Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials.

OBJECTIVE: To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively). METHODS: The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84. RESULTS: 277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25). CONCLUSIONS: According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.

Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial.

OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.

Integrative analysis of purine metabolites and gut microbiota in patients with neuromyelitis optica spectrum disorders after mycophenolate mofetil treatment.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a recurring inflammatory demyelinating disease that is commonly observed in Asian countries like China. Prior investigations have shown that mycophenolate mofetil (MMF) with better biocompatibility compared to azathioprine (AZA), and can prevent relapses of NMOSD, but the efficacy was controversially reported in different NMOSD cases. We aimed to explore the factors that weaken efficacy of MMF in NMOSD. METHODS: A total of 34 NMOSD patients treated with MMF were prospectively enrolled and grouped according to the therapeutic efficacy as effective group (EG, n = 23) versus less-effective group (LEG, n = 11). The purine metabolites were profiled in serum samples and gut microbiota was analyzed using 16S rRNA sequencing with stool samples from the same patients. RESULTS: Purine salvage pathway (PSP) metabolites (inosine, hypoxanthine, xanthine, guanine and uric acid) in the serum of NMOSD patients were elevated in the LEG compared to EG (p < 0.05). Additionally, the richness and microbial diversity of gut microbiota was found to be similar between EG and LEG patients. However, LEG patients had increased presence of Clostridium and Synergistes but decreased abundance of the Coprococcus genus. CONCLUSIONS: The PSP metabolites and composition of the gut microbiota were changed between patients with or without optimal clinical response after MMF treatment. This may help us to understand the pharmacodynamics of MMF in NMOSD.

Coexistence of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome and membranous nephropathy: A case report.

Overlap syndrome is the combination of autoimmune liver diseases, and this term usually describes the coexistence of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) in the same patient. Membranous nephropathy (MN) is the most common pattern of idiopathic nephrotic syndrome in patients without diabetes. The coexistence of PBC-AIH overlap syndrome and MN is very rare. Herein, the patient we describe exhibited large amounts of proteinuria and hepatic dysfunction nearly at the same time. We administered azathioprine to our patient. Fortunately, the patient demonstrated a good response to azathioprine, including a partial reduction in proteinuria from ~ 12.5 g/D to 2.62 g/D after 21 months of observation and the improvement of liver function. Our findings suggest that azathioprine may be a suitable treatment option for patients presenting with coexisting PBC-AIH overlap syndrome and MN.

Evaluation of exclusive enteral nutrition and corticosteroid induction treatment in new-onset moderate-to-severe luminal paediatric Crohn's disease.

To induce remission in luminal paediatric Crohn's disease (CD), the ESPGHAN/ECCO guideline recommends treatment with exclusive enteral nutrition (EEN) or oral corticosteroids. In newly diagnosed moderate-to-severe paediatric CD patients, we determined the proportion of patients in which EEN or corticosteroids induced remission and maintained remission on azathioprine monotherapy. We included patients from the "TISKids" study assigned to the conventional treatment arm. Patients were aged 3-17 years and had new-onset, untreated luminal CD with weighted paediatric CD activity index (wPCDAI) > 40. Induction treatment consisted of EEN or oral corticosteroids; all received azathioprine maintenance treatment from start of treatment. The primary outcome of this study was endoscopic remission defined as a SES-CD score < 3 without treatment escalation at week 10. Secondary outcomes included proportion of patients without treatment escalation at week 52. In total, 27/47 patients received EEN and 20/47 corticosteroids. At baseline, patient demographics and several inflammation parameters were similar between the two treatment groups. At 10 weeks, clinical remission rates were 7/23 (30%) for EEN and 7/19 (37%) for corticosteroids (p = 0.661). Twenty-nine of 47 consented to endoscopy at 10 weeks, showing endoscopic remission rates without treatment escalation in 2/16 (13%) of EEN-treated patients and in 1/13 (8%) of corticosteroid-treated patients (p = 1.00). At week 52, 23/27 (85%) EEN-treated patients received treatment escalation (median 14 weeks) and 13/20 (65%) corticosteroid-treated patients (median 27 weeks), p = 0.070.Conclusion: In children with moderate-to-severe newly diagnosed CD, induction treatment with EEN or CS regularly is insufficient to achieve endoscopic remission without treatment escalation at week 10. Trial registration number: NCT02517684 What is Known: • Endoscopic remission is associated with a low risk of disease progression. • FL-IFX was superior to conventional treatment in achieving and maintaining remission in paediatric patients with moderate-to-severe CD the first year from diagnosis. What is New: • In children with newly diagnosed moderate-to-severe CD, clinical remission rates and endoscopic remission rates without treatment escalation at week 10 were 30% and 13% after EEN and 37% and 8% after corticosteroid induction treatment. • The current treatment target was often not achieved by either EEN or corticosteroid induction treatment after bridging to azathioprine.

Continuous function of 80 primary renal allografts for 30-47 years with maintenance prednisone and azathioprine/mycophenolate mofetil therapy: A clinical mosaic of long-term successes.

Eighty primary renal allograft recipients, 61 living-related and 19 deceased donor, transplanted from 1963 through 1984 had continuous graft function for 30-47 years. They were treated with three different early immunosuppression programs (1963-1970: thymectomy, splenectomy, high oral prednisone; 1971-1979: divided-dose intravenous methylprednisolone; and 1980-1984: antilymphocyte globulin) each with maintenance prednisone and azathioprine, and no calcineurin inhibitor. Long-term treatment often included the anti-platelet medication, dipyridamole. Although both recipient and donor ages were young (27.2 ± 9.5 and 33.1 ± 12.0 years, respectively), six recipients with a parent donor had >40-year success. At 35 years, death-censored graft survival was 85.3% and death with a functioning graft 84.2%; overall graft survival was 69.5% (Kaplan-Meier estimate). Biopsy-documented early acute cellular and highly probable antibody-mediated rejections were reversed with divided-dose intravenous methylprednisolone. Complications are detailed in an integrated timeline. Hypogammaglobulinemia identified after 20 years doubled the infection rate. An association between a monoclonal gammopathy of undetermined significance and non-plasma-cell malignancies was identified. Twenty-seven azathioprine-treated patients tested after 37 years had extremely low levels of T1/T2 B lymphocytes representing a "low immunosuppression state of allograft acceptance (LISAA)". The lifetime achievements of these patients following a single renal allograft and low-dose maintenance immunosuppression are remarkable. Their success evolved as a clinical mosaic.

Wind of Change in the Treatment of Childhood-Onset Takayasu Arteritis: a Systematic Review.

PURPOSE OF REVIEW: We lack evidence-based data for the treatment of childhood-onset Takayasu arteritis (c-TA) since it is a rare disease in children. In this systematic literature review, we aimed to evaluate the treatment choices in c-TA patients and integrate our experience for the treatment of our patients in the recent years/in the biologic era. RECENT FINDINGS: We reviewed 24 articles addressing treatments of 413 c-TA patients. Steroids were given to 352 patients (85.2%) as the main immunosuppressive therapy. Other immunosuppressive agents included methotrexate (37.3%), cyclophosphamide (24.5%), azathioprine (16.9%), and mycophenolate mofetil (7.9%). Besides, various biological agents were used, including tumor necrosis factor-alpha inhibitors in 70 of 107 c-TA patients (65.4%) and interleukin-6 inhibitors in 33 of them (30.8%). Biologics are increasingly used in our center as well. Even in severe patients, CYC is switched to either anti-TNF or antiIL6 once disease control is achieved. Recently, in addition to conventional immunosuppressants, biologics are increasingly used in c-TA. We have revised our treatment protocol to start with 1-3 doses of high-dose steroids and CYC, in a child with TA with types III-V involvement and high acute phase reactants; once clinical features subside and CRP normalizes, biologics should be started to replace CYC while decreasing the steroid dose.

Myocardial dissection complicating left sinus of Valsalva aneurysm in silent takayasu arteritis.

BACKGROUND: Myocardial dissection (MD) in a left sinus of Valsalva aneurysm (LSVA) is a rare condition that may lead to a fatal complication. Determining the MD etiology is challenging because of various possibilities ranging from congenital to acquired diseases. Here, we discuss an approach for determining the etiology of MD complicating LSVA in Takayasu arteritis (TA) and its treatment. CASE PRESENTATION: A 41-year-old man presented with dyspnea on heavy activities and a history of consciousness loss at the age of 24 years. He was diagnosed with dilated cardiomyopathy and MD complicating LSVA in TA based on combined clinical and pathognomonic diagnostic criteria of TA evaluated using vascular Doppler and computed tomography angiography of the aorta. The patient refused to undergo surgery and received an optimal dose of chronic heart failure therapy, a high-dose steroid, and azathioprine. The patient experienced some improvements in clinical condition, functional outcome, and inflammatory markers at 1-year follow-up. CONCLUSIONS: Clinical criteria and various imaging modalities may be used to determine the etiology of MD complicating LSVA in silent TA. As an alternative to surgery, the optimal medical treatment might result in a satisfactory outcome.

Refractory palmo-plantar discoid lupus erythematosus successfully treated with mycophenolate mofetil: Unusual localization and literature review.

Palmo-plantar lesions in discoid lupus erythematosus (DLE) can be considered a very distinct rarity, generally refractory to conventional treatments. We present a 47-year-old African female patient with a 6-month clinical history of palm and soles erosions. Clinical examination revealed painful multiple, well defined, erosions with an erythematous and scaly central area and peripherical post-inflammatory hyperchromic border bilaterally distributed on the palmo-plantar surfaces. Pterygium inversum unguis involved all nails of both hands. Histological analysis and direct immunofluorescence study confirmed palmo-plantar DLE. Therapy with mycophenolate mofetil (MMF) was initiated with a progressive clearing of palmo-plantar lesions and a drastic reduction of pain. Therapy was well tolerated, neither side effects nor altered laboratory investigations were observed. Our case and literature review confirm that MMF may be an effective approach for the management of refractory palmo-plantar DLE with a safer profile than Azathioprine regarding adverse effects and cutaneous malignancies risk.

Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial.

OBJECTIVES: In patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period. DESIGN: Consecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn's disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable pharmacokinetics of the second anti-TNF were defined by the appearance of undetectable trough levels of anti-TNF with high antibodies (drug-sensitive assay) or by that of antibodies (drug-tolerant assay). RESULTS: Ninety patients (48 CDs) were included, and 45 of them received AZA after randomisation. The second anti-TNF was adalimumab or infliximab in 40 and 50 patients, respectively. Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy (p<0.001; median time of clinical failure since randomisation 18 vs >24 months). At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22 versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy. Only the use of combination therapy was associated with favourable outcomes after anti-TNF switch. CONCLUSION: In case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF. TRIAL REGISTRATION NUMBER: 03580876.

Oral Curcumin No More Effective Than Placebo in Preventing Recurrence of Crohn's Disease After Surgery in a Randomized Controlled Trial.

BACKGROUND AND AIMS: Recurrence of Crohn's disease (CD) after surgery is a major concern. Curcumin has anti-inflammatory properties and induces endoscopic remission in patients with ulcerative colitis. We investigated the efficacy of curcumin vs placebo in preventing post-operative recurrence of CD, based on endoscopic and clinical indices, in patients receiving concomitant thiopurine therapy. METHODS: We conducted a double-blind randomized controlled trial at 8 referral centers in France, from October 2014 through January 2018, of 62 consecutive patients with CD undergoing bowel resection. Patients received azathioprine (2.5 mg/kg) and were randomly assigned to groups given oral curcumin (3 g/day; n = 31) or an identical placebo (n = 31) for 6 months, and were then evaluated by colonoscopy. We also collected data on CD activity index, results from laboratory tests, and answers to quality of life questionnaires during this 6-month period. The primary endpoint was postoperative recurrence of CD in each group (Rutgeerts' index score ≥i2) at month 6 (determined by central reading). An interim analysis (intent to treat) was scheduled after 50% of the patients were enrolled. RESULTS: At month 6, postoperative recurrence (Rutgeerts' index score ≥i2) occurred in 18 patients (58%) receiving curcumin and 21 patients (68%) receiving placebo (P = .60). A significantly higher proportion of patients receiving curcumin (55%) had a severe recurrence of CD (Rutgeerts' index score ≥i3) than patients receiving placebo (26%) (P = .034). We observed a clinical recurrence of CD (CD activity index score >150) at month 6 in 45% of patients receiving placebo and 30% of patients receiving curcumin (P = .80). Quality of life scores at month 6 did not differ significantly between groups (P = .80). Severe adverse events developed in 6% of patients receiving placebo and 16% of patients receiving curcumin (P = .42). CONCLUSIONS: In a randomized controlled trial of patients who underwent surgery for CD and received thiopurine treatment, we found that curcumin was no more effective than placebo in preventing CD recurrence. There were no significant differences between groups in quality of life or severe adverse events. The study was discontinued after interim analysis due to futility. ClinicalTrials.gov no: NCT 02255370.

Long-term outcome of a randomised controlled trial comparing tacrolimus with mycophenolate mofetil as induction therapy for active lupus nephritis.

OBJECTIVES: To report the 10-year outcome of lupus nephritis (LN) treated with mycophenolate mofetil (MMF) or tacrolimus (TAC) induction in a randomised controlled trial. METHODS: Patients with active LN were treated with MMF or TAC combined with high-dose prednisolone. Responders were switched to azathioprine (AZA) at month 6. Clinical outcomes at 10 years (renal flares, renal function decline and mortality) were assessed. Factors affecting prognosis were studied by Cox regression. Urine protein-to-creatinine ratio (uPCr) and estimated glomerular filtration rate (eGFR) at different time points were evaluated for their prediction of a poor prognosis by receiver operating characteristic (ROC) analysis. RESULTS: 150 patients were studied (age 35.5±12.8 years). Complete renal response rate was similar between MMF (59%) and TAC-treated patients (62%; p=0.71). AZA maintenance was given to 79% patients. After 118.2±42 months, proteinuric and nephritic renal flares occurred in 34% and 37% of the MMF, and 53% and 30% of the TAC groups of patients, respectively (p=0.49). The cumulative incidence of a composite outcome of ↓eGFR ≥30%, chronic kidney disease stage 4/5 or death at 10 years was 33% in both groups (p=0.90). Factors independently associated with a poor renal prognosis were first-time LN (HR 0.12 (0.031 to 0.39); p=0.01), eGFR (HR 0.98 (0.96 to 0.99); p=0.008) and no response at month 6 (HR 5.18 (1.40 to 19.1); p=0.01). ROC analysis revealed an uPCr >0.75 and eGFR of <80 mL/min at month 18 best predicted a poor renal prognosis. CONCLUSIONS: Long-term data confirmed non-inferiority of TAC to MMF as induction therapy of LN. An uPCr≤0.75 and eGFR of ≥80 mL/min at month 18 best predicted a favourable 10-year outcome and may be suitable targets for induction/consolidation therapy. TRIAL REGISTRATION NUMBER: NCT00371319.

New therapeutic strategies in lung vasculitis.

PURPOSE OF REVIEW: To summarize the latest publications and provide a practical overview of treatment strategies for lung vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). RECENT FINDINGS: In patients with severe ANCA-associated vasculitis, plasma exchange, as adjunctive therapy to standard treatment, is not associated with improved survival or reduced risk of end-stage kidney disease. A regimen with reduced dose of glucocorticoids is equally effective to induce remission as a standard regimen. In patients without organ or life-threatening disease, mycophenolate mofetil can be used in combination with oral glucocorticoid therapy to induce remission, however, with a higher risk of relapse than when using rituximab or cyclophosphamide. For maintenance of remission, a tailored regimen of rituximab infusion was equivalent to a fixed regimen, with fewer perfusions. Belimumab, a human IgG1(Equation is included in full-text article.)monoclonal antibody against B-lymphocyte stimulator, did not decrease the relapse rate when added to azathioprine and glucocorticoids. Avacopan, a complement C5a receptor inhibitor, was effective in replacing high-dose glucocorticoids in achieving complete remission of vasculitis. SUMMARY: Significant advances have been made in the treatment strategy to both induce remission and maintain remission in patients with ANCA-associated vasculitis. The choice should take into consideration efficacy, cost-effectiveness, safety profile, ease of use, and possibility of individual tailoring of treatment.

Discontinuation of Immunosuppressive Medications in Children With Inflammatory Bowel Disease on Combination Therapy.

We determined the frequency and factors associated with the first clinical relapse after immunomodulator (IM) withdrawal in a cohort of children with inflammatory bowel disease on combination therapy. A total of 105 patients (89 with Crohn disease [CD]) in clinical remission were included (91 [86.7%] were on infliximab, 53 [50.5%] with methotrexate, and 52 on azathioprine). The median duration of combination therapy was 2.1 years (interquartile range [IQR] 1.3-2.8). Only 11 (10.5%) patients experienced a clinical relapse over a median duration of follow-up of 12.0 months (IQR 5.0-19.0) after IM discontinuation. The median baseline pediatric CD activity index in those with CD who relapsed after IM discontinuation was 47.5 (IQR: 35.0-55.0) versus those who did not relapse (median 35.0, IQR: 20.0-52.5; P = 0.04). In the patients who did not relapse, the median IFX trough level at IM discontinuation was 6.2 and 3.8 µg/mL in those who relapsed.

Impact of thiopurines on the natural history and surgical outcome of ulcerative colitis: a cohort study.

OBJECTIVE: Thiopurines are used as maintenance therapy in ulcerative colitis (UC), but whether these drugs influence the natural history of the disease is unknown. We aimed to assess the effect of thiopurines in terms of colectomy, hospital admission, progression in disease extent and anti-tumour necrosis factor (TNF) therapy within 10 years from initiation. DESIGN: Patients diagnosed with UC within the Örebro University Hospital catchment area, during 1963-2010, who initiated thiopurines (n=253) were included. To overcome the risk of confounding by indication, we compared patients who stopped treatment within 12 months because of an adverse reaction (n=76) with patients who continued therapy or discontinued due to other reasons (n=177) and assessed long-term outcomes using Cox regression with adjustment for potential confounding factors. RESULTS: The cumulative probability of colectomy within 10 years was 19.5% in tolerant patients compared with 29.0% in intolerant (adjusted HR 0.49; 95% CI 0.21 to 0.73). The probability of hospital admission was 34.0% in tolerant versus 56.2% in intolerant patients (adjusted HR 0.36; 95% CI 0.23 to 0.56). The risk for progression in disease extent was 20.4% in tolerant patients compared with 48.8% in intolerant (adjusted HR 0.47; 95% CI 0.21 to 1.06). Within 10 years, 16.1% of tolerant and 27.5% of intolerant patients received anti-TNF therapy (adjusted HR 0.49; 95% CI 0.26 to 0.92). CONCLUSION: Based on the novel approach of comparing patients tolerant and intolerant to thiopurines, we reveal that thiopurines have a profound beneficial impact of the natural history and long-term colectomy rates of UC.

Combination Therapy With Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis.

BACKGROUND & AIMS: Among immunosuppressive- and biologic-naïve patients with moderately-to-severely active Crohn's disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics. METHODS: We analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure-response relationships were compared. RESULTS: Within quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab-in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy. CONCLUSION: Among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov, NCT00094458.

Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Luminal Crohn's Disease.

BACKGROUND & AIMS: Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. METHODS: We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. RESULTS: The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. CONCLUSIONS: Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.

Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.

OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER: NCT00414128.

What's new in atopic eczema? An analysis of systematic reviews published in 2016. Part 1: treatment and prevention.

This review is part of a series of annual updates summarizing the evidence base for atopic eczema (AE). It provides a summary of key findings from 28 systematic reviews that were published or indexed during 2016 with a focus on treatment and prevention of AE. There is reasonable evidence of benefit for topical corticosteroids, calcineurin inhibitors, a glycyrrhetinic acid-containing preparation (Atopiclair® ), oral ciclosporin, oral azathioprine, narrowband ultraviolet B radiation and education programmes. Overall, there is evidence that topical corticosteroids and calcineurin inhibitors have similar efficacy and that both can prevent AE flares when used twice weekly as maintenance therapy. However, topical calcineurin inhibitors are costlier and have more adverse reactions, thus topical corticosteroids should remain the standard of care for patients with AE. There is no evidence that multiple applications are better than once-daily application of topical corticosteroid. There is inconsistent evidence to support omalizumab and specific allergen immunotherapy use in AE. There is some evidence that vitamin D supplementation and synbiotics reduce AE severity, although the margin of improvement may not be clinically meaningful. There is little evidence to support the use of wet wraps or of complementary/alternative medicine (including Chinese herbal medicine). There is some evidence to suggest that a diet high in fish in infancy may be preventative for AE, but other dietary interventions for the prevention of AE show little promise. This review provides a succinct guide for clinicians and patients wishing to remain up to date with the latest evidence for the treatment and prevention of AE.