a week at the time of acute viral infection seems to be effective in the prevention of relapses but the results of a larger RCT are awaited. Recently, corticosteroid dosing to treat relapses has been questioned, with data suggesting lower doses may be as effective. The need for large RCTs to address the question of whether corticosteroid doses can be reduced was the conclusion of the authors of the recent corticosteroid therapy for nephrotic syndrome in children Cochrane update. This review summarizes development in thinking on corticosteroid use in SSNS and makes suggestions for areas that merit further scrutiny.

Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome

Calcineurin inhibitors are an established first-line corticosteroid-sparing therapy for patients with corticosteroid-dependent nephrotic syndrome (CDNS), whereas B-lymphocyte-depleting therapy is mostly used as a rescue for calcineurin inhibitor-resistant cases. The positive efficacy and safety profile of rituximab raises the question of whether it could be used as a first-line alternative to calcineurin inhibitor therapy. To compare the efficacy of rituximab and tacrolimus in maintaining relapse-free survival among children with CDNS. A parallel-arm, open-label, randomized clinical trial was performed from May 8, 2015, to September 20, 2016, with 1-year follow-up in a single-center, tertiary care unit. A total of 176 consecutive children aged 3 to 16 years with CDNS not previously treated with corticosteroid-sparing agents were screened for eligibility. The children received either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375 mg/m2). Twelve-month relapse-free survival in the intention-to-treat population. Of the 176 children screened for eligibility, 120 were randomized and all but 3 patients completed 1 year of follow-up. The groups were comparable, with mean (SD) age of 7.2 (2.8) years, 32 boys (53.3%) in each group, mean (SD) disease duration of 2.5 (1.5) years and 2.3 (1.7) in the tacrolimus and rituximab groups, respectively, disease duration less than 1 year among 15 children (25.0%) in each group, median (interquartile range) of 4 (3-5) relapses in each group, and mean (SD) cumulative prednisolone dose of 246 (48) mg/kg and 239 (52) mg/kg in the prestudy year in the tacrolimus and rituximab groups, respectively. Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95% CI, 1.93-14.07). Among the patients who experienced relapse, median time to first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Only 2 patients in the rituximab group had more than 1 relapse during the study period compared with 10 patients in the tacrolimus group. The cumulative corticosteroid dose during the 12-month study period was lower with rituximab compared with tacrolimus (mean [SD], 25.8 [27.8] vs 86.3 [58.0] mg/kg). Although both treatments were well tolerated, mild to moderate infections were twice as common in the tacrolimus group (26 [43.3%] vs 13 [21.7%] events). In children with CDNS, rituximab appears to be more effective than tacrolimus in maintaining disease remission and minimizing corticosteroid exposure and, given its good tolerability and lack of nephrotoxic effects, may be considered as first-line corticosteroid-sparing therapy. ClinicalTrials.gov Identifier: NCT02438982; Clinical Trial Registry of India: CTRI/2014/01/004355.

Efficacy of Levamisole as a single agent in maintaining remission in steroid dependant nephrotic syndrome

Introduction Levamisole (LEV) is an anti-helminthic drug which subsequently has shown immunomodulatory properties. It has been used successfully in conjunction with low-dose alternate-day prednisolone in steroid dependant nephrotic syndrome (SDNS). This randomized controlled study was carried out between years 2002 and 2005 at a single centre in Sri Lanka to evaluate the efficacy of LEV as a single agent following a prolonged period of combination therapy of LEV and prednisolone. Method Sequential Children with SDNS in stable remission who had been treated with LEV and low dose alternate-day prednisolone (0.1-0.6mg/kg) for 2 years were recruited and randomised into one of two groups. The test group received LEV (2.5 mg/kg) on alternate-days for one year and the control group received no treatment. Urine protein excretion was performed and recorded by parents on daily basis and the finding of 3+ or more proteinuria for three consecutive days was diagnostic of relapse. Results There were 42 in the test group (median age 8.4 years) and 34 in the control group (median age 7.2 years). During one year of follow up, 26/34 in the control group and 8/42 in the test group suffered a relapse. (p Conclusion Levamisole is safe, affordable and effective as a single agent in maintaining remission in SDNS.

LEOPARD: A Phase II Study of Post Autologous Stem Cell Transplantation (ASCT) Maintenance Lenalidomide and Prednisolone for Myeloma (MM), Incorporating Minimal Residual Disease (MRD) Assessments

Background Despite improved outcomes achieved with high dose melphalan conditioned ASCT for MM patients, relapse is inevitable. Consolidation/maintenance therapy with novel agents following ASCT can prolong progression free (PFS) and overall survival (OS) as well as further improve depth of response, the latter being associated with superior survival. More sensitive techniques are now available to monitor minimal residual disease (MRD). Aim To document disease response changes in MM patients receiving maintenance lenalidomide and alternate-day prednisolone (RAP) after a single ASCT. To sequentially quantify MRD in those patients achieving an immunofixation negative (IF-) complete response (CR) utilizing freeLite chain (FLC), hevyLite chain (HLC, in patients with intact IgG or IgA immunoglobulin) and multiparameter flow cytometry (MFC). To assess PFS/OS and safety/tolerability. Methods Phase II, open label, single arm, multi-center study. Newly diagnosed patients with MM were commenced on RAP (lenalidomide 10mg/continuous daily increasing to 15mg after 8 weeks and alternate day prednisolone 50mg) 6-8 weeks after a single MEL200 ASCT as part of first-line therapy. RAP was continued until unacceptable toxicity or relapse/progression. Serum for FLC/HLC was collected every 2 months. Patients achieving an IF- CR had serial BMATs for MFC. This is an interim analysis of the first 30 of a total of 60 patients recruited to the study. Results This analysis included 30 patients (M 17, F 13), median age 61 years (range 46-71), ISS stage I: 11, II/III: 19. 27 patients had diagnostic cytogenetics +/- FISH performed - 10 had poor risk features (t(4;14), t(14;16), del17p, del13 and/or +1q). After a median 549 days (range 385-768), 16 patients remain on therapy. Median PFS was 470 days (range 64-768), median OS was 514 days (range 247-768). Discontinuation was due to relapse/progressive disease in 8, AEs in 5 and poor compliance in 1. 4 patients have died; 3 due to MM and 1 due to therapy related AML [tAML]. The best achieved overall response rate (ORR) was 100%, with 19 IF- CR (63%) (13 stringent CR [sCR]), 10 VGPR (33%) and 1 PR (3%). 16 patients demonstrated an enhanced response while on RAP, including conversion to CR (n=3) or sCR (n=10) (6/10 were MFC negative [MFC-]). Median time to achieving best response was 111 days (range 28-287). 18 patients who achieved IF- CR had MFC studies and 11 were MFC-: of these 11, 5 had normal (FLC-) and 6 abnormal (FLC+) FLC ratios. Five of the 18 were MFC+, 4 of whom were FLC- and have not relapsed. Two of the 18 fluctuated between MFC+ and MFC-. Seven IF- CR patients had HLC analysis; 5/7 patients were MFC- in all samples, 3 of which also had normal HLC ratios (HLC-) and were FLC-. 2/7 patients were MFC+/HLC-. 10 patients relapsed/progressed after a median of 229 days (64-621), 5 from IF- CR (3 sCR). 5/8 with diagnostic cytogenetics had poor risk features, all with +1q in addition to other abnormalities. 3/19 remaining patients with cytogenetics who did not progress have +1q, suggesting a trend (p=0.07) to worse PFS in those with 1q+. In those who relapsed from IF- CR: 2 converted from MFC- to MFC+ prior to relapse/HLC-, 1 was FLC+ and 1 converted to FLC+ at relapse; 2 were MFC-/FLC- converting to FLC+ at relapse; 1 was MFC+/FLC+). All grade haematologic AEs comprised thrombocytopenia 7/30 (23%) (grade 3/4: 4), neutropenia 2/30 (grade 3: 1) and anaemia 3/30(grade 3: 1). All grade non-haematologic adverse events regardless of relatedness to study treatment (>10%) were: infections (URTI: 53%, LRTI: 23%, VZV reactivation: 23%, UTI: 13%), diarrhoea (37%), fatigue (27%), muscle cramps (23%), insomnia (23%), mouth ulcers (13%), peripheral oedema (13%). There was 1 second primary malignancy (SPM) - tAML. This occurred 461 days after commencing RAP. AEs leading to discontinuation were thrombocytopenia (3 patients), central retinal vein thrombosis and tAML. 11 patients tolerated lenalidomide dosing as per protocol, 6 were not increased from 10 to 15mg, 8 required dose modification for AEs (6 to 10mg; 2 to 5mg) and 5 were discontinued due to AEs. Conclusion RAP maintenance improved depth of response post-ASCT with some achieving best response > 8 months after initiation. ORR was 100%, with high rates of CR (20%) and sCR (43%). Correlation between MFC and serological testing appears poor. Many patients who relapsed had poor-risk cytogenetics (+1q), suggesting that these patients may benefit less from RAP maintenance. Disclosures: Off Label Use: Lenalidomide not approved for maintenance therapy post ASCT in Australia. Spencer: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Genotypes of the renin-angiotensin system and glucocorticoid complications.

Angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) are recognized as important regulators of body mass index (BMI) and systemic blood pressure (BP). An association between these single nucleotide polymorphisms (SNP) of AGT and ACE genes and obesity or hypertension has been established. This study examined relationships between the molecular variants of the AGT and ACE genes and bodyweight or BP in children treated with glucocorticoids for nephrotic syndrome. Twenty Japanese children (male, n = 14; female, n = 6; age, 2-13 years) were genotyped for AGT polymorphisms (M235T and A-6G) and the ACE polymorphisms (insertion/deletion: I/D and rs4341). All of the children studied were treated with daily prednisolone 2 mg/kg for 4 weeks and thereafter alternate-day prednisolone for 8 weeks. BMI, BMI z-scores, blood lipids, renal function and BP in each group were evaluated during the study period. BMI and BMI z-scores during the glucocorticoid therapy were significantly higher in the TT genotype of the AGT M235T polymorphisms and the AA genotype of the AGT A-6G polymorphisms compared to other genotypes (P < 0.05). In contrast, the molecular variant of ACE I/D and rs4341 genotypes did not change bodyweight during the glucocorticoid exposure. It was evident, however, that the BP and blood lipids and renal function were not significantly influenced by the AGT and ACE polymorphisms. The TT genotype of the AGT M235T and the AA genotype of the A-6G polymorphisms may predispose children to bodyweight gain when initially treated with glucocorticoids for nephrotic syndrome.

Leopard: A Phase II Study of Maintenance Lenalidomide and Prednisolone Post Autologous Stem Cell Transplantation (ASCT) for Myeloma, Incorporating Minimal Residual Disease Assessments

BackgroundDespite improved outcomes achieved with high dose melphalan conditioned ASCT for Myeloma (MM) patients, relapse is inevitable. Maintenance therapy following ASCT improves the depth of response achieved by induction therapy and prolongs both progression free (PFS) and overall survival (OS). Achievement of stringent (s) complete response (CR) is predictive of improved outcome, as is minimal residual disease (MRD) negativity (-neg) assessed by sensitive techniques such as multiparameter flow cytometry (MFC) of bone marrow (BM).AimTo document disease response changes, PFS/OS in MM patients receiving maintenance lenalidomide and alternate-day prednisolone (RAP) after ASCT. To sequentially quantify MRD in patients achieving a complete response (CR) utilising freeLite chain (FLC) and MFC. To assess safety and tolerability.MethodsPhase II, open label, single arm, multi-centre study. Newly diagnosed patients with MM commenced RAP maintenance (lenalidomide 10mg/continuous daily increasing to 15mg after 8/52 and alternate day prednisolone 50mg) 6-8 weeks after a single MEL200 ASCT as part of first-line therapy. RAP continued until toxicity or relapse/progression. Serum for FLC was collected every 2/12, patients achieving CR had serial BM MFC. Statistical analysis: Prism v5.0a.Results60 patients (M=37, F=23), with a median age of 61 years (range 41-71) commenced RAP maintenance. ISS stage at diagnosis: I: 20, II/III: 37 (3 unknown). 51/60 patients had diagnostic cytogenetics ± FISH performed – 15 had poor risk features (t(4;14), t(14;16), del17p, del13, +1q21), 11/15 had +1q21.After a median 23 months (range 12-36) following initiation of RAP, 33 patients remain on therapy. One patient has been lost to follow-up. Discontinuation was due to relapse/progressive disease (10), AEs (13), physician choice (2), poor compliance (1) and death (1). 15 patients have relapsed/progressed, 11 patients have died; 7 due to MM, 2 due to therapy related AML (tAML) and 2 other.Both the median PFS and OS have not been reached. When looking at the association between survival and poor risk cytogenetics ± FISH, those with +1q21 had both inferior PFS and OS: median PFS was 646 days vs not reached (NR) for those without +1q21 (P=0.04), median OS was 701 days vs NR for those without +1q21(P=0.013).34 patients improved their post ASCT response on RAP. Best response was CR in 36 (60% - 25 sCR), 21 VGPR (35%) and 2 PR (3%), achieved in a median of 77 days (range, 0-447). 30 of 36 patients in CR went on to have sequential MRD studies: 21/30 were multiply MRD-neg and 9/30 were multiply MRD-pos. There was no difference in PFS between MRD-pos and MRD-neg patients (p=0.3). Of the MRD-neg patients, 16/21 had predominantly normal FLC ratios (sCR), 4/21 MRD-neg patients relapsed, 3 had normal FLC ratios. Of the MRD-pos patients, 6/9 had normal FLC ratios (sCR), 3/9 MRD-pos relapsed. Correlation between MRD neg and sCR was poor (r2=0.05) and there was no difference in relapse rate between patients achieving MRD-neg versus those who achieved sCR.All grade haematologic AEs comprised thrombocytopenia 15/60 (25%)(grade 3/4: 6 [10%]), neutropenia 10/60 (grade 3: 5), and anaemia 5/60 (%)(grade 3: 1). All grade non-haematologic AEs regardless of relatedness to study treatment (>10%) were: infections (URTI: 35%, LRTI: 25%, VZV reactivation: 13%), diarrhoea (38%), insomnia (32%), fatigue (26%), peripheral neuropathy (20%), cramps (18%), hyperglycemia (12%). There have been six second primary malignancies (SPMs) – 2 tAML (onset post C1D1: 15m, 21m), 1 adenocarcinoma of bowel (onset post C1D1: 30m) and 3 skin cancers (SCCs). AEs leading to discontinuation were myelosuppression (9), SPM (2), retinal vein thrombosis (1) and fatigue (1).24 patients (40%) tolerated lenalidomide dosing as per protocol, 13 were not increased from 10mg/d to 15mg day, and 23 required dose modifications for AEs.ConclusionRAP maintenance improved depth of response post-ASCT (including conversion to deeper response categories > 14months), with high rates of CR/sCR (60%). Neither MFC or FLC demonstrated superiority over the other for prediction of outcome and correlation between the two was poor. Recapitulating earlier findings of an interim analysis, patients with +1q21 had inferior PFS/OS, suggesting that this group may benefit less from RAP maintenance. Only 21% of patients discontinued RAP due to toxicity, comparable to IFM 2005-02 and CALGB 100104 studies. DisclosuresOff Label Use: Lenalidomide used as maintenance post-ASCT. Spencer:Takeda: Consultancy, Honoraria; janssen-Cilag: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria, Research Funding.

Isolated Bilateral Uveitis in Child With Hypereosinophilic Syndrome

The ocular involvement has rarely been described in hypereosinophilic syndrome (HES). We report an 8-year-old girl with HES and isolated bilateral uveitis as end-organ damage. Almost 20 months after detection of persistent asymptomatic eosinophilia, she developed complete loss of vision in right eye due to retinal detachment and decreased vision in left eye. We treated this organ-threatening condition with prednisolone and imatinib mesylate, although she was negative for FIP1L1-PDGRFA fusion gene. The vision in her left eye returned to normal. At present, the child is on alternate-day low-dose prednisolone and daily imatinib. Early recognition and aggressive treatment is essential in HES with ocular involvement to save vision. Imatinib is a useful adjuvant drug even in PDGRFA/FIP1L1-negative HES.

Membranoproliferative glomerulonephritis Type 3 associated with Kabuki syndrome

First described in Japanese patients, Kabuki syndrome (KS) is a congenital condition associated with multiple anomalies and mental retardation. Although urological and immune abnormalities are common in KS, immune complex nephritis such as membranoproliferative glomerulonephritis (MPGN) has not yet been reported. We describe the first reported case of a KS patient with common variable immunodeficiency (CVI) and recurrent otitis media who developed severe proteinuria and hematuria due to MPGN Type 3 detected during the school urinary screening program in Japan. The patient was intravenously treated with methylprednisolone pulses followed by alternate-day prednisolone and an angiotensin receptor blocker. The patient showed remarkable improvement in both histological and urinary analyses. This case report suggests that immune abnormalities associated with KS can play an important role in the development of MPGN. Urinalysis should be regularly performed in KS patients with hypogammaglobulinemia and/or recurrent infection.

Leopard: A Phase II Study Of Post Autologous Stem Cell Transplantation (ASCT) Maintenance Lenalidomide and Prednisolone For Myeloma (MM), Incorporating Minimal Residual Disease (MRD) Assessments

BackgroundDespite improved outcomes achieved with high dose melphalan conditioned ASCT for MM patients, relapse is inevitable. Consolidation/maintenance therapy with novel agents following ASCT can prolong progression free (PFS) and overall survival (OS) as well as further improve depth of response, the latter being associated with superior survival. More sensitive techniques are now available to monitor minimal residual disease (MRD). AimTo document disease response changes in MM patients receiving maintenance lenalidomide and alternate-day prednisolone (RAP) after a single ASCT. To sequentially quantify MRD in those patients achieving an immunofixation negative (IF-) complete response (CR) utilizing freeLite chain (FLC), hevyLite chain (HLC, in patients with intact IgG or IgA immunoglobulin) and multiparameter flow cytometry (MFC). To assess PFS/OS and safety/tolerability. MethodsPhase II, open label, single arm, multi-center study. Newly diagnosed patients with MM were commenced on RAP (lenalidomide 10mg/continuous daily increasing to 15mg after 8 weeks and alternate day prednisolone 50mg) 6-8 weeks after a single MEL200 ASCT as part of first-line therapy. RAP was continued until unacceptable toxicity or relapse/progression. Serum for FLC/HLC was collected every 2 months. Patients achieving an IF- CR had serial BMATs for MFC. This is an interim analysis of the first 30 of a total of 60 patients recruited to the study. ResultsThis analysis included 30 patients (M 17, F 13), median age 61 years (range 46-71), ISS stage I: 11, II/III: 19. 27 patients had diagnostic cytogenetics +/- FISH performed - 10 had poor risk features (t(4;14), t(14;16), del17p, del13 and/or +1q). After a median 549 days (range 385-768), 16 patients remain on therapy. Median PFS was 470 days (range 64-768), median OS was 514 days (range 247-768). Discontinuation was due to relapse/progressive disease in 8, AEs in 5 and poor compliance in 1. 4 patients have died; 3 due to MM and 1 due to therapy related AML [tAML].The best achieved overall response rate (ORR) was 100%, with 19 IF- CR (63%) (13 stringent CR [sCR]), 10 VGPR (33%) and 1 PR (3%). 16 patients demonstrated an enhanced response while on RAP, including conversion to CR (n=3) or sCR (n=10) (6/10 were MFC negative [MFC-]). Median time to achieving best response was 111 days (range 28-287). 18 patients who achieved IF- CR had MFC studies and 11 were MFC-: of these 11, 5 had normal (FLC-) and 6 abnormal (FLC+) FLC ratios. Five of the 18 were MFC+, 4 of whom were FLC- and have not relapsed. Two of the 18 fluctuated between MFC+ and MFC-. Seven IF- CR patients had HLC analysis; 5/7 patients were MFC- in all samples, 3 of which also had normal HLC ratios (HLC-) and were FLC-. 2/7 patients were MFC+/HLC-.10 patients relapsed/progressed after a median of 229 days (64-621), 5 from IF- CR (3 sCR). 5/8 with diagnostic cytogenetics had poor risk features, all with +1q in addition to other abnormalities. 3/19 remaining patients with cytogenetics who did not progress have +1q, suggesting a trend (p=0.07) to worse PFS in those with 1q+. In those who relapsed from IF- CR: 2 converted from MFC- to MFC+ prior to relapse/HLC-, 1 was FLC+ and 1 converted to FLC+ at relapse; 2 were MFC-/FLC- converting to FLC+ at relapse; 1 was MFC+/FLC+).All grade haematologic AEs comprised thrombocytopenia 7/30 (23%) (grade 3/4: 4), neutropenia 2/30 (grade 3: 1) and anaemia 3/30(grade 3: 1). All grade non-haematologic adverse events regardless of relatedness to study treatment (>10%) were: infections (URTI: 53%, LRTI: 23%, VZV reactivation: 23%, UTI: 13%), diarrhoea (37%), fatigue (27%), muscle cramps (23%), insomnia (23%), mouth ulcers (13%), peripheral oedema (13%). There was 1 second primary malignancy (SPM) - tAML. This occurred 461 days after commencing RAP. AEs leading to discontinuation were thrombocytopenia (3 patients), central retinal vein thrombosis and tAML.11 patients tolerated lenalidomide dosing as per protocol, 6 were not increased from 10 to 15mg, 8 required dose modification for AEs (6 to 10mg; 2 to 5mg) and 5 were discontinued due to AEs. ConclusionRAP maintenance improved depth of response post-ASCT with some achieving best response > 8 months after initiation. ORR was 100%, with high rates of CR (20%) and sCR (43%). Correlation between MFC and serological testing appears poor. Many patients who relapsed had poor-risk cytogenetics (+1q), suggesting that these patients may benefit less from RAP maintenance. Disclosures:Off Label Use: Lenalidomide not approved for maintenance therapy post ASCT in Australia. Spencer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Lip hypertrophy due to cyclosporine therapy

A 5-year-old male child, diagnosed as having initial steroid-resistant nephrotic syndrome, was administered oral cyclosporine (5 mg/kg/day) along with alternate-day prednisolone. He developed severe lip and gingival hypertrophy, had difficulty in lip closure and his gingiva was visible through the lips at rest (Fig. 1). As the child attained only partial remission after 12 weeks of cyclosporine therapy, his medication was changed to tacrolimus. The lip hypertrophy decreased within 10 weeks of tacrolimus therapy, he was able to close his lips as the gingival hypertrophy also decreased and he achieved complete remission (Fig. 2). Gingival hypertrophy is a well-known side-effect of cyclosporine therapy; however, lip hypertrophy is a rarely noted side-effect [1]. Histopathological examination of the hypertrophied lip showed inflammatory papillary hyperplasia with focal ulceration and plasma cell infiltration. It has been reported that cyclosporine affects signaling molecules in fibroblasts differently from other cell types, and an increase in AP-1 transcription factor activity may affect the expression of fibrogenic molecules in gingiva and promote gingival overgrowth [2]. Tacrolimus has lesser incidence and severity of hirsutism, gingivitis, and gingival hyperplasia as compared to cyclosporine [3]. Azithromycin can also reduce cyclosporine-induced lip and gingival hypertrophy [4]. In rare cases surgical reduction may be required. Clinicians using cyclosporine should be aware of lip hypertrophy and its management.

Corticosteroid Therapy for Steroid-Sensitive Nephrotic Syndrome in Children

Idiopathic nephrotic syndrome, although a rare disease, is the most common primary glomerular disease among children. It causes substantial morbidity because it typically runs a relapsing course punctuated with prolonged periods of corticosteroids and other immunosuppressive medication. It affects

Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome

There are limited data on the relative efficacy and safety of calcineurin inhibitors and alkylating agents for idiopathic steroid-resistant nephrotic syndrome in children. To clarify this, we compared tacrolimus and intravenous cyclophosphamide therapy in a multicenter, randomized, controlled trial of 131 consecutive pediatric patients with minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis, stratified for initial or late steroid resistance. Patients were randomized to receive tacrolimus for 12 months or 6-monthly infusions of intravenous cyclophosphamide with both arms receiving equal amounts of alternate-day prednisolone. The primary outcome of complete or partial remission at 6 months, based on spot urine protein to creatinine ratios, was significantly higher in children receiving tacrolimus compared to cyclophosphamide (hazard ratio 2.64). Complete remission was significantly higher with tacrolimus (52.4%) than with cyclophosphamide (14.8%). The secondary outcome of sustained remission or steroid-sensitive relapse of nephrotic syndrome at 12 months was significantly higher with tacrolimus than cyclophosphamide. Treatment withdrawal was higher with cyclophosphamide, chiefly due to systemic infections. Compared to cyclophosphamide, 3 patients required treatment with tacrolimus to achieve 1 additional remission. Thus, tacrolimus and prednisolone are effective, safe, and preferable to cyclophosphamide as the initial therapy for patients with steroid-resistant nephrotic syndrome.

Long-Term Outcome of Polymyositis Treated with High Single-Dose Alternate-Day Prednisolone Therapy

Background: We previously reported no difference in the efficacies of high-dose alternate-day (ADT) and daily-dose (DDT) prednisolone therapies in myositis patients, but that the incidence of side effects was lower in the former. The aim of the present study was to compare the long-term outcomes of both treatments in polymyositis patients. Methods: We compared clinical courses, efficacies, adverse reactions, and outcomes of 115 consecutive, biopsy-proven polymyositis patients treated between 1970 and 2008 with ADT (32 patients) or DDT (83 patients). Results: Mean onset ages, disease severity, incidences of malignancy, and response rates did not differ between the ADT and DDT groups. Adverse reactions (incidence of diabetes) were significantly higher in the DDT group. In this group, the incidences of hyperlipidemia, infection, hypertension, and psychiatric symptoms were also slightly higher, but not significantly so. The 20-year survival rate of the ADT group (68%) was significantly higher (p = 0.0112) than that of the DDT group (37%). Conclusion: ADT might be useful as an initial treatment option for polymyositis.

Short-term efficacy of rituximab versus tacrolimus in steroid-dependent nephrotic syndrome

Although therapy with intravenous (IV) rituximab and tacrolimus reduces the relapse rate in steroid-dependent nephrotic syndrome (SDNS), studies on comparative efficacy are lacking. We retrospectively reviewed the records of patients with difficult-to-treat SDNS who had previously received levamisole, cyclophosphamide and/or mycophenolate mofetil, then treated with either rituximab or tacrolimus and followed for 12 months. Between January 2009 and April 2010, ten patients received two to three doses of IV rituximab (375 mg/m(2)/week) and 13 received tacrolimus (0.1-0.2 mg/kg/day) for 12 months; none had previously received either agent. Patients received tapering doses of alternate-day prednisolone; other immunosuppressive agents were discontinued. The mean age of the patients at treatment initiation with rituximab and tacrolimus was 12.2 ± 2.3 and 12.3 ± 3.0 years, respectively. The respective pre-treatment relapse rates (3.1 ± 1.1 and 3.5 ± 1.6 relapses per year) and cumulative prednisolone dose (137.2 ± 69.4 and 140.5 ± 59.0 mg/kg/year) were similar. Therapy resulted in a decline in relapse rate in both groups (P < 0.001). The number of relapses in the rituximab and tacrolimus groups was similar at 6 months (0.3 ± 0.5 vs. 0.3 ± 0.6 episodes, respectively), 12 months (0.8 ± 1.0 vs. 0.9 ± 1.1 episodes) and last follow-up (1.2 ± 1.0 vs. 1.5 ± 1.3 episodes). There were no differences in relapse-free survival at 6, 12 and 18 months. Therapy resulted in a significant decline in the cumulative prednisolone dose (67.2% in the rituximab group and 43.6% in the tacrolimus group) and a reduced body mass index. These findings suggest that in our patients with difficult-to-treat SDNS, treatment with two to three doses of rituximab was as effective as 12 months of therapy with tacrolimus in terms of steroid sparing and reduction in the relapse rate.

The successful treatment of rapidly progressive idiopathic membranoproliferative glomerulo-nephritis Type 1 in a 4-year-old male pediatric patient

A multivariate analysis [4] revealed that the presence of crescent formation on initial biopsy irrespective of type of membranoproliferative glomerulonephritis (MPGN) was independently associated not only with end-stage renal disease but also with post-transplantation recurrence. In this study, we reported on a 4-year-old male pediatric patient requiring hemodialysis due to rapidly progressive idiopathic MPGN Type 1 with severe nephrotic syndrome and extensive cellular crescent formation on initial biopsy. The patient had been treated intravenously (i.v.) with 9 pulses of methylprednisolone, followed by daily prednisolone, resulting in the withdrawal of dialysis within 1 month. However, since active lesions in the second renal biopsy such as cellular crescents still remained and nephrotic range proteinuria had persisted for more than 2 months, the patient received additional 3 i.v. pulses of methylprednisolone, followed by combinations of alternate-day prednisolone, mizoribine, dipyridamole and warfarin, which lead to complete remission in a short-period of time. The patient has been off the combination therapy for 10 months because the third biopsy prior to the termination of this regimen showed decreased inflammatory activity. There is currently no established protocol for children with crescentic MPGN due to a rarity of its clinicopathological presentation. This case report indicates that early treatment with multiple pulses of methylprednisolone followed by the short-term combination therapy may be of benefit for children with rapidly progressive idiopathic MPGN Type 1, even when both diffuse crescentic changes and nephrotic syndrome are present at onset.

Daily Corticosteroids Reduce Infection-associated Relapses in Frequently Relapsing Nephrotic Syndrome

Relapses of nephrotic syndrome often follow minor infections, commonly of the upper respiratory tract. Daily administration of maintenance prednisolone during intercurrent infections was examined to determine whether the treatment reduces relapse rates in children with frequently relapsing nephrotic syndrome. In a randomized controlled trial (nonblind, parallel group, tertiary-care hospital), 100 patients with idiopathic, frequently relapsing nephrotic syndrome eligible for therapy with prolonged low-dose, alternate-day prednisolone with or without levamisole were randomized to either receive their usual dose of alternate-day prednisolone daily for 7 days during intercurrent infections (intervention group) or continue alternate-day prednisolone (controls). Primary outcome was assessed by comparing the rates of infection-associated relapses at 12-month follow-up. Secondary outcomes were the frequency of infections and the cumulative amount of prednisolone received in both groups. Patients in the intervention group showed significantly lower infection-associated (rate difference, 0.7 episodes/patient per year; 95% confidence intervals [CI] 0.3, 1.1) and lower total relapse rates (0.9 episodes/patient per year, 95% CI 0.4, 1.4) without increase in steroid toxicity. Poisson regression, adjusted for occurrence of infections, showed that daily administration of prednisolone during infections independently resulted in 59% reduction in frequency of relapses (rate ratio, 0.41; 95% CI 0.3, 0.6). For every six patients receiving this intervention, one showed a reduction of relapse frequency to less than three per year. Daily administration of maintenance doses of prednisolone, during intercurrent infections, significantly reduces relapse rates and the proportion of children with frequently relapsing nephrotic syndrome.