Differences in rituximab use between pediatric rheumatologists and nephrologists for the treatment of refractory lupus nephritis and renal flare in childhood-onset SLE

Background Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare. Methods Members of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination. Results Seventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p < 0.05). Conclusions Therapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN.

POS0107 TAPERING BELIMUMAB IN PATIENTS WITH SLE: A SINGLE CENTER EXPERIENCE

Background:In Italy, the use of belimumab has been authorized since 2013, in patients with active systemic lupus erythematosus (SLE) with positive anti–double-stranded DNA and low C3 or C4 levels, despite standard therapy. Belimumab is effective in reducing disease activity and number of flares and in blocking damage progression. To our knowledge, no data are available on dose tapering of belimumab in SLE patients chronically treated with it.Objectives:The aim of this retrospective study was to analyse prevalence of tapering in a single cohort and to evaluate disease activity after tapering.Methods:Patients, who received intravenous belimumab (10mg/kg) for at least 12 months between June 2013 and December 2020 were enrolled. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC-SDI), Physician Global Assessment (PGA), C3 and C4 levels, and prednisone daily dose were recorded at baseline and every six-months. Follow-up was stopped when patients switched to subcutaneous belimumab or when it was discontinued for more than 6 months (interrupted). Dose tapering was defined as the prolongation of the regular dose interval, after initial treatment based on the registered dosage.Results:Between June 2013 and December 2020, 48 patients received intravenous belimumab for at least 12 months (100% Caucasians, 94% females). All patients received standard belimumab dosage of 10mg/Kg every 4 weeks. Fourteen (29.1%) of 48 patients lengthened the dosing interval to 5 weeks; a subsequent lengthening of the interval occurred in 7 patients every 6 weeks and in 1 patient belimumab was gradually tapered to every 13 weeks.Twelve months (T12) after belimumab introduction, 3 patients (6.2%) were receiving a tapered dosage; at T24, 9 out of the 37 (24.3%), at T36 9 out of 21 (42.8%), and at T48 8 out of 18 (44.4%). Differences in disease activity, damage, concomitant medications, disease duration at belimumab introduction (baseline) were evaluated among patients that maintained the standard interval versus the group that received a tapered dose. Notably, no differences were found among the two groups (standard dose vs tapering) concerning median age at baseline (41, IQR 31-47.5 vs 38, IQR 32.2-51.5), disease duration (median 11, IQR 7.2-16 vs 9, IQR 5.5-14.5), median prednisone daily dosage (7.1mg, IQR 5-11.9 versus 11mg, IQR 7.6-17.5) and median SLEDAI-2K (8, IQR 6-9.75 vs 8, IQR 5-10). Differences in concomitant medications or clinical manifestations are reported in Figure 1A.Among the group that received the standard dose, 7 patients discontinued the treatment (20.6%), specifically 2 renal flares and one adverse event occurred. Whereas, in the reduced dose group, 2 discontinuations occurred (14.3%) due to a pregnancy and a renal flare. Noteworthy, the patient with the renal flare resumed subcutaneous belimumab 12 months after the flare. Finally, the disease activity was analysed in the 12 months after the first drug reduction (Figure 1B-E), with no sign of worsening of evaluated parameters (Figure 1B-1E), but with a significant reduction of steroids and SLEDAI-2K, 6 months after tapering.Conclusion:In our single retrospective cohort, we have demonstrated that belimumab tapering seems to be safe and not associated with a worsening disease activity over the following months. However, further studies are required to identify eligibility criteria and to determine the optimal dose-tapering strategy both for the intravenous and the subcutaneous formulations.Figure 1.Disclosure of Interests:None declared

Differences in Rituximab Use Between Pediatric Rheumatologists and Nephrologists for the Treatment of Refractory Lupus Nephritis and Renal Flare in Childhood-Onset Sle

Background: Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare.Methods: Members of Childhood Arthritis and Rheumatology Research Alliance and the American Society for Pediatric Nephrology were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: 1) refractory disease after induction treatment with corticosteroid and cyclophosphamide and 2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included cyclophosphamide, mycophenolate mofetil, rituximab, and others, alone or in combination.Results: Treatment choices between nephrologists and rheumatologists were highly variable. A majority (>50%) consensus of either nephrologists or rheumatologists on treatment choice was only achieved in two of six total follow up scenarios for refractory LN or flare. Rheumatologists in comparison to nephrologists chose more therapy options that contained rituximab in five of six scenarios. These differences were statistically significant (p < 0.05). Conclusions: Therapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN.

Clinico-pathological associations of serum VCAM-1 and ICAM-1 levels in patients with lupus nephritis

Objective We investigated the clinico-pathological associations of serum VCAM-1 and ICAM-1 levels in patients with biopsy-proven Class III/IV±V lupus nephritis (LN). Methods Serum VCAM-1 and ICAM-1 levels were determined by ELISAs. Sera from patients with non-renal SLE or non-lupus chronic kidney disease (CKD), and healthy subjects served as controls. Results Seropositivity rate for VCAM-1 and ICAM-1 was 93.10% and 37.93% respectively at the time of nephritic flare, and 44.83% and 13.79% respectively at remission, with both showing higher levels during flare ( P < 0.05, for both). VCAM-1 level correlated with proteinuria, serum creatinine, and anti-dsDNA antibodies, and inversely correlated with C3. VCAM-1 level also correlated with leukocyte infiltration and fibrinoid necrosis/karyorrhexis scores in active LN kidney biopsies. ICAM-1 level correlated with proteinuria, but not anti-dsDNA or C3, nor histopathological features. VCAM-1 level increased 4.5 months before renal flare, while ICAM-1 increase coincided with flare, and both decreased after treatment. ROC analysis showed that VCAM-1 distinguished active LN from healthy subjects, LN in remission, active non-renal lupus, and CKD (ROC AUC of 0.98, 0.86, 0.93 and 0.90 respectively). VCAM-1 level in combination with either proteinuria or C3 was superior in distinguishing active LN from remission compared to the measurement of individual markers. Serum ICAM-1 level distinguished active LN from healthy subjects and LN patients in remission (ROC AUC of 0.75 and 0.66 respectively), but did not distinguish between renal versus non-renal lupus. ICAM-1 level in combination with markers of endothelial cell activation (syndecan-1, hyaluronan and thrombomodulin) was superior to proteinuria, anti-dsDNA, or C3 in distinguishing active LN from quiescent disease. Conclusion Our findings suggest potential utility of serum VCAM-1 and ICAM-1 in clinical management. Monitoring VCAM-1 may facilitate early diagnosis of flare. Combining selected biomarkers may be advantageous in diagnosing active LN. VCAM-1 may have a pathogenic role in renal parenchymal inflammation in active LN.

Machine Learning for Prediction and Risk Stratification of Lupus Nephritis Renal Flare

Background: Renal flare of lupus nephritis (LN) is strongly associated with poor kidney outcomes, and predicting renal flare and stratifying its risk are important for clinical decision-making and individualized management to reduce LN flare. Methods: We randomly divided 1,694 patients with biopsy-proven LN, who had achieved remission after treatment, into a derivation cohort (n = 1,186) and an internal validation cohort (n = 508), at a ratio of 7:3. The risk of renal flare 5 years after remission was predicted using an eXtreme Gradient Boosting (XGBoost) method model, developed from 59 variables, including demographic, clinical, immunological, pathological, and therapeutic characteristics. A simplified risk score prediction model (SRSPM) was developed from important variables selected by XGBoost model using stepwise Cox regression for practical convenience. Results: The 5-year relapse rates were 39.5% and 38.2% in the derivation and internal validation cohorts, respectively. Both the XGBoost model and the SRSPM had good predictive performance, with a C-index of 0.819 (95% confidence interval [CI]: 0.774–0.857) and 0.746 (95% CI: 0.697–0.795), respectively, in the validation cohort. The SRSPM comprised 6 variables, including partial remission and endocapillary hypercellularity at baseline, age, serum Alb, anti-dsDNA, and serum complement C3 at the point of remission. Using Kaplan-Meier analysis, the SRSPM identified significant risk stratification for renal flares (p < 0.001). Conclusions: Renal flare of LN can be readily predicted using the XGBoost model and the SRSPM, and the SRSPM can also stratify flare risk. Both models are useful for clinical decision-making and individualized management in LN.

Early predictors of renal outcome in patients with proliferative lupus nephritis: a 36-month cohort study

Objectives To identify predictors of complete renal response (CRR) and renal flares in SLE patients with active proliferative LN. Methods This was a retrospective cohort study over 36 months including patients with biopsy-proven proliferative LN (class III/IV), from two European tertiary centres. CRR and renal flare were defined as proteinuria &lt;0.5 g/day with normal renal function and proteinuria &gt;1 g/day after CRR attainment, respectively. Demographic, clinical and analytic parameters were evaluated as early predictors of renal outcome, using survival analysis. Candidate variables were tested as predictors for CRR at time 0, 3 and 6 months after starting induction treatment. Potential predictors for renal flare were evaluated at time of reaching CRR. Variables with P &lt; 0.10 on univariate analysis with log-rank tests were further tested with multivariate Cox proportional hazards regression models. Results We included 104 patients [81.7% female, mean (s.d.) age at baseline 32.0 (13.3) years]. Over follow-up, 91.7% reached CRR, within a median time of 6.0 months. Proteinuria &lt;2 g/day at baseline [hazard ratio (HR) = 1.80, 95% CI 1.16, 2.79, P &lt; 0.01] and 3 months (HR = 2.32, 95% CI 1.24, 4.32, P &lt; 0.01) after starting induction therapy were independent predictors of CRR. Renal flares occurred in 18.4% of patients reaching CRR, after a mean time of 16.5 (8.6) months. Age up to 25 years at time of LN diagnosis (HR = 5.41, 95% CI 1.72, 16.97, P &lt; 0.01) and positive anti-RNP (HR = 3.52, 95% CI 1.21, 10.20, P = 0.02) were independent predictors of renal flares. Conclusion In patients with SLE and proliferative LN, factors assessed at baseline and 3 months from starting induction treatment can predict CRR and renal flares once CRR is achieved.

O19 A Complex Case of Systemic Lupus Erythematosus with Class IV Lupus Nephritis in a 15-year-old Egyptian Girl

Case report - Introduction We present a case of 15-year-old girl referred to rheumatology clinic by Infectious disease consultant in a private hospital. Her presentation included fever, inflammatory joint pains, butterfly rash and finger pulp infarcts. Her immunology showed highly positive anti DsDNA (&gt;1000), positive anti smith and anti Ro antibodies. This case eludes challenges of management as she went on to develop lupus nephritis. She was treated with IV Methylprednisolone pulse therapy followed by tapering course of steroids, Mycophenolate Mofetil and Hydroxychloroquine. The immunosuppressive treatment including cyclophosphamide and Rituximab could not be given due to lack of approval by her insurance provider. Case report - Case description This 15-yearold Egyptian young girl presented initially in September 2019 to Emergency department with fever and facial rash. This episode was treated as allergic urticaria. Subsequently, she was referred to see the Infectious disease consultant who requested multiple investigations including blood culture, anti DsDNA and ENA antibodies. She presented to Rheumatology clinic with malar rash, mouth ulcers, finger pulp infarcts and joint pains. Her Immunology showed ANA 1:640, Anti DsDNA 1031, Anti Ro 27, Anti Sm 30, Anti nRNP/Sm 28 and elevated Urinary Albumin/Creatinine ratio (27 mg/mmol). A diagnosis of Systemic Lupus Erythematosus with Lupus Nephritis was made. She was initiated on tapering course of steroids (30 mg starting dose) and Plaquanil 400 mg. The follow up visit confirmed improvement (including facial rash) and urine ACR of 17 mg/mmol. The steroids were tapered by 5 mg every 2 weeks and Azathioprine was considered. Unfortunately, she developed renal flare in December 2019 which coincided with reduction in steroid. Urine ACR value 383 mg/mmol, ESR 110 and Anti DsDNA was &gt;1000. The request to offer induction therapy with Rituximab (as she was not keen for Cyclophosphamide) did not receive approval by her insurance company. Her case was reviewed by nephrologist, biopsy was not done at this stage. Her condition was managed with Mycophenolate and Pulse steroid therapy. In February 2020, she had further renal flare (Urine ACR 694 mg/mmol) and that required increase in the dose of steroids. Unfortunately, there was still disapproval by insurance company despite multiple requests. Over the course of next 3 months, there was poor compliance with clinic attendance coinciding with COVID-19pandemic. Her medication included oral Prednisolone 15 mg OD, Mycophenolate 3 gm and Hydroxychloroquine 400 mg. More recently, she has had significant renal flare treated under Nephrologist with Pulse therapy of IV Methylprednisolone with lack of approval to give Rituximab by her insurance provider. Case report - Discussion This is a challenging case of Lupus nephritis in a young adolescent girl seen in a private hospital in Riyadh, Kingdom of Saudi Arabia. She was concerned about her appearance in her first presentation due to disfiguring facial rash. This rash completely resolved, and patient was very satisfied to the extent of some lack of engagement in follow up subsequently. This clinic is based in a busy and popular private hospital in Riyadh where non-Arabic speaking clinician rely on translator to communicate with patient and this can make the consultation further challenging. The clinician must make sure, in brief consultation time, to get the exact message across. My experience did teach me that there were certain times when medications were not taken as intended due to lack of full understanding by the patient. In a private hospital setting, patient can choose their own compliance with clinic attendance as per their convenience and understanding of the condition. This aspect also contributed towards management challenges and control of her disease. The most limiting and frustrating factor to manage this case has also been the lack of engagement and approval by the insurance provider. I made multiple medical requests for their attention and unfortunately all were rejected. The local healthcare system in Kingdom of Saudi Arabia allows expat patients to be seen primarily in private hospitals under the cover of their employer insurance. This also led to lack of sharing expertise and treatment facilities with the regional specialist rheumatology centre, which is mainly designed to cater for local nationals. I am seriously considering making a “special request” for this case to be accepted in the Ministry hospital so Cyclophosphamide and/or Rituximab can be considered. Case report - Key learning points Should we have considered Mycophenolate at very initial presentation and could that have led to different and better clinical outcome?Would renal biopsy change management significantly and how best we can persuade patient and Nephrologist?How else we can engage this young adolescent girl as she was more concerned about her cosmetic appearance and since skin has responded very well, she may not feel too convinced on the need for ongoing treatment and also attending clinic appointment?Perhaps we could have referred her case as a “special request” to local specialist Rheumatology center so she could have been considered for treatment options like Rituximab and cyclophosphamide. The local healthcare in Saudi Arabia permits local nationals to be seen in local and private hospitals whilst expats are catered only in private hospital unless there is exception due to availability of treatment or expertise, where process of acceptance can also be complex and time demanding.

The Prevalence and Causes of Non-adherence to Immunosuppressive Medications in Patients with Lupus Nephritis Flares

Background: Lupus nephritis is one of the major manifestations of SLE. Poor adherence to medications is an important cause of not achieving treatment targets. Methods : We assessed patients’ adherence to immune-suppressive medications in patients with Lupus nephritis using the Morisky, Green, and Levine (MGL) Adherence Scale. The aim was to study the effect of non-adherence on the occurrence of renal flares. Results: We recruited 104 patients with lupus nephritis. Sixty-six patients had flares of LN. There was a high prevalence of non-adherence to medications (n=68). Patients who were non-adherent to treatment had more renal flares (p= 0.02). Duration of lupus since diagnosis was significantly higher in patients who had renal flares. Using regression analysis, non-adherence to medications was associated with 3.7 higher risk of developing a single renal flare and 4.9 higher risk of developing more than one renal flare. Causes of non-adherence were medications side effects in 43% of patients, financial issues in 31% or forgetfulness in 26%. Conclusion: Non-adherence to immunosuppressive medications has a high prevalence in patients with lupus nephritis and is correlated with the number of renal flares.

Elevated Urinary Neutrophil Gelatinase-Associated Lipocalin Is a Biomarker for Lupus Nephritis: A Systematic Review and Meta-Analysis

Objective. Lupus nephritis (LN) is a major and severe complication of systemic lupus erythematosus (SLE). Neutrophil gelatinase-associated lipocalin (NGAL), as a promising next-generation biomarker in clinical nephrology, has received extensive attention. However, its diagnostic performance in LN has high variability. Therefore, we performed an updated meta-analysis to further evaluate the diagnostic accuracy of urinary NGAL (uNGAL). Materials and Methods. PubMed, Embase, and Cochrane Library were searched from inception to October 27, 2019. Meta-analysis was performed with a bivariate random effects model. Additionally, the summary receiver operating characteristic (SROC) curves were established. The sources of heterogeneity were explored by meta-regression, subgroup analysis, and sensitivity analysis. Publication bias was assessed using the Deeks test. Results. 19 articles consisting of 21 eligible studies were included. In diagnosing LN, the estimates (95% confidence interval (CI)) were as follows: sensitivity, 0.84 (0.71-0.91); specificity, 0.91 (0.70-0.98); and the SROC-AUC value, 0.92 (0.90-0.94). In identifying active LN, the estimates were as follows: sensitivity, 0.72 (0.56-0.84); specificity, 0.71 (0.51-0.84); and the AUC value, 0.77 (0.74-0.81). With respect to predicting renal flare, the estimates were as follows: sensitivity, 0.80 (0.57-0.92); specificity, 0.67 (0.58-0.75); and the AUC value, 0.74 (0.70-0.78). For the studies to distinguish proliferative LN, the estimates were as follows: sensitivity, 0.87 (0.66-0.97), and specificity, 0.69 (0.39-0.91). Deeks’ funnel plot suggested that there was no significant publication bias. Conclusions. Our meta-analysis indicates that uNGAL was a useful biomarker for diagnosis, estimation of activity, and prediction of renal flare of LN. In addition, the usefulness of uNGAL to distinguish pathological types of LN needs to be further investigated.