Hydroxychloroquine in the Pregnancies of Women with Lupus: A Meta-Analysis of Individual Participant Data

Objective: Multiple guidelines recommend continuing hydroxychloroquine (HCQ) for systemic lupus erythematosus (lupus) during pregnancy based on observational data. The goal of this individual patient data meta-analysis was to combine multiple datasets to compare pregnancy outcomes in women with lupus on and off HCQ. Methods: Eligible studies included prospectively-collected pregnancies in women with lupus. After a manuscript search, 7 datasets were obtained. Pregnancy outcomes and lupus activity were compared for pregnancies with a visit in the first trimester in women who did or did not take HCQ throughout pregnancy. Birth defects were not systematically collected. This analysis was conducted in each dataset and results were aggregated to provide a pooled odds ratio. Results: Seven cohorts provided 938 pregnancies in 804 women. After selecting one pregnancy per patient with a 1st trimester visit, 668 pregnancies were included; 63% took HCQ throughout pregnancy. Compared to pregnancies without HCQ, those with HCQ had lower rates of highly active lupus, but did not have different rates of fetal loss, preterm birth, or preeclampsia. Among women with low lupus activity, HCQ reduced the risk for preterm delivery. Conclusion: This large study of prospectively-collected lupus pregnancies demonstrates a decrease in SLE activity among woman who continue HCQ through pregnancy and no harm to pregnancy outcomes. Like all studies of HCQ in lupus pregnancy, this study is confounded by indication and non-adherence. As this study confirms the safety of HCQ and diminished SLE activity with use, it is consistent with current recommendations to continue HCQ throughout pregnancy.

Fetal and maternal outcome in patients with active lupus nephritis: comparison between new-onset and pre-existing lupus nephritis

Background This study aimed to investigate fetal and maternal outcomes in women with active lupus nephritis (LN). Specifically, we compared women who had new-onset LN and those with pre-existing LN during pregnancy. Methods Patients with active LN during pregnancy were divided into the new-onset group (LN first occurred during pregnancy) and the pre-existing group (a history of LN) on the basis of the onset time of LN. Data on clinical features, laboratory findings, and pregnancy outcome were collected and analyzed between the two groups. Multivariate logistic regression analysis was used to compare the effects of active LN on adverse pregnancy outcomes. Results We studied 73 pregnancies in 69 women between 2010 and 2019. Of these, 38 pregnancies were in the pre-existing LN group and 35 were in the new-onset group. Patients with pre-existing LN had a higher risk of composite adverse fetal outcomes than those with new-onset LN [adjusted odds ratio (ORs), 44.59; 95% confidence interval (CI), 1.21–1664.82; P = 0.039]. However, the two groups had similar adverse maternal outcomes (ORs, 1.24; 95% CI, 0.36–4.29). Serum albumin and proteinuria significantly improved after pregnancy (P < 0.001). Kaplan–Meier analysis showed that the long-term renal outcome was similar between the two groups. Conclusions Pregnant patients with pre-existing LN were associated with a higher risk of composite adverse fetal outcomes than those with new-onset LN. However, these two groups of patients had similar adverse maternal outcomes. The long-term renal outcomes were not different after pregnancy between these two groups.

Use of Belimumab for Prophylaxis of Chronic Graft-Versus-Host Disease

The most transformative approach for controlling chronic Graft-versus-Host Disease (cGvHD) after allogeniec hematopoietic cell transplantation (alloHCT) would be the prevention of its most severe and irreversible clinical manifestations instead of treating already established disease. Belimumab is a monoclonal antibody, approved for treatment of systemic lupus erythematosus and active lupus nephritis, which inhibits binding of B-cell-activating factor (BAFF) to its receptors on B cells, thus inhibiting the survival of autoreactive B cells. Given the role of B cells in cGvHD pathophysiology and the now substantiated role of BAFF in promoting B Cell Receptor signaling in cGvHD (Jia W et al Blood 2021), belimumab might have a role in prevention of cGvHD. We hypothesized that targeting BAFF early after alloHCT would be well-tolerated and have a favorable effect on the incidence and severity of cGvHD. We are presenting data on the first 8/10 patients (Pts) enrolled in the single-center, investigator-initiated phase-1 trial. Belimumab was administered i.v. at 10 mg/kg every 2 weeks for 3 doses followed by 4 doses at monthly intervals, for a total of 7 doses, starting 50-80 days after alloHCT. All Pts were adults who received mobilized peripheral blood grafts from fully matched related or unrelated donors after myeloablative or non-myeloablative conditioning. GvHD prophylaxis was with tacrolimus and methotrexate; one Pt received post-transplant cyclophosphamide. All Pts were in complete remission on day +30 after alloHCT. Pts who received ≥1 dose of belimumab were evaluable for safety and ≥2 doses for efficacy assessment. cGvHD was diagnosed according to the NIH criteria. All analyses are descriptive. Specimens for correlative studies are cryopreserved until the study end. We found that Pts tolerated belimumab well, with no reported grade ≥3 treatment-related adverse events. There were no significant infections or myelosuppression. Seven out of eight Pts on the study received all 7 doses of belimumab, as planned. Of those 7 Pts, 5 Pts are without any evidence of cGvHD and completely off immunosuppression at the median of 18 months (mo) after completing belimumab (median of 24 mo after alloHCT). Seven mo after completing belimumab on study, 1 Pt developed cGvHD involving skin, eyes and liver, and died from complications of pneumonia and liver failure due to longstanding hemochromatosis, iron overload and possible liver GvHD. Another Pt relapsed with leukemia 1 mo after completing belimumab. He is now in remission after treatment with enasidenib and 2 donor lymphocyte infusions (DLI), 12 mo after completing belimumab (18 mo after alloHCT); he developed mild eye GvHD following DLI. One out of eight Pts on the study stopped treatment early, after receiving only 3 doses, due to thrombocytopenia (unrelated to belimumab) and insurance issues. He was found to have relapsed lymphoma 3 mo later, was treated with venetoclax and DLI, and remains in remission with no evidence of cGvHD 15 mo after stopping belimumab. Two additional patients are being enrolled. Immune reconstitution studies are showing that B-cell counts remain low 1 year out of transplant in all Pts (Figure 1). This preliminary data describes for the first time the use of belimumab for prophylaxis of cGvHD. Overall, belimumab was very well tolerated. Only 1 Pt on the study developed cGvHD. It is worth noting that his cGvHD developed 7 mo after completing belimumab suggesting that a longer duration of therapy should be tested in future studies. The 2 Pts with relapsed disease both had high risk malignancies. Risk stratification of high risk patients will be critical in future prospective studies. While more Pts are needed to further assess the impact of prophylactic belimumab on the incidence of cGVHD, these preliminary results are encouraging. Absence of severe infections is reassuring. B-cell reconstitution was delayed, as expected. Ongoing correlative studies will further evaluate BAFF levels and B-cell subset reconstitution after alloHCT. Figure 1 Figure 1. Disclosures Pusic: Syndax: Other: Advisory Board. Sarantopoulos: Rigel: Other: Advisory Board. Uy: Macrogenics: Research Funding; Jazz: Consultancy; Genentech: Consultancy; Astellas: Honoraria, Speakers Bureau; Novartis: Consultancy; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Agios: Consultancy. OffLabel Disclosure: Drug: Belimumab This study: Belimumab for prophylaxis of chronic GvHD. Approved indication: Belimumab is approved for treatment of systemic lupus erythematosus and active lupus nephritis.

Comparison of iguratimod and conventional cyclophosphamide with sequential azathioprine as treatment of active lupus nephritis: study protocol for a multi-center, randomized, controlled clinical trial (iGeLU study)

Background Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up. Methods/design This study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test. Discussion Most patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20–35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients. Trial registration ClinicalTrials.govNCT 02936375. Registered on October 18, 2016.

De novo lupus-like glomerulonephritis after pediatric non-kidney organ transplantation

Background We propose a novel clinically significant finding, de novo lupus-like glomerulonephritis (DNLLGN), in patients with autoantibodies and kidney abnormalities in pediatric liver transplant (LT) and intestinal inclusive transplants (ITx). Methods We describe the clinical, serologic, and histopathologic presentation and kidney outcomes in eight patients from our center found to have DNLLGN on kidney biopsy. Results Pediatric recipients of non-kidney solid organ transplants developed an unusual de novo immune complex glomerulonephritis with morphologic similarity to lupus nephritis. Six had isolated LT (0.9% of all pediatric LT at our center) and two had ITx (2.1% of all ITx). Five (63%) presented with nephrotic syndrome. Five patients had autoantibodies. Patients underwent kidney biopsy at a mean of 11.5 years in LT and 2.8 years in ITx after the index transplant. Biopsies demonstrated changes similar to focal or diffuse active lupus. Follow-up eGFR at a mean of 6 years after biopsy showed a mean decrease of 30 ml/min/1.73 m2 in all patients (p = 0.11). Conclusions DNLLGN has not been previously recognized in this clinical setting, yet 8 kidney biopsies from pediatric recipients of LT and ITx at our center in 25 years demonstrated this finding. DNLLGN appears to be an under-reported phenomenon of clinical significance. Graphical abstract

Sex-dependent Lupus Ruminococcus blautia gnavus strain induction of zonulin-mediated intestinal permeability and autoimmunity

Imbalances in the gut microbiome are suspected as contributors to the pathogenesis of Systemic Lupus Erythematosus, and our studies and others have documented that patients with active Lupus nephritis have expansions of the obligate anaerobe, Ruminococcus blautia gnavus (RG). To investigate whether the RG strains in Lupus patients have in vivo pathogenic properties, we colonized C57BL/6 mice with individual RG strains from healthy adults or those from Lupus patients. These strains had a similar capacity for murine intestinal colonization, in antibiotic-preconditioned specific-pathogen-free, as well as germ-free adults, and their neonatally colonized litters. Lupus-derived RG strains induced high levels of intestinal permeability that was significantly greater in female than male mice, whereas the RG species-type strain (ATCC29149/VPI C7-1) from a healthy donor had little or no effects. Lupus RG strain-induced functional alterations were associated dysregulated occluden transcript production in the ileal wall as well as raised serum levels of zonulin, a regulator of tight junction formation between cells that form the gut barrier. Notably, the level of Lupus RG-induced intestinal permeability was significantly correlated with serum IgG anti RG cell-wall lipoglycan antibodies, and to anti-native DNA autoantibodies that are a biomarker for SLE. Strikingly, gut permeability was completely reversed by oral treatment with larazotide acetate, an octapeptide that is a specific molecular antagonist of zonulin. Taken together, these studies document a molecular pathway by which RG strains from Lupus patients induce a leaky gut and autoimmunity that have been implicated in the pathogenesis of flares of clinical Lupus disease.

The role of Dickkopf-1 as a biomarker in systemic lupus erythematosus and active lupus nephritis

Background Systemic lupus erythematosus (SLE) is a chronic disease which is mainly attributed to autoantibodies, cytokines, and immune complex deposition. Studies have demonstrated that cytokines and autoantibodies were strongly associated with renal diseases and can be used for the prediction of patients with lupus nephritis (LN). However, antibodies to dsDNA and the reduction of complements were also detected in non-LN patients as well as clinically non-active SLE patients. The current study was performed to detect the role of serum DKK-1 as a biomarker for the identification of SLE patients and patients with LN and its relation to disease activity and severity. The study was conducted on fifty clinically diagnosed SLE patients who were diagnosed according to Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, in addition to thirty healthy control volunteers matched for age and sex. Assessment of SLE disease activity was done using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Assessment of SLE disease severity was done using the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) damage index. Serum levels of DKK-1 were measured for all participants by ELISA using commercially available kits. Results DKK-1 serum levels were significantly higher among active lupus nephritis cases as compared with SLE cases with no LN and with healthy controls (9197.60 μg/uL ± 2939.2 μg/uL vs. 6405.15 μg/uL ± 2018.91 μg/uL vs. 2790.33 μg/uL ± 833.49 μg/uL) respectively (p-values < 0.001). DKK-1 concentration was significantly higher among SLE patients with positive as compared with negative anti-double-stranded DNA (dsDNA) antibodies (p-value < 0.001). According to receiver operating characteristic (ROC) curve analysis, serum DKK-1 level diagnosed the SLE at a statistically significant level with a 98% sensitivity and 70% specificity and serum DKK-1 level also diagnosed active lupus nephritis at a 90% sensitivity and 63% specificity. Conclusion DKK-1 could diagnose SLE and lupus nephritis with high sensitivity and specificity. Serum DKK-1 is a reliable biomarker for the identification of SLE and patients with LN and could be used as a key molecule for the diagnosis of SLE and as a prognostic indicator of LN.

Elevated urinary IL-36γ in patients with active lupus nephritis and response to treatment

Introduction IL-36 is a new member of the IL-1 family with pro-inflammatory properties. Serum levels of IL-36 are elevated in patients with Systemic Lupus Erythematosus (SLE). However, no data is available on urinary levels of IL-36 in Lupus Nephritis (LN). In psoriasis expression of IL-36 is site specific and expressed in skin. Hence, we studied urinary levels of IL-36 cytokines in SLE patients. Methods A total of 196 patients with SLE [97 active LN patients (ALN), 42 inactive LN (ILN) and 57 active lupus patients with no renal involvement (ANR)] and 25 healthy subjects were recruited for the study after obtaining informed consent. Urinary and plasma IL-36α, IL-36γ and IL-36Ra levels were measured by ELISA. Results Out of 196 patients 178 were females. Urinary IL-36γ levels in SLE patients [0(14.3) pg/ml] were significantly higher than healthy controls [0(0) pg/ml, (P < 0.01)]. Patients with ALN [0(40.6) pg/ml] had significantly higher IL-36γ when compared to ANR [0(0) pg/ml] as well as ILN [0(0) pg/ml]. Urinary IL-36γ levels in ALN patients had a fair correlation with renal SLEDAI (r = 0.26, P = 0.004).The levels reduced significantly post 3 months in patients with ALN. No inverse relationship was noted between IL-36Ra and IL-36α/IL36γ levels. Conclusion Urinary IL-36γ is produced locally in kidney, correlates with renal disease activity and reduces upon treatment, suggesting that it may have a role in pathogenesis of LN.