Remission Maintenance Therapy Research Articles

Vedolizumab for the Induction of Remission in Treatment-refractory Microscopic Colitis in a Pediatric Patient.

Vedolizumab for the Induction of Remission in Treatment-refractory Microscopic Colitis in a Pediatric Patient.

DOP75 Efficacy of tofacitinib dose escalation to 10 mg BID in patients with UC after completing maintenance therapy in remission and losing response: Data from OCTAVE open-label, long-term extension study

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib were demonstrated in patients with moderate to severe UC in three Phase 3 studies.1 Here, we investigated outcomes in a subpopulation of the ongoing, open-label, long-term extension study (OLE) (OCTAVE Open; NCT01470612; May 2019; database not locked), including maintenance of remission patients receiving tofacitinib 5 mg twice daily (BID) who were dose-escalated to 10 mg BID due to flare. Methods Analysis included the maintenance remission–dose-escalation subpopulation: patients who achieved remission at Week 52 in OCTAVE Sustain (tofacitinib 5 or 10 mg BID, or placebo), entered OLE (5 mg BID), but were dose-escalated to 10 mg BID due to flare (based on total Mayo score [MS]; local read endoscopy). Remission: total MS ≤2 with no subscore >1, and rectal bleeding (RB) subscore 0. Dose escalation during OLE was permitted if patients experienced a flare, defined as ≥3 increase from maintenance study baseline total MS and ≥1 increase in RB and endoscopic subscore (ES; unless ES=3 at baseline and remained 3) after ≥8 weeks of treatment in OLE. Kaplan–Meier for estimation of time to dose escalation was assessed in all OLE maintenance remission population relative to OLE baseline. Partial MS remission (≤2 with no subscore >1; no ES) assessed at Months (M)3, 6, 9 and 12 post-dose-escalation; mucosal healing (MH; ES ≤1) and remission assessed at M12 post-dose-escalation. Adverse events (AEs) also assessed. Results Of the 944 patients enrolled in OLE, 162 were in remission at baseline and received tofacitinib 5 mg BID, and 41 were dose-escalated to 10 mg BID due to flare (22 had prior TNFi failure). The cumulative proportion of patients with dose escalation was 4.3%, 10.6%, 12.6% and 13.2% at M3, 6, 9 and 12 of OLE, respectively. Partial MS remission was 75.0% at M3, and partial MS remission, MH and remission were 95.0%, 63.6% and 57.6%, respectively, at M12 post-dose escalation (Table). One case each of serious infection, herpes zoster (non-serious; opportunistic infection) and malignancy were reported (see Table). Conclusion For patients with moderate to severe UC who entered OLE in remission, received tofacitinib 5 mg BID but flared and were dose-escalated to 10 mg BID, response was recaptured for most by M3 post-dose-escalation and remission was recaptured in the majority by M12. Safety in this subpopulation was generally consistent with that observed in the overall tofacitinib UC programme.2 Due to the small sample size and open-label nature, results should be interpreted with caution. References

P412 Maintenance therapy of vedolizumab (VDZ) after induction of remission by tacrolimus (TAC) in patients with refractory ulcerative colitis (UC)

Abstract Background The number of patients with ulcerative colitis (UC) is increasing. As the number of patients increases, patient backgrounds become diverse, and treatment choices that match the background are required. Most UCs are mild, but about 30% are more than moderate. UCs with moderate or higher illness have resistance/dependence to steroids and are difficult to introduce remission. In recent years, many new drugs have appeared for remission induction therapy. However, in UC treatment, maintenance therapy that suppresses relapse after induction of remission is important. Maintaining long-term remission prevents deterioration in the quality of life and reduces the incidence of UC-related colorectal cancer. To that end, it is important to consider remission maintenance therapy. In patients with intractable UC who have been in remission with tacrolimus (TAC) and used vedolizumab (VDZ) as maintenance therapy, patient background, relapse rate (observation period 181.5 ± 25.9 days), (3) safety of TAC and VDZ combination The sex was examined. Methods Seven patients who received remission with TAC and maintained remission with VDZ between November 2018 and June 2019 were included. (1) Patient background at the time of introduction of TAC and VDZ, TAC administration period (day) until the start of VDZ, (2) Relapse rate, (3) AZA use history, side effects, and adverse events caused by the combined use of VED. Results (1) Patient background was age at TAC introduction (age) 44.4 ± 19.7, sex (male / female) 3/4, disease duration (year) 12 ± 11.5, CAI 14.4 ± 2.9, Hb 11 ± 0.8, CRP 5.5 ± 3.6, Endoscopic score (Mayo 3 ± 0, UCEIS 7 ± 1.1), CAI at the time of VDZ introduction 6 ± 3.3, Hb 11.3 ± 2.0, CRP 0.4 ± 0.5, TAC administration period until VDZ start 140 ± It was 155. (2) Six patients had a history of AZA use. 4 out of 6 cases with AZA history side effect due to AZA was observed. The side effects of AZA were leukopenia in 2 cases, headache in 2 cases, and liver injury in 1 case. (There were duplicate cases) (3) No adverse events were observed due to the combined use of TAC and VDZ. Conclusion TAC has clinical remission or symptom improvement for refractory UCVDZ had been administered since then. In cases where administration of AZA was difficult, VDZ was selected as maintenance therapy. There were no serious side effects from the combined use of TAC and VDZ. TAC is a drug that has a rapid effect. However, long-term administration of TAC is at risk for kidney damage. Therefore, we considered that maintenance therapy with VDZ after TAC is effective.

Effectiveness and limitations of thiopurines as remission maintenance therapy after calcineurin inhibitor treatment in ulcerative colitis

Effectiveness and limitations of thiopurines as remission maintenance therapy after calcineurin inhibitor treatment in ulcerative colitis

A case of anti-neutrophil cytoplasmic antibody-associated vasculitis with anti-glomerular basement membrane antibodies that was successfully treated with mizoribine as a safe and effective remission maintenance therapy with prednisolone and plasma exchange

We herein report the case of myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with anti-glomerular basement membrane (anti-GBM) antibody positivity that successfully treated with mizoribine (MZR) as an immunosuppressive drug for remission maintenance therapy after the initiation of dialysis in addition to plasma exchange (PE) and glucocorticoid treatment to control the disease condition. A 79-year-old woman developed serious renal dysfunction and pulmonary alveolar hemorrhaging due to MPO–ANCA and anti-GBM antibody double-positive vasculitis. She was started on hemodialysis and was treated with methylprednisolone (m-PSL) pulse therapy with PE, followed by oral prednisolone (PSL). The pulmonary alveolar hemorrhaging disappeared, and both antibody titers immediately decreased but then rose again. Thus, m-PSL pulse therapy performed again in combination with combined with MZR treatment. Her poor renal function was irreversible; however, this therapy decreased both antibody titers, and they did not increase again. The patient developed pancytopenia and hyperuricemia. It was considered likely that these conditions developed in association with MZR treatment. We, therefore, measured the patient’s blood concentration of MZR, and the maintenance dose was finally set at 50 mg after each dialysis session. The patient’s pancytopenia and hyperuricemia improved and PSL could be smoothly tapered. This is the first case report of the use of MZR for remission maintenance therapy in a patient on hemodialysis who was positive for both ANCA and anti-GBM antibodies. The findings suggest that MZR can be used safely and effectively in such cases.

Effects of Clinical Characteristics, Laboratory Parameters and Treatment Regimens on Prognosis of Patients with Multiple Myeloma

To study the effects of clinicopathological features, laboratory parameters and treatment regimens on the prognosis of patients with multiple myeloma. The clinical data of 97 patients with multiple myeloma treated with chemotherapy in Department of Hematology, the 1st Hospital of Hainan Medical College were analyzed retrospectively. The clinicopathological features (age, sex, severe anemia, light chain type, hypoproteinemia, paraplegia, renal injury, amyloidosis, complex karyotype, bone disease classification, Eastern Cooperative Oncology Group (ECOG) physical status score, complete remission, etc.), laboratory parameters (C-reactive protein, lactate dehydrogenase, blood calcium, serum β2 microglobulin, etc.), and treatment schemes (thalidomide maintenance treatment) were recorded. The patients were followed up for 1-60 months, and their total survival time were recorded. A single factor and multiple factors were used to analyze the factors affecting the total and early mortality of the patients. The survival curves were plotted by the Kaplan-Meier method and the survival analysis was carried out by Log-rank test. Among 97 patients, 29 cases (29.90%) achieved complete remission, and 56 cases (57.73%) achineved partial remission. The total effective rate was 87.63% (85/97). At the end of the follow-up, 19 cases (19.59%) died, and 1, 3 and 5 year survival rates were 80.41%, 71.13% and 37.11% respectively. The median overall survival time was 29 (1-60) months. The results of single factor analysis showed that age, hypoproteinemia, severe anemia, paraplegia, renal injury, amyloidosis, complex karyotype, complete remission and thalidomide maintenance therapy were the factors affecting the prognosis of the patients (all P＜0.05). Further multiple factor Logistic regression analysis showed that age and hypoproteinemia, severe anemia, paraplegia, amyloidosis, complex karyotype and thalidomide maintenance treatment were factors affecting the prognosis (P＜0.05). Of the 97 patients, 8 cases died early. The results of single factor analysis showed that amyloidosis and severe anemia were risk factors for early death (all P＜0.05), and further multivariate Logistic regression analysis showed that amyloidosis was an independent risk factor for early death (P＜0.05). There are many adverse factors affecting the prognosis of patients with multiple myeloma, such as age, hypoproteinemia, severe anemia, paraplegia, amyloidosis, complex karyotype and so on. The risk of early death in the patients with amyloidosis is higher, and salidomide maintenance therapy can help to prolong the life span of the patient.

Do clinical and laboratory parameters predict thiopurine metabolism and clinical outcome in patients with inflammatory bowel diseases?

The thiopurines azathioprine and 6-mercaptopurine are frequently used for remission maintenance in patients with inflammatory bowel diseases. However, there are therapy failures, and it is unclear whether clinical and laboratory parameters can be used to predict thiopurine metabolite concentrations (as a surrogate for adequate remission maintenance therapy) and clinical outcome in these patients. In this retrospective analysis of clinical routine patient data, multivariate statistical models based on Linear Mixed Models regression and Generalized Estimating Equations logistic regression were developed. The adequacy of the models was assessed using Pearson's correlation and a receiver operating characteristic curve. This study included 273 patients and 1158 thiopurine metabolite measurements as well as routine laboratory and clinical data. In the statistical models, thiopurine metabolite concentrations and the odds of non-remission based on different clinical and laboratory parameters were computed. Correlation (r2) between predicted and measured thiopurine metabolites were 0.40 (p < 0.001) for 6-thioguanine nucleotides and 0.53 (p < 0.001) for 6-methyl-mercaptopurine nucleotides, respectively. The model for remission classified data sets in remission and non-remission with a sensitivity of 63% and a specificity of 73%. The area under the receiver operating characteristic curve of the model was 0.72. Although the models are not yet accurate enough to be used in clinical routine, model-based prediction of thiopurine metabolite concentrations and of outcome is feasible. Until more accurate models are developed and validated, traditional therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel diseases under thiopurine therapy stays the best tool to individualize therapy.

Biopsy utility in the workup of ANCA-associated vasculitis

ANCA - associated Vasculitis (AAV) positive biopsy is supportive of vasculitis diagnosis, the aim of this manuscript is that renal biopsy is not always compulsory in the diagnosis and management of AAV. 79 years old, Caucasian women, admitted with AAV suspicion, MPO positive. A Microscopic polyangiitis with a pulmonary – renal syndrome was diagnosed after other AAV were excluded. Remission induction and maintenance therapy was made. In 6 months the patient presented a considerable improvement with lower MPO value, ESR and a stabilization of kidney function. Renal biopsy has to be performed in the majority of patients with the suspicion or renal AAV, although in this case it was not performed considering that the patient was on chronic anticoagulation and renal biopsy was not essential for the diagnosis. We suggest that renal biopsy is a valuable method in establishes the aetiology of kidney disease and that it could be dismissed in AAV with suggestive clinical presentation and low suspicion for secondary vasculitis.

Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis

Objectives: To provide evidence for the revision of clinical practice guideline (CPG) for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the Japan Research Committee for Intractable Vasculitis.Methods: PubMed, CENTRAL, and the Japan Medical s Society were searched for articles published between January 1994 and January 2015 to conduct systematic review (SR), and the quality of evidence was assessed with GRADE approach.Results: Nine randomized controlled trials (RCTs) and two non-RCTs were adopted for remission induction therapy, three RCTs and two non-RCTs for plasma exchange, and five RCTs and one non-RCT for remission maintenance therapy. A significant difference was found in efficacy and safety for the following comparisons. In the non-RCT adopted for remission induction therapy, glucocorticoid (GC) + cyclophosphamide (CY) was significantly superior to GC monotherapy regarding remission. GC + intravenous CY for remission induction therapy was superior to GC + oral CY regarding death at one year, serious adverse events, and serious infection. Concomitant use of plasma exchange for remission induction therapy of AAV with severe renal dysfunction reduced risk of end-stage renal disease versus non-users at month 3.Conclusion: This SR provided necessary evidence for developing CPG for the management of ANCA-associated vasculitis.

2017 Clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis

Objective: The Japan Research Committee for Intractable Vasculitis has fully revised the clinical practice guidelines (CPG) for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) to improve and standardize the medical treatment of the disease in Japan.Methods: The previous CPG was published in a classical review style in Japanese in 2011 and 2014. We adopted the Grading of Recommendations Assessment, Development and Evaluation system for this revision, and various stakeholders, including patients, participated in it. The expected users of this CPG are AAV patients in Japan and their families and healthcare professionals, including both AAV specialists and non-specialists. We set clinical questions concerning the three important clinical topics of remission induction therapy, plasma exchange, remission maintenance therapy, and developed eight recommendation statements.Results: For remission induction therapy for newly developed AAV, we weakly recommend glucocorticoid (GC) plus intravenous cyclophosphamide pulse (IVCY) or oral cyclophosphamide (POCY) rather than GC alone, and IVCY rather than POCY. We also weakly recommend CY rather than rituximab. In the case of AAV with severe renal impairment, we weakly recommend plasma exchange as a conjunction therapy. We weakly recommend azathioprine for remission maintenance therapy.Conclusion: The revised CPG has demonstrated evidence-based treatment recommendations for AAV.

Targeted immunotherapy strategies in ANCA-associated vasculitis

Targeted immunotherapy is substantially improving the management of ANCA-associated vasculitides (AAV), which include granulomatosis with polyangiitis (GPA, Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). This article reviews the current role for targeted immunotherapy in AAV, its validated indications, and avenues for further development. Rituximab is a validated induction treatment for GPA and severe MPA. Rituximab in these indications is not less effective than cyclophosphamide and is particularly useful in patients with refractory or relapsing disease, women of childbearing potential, and patients previously treated with cyclophosphamide. Rituximab is more effective than cyclophosphamide for treating relapses. For remission maintenance therapy, which is indispensable, rituximab has been proven superior over conventional immunosuppressive treatment. Rituximab is licensed in the USA and in Europe for the induction treatment of severe forms of GPA and MPA. An extension study for remission maintenance therapy is ongoing. In EGPA, although maintenance treatment with the interleukin-5 antagonist mepolizumab is effective in decreasing glucocorticoid requirements and in alleviating asthma and sinonasal symptoms, its efficacy on the vasculitis remains somewhat unclear. Mepolizumab is licensed for use in EGPA, and rituximab is also being evaluated as an induction and maintenance agent. Immunoglobulins can be helpful as an adjuvant treatment for active AAV with severe immunedepression, notably when infections occur. Plasma exchange is indicated in AAV with advanced renal dysfunction and, perhaps, in the event of alveolar hemorrhage, a possibility that will be assessed in 2018 in a large international study.

Risk Factors for Relapse of Antineutrophil Cytoplasmic Antibody-associated Vasculitis in Japan: A Nationwide, Prospective Cohort Study.

The aim was to elucidate the prognosis and risk factors associated with relapse during longterm remission maintenance therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Patients with newly diagnosed AAV (n = 156) were registered in the Remission Induction Therapy in Japanese patients with ANCA-associated Vasculitides (RemIT-JAV) study, and among them, 83 patients who achieved remission were enrolled and followed up for 24 additional months in our nationwide, prospective cohort study (Co-RemIT-JAV; registration number UMIN 000006373). Patterns of maintenance therapy, effectiveness, and safety were evaluated from months 25 to 48 after the RemIT-JAV. The primary outcome measure was the rate of relapse. Secondary outcome measures included overall and renal survival, risk factors associated with relapse, and incidence rates of serious infections. The patients comprised 35 men and 48 women aged 65.3 ± 12.6 years. Between months 25 and 48, the survival rate was 95% (79/83). Causes of death included 1 thyroid cancer, 1 infection, and 2 unknown reasons. Four patients had developed endstage renal disease (ESRD) by Month 24; 1 developed ESRD beyond Month 25. The relapse rate was 24% (20/83) from months 25 to 48. Multivariable analysis revealed that oral prednisolone ≤ 2.5 mg/day at Month 24 was a significant risk factor for relapse between months 25 and 48 (HR = 3.1, 95% CI 1.1-8.5). One-quarter of patients with AAV relapsed during maintenance therapy, and relapse was associated with the dose of oral prednisolone 24 months after the initiation of remission induction therapy in Japan.

Nocardia cyriacigeorgica pneumonia in ulcerative colitis patient receiving infliximab despite TMP/SMX prophylaxis

Introduction Infliximab is an effective therapy for induction and maintenance of remission in patients with refractory ulcerative colitis (UC). Treatment with TNF-alpha inhibitors is associated with an increased risk of infection. In this case, we will discuss an uncommon cause of infection associated with infliximab therapy despite antibiotic prophylaxis. Case description 78-year-old man with history of UC maintained on infliximab infusion every 8-weeks was found to have pulmonary infiltrates on chest computed tomography (CT). His UC history was notable for recent Pneumocystis jiroveci pneumonia while on infliximab requiring intravenous Trimethoprim/Sulfamethoxazole (TMP/SMX) treatment for 21 days followed by single strength oral TMP/SMX for secondary prophylaxis. On evaluation, the patient endorsed weakness, generalized fatigue, and shortness of breath with activities. His lab was notable for mild anemia in the absence of leukocytosis. Result and conclusion Bronchoscopy was performed and bronchoalveolar lavage fluid was sent to the microbiology laboratory for culture. After 30 days of incubation, the culture returned partially acid fast, branching, Gram-positive rod shaped bacteria consistent with Nocardia cyriacigeorgica. The isolate was susceptible to TMP/SMX (0.25/4.75μg/Ml). Patient was started on therapeutic dose of oral TMP/SMX at 5 mg/kg of the trimethoprim component for 6 months. Infliximab was subsequently held. Repeat chest CT scan at 6 months showed resolution of patchy ground glass and nodular infiltrates. Take-home message This case highlights the importance of considering Nocardia infection in ulcerative colitis patients receiving infliximab therapy presenting with shortness of breath and new infiltrates on chest imaging. In addition, patients receiving prophylaxis with TMP/SMX are still at risk for this infection because the effectiveness of prophylactic doses of TMP/SMX in preventing disease remains unclear.

Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis

ObjectivesA prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).MethodsPatients with AAV were recruited 18–24...

Children with low‐risk acute lymphoblastic leukemia are at highest risk of second cancers

The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial

BackgroundRituximab is effective as therapy for induction of remission in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the effect of rituximab is not sustained, and subsequent relapse rates are high, especially in patients with a history of relapse. There is a need to identify whether maintenance therapy with rituximab is superior to the current standard of azathioprine or methotrexate for prevention of relapse following induction with rituximab.Methods/designRITAZAREM is an international, multicenter, open-label, randomized controlled trial designed to demonstrate the superiority of repeated doses of intravenous rituximab compared to daily orally administered azathioprine as a relapse prevention strategy in patients with AAV with relapsing disease who undergo induction of remission with rituximab. Patients with AAV will be recruited at the time of relapse and will receive rituximab and glucocorticoid induction therapy. If the disease is controlled by 4 months, patients will be randomized in a 1:1 ratio to receive rituximab (1000 mg every 4 months for five doses) or azathioprine (2 mg/kg/day) as maintenance therapy. Patients will be followed for a minimum of 36 months. The primary outcome is the time to disease relapse. It is estimated that 190 patients will need to be recruited to ensure that at least 160 are randomized.DiscussionThe RITAZAREM trial will provide the largest trial dataset for the use of rituximab as remission-induction therapy for patients with AAV comparing two remission-maintenance strategies following induction with rituximab, and explore whether prolonged B-cell depletion leads to sustained treatment-free remissions after discontinuation of immunosuppressive therapy.Trial registrationClinicalTrials.gov identifier: NCT01697267. Registered on 31 August 2012.

DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial

Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m2 once per day and methotrexate 20 mg/m2 once per week, targeted to a leucocyte count of 1·5-3·0 × 109 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/μg DNA increase, 95% CI 0·67-0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0·0001). Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation.

Rituximab in ANCA-Associated Vasculitis.

The purpose of this review is to describe the efficacy and safety of rituximab (RTX) as a remission induction and maintenance therapy in ANCA-associated vasculitis (AAV). A PubMed search was carried out to track down articles published between February 2006 and February 2016. Randomized controlled trials (RCTs) that encompassed patients with AAV were included. The American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) 2014-2015 online abstracts were also reviewed whether they were RTCs or not. Ten PubMed RCTs were analyzed along with eight ACR and four EULAR abstracts. RTX was not inferior to cyclophosphamide (CYC) for remission induction in AAV; it was superior to CYC in patients with relapsing disease and superior for remission maintenance in comparison with azathioprine (AZA). Rituximab is a therapeutic option to induce and maintain remission in patients with AAV.

Long-Term Outcome of 102 Cases of Lupus Nephritis: A Single-Center Cohort Study in Japan

Background: The mortality rate is higher in SLE patients with lupus nephritis (LN) than in those without nephropathy. Objectives: The aim of this study was to identify the factors affecting the long-term renal outcome in 102 patients with LN. Methods: This was a retrospective cohort study. Logistic regression analysis was used in a model to determine how independent variables predicted the outcome. The survival analysis was based on the Kaplan-Meier curve with subjects censored for death. Results: The 15-year survival rate was 93.5%, and the renal function non-deterioration rate was 78.3%. No influence of individual types of immunosuppressant drugs used was found on the renal function deterioration rate. In this study, the results of analysis identified only daily urinary protein excretion level as having any significant effect on the risk of progression of LN to renal failure. Conclusions: These results suggest that remission induction therapy and maintenance therapy focused on long-term preservation of renal function need to be selected for LN patients with a high daily urinary protein value at the start of treatment and for LN patients who fail to show any reduction of the daily urinary protein excretion level to 0.5 g or less at one year after the biopsy.

Anti-tuberculous therapy for maintenance of remission in Crohn's disease.

There have been a number of studies with conflicting results which have examined the effect of anti-tuberculous therapy in Crohn's disease. A meta-analysis was performed to evaluate the use of anti-tuberculous therapy for the maintenance of remission in Crohn's disease. To evaluate the effects of anti-tuberculous therapy for the maintenance of remission in patients with Crohn's disease. We searched MEDLINE, EMBASE, the Cochrane LIbrary, and the Cochrane IBD Group Specialized Register from inception to June 22, 2015. Randomized controlled trials (RCTs) of anti-tuberculous therapy compared to placebo or another active therapy in patients with quiescent Crohn's disease were considered for inclusion. At least two authors independently extracted data and assessed the quality of included studies using the Cochrane risk of bias tool. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes.. The primary outcome was relapse. Secondary outcomes included adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary and secondary outcomes was evaluated using the GRADE criteria. Four placebo-controlled RCTs including 206 participants were included. Three trials included an 8 to 16 week induction phase with tapering corticosteroids (prednisone, prednisolone or methylprednisolone) as induction therapy. Anti-tuberculous therapy included monotherapy with clofazimine, combination therapy with clofazimine, rifampin, ethambutol, and dapsone or combination therapy with clarithromycin, rifabutin and clofazimine. All of the studies were rated as unclear risk of bias for allocation concealment, three were rated as unclear risk of bias for random sequence generation and two were rated as unclear risk of bias for blinding or participants and personnel. There was a statistically significant difference in relapse rates favoring anti-tuberculous therapy over placebo. Thirty-nine per cent (44/112) of patients in the anti-tuberculous therapy group relapsed at 9 months to 2 years compared to 67% (63/94) of placebo patients (RR 0.58, 95% CI 0.45 to 0.75, I(2) = 47%). A GRADE analysis indicates that the overall quality of the evidence supporting this outcome was very low due to unknown risk of bias and sparse data. Adverse events occurred more frequently in the anti-tuberculous therapy group (37/159) compared to the placebo group (14/163) with a pooled RR of 2.57 (95% CI 1.45 to 4.55; N=322; studies=4, I(2)=64%). A GRADE analysis indicates that the overall quality of the evidence supporting this outcome was very low due to unknown risk of bias, unexplained heterogeneity and sparse data. There was no difference in withdrawals due to adverse events. Nine per cent (14/159) of anti-tuberculous therapy patients withdrew due to adverse events compared to 7% (11/163) of placebo patients (RR 1.29, 95% CI 0.60 to 2.77, I(2) = 0%). Common adverse events included increased skin pigmentation and rashes. No serious adverse events were reported in any of the included studies. Anti-tuberculous therapy may provide a benefit over placebo for the prevention of relapse in participants with Crohn's disease in remission. However, this result is very uncertain due to unclear study quality and the small numbers of patients assessed. Further studies are needed to provide better quality evidence for the use of anti-tuberculous therapy for maintaining remission in people with quiescent Crohn's disease.