Azathioprine Maintenance Research Articles

EULAR recommendations 2023 on the treatment of systemic lupus erythematosus-Implications for treatment in Germany

The 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus (SLE) faced several tasks: the newly approved medications anifrolumab and voclosporin as well as the additional approval of belimumab for lupus nephritis had to be conceptionally fitted into the management of SLE. Novel data on hydroxychloroquine and glucocorticoids, additional results for the treat-to-target goals remission and low disease activity and experience with respect to vaccinations and infections had to be considered. Additionally, EULAR specified aslightly modified structure. The update was further developed with 5overarching principles and 13recommendations. An SLE activity score is required for each patient visit. All SLE patients should receive hydroxychloroquine at atarget dose of 5 mg/kg body weight. Glucocorticoids should only be used if necessary and reduced to not more than 5 mg prednisone equivalent daily in the long-term or, even better, tapered off. If the target of remission or low disease activity is not reached, methotrexate, azathioprine, mycophenolate and/or belimumab or anifrolumab should be used. For lupus nephritis, Euro-Lupus cyclophosphamide or mycophenolate are options for induction therapy and mycophenolate or azathioprine for maintenance. In the case of severe nephritis, the addition of belimumab or acalcineurin inhibitor (voclosporin or tacrolimus) should be considered. It is important that treatment should be continued for at least 3years. This review article describes the details of the new recommendations against the background of relevant studies in recent years and classifies them in the clinical context.

II Brazilian Society of Rheumatology consensus for lupus nephritis diagnosis and treatment

ObjectiveTo develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).MethodsTwo methodologists and 20 rheumatologists from Lupus Comittee of Brazilian Society of Rheumatology participate in the development of this guideline. Fourteen PICO questions were defined and a systematic review was performed. Eligible randomized controlled trials were analyzed regarding complete renal remission, partial renal remission, serum creatinine, proteinuria, serum creatinine doubling, progression to end-stage renal disease, renal relapse, and severe adverse events (infections and mortality). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to develop these recommendations. Recommendations required ≥82% of agreement among the voting members and were classified as strongly in favor, weakly in favor, conditional, weakly against or strongly against a particular intervention. Other aspects of LN management (diagnosis, general principles of treatment, treatment of comorbidities and refractory cases) were evaluated through literature review and expert opinion.ResultsAll SLE patients should undergo creatinine and urinalysis tests to assess renal involvement. Kidney biopsy is considered the gold standard for diagnosing LN but, if it is not available or there is a contraindication to the procedure, therapeutic decisions should be based on clinical and laboratory parameters. Fourteen recommendations were developed. Target Renal response (TRR) was defined as improvement or maintenance of renal function (±10% at baseline of treatment) combined with a decrease in 24-h proteinuria or 24-h UPCR of 25% at 3 months, a decrease of 50% at 6 months, and proteinuria < 0.8 g/24 h at 12 months. Hydroxychloroquine should be prescribed to all SLE patients, except in cases of contraindication. Glucocorticoids should be used at the lowest dose and for the minimal necessary period. In class III or IV (±V), mycophenolate (MMF), cyclophosphamide, MMF plus tacrolimus (TAC), MMF plus belimumab or TAC can be used as induction therapy. For maintenance therapy, MMF or azathioprine (AZA) are the first choice and TAC or cyclosporin or leflunomide can be used in patients who cannot use MMF or AZA. Rituximab can be prescribed in cases of refractory disease. In cases of failure in achieving TRR, it is important to assess adherence, immunosuppressant dosage, adjuvant therapy, comorbidities, and consider biopsy/rebiopsy.ConclusionThis consensus provides evidence-based data to guide LN diagnosis and treatment, supporting the development of public and supplementary health policies in Brazil.

Randomised clinical trial: First-line infliximab biosimilar is cost-effective compared to conventional treatment in paediatric Crohn's disease.

Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease. We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036). First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease. NCT02517684.

IgG4-related disorders of the gastrointestinal tract: Experience from a tertiary care centre with systematic review of Indian literature.

IgG4-related disease (IgG4-RD) is a rare disease entity in India. We aimed at studying the clinical profile of IgG4-RD of gastrointestinal tract (GIT) from our centre, while systematically reviewing data from India. Retrospective review of IgG4-RD of GIT was done using electronic medical records between January 2013 and July 2022. Literature search was done for studies of IgG4-RD of the GIT reported from India from 2000 till January 2023. Case series, case reports of IgG4-RD of GIT and case reports describing GIT with multi-organ involvement were included in the review. Primary outcome measure was response to treatment. Secondary outcome measure was relapse after remission. Thirty-one patients were included with 71% (22/31) having autoimmune pancreatitis. The diagnosis was achieved on surgical specimen in 35% (11/31) patients. Steroid was given to 64% (20/31) patients with remission achieved in 70% (14/20) patients. Four patients exhibitted response to prolonged course of steroids with maintenance azathioprine. Relapse was seen in four (20%) patients who achieved remission. Of 731 articles screened, 48 studies (four case series and 44 case reports) were included in the literature review. Of 95 patients described, steroids were given to 65.2% (62/95), while surgery was done in 33.6% (32/95). Remission was seen in 96.6% (85/88) with relapse occurring in 11.4% (10/88) patients on follow-up. One-third patients of IgG4-RD of GIT are diagnosed after surgery. Response to steroids is good with relapse occurring in up to 12% patients.

THU381 A Case of Severe Type B Insulin Resistance Successfully Treated With Combined Immunosuppressive Therapy

Abstract Disclosure: A.K. Sumal: None. D.S. Martinez: None. Background: Type B insulin resistance is a rare autoimmune disorder caused by autoantibodies against the insulin receptor and is characterized by markedly high insulin requirements, severe catabolism, and a mortality rate over 50%. Clinical Case: A 50-year-old woman with Sjogren’s syndrome and a one-year history of diabetes treated with insulin presented with diabetic ketoacidosis (DKA) and was found to have type B insulin resistance. Initial laboratory workup demonstrated DKA with a blood glucose of 464 mg/dL (n: 65–99 mg/dL), CO2 8 mmol/L (n: 20–30 mmol/L), anion gap 16 (n: 8–12), pH 7.08 (n: 7.30–7.40) on venous blood gas, 2+ ketonuria, and a hemoglobin A1c of 11.7% (n: &amp;lt;5.7%). Additional workup revealed negative glutamic acid decarboxylase-65, insulin antigen-2, and insulin antibodies, positive C-peptide 2.7 ng/mL (n: 1.1–4.3 ng/mL), and elevated adiponectin 41 ug/mL (n: 5–28 ug/mL). Her physical exam was notable for 100 lb weight loss and extensive acanthosis nigricans, facial acne, and hirsutism. She was started on IV insulin infusion with resolution of her DKA but required more than 5000 units of insulin per day to obtain glycemic control. Due to the suspicion of type B insulin resistance, she was treated with metformin 1000 mg twice daily and pioglitazone 45 mg daily to reverse her hypercatabolic state and combined immunosuppressive therapy consisting of 2 cycles of rituximab 750 mg/m2 infusion, cyclophosphamide 100 mg daily, and dexamethasone 40 mg for 4 days administered 14 days apart based on a 2018 NIH protocol. Her serum was sent for confirmatory insulin receptor autoantibody testing, which is pending. Over the next 30 days, her insulin requirements improved immensely, and she was ultimately discharged without insulin in clinical remission. To prevent recurrence and hypoglycemia associated with low titers of insulin receptor autoantibodies, she was started on azathioprine 100 mg daily as maintenance therapy. Three months later, she was seen in endocrine clinic in sustained remission with a hemoglobin A1c of 6.0% and resolution of her acanthosis nigricans and hyperandrogenism. Review of her continuous glucose monitor showed no episodes of hypoglycemia. Conclusion: This rare case demonstrates the successful treatment of type B insulin resistance using metformin, pioglitazone, and combination immunosuppressive therapy with rituximab, cyclophosphamide, and pulse-dose steroids, followed by maintenance azathioprine. With a mortality rate over 50%, the use of combined immunosuppressive therapy has transformed this condition into a curable form of diabetes and should be recommended in all patients with type B insulin resistance. Presentation: Thursday, June 15, 2023

OA15 Missing the wood(-y induration) for the trees

OA15 Missing the wood(-y induration) for the trees

In relapsing AAV with rituximab-induced remission, maintenance rituximab vs. azathioprine reduced relapse at ≥32 mo.

Smith RM, Jones RB, Specks U, et al; RITAZAREM co-investigators. Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial. Ann Rheum Dis. 2023;82:937-944. 36958796.

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

ObjectiveFollowing 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...

Serum immune profiling in pediatric Crohn's disease demonstrates stronger immune modulation with first-line infliximab than conventional therapy and pre-treatment profiles predict clinical response to both treatments.

Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual pediatric Crohn's disease (CD) patients is needed. We assessed how serum immune profiles before and after first-line infliximab (FL-IFX) or conventional (CONV) induction therapy associate with disease remission at week 52. pre- (n=86), and 10-14 week post-treatment (n=84) sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomised to FL-IFX (n=48; five 5mg/kg infusions over 22 weeks) or CONV (n=43; exclusive enteral nutrition or oral prednisolone); both groups received azathioprine maintenance. The relative concentrations of 92 inflammatory proteins were determined with Olink Proteomics; fold changes (FC) with |Log2FC|>0.5 after FDR adjustment were considered significant. FL-IFX modulated a larger number of inflammatory proteins and induced stronger suppression than CONV; 18/30 proteins modulated by FL-IFX were not regulated by CONV. Hierarchical clustering based on IFX-modulated proteins at baseline revealed two clusters of patients: CD-hi patients had significantly higher concentrations of 23/30 IFX-modulated proteins (including oncostatin-M, TNFSF14, HGF, TGF-α) and higher clinical disease activity, CRP and blood neutrophils at baseline than CD-lo patients. Only 24% of CD-hi FL-IFX-treated patients maintained remission without escalation at week 52 vs 58% of CD-lo FL-IFX-treated patients. Similarly, 6% of CD-hi CONV-treated patients achieved remission vs 20% of CONV-treated CD-lo patients. Clustering based on immune profiles post-induction therapy did not relate to remission at week 52. FL-IFX leads to stronger reductions and modulates more immune proteins than CONV. Stratification on pre-treatment profiles of IFX-modulated proteins directly relates to maintenance of remission without treatment escalation.

P448 Long term effectiveness of first-line infliximab treatment compared to conventional treatment in paediatric moderate-to-severe Crohn’s disease – an update from the TISKids study

Abstract Background Current guidelines recommend first-line anti-TNF therapy (start at diagnosis) only in children with high risk for a complicated disease course. However, previous results of the TISKids study showed that first-line infliximab (FL-IFX) treatment (5 infusions in total) combined with azathioprine (AZA) was more effective to achieve clinical remission without treatment escalation at week 52 compared to conventional induction treatment (CONV) with AZA in therapy-naïve children with moderate-to-severe CD, irrespective of having high risk for development of complications1. The aim of our study was to investigate the effects at 3-year follow-up of the TISKids cohort. Methods The TISKids study is a multicentre, open-label randomised controlled trial in which untreated patients with a new diagnosis of CD (3–17 years old, weighted paediatric CD activity index score &amp;gt;40) were included. Patients were randomised to FL-IFX (5 infusions of 5 mg/kg infliximab at weeks 0, 2, 6, 14, 22) or CONV (EEN or prednisolone). Both treatment groups were combined with AZA maintenance. The primary outcome was biochemical remission (faecal calprotectin &amp;lt;250 ug/g) without need for additional biological treatment at 3 years. Secondary outcomes were time to additional biological treatment and number of patients with luminal surgery until 3 years. Additional biological treatment in the FL-IFX group included intensification, continuation or restart of IFX. Differences in proportions were tested using the Chi-square or Fisher-exact test, time to additional biological was analysed using Kaplan-Meier method with log-rank test. Results In total, 50 patients received FL-IFX and 47 CONV. One patient from each group was lost to follow-up, data at 3 years was available in 89/97 patients. At 3 years, 5/43 (12%) FL-IFX patients were in biochemical remission without need for additional biological treatment compared to 4/42 (10%) CONV patients (p=1.00). The time to additional biological treatment was significantly longer for the FL-IFX patients (median 63 weeks) compared to CONV patients (median 32 weeks), p=0.019. The number of luminal surgeries (all ileocaecal resections) until 3 years was not significantly different between FL-IFX (n=2/46, 4%) compared to CONV (n=5/43, 12%), p=0.256. Conclusion These results imply that there still is a significant benefit of FL-IFX during 3 years of follow-up (longer time to additional biological treatment compared to CONV), demonstrating durability of providing effective induction treatment. Further research should identify in which patient and when IFX may be stopped and which maintenance treatment would be appropriate in order to sustain and further optimize the benefits of FL-IFX treatment. 1. Jongsma MME et al. Gut. 2020. PMID: 33384335

Human leukocyte antigen association with azathioprine-induced drug hypersensitivity reactions in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

Azathioprine (AZA) drug hypersensitivity reaction (DHR) is an uncommon yet potentially lethal condition that often goes unrecognised in patients with anti-Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV). We conducted a retrospective review of AAV patients on AZA maintenance therapy (N = 35). Participants were categorised into those who had experienced AZA-DHR (N = 15) and those who were AZA-tolerant (N = 20). Human leukocyte antigen (HLA) typing was performed in both groups. The primary endpoint was identification of a HLA gene association with AZA-DHR in the context of AAV. HLA-C*06:02, was solely expressed in AZA-DHR patients (33.3 %), whilst no patient who tolerated AZA carried this allele (0.0 %). This yielded a positive predictive value of 100 % for HLA-C*06:02 in predicting AZA-DHR in AAV patients, negative predictive value of 66.7 %, sensitivity of 33.3 % and specificity of 100 %. HLA-C*06:02 may predict the development of AZA-DHR in patients with AAV and inform safer therapeutic choice.

Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population

Belimumab improved kidney outcomes in patients with active lupus nephritis (LN) in BLISS-LN, leading to its approval in the United States and the European Union. As data on treatment of East Asian patients with LN are limited, we evaluated the efficacy and safety of belimumab in the BLISS-LN East Asian subgroup. Prespecified subgroup analysis of BLISS-LN, a phase 3, placebo-controlled, randomized 104-week trial. Adults with biopsy-proven, active LN were randomized (1:1) to belimumab or placebo, plus standard therapy. Patients were administered intravenous belimumab 10mg/kg, or placebo, plus standard therapy (oral glucocorticoids and either cyclophosphamide for induction followed by azathioprine for maintenance, or mycophenolate mofetil for both induction and maintenance). At the investigator's discretion, 1-3 intravenous pulses of methylprednisolone, 500-1,000mg each, could be administered during induction. The primary end point was primary efficacy renal response (PERR; ie, urinary protein-creatinine ratio≤0.7g/g, estimated glomerular filtration rate no more than 20% below preflare value or≥60mL/min/1.73m2, and no treatment failure) at week 104. Key secondary end points included complete renal response (CRR; urinary protein-creatinine ratio<0.5g/g, estimated glomerular filtration rate no more than 10% below preflare value or≥90mL/min/1.73m2, and no treatment failure) at week 104; PERR at week 52; time to kidney-related event or death; and safety. PERR and CRR were analyzed using a logistic regression model, and time to a kidney-related event or death was analyzed using a Cox proportional hazards regression model. 142 patients from mainland China, Hong Kong, South Korea, and Taiwan were included (belimumab, n=74; placebo, n=68). At week 104, more belimumab than placebo patients achieved PERR (53% vs 37%; OR, 1.76 [95% CI, 0.88-3.51]) and CRR (35% vs 25%; OR, 1.73 [95% CI, 0.80-3.74]). At week 52, more belimumab than placebo patients achieved PERR (62% vs 37%; OR, 2.74 [95% CI, 1.33-5.64]). Belimumab reduced the risk of a kidney-related event or death compared with placebo at any time (HR, 0.37 [95% CI, 0.15-0.91]). Safety was similar across treatment groups. Small sample size and lack of formal significance testing. Safety and efficacy profiles were consistent with BLISS-LN overall population, supporting benefits of belimumab treatment in the East Asian subgroup with LN. This study was funded by GSK (GSK study no. BEL114054). Registered at ClinicalTrials.gov with study number NCT01639339.

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: NCT02517684What 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.

P100 Serum inflammatory protein profiling to corroborate selection of therapy naïve moderate-to-severe pediatric Crohn’s disease patients eligible for first-line infliximab treatment

Abstract Background Early intervention with biologic therapy, especially with anti-Tumor Necrosis Factor-a, is very effective and now more commonly used to prevent disease progression and complications in Crohn’s disease (CD). However, a rational approach to decide which patient should be treated First-line Infliximab (FL-IFX) is lacking. In this study, using serum from a randomized control trial, we assessed how changes in immune profiles prior to therapy and after the first standardized induction treatment with either FL-IFX or conventional treatment (CONV) related to maintaining disease remission at week 52. Methods Serum samples from therapy naive moderate to severe CD patients from the TISKIDS study1 were used at time of diagnosis and at 10–14 weeks after induction therapy with FL-IFX (n=48) and CONV (n=43). FL-IFX consisted of 5 IFX infusions (5 mg/kg) combined with azathioprine (AZA) maintenance. CONV consisted of induction therapy with Exclusive Enteral Nutrition or oral prednisolone combined with AZA maintenance. Concentrations of 92 inflammatory proteins were determined with Olink Proteomics®. Significant differences in mean protein NPX after FDR adjustment with log2fold &amp;gt; 0.5 were considered meaningful. Results After 10–14 weeks of induction therapy, FL-IFX suppressed a larger number inflammatory proteins and induced stronger suppression compared to CONV. Of the 30 significantly modulated FL-IFX target proteins 18 were differentially regulated by FL-IFX only. Hierarchical clustering of patients based on their baseline profiles of the 30 IFX-modulated proteins revealed 2 patient clusters, a CD-hi cluster with significantly higher baseline clinical disease activity, CRP and blood neutrophil concentrations compared to the CD-lo cluster. The CD-hi cluster had an increased abundance of 23/30 proteins amongst which Oncostatin-M, TNFSF14, HGF and TGF-alpha compared to the CD-lo cluster (Figure 1A). Of the CD-lo patients treated with FL-IFX, 58% reached clinical disease remission without treatment escalation at week 52, while this was only 24% for CD-hi patients treated with FL-IFX. Only 20% of the CD-lo patients treated with CONV reached remission while this was only 6% for the CONV treated patients in the CD-hi group (Figure 1B). Strikingly, similar clustering using the immune profiles after 10–14 weeks induction therapy did not predict remission at week 52. Conclusion FL-IFX achieves stronger reduction and modulates more inflammatory serum immune protein concentrations than CONV. Stratification of patients according to profiles of IFX-modulated proteins prior to therapy identifies patients with a lower chance of reaching clinical remission without treatment escalation at week 52. Reference 1. Jongsma MME et al. Gut. 2020 Dec; DOI:10.1136/ PMID:33384335

Cost-Effectiveness of Rituximab (Fixed Schedule vs Tailored Dose) Compared With Azathioprine Maintenance Therapy in Adults With Generalized Antineutrophil Cytoplasm Antibody-Associated Vasculitis in Colombia

ObjectivesAzathioprine has been the therapy of choice for the maintenance of remission in patients with antineutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis, but recent studies show that rituximab could be more effective. To evaluate the cost-effectiveness of azathioprine, fixed-schedule rituximab, and tailored-dose rituximab for ANCA-associated systemic vasculitis. MethodsA Markov model from the perspective of the Colombian healthcare system was designed with annual cycles and a 5-year time horizon, charting the following states: remission, minor relapse, major relapse, and death. The discount rate was 5%. Transition probabilities were obtained from a systematic literature review. The costs (1 US dollar = 2956 Colombian pesos in 2018) were estimated based on national drug registries and official fee manuals for procedures, along with other resources. The main outcomes were quality-adjusted life-years (QALYs) taken from the Tufts registry. Univariate and multivariate sensitivity analyses were performed. ResultsFinal costs were $1446 for azathioprine, $4898 for tailored-dose rituximab, and $6311 for fixed-schedule rituximab. QALYs gained were 3.18, 4.08, and 3.98, respectively. Rituximab was cost-effective (cost per incremental QALY gained: $4919, and $6865), and tailored-dose administration had a lower cost. Sensitivity analyses did not affect the results. ConclusionsTailored-dose rituximab was the most cost-effective treatment for ANCA-associated vasculitis. Azathioprine presented worse effectiveness and lower cost, and fixed-schedule rituximab was dominated by tailored-dose rituximab.

47-Year-Old Woman With Bilateral Flank Pain

47-Year-Old Woman With Bilateral Flank Pain

Treatment for Severe Lupus Nephritis: A Cost-Effectiveness Analysis in China.

Background: Lupus nephritis (LN) is the most common secondary glomerular diseases that will cause end-stage renal disease (ESRD) and renal-related death. The cost-effectiveness of various treatments for LN recommended by official guidelines has not been investigated in China. Our study is to evaluate clinical prognosis and cost-effectiveness of the current treatments for severe LN.Methods: A Markov model was simulated for 1,000 LN patients of 30 years old, over a 3-years and 30-years lifetime horizon respectively. We assessed the cost-effectiveness of six therapeutic strategies from a societal perspective, with cyclophosphamide (CYC) or mycophenolate mofetil (MMF) induction therapy followed by CYC, MMF or azathioprine (AZA) maintenance therapy. Main outcomes included quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and clinical prognosis. One and three times gross domestic product (GDP) per capita were used as the willingness-to-pay (WTP) thresholds. We also carried out sensitivity analysis under a lifetime horizon.Results: Compared with the baseline strategy of CYC induction and maintenance, for a 3-years horizon the most cost-effective strategy was CYC induction and AZA maintenance with $448 per QALY gained, followed by MMF induction and AZA maintenance which however was not cost-effective under the one times GDP per capita WTP threshold. For a lifetime horizon, CYC induction and AZA maintenance remained the most cost-effective strategy but MMF induction and maintenance became cost-effective under the one times GDP per capita WTP threshold and achieved a higher complete remission rate (57.2 versus 48.9%) and lower risks of ESRD (3.3 versus 5.8%) and all-cause mortality (36.0 versus 40.8%). The risk of developing ESRD during maintenance was the most influential parameter affecting ICER.Conclusions: The strategy of CYC induction followed by AZA maintenance was the most cost-effective strategy in China for short-term treatment, while the strategy of MMF in both induction and maintenance became cost-effective and yielded more desirable clinical outcomes for lifetime treatment. The uncertainty analysis supported the need for monitoring the progression to ESRD.

P019 Differential effects of first-line IFX and conventional treatment on inflammatory serum proteins of paediatric moderate- to-severe Crohn’s disease patients

Abstract Background Recently, we established that First-line infliximab (FL-IFX) was superior to conventional treatment (CONV) in achieving and maintaining clinical remission in newly diagnosed paediatric patients with moderate-to-severe Crohn’s disease (CD) (PMID: 33384335). Selection of patients eligible for FL-IFX can be corroborated by combining clinical criteria with immunological biomarkers relating to the patients’ underlying immunopathology. Therefore, we investigated differential effects of FL-IFX and CONV induction treatment on serum inflammatory protein concentrations and assessed whether stratification of CD patients according to baseline serum profiles of IFX-modulated proteins relates to maintaining remission at week 52. Methods In the TISKIDS randomised controlled trial, newly diagnosed therapy-naïve CD patients with a weighted paediatric CD activity index (wPCDAI) &amp;gt;40 were included. FL-IFX consisted of 5 IFX infusions (5 mg/kg) combined with azathioprine (AZA) maintenance treatment. CONV treatment consisted of induction therapy with Exclusive Enteral Nutrition or oral prednisolone combined with AZA maintenance. Serum samples of 48 FL-IFX and 43 CONV patients, collected at time of diagnosis and after 10–14 weeks of induction treatment, were available. Concentrations of 92 inflammatory proteins were determined with Olink Proteomics® proximity extension technology. Hierarchical clustering was performed to stratify patients according to their serum immune profiles. Clinical disease remission was defined as wPCDAI&amp;lt;12.5. Results At baseline, prior to therapy, clinical disease characteristics and serum inflammatory protein concentrations did not significantly differ between FL-IFX and CONV treated patients. After 10–14 weeks, FL-IFX reduced 28 proteins and enhanced 2 proteins while CONV treatment reduced 13 proteins and enhanced 1 protein. Eighteen proteins were differentially regulated by FL-IFX only. Hierarchical clustering of patients based on their baseline profiles of the 30 IFX-modulated proteins revealed 2 patient clusters. The CD-hi cluster had an increased abundance of 24/30 proteins amongst which Oncostatin-M, TNFSF14, HGF and TGF-alpha and higher clinical inflammatory parameters compared to the CD-lo cluster. Crucially, both baseline inflammatory protein profile and type of induction therapy significantly determined whether patients reached clinical disease remission without treatment escalation at week 52; with CD-hi patients having the lowest change. Conclusion FL-IFX achieves stronger reduction and modulates more proteins than CONV treatment. Stratification of patients according to profiles of IFX-modulated proteins discerns patients with a lower chance of reaching clinical remission without treatment escalation at week 52.

Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis

This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT*3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P = 8.26 × 10–7; OR = 7.5; 95% CI 3.08–18.3) and neutropenia (P = 3.54 × 10–6; OR = 8.05; 95% CI 2.96–21.9); however, no significant association with myelosuppression was observed for TPMT*3C and ITPA variants (P > 0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P = 0.556), nor was there a significant difference between patients with variant alleles of TPMT*3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.

Comparison of relapse rates in Behçet’s disease with venous involvement on different doses of azathioprine therapy, a retrospective observational study

The aim of this study was to investigate relapse rates in azathioprine (AZA) maintenance therapy at different doses in Behçet's disease (BD) with venous involvement. Clinical records of patients who met the diagnostic criteria of International Study Group (ISG) for BD, were diagnosed with venous involvement of BD for at least 6months and sustained clinical remission with AZA for at least 3months were analyzed retrospectively. The analysis cohort was divided into 2 groups based on AZA dose (Group A: ≥ 2mg/kg/d and Group B: <2mg/kg/d). Relapse was defined as requiring another antirheumatic/immunosuppressive drug or more than dose of 10mg/d of prednisolone. Of 78 patients who were included into the study, there was no significant difference between the 2 groups in terms of age, gender and clinical characteristics. Mean relapse-free survival time was found to be higher in group A compared to group B (111.6±11.2, 95% CI 89.5±133.8 versus 51.5±6.1, 95% CI 39.5±63.4 months). Relapse-free survival rate was less in the group receiving low-dose AZA and shows the importance of effective dose of AZA in maintenance therapy.