Modifying T cell phenotypes using TYK2 inhibitor and its implications for the treatment of systemic lupus erythematosus.

OBJECTIVES: The tuning effects of JAK/TYK2 inhibitors on the imbalance between T follicular helper (Tfh) and T regulatory (Treg) cells, related to systemic lupus erythematosus (SLE) pathogenesis, were investigated using human peripheral blood samples. METHODS: Peripheral blood mononuclear cells from untreated patients with SLE and healthy controls were analysed. Tfh1 cells were identified in nephritis tissue, and the effect of Tfh1 cells on B-cell differentiation was examined by coculturing naïve B cells with Tfh1 cells. RESULTS: Tfh1 cell numbers were increased in the peripheral blood of patients, and activated Treg cell counts were decreased relative to Tfh1 cell counts. This imbalance in the Tfh to Treg ratio was remarkably pronounced in cases of lupus nephritis, especially in types III and IV active nephritis. Immunohistochemistry revealed Tfh1 cell infiltration in lupus nephritis tissues. Co-culture of Tfh1 cells (isolated from healthy individuals) with naïve B cells elicited greater induction of T-bet+ B cells than controls. In JAK/TYK2-dependent STAT phosphorylation assays using memory CD4+ T cells, IL-12-induced STAT1/4 phosphorylation and Tfh1 cell differentiation were inhibited by both JAK and TYK2 inhibitors. However, phosphorylation of STAT5 by IL-2 and induction of Treg cell differentiation by IL-2+TGFß were inhibited by JAK inhibitors but not by TYK2 inhibitors, suggesting that TYK2 does not mediate the IL-2 signalling pathway. CONCLUSIONS: Tfh1 cells can induce T-bet+ B cell production and may contribute to SLE pathogenesis-associated processes. TYK2 inhibitor may fine-tune the immune imbalance by suppressing Tfh1 differentiation and maintaining Treg cell differentiation, thereby preserving IL-2 signalling, unlike other JAK inhibitors.

Serum antineutrophil cytoplasmic antibody positivity at the time of renal biopsy is associated with disease activity of lupus nephritis.

OBJECTIVE: To investigate the correlations between serum antineutrophil cytoplasmic antibody (ANCA) and clinicopathological features, induction treatment response, and prognosis of lupus nephritis (LN) patients. METHODS: In this retrospective study, biopsy-proven LN patients from October 2010 to September 2020 were tested for serum ANCA by indirect immunofluorescence and ELISA and were divided into ANCA-positive group and ANCA-negative group. The clinicopathological data of the two groups were analyzed and compared. RESULTS: Thirty-five of 115 patients (30.43%) were seropositive for ANCA. ANCA-positive patients had significantly higher systemic lupus erythematosus activity index and activity index scores, higher 24-h urinary protein, and lower complement three levels (p = 0.001, 0.028, 0.023, 0.009, respectively). The incidences of oral ulcers, thrombocytopenia, and leukocyturia, and the positive rates of anti-dsDNA antibody and anti-histone antibody were significantly higher in ANCA-positive group (p = 0.006, 0.019, 0.012, 0.001, 0.019, respectively). Class IV LN and fibrinoid necrosis/karyorrhexis were significantly more common in the ANCA-positive group (p = 0.027, 0.002). There was no significant difference in the total remission rate of ANCA-positive patients receiving cyclophosphamide and mycophenolate mofetil as induction therapies (83.33% vs. 66.67%, p > 0.05), while patients receiving cyclophosphamide as induction therapy had a higher total remission rate than those receiving other immunosuppressants (83.33% vs. 20%, p = 0.028). CONCLUSIONS: LN patients with ANCA seropositivity at renal biopsy have a significantly higher disease activity, and their pathological manifestations are predominantly proliferative LN. These patients require a more active immunosuppressive therapy with cyclophosphamide or mycophenolate mofetil to improve their remission rate.

Sodium-Glucose Cotransporter-2 Inhibitors and Nephritis Among Patients With Systemic Lupus Erythematosus.

Importance: Lupus nephritis is a major complication of systemic lupus erythematosus (SLE). Randomized clinical trials have shown nephroprotective and cardioprotective effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is). Objective: To investigate whether the use of SGLT2is is associated with the onset and progression of lupus nephritis and other kidney and cardiac outcomes in patients with SLE and type 2 diabetes. Design, Setting, and Participants: This multicenter cohort study used the US Collaborative Network of the TriNetX clinical data platform to identify patients with SLE and type 2 diabetes from January 1, 2015, to December 31, 2022. Data collection and analysis were conducted in September 2023. Exposures: Individuals were categorized into 2 groups by SGLT2i use or nonuse with 1:1 propensity score matching. Main Outcomes and Measures: The Kaplan-Meier method and Cox proportional hazards regression models were used to calculate the 5-year adjusted hazard ratios (AHRs) of lupus nephritis, dialysis, kidney transplant, heart failure, and mortality for the 2 groups. Results: From 31 790 eligible participants, 1775 matched pairs of SGLT2i users and nonusers (N = 3550) were selected based on propensity scores. The mean (SD) age of matched participants was 56.8 (11.6) years, and 3012 (84.8%) were women. SGLT2i users had a significantly lower risk of lupus nephritis (AHR, 0.55; 95% CI, 0.40-0.77), dialysis (AHR, 0.29; 95% CI, 0.17-0.48), kidney transplant (AHR, 0.14; 95% CI, 0.03-0.62), heart failure (AHR, 0.65; 95% CI, 0.53-0.78), and all-cause mortality (AHR, 0.35; 95% CI, 0.26-0.47) than SGLT2i nonusers. Conclusions and Relevance: In this cohort study of patients with SLE and type 2 diabetes, SGLT2i users had a significantly lower risk of lupus nephritis, dialysis, kidney transplant, heart failure, and all-cause mortality than nonusers. The findings suggest that SGLT2is may provide some nephroprotective and cardioprotective benefits.

Combination of anti-SSA/Ro60 and anti-dsDNA serotype is predictive of belimumab renal response in patients with lupus nephritis.

OBJECTIVES: To investigate the effectiveness of belimumab on active lupus nephritis (LN) and explore the predictors, including serological biomarkers, of renal response to belimumab in a real-world setting. METHODS: This multicentre, real-world observational study enrolled patients with active LN receiving intravenous belimumab as an add-on therapy with 24-hour urine protein≥1 g and estimated glomerular filtration rate≥30 mL/min/1.73 m2 at baseline. Complete renal response (CRR), partial renal response (PRR), no renal response (NRR) and primary efficacy renal response (PERR) were evaluated. Multivariable logistic regression was used to identify risk factors for NRR to belimumab at 6 months. RESULTS: Among the 122 patients enrolled, the proportions of patients achieving CRR, PRR, NRR and PERR were 35.9%, 17.1%, 47.0% and 44.4% at 6 months (n=117) and 55.6%, 19.4%, 26.4% and 58.3% at 12 months (n=72), respectively. Proteinuria, daily prednisone dosage and Systemic Lupus Erythematosus Disease Activity Index 2000 scores significantly decreased at 6 and 12 months (p<0.0001). NRR at 6 months (NRR6) was the strongest negative predictor of CRR at 12 months. Baseline anti-dsDNA positivity inversely predicted NRR6 (OR=0.32,95% CI=0.10 to 0.98, p=0.049), while anti-SSA/Ro60 positively predicted NRR6 (OR=3.16, 95% CI=1.14 to 8.74, p=0.027). The combination of anti-SSA/Ro60 and anti-dsDNA serotype quantitatively predicted belimumab renal response. CONCLUSION: The effectiveness of belimumab was reproducible in Chinese patients with active LN. The simple yet interesting serotype predictive model needs further validation and its possible underlying mechanistic relevance deserves further exploration.

Mycophenolate mofetil vs. cyclophosphamide-based induction regimens for lupus nephritis: Outcomes at a tertiary care centre in Lahore, Pakistan.

Objectives: To compare the efficacy of mycophenolate mofetil with intravenous cyclophosphamideas induction therapy in lupus nephritis. METHODS: The observational, prospecrive, cohort study was conducted at the Rheumatology Department of Fatima Memorial Hospital, Lahore, Pakistan, from July 2016 to June 2019, and comprised lupus nephritis patients. For induction therapy, the patients were assigned at the discretion of the treating rheumatologist to mycophenolate mofetil group MMF, and intravenous cyclophosphamide group CYC. The latter group was further divided into NIH subgroup that received the therapy as per the protocol of the National Institutes of Health, and ELNT subgroup which recived the therapy as per the Euro Lupus Nephritis Trial protocol. Maintenance therapy in all groups was mycophenolate mofetil. Tacrolimus was added in case of non-response. The outcome was the achievement of complete renal response at 6, 12 and 24 months. Data was analysed using SPSS 26. RESULTS: Of the 131 patients, 126(96.2%) were females. The overall mean age was 27±7.7 years. There were 58(44.2%) patients in group MMF and 73(55.7%) in group CYC, which had subgroup NIH 46(63%) and subgrpup ELNT 27(37%). The complete renal response rates at 6, 12, and 24 months were 22 (43.1%), 35 (71.4%), and 40(83.3%) for group MMF; 5(12.5%), 9(22%) and 24 (58.5%) for subgroup NIH, and 6(26.1%), 8(36.4%) and 14(63.6%) for subgroup ELNT. Group MMF outcomes were significantly better than the rest (p<0.05). CONCLUSIONS: Mycophenolate mofetil induction therapy was more effective than intraveenous cyclophosphamide in terms of achieving remission at 6, 12 and 24 months.

Navigating the diagnostic maze: A case presentation of C1q vasculitis mimicking hypocomplementemic urticarial vasculitis in a patient with systemic lupus erythematosus.

In rare instances, patients with SLE may exhibit atypical clinical manifestations, such as Hypocomplementemic Urticarial Vasculitis, which can pose diagnostic challenges. Here, we present a case report of a 28-year-old female with a history of SLE with lupus nephritis clase IV who developed HUV-like symptoms, ultimately leading to a diagnosis of C1q Vasculitis. This case underscores the importance of considering C1q Vasculitis in SLE patients presenting with HUV-like features and highlights Rituximab as a promising therapeutic option for managing this rare condition.

Advances in the pharmacological management of systemic lupus erythematosus.

INTRODUCTION: Despite setbacks in clinical trials for systemic lupus erythematosus (SLE), three drugs have been approved for SLE and lupus nephritis (LN) treatment in the past decade. Several ongoing clinical trials, some viewed optimistically by the scientific community, underscore the evolving landscape. Emerging clinical data have established specific therapeutic targets in routine clinical practice for treating SLE, aiming to improve long-term outcomes. AREAS COVERED: Research related to treatment of SLE and LN is discussed, focusing on randomized clinical trials during the last 5 years and recommendations for the management of SLE published by the European Alliance of Associations for Rheumatology (EULAR), American College of Rheumatology (ACR), Asia Pacific League of Associations for Rheumatology (APLAR), and Pan-American League of Associations of Rheumatology (PANLAR). EXPERT OPINION: The landscape of SLE and LN treatments is evolving, as new drugs and combination treatment approaches redefine the traditional concepts of induction and maintenance treatment phases. As the therapeutic armamentarium in SLE continues to expand, the research focus is shifting from the imperative for new therapies to advancing our understanding of optimal treatment selection for individual patients, steering toward precision medicine strategies.

Ursolic acid alleviates lupus nephritis by suppressing SUMO1-mediated stabilization of NLRP3.

BACKGROUND: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that affects multiple organs and cause a wide range of severe clinical manifestations, including lupus nephritis (LN), which is a major risk factor for morbidity and mortality in individual with SLE. Ursolic acid (UA) is a natural compound with favorable anti-inflammatory properties and has been employed to treat multiple disease, including inflammatory diseases, diabetes, and Parkinson's disease. However, its therapeutic potential on LN and the underlying mechanisms remains unclear. PURPOSE: This aim of this study was to investigate the impact of UA on LN and its underlying mechanism. METHODS: MRL/lpr lupus-prone mouse model was used and UA was administered orally for 8 weeks. Dexamethasone was used as a positive control. After 8 weeks of administration, the spleen-to-body-weight ratio, renal function, urine albumin excretion, cytokines levels, and the deposition of immune complex were measured. The primary mouse glomerular mesangial cells (GMCs) and SV40-MES-13 were stimulated by lipopolysaccharide (LPS), either alone or in combination with nigericin, to establish an in vitro model. The activation of NLRP3 inflammasome were investigated both in vivo and in vitro using qRT-PCR, immunoblotting, and immunofluorescence. RESULTS: Our results revealed that UA prominently alleviated LN in MRL/lpr lupus-prone mice, leading to a significant reduction in proteinuria production, infiltration of immune cells infiltration, and histopathological damage in the renal tissue. In addition, UA exerted inhibitory effects on the secretion of IL-1ß, IL-18, and caspase-1, pyroptosis, and ASC speck formation in primary mouse GMCs and SV40-MES-13 cells. Furthermore, UA facilitated the degradation of NLRP3 by suppressing SUMO1-mediated SUMOylation of NLRP3. CONCLUSION: UA possess a therapeutical effect on LN in MRL/lpr mice by enhancing the degradation of NLRP3 through inhibition of SUMO1-mediated SUMOylation of NLRP3. Our findings provide a basis for proposing UA as a potential candidate for the treatment of LN.

STAT3 inhibition ameliorates renal interstitial inflammation in MRL/lpr mice with diffuse proliferative lupus nephritis.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is one of the most common and severe clinical syndromes of diffuse proliferative lupus nephritis (DPLN), of which poor prognosis is indicated by aggravated renal function deterioration. However, the specific therapy and mechanisms of AKI in DPLN remain to be explored. METHODS: The correlation between AKI and clinical pathological changes in DPLN patients was analyzed. Expression of STAT3 signaling was detected in MRL/lpr mice with DPLN using immunohistochemical staining and immunoblotting. Inhibition of STAT3 activation by combination therapy was assessed in MRL/lpr mice. RESULTS: Correlation analysis revealed only the interstitial leukocytes were significantly related to AKI in endocapillary DPLN patients. MRL/lpr mice treated with vehicle, which can recapitulate renal damages of DPLN patients, showed upregulation of STAT3, pSTAT3 and caspase-1 in renal cortex. FLLL32 combined with methylprednisolone therapy significantly inhibited the STAT3 activation, improved acute kidney damage, reduced the interstitial infiltration of inflammatory cells and decreased the AKI incidence in MRL/lpr mice. CONCLUSION: STAT3 activation may play an important role in the pathogenesis of DPLN and the development of AKI. Hence, STAT3 inhibition based on the combination of FLLL32 with methylprednisolone may represent a new strategy for treatment of DPLN with AKI.

The STING inhibitor (ISD-017) reduces glomerulonephritis in 129.B6.Fcgr2b-deficient mice.

The absence of stimulator of interferon genes (STING) in 129.B6.Fcgr2b-deficient mice rescue lupus phenotypes. The administration of a STING inhibitor (ISD017) into the young 129.B6.Fcgr2b-deficient mice prevents lupus nephritis development. This study mainly aimed to evaluate the effects of STING inhibition (ISD107) on established SLE in mice to prove that ISD017 could be a good therapeutic drug to reverse the already set-up autoimmunity and kidney impairment. Twenty-four-week-old Fcgr2b-deficient mice were treated with cyclophosphamide (25 mg/kg, intraperitoneal, once per week), ISD017 (10 mg/kg, intraperitoneal, three times per week), or control vehicle for 8 weeks, and were analyzed for phenotypes. Both ISD017 and cyclophosphamide treatment increased long-term survival and reduced the severity of glomerulonephritis in Fcgr2b-deficient mice. While cyclophosphamide reduced activated B cells (B220+GL-7+), ISD017 decreased activated T cells (CD4+CD69+) and neutrophils (Ly6c+Ly6g+) in Fcgr2b-deficient mice. In addition, ISD017 reduced IL-1ß and interferon-inducible genes. In summary, ISD017 treatment in symptomatic 129.B6.Fcgr2b-deficient mice reduced the severity of glomerulonephritis and increased long-term survival. ISD017 worked comparably to cyclophosphamide for treating lupus nephritis in 129.B6.Fcgr2b-deficient mice. ISD017 reduced activated T cells and neutrophils, while cyclophosphamide targeted activated B cells. These results suggested that STING inhibitors can potentially be a new therapeutic drug for treating lupus.

Membranous lupus nephritis secondary to secukinumab therapy: A case report and literature review.

The interleukin (IL)-17 axis is involved in many inflammatory and autoimmune diseases. Secukinumab, an IL-17 inhibitor, has been approved for psoriasis treatment. There are accumulating cases of lupus erythematosus induced by IL-17 inhibition. Lupus nephritis after IL-17 inhibition has not been reported. We report the case of a 57-year-old man who developed membranous lupus nephritis after secukinumab treatment for psoriasis. Anti-SSA and PM-Scl antibodies were positive. dsDNA, anti-Smith, and anti-histone antibodies were negative, and serum complement was low. Secukinumab was discontinued, while tacrolimus was initiated, subsequently switched to cyclosporin, belimumab, glucocorticosteroid, and hydroxychloroquine with a good response. The relationship between lupus erythematosus and IL-17 inhibition requires further research.

Systemic Lupus Erythematosus: A Review.

Importance: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and immune-mediated injury to multiple organ systems, including the mucocutaneous, musculoskeletal, hematologic, and kidney systems. Approximately 3.4 million people worldwide have received a diagnosis of SLE. Observations: Approximately 90% of people with SLE are female. Although there are no uniformly accepted diagnostic criteria for SLE, the 2019 European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism)/American College of Rheumatology classification criteria developed for scientific study are an estimated 96.1% sensitive and 93.4% specific for SLE. These classification criteria include both clinical factors, such as fever, cytopenia, rash, arthritis, and proteinuria, which may be indicative of lupus nephritis; and immunologic measures, such as SLE-specific autoantibodies and low complement levels. Approximately 40% of people with SLE develop lupus nephritis, and an estimated 10% of people with lupus nephritis develop end-stage kidney disease after 10 years. The primary goal of treatment is to achieve disease remission or quiescence, defined by minimal symptoms, low levels of autoimmune inflammatory markers, and minimal systemic glucocorticoid requirement while the patient is treated with maintenance doses of immunomodulatory or immunosuppressive medications. Treatment goals include reducing disease exacerbations, hospitalizations, and organ damage due to the disease or treatment toxicity. Hydroxychloroquine is standard of care for SLE and has been associated with a significant reduction in mortality. Treatments in addition to hydroxychloroquine are individualized, with immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, typically used for treating moderate to severe disease. Three SLE medications were recently approved by the Food and Drug Administration: belimumab (for active SLE in 2011 and for lupus nephritis in 2020), voclosporin (for lupus nephritis), and anifrolumab (for active SLE). Conclusions and Relevance: Systemic lupus erythematosus is associated with immune-mediated damage to multiple organs and increased mortality. Hydroxychloroquine is first-line therapy and reduces disease activity, morbidity, and mortality. When needed, additional immunosuppressive and biologic therapies include azathioprine, mycophenolate mofetil, cyclophosphamide, belimumab, voclosporin, and anifrolumab.

Risk stratification for infection during immunosuppressive therapy in patients with lupus nephritis: A nested case-control study.

BACKGROUND: The current prediction models for the risk of infection during immunosuppressive treatment for lupus nephritis (LN) lack a prediction time window and have poor pertinence. This study aimed to develop a risk stratification to predict infection during immunosuppressive therapy in patients with LN. METHODS: This retrospective nested case-control study collected patients with LN treated with immunosuppressive therapy between 2014 and 2022 in the Nephrology ward in Huashan Hospital affiliated to Fudan University and Huashan Hospital Baoshan Branch. Cases were defined as patients who experienced infection during the follow-up period; patients were eligible as controls if they did not have infection during the follow-up period. RESULTS: There were 53 patients with infection by CTCAE V5.0 grade ≥2. According to the 1:3 nested matching, the 53 patients with infection were matched with 159 controls. In the multivariable logistic regression model, the change rate of fibrinogen (OR = 0.97, 95% CI: 0.94-0.99, p = 0.008), leukopenia (OR = 8.68, 95% CI: 1.16-301.72, p = 0.039), and reduced albumin (OR = 6.25, 95% CI: 1.38-28.24, p = 0.017) were independently associated with infection. The AUC of the ROC curve in the validation set of the multivariable logistic regression model in the internal random sampling was 0.864. The scores range from -2 to 10. The infection risk stratification ranges from 2.8% at score -2 to 97.5% at score 10. CONCLUSION: A risk stratification was built to predict the risk of infection in patients with LN undergoing immunosuppressive therapy.

New and emerging therapies for systemic lupus erythematosus.

Systemic Lupus Erythematosus (SLE) and lupus nephritis treatment is still based on non-specific immune suppression despite the first biological therapy for the disease having been approved more than a decade ago. Intense basic and translational research has uncovered a multitude of pathways that are actively being evaluated as treatment targets in SLE and lupus nephritis, with two new medications receiving FDA approval in the last 3 years. Herein we provide an overview of targeted therapies for SLE including medications targeting the B lymphocyte compartment, intracellular signaling, co-stimulation, and finally the interferons and other cytokines.

Zhen-Wu-Tang ameliorates lupus nephritis by diminishing renal tissue-resident memory CD8+ T cells via suppressing IL-15/STAT3 pathway.

Zhen-Wu-Tang (ZWT), a conventional herbal mixture, has been recommended for treating lupus nephritis (LN) in clinic. However, its mechanisms of action remain unknown. Here we aimed to define the immunological mechanisms underlying the effects of ZWT on LN and to determine whether it affects renal tissue-resident memory T (TRM) cells. Murine LN was induced by a single injection of pristane, while in vitro TRM cells differentiated with IL-15/TGF-ß. We found that ZWT or mycophenolate mofetil treatment significantly ameliorated kidney injury in LN mice by decreasing 24-h urine protein, Scr and anti-dsDNA Ab. ZWT also improved renal pathology and decreased IgG and C3 depositions. In addition, ZWT down-regulated renal Desmin expression. Moreover, it lowered the numbers of CD8+ TRM cells in kidney of mice with LN while decreasing their expression of TNF-α and IFN-γ. Consistent with in vivo results, ZWT-containing serum inhibited TRM cell differentiation induced by IL-15/TGF-ß in vitro. Mechanistically, it suppressed phosphorylation of STAT3 and CD122 （IL2/IL-15Rß）expression in CD8+ TRM cells. Importantly, ZWT reduced the number of total F4/80+CD11b+ and CD86+, but not CD206+, macrophages in the kidney of LN mice. Interestingly, ZWT suppressed IL-15 protein expression in macrophages in vivo and in vitro. Thus, we have provided the first evidence that ZWT decoction can be used to improve the outcome of LN by reducing CD8+ TRM cells via inhibition of IL-15/IL-15R /STAT3 signaling.

Clinicopathological correlation of patients with lupus nephritis: Data from a tertiary center in Saudi Arabia.

Systemic lupus erythematosus mainly affects young women, and approximately half of systemic lupus erythematosus patients develop lupus nephritis (LN). However, data on the types and remission rates of LN in Saudi Arabia are limited. Therefore, we aimed to highlight the LN remission rates in our population. A retrospective record review was conducted between January 2007 and December 2020 in a tertiary center in the western region of Saudi Arabia to determine the remission rates among patients with biopsy-proven LN who met the EULAR\ACR 2019 classification criteria. We identified 59 patients with biopsy-proven LN, mostly in young women. The common histopathological pattern was Class IV LN in 26 patients (44%). Three induction protocols were identified, along with systemic steroids: the high-dose cyclophosphamide protocol in 21 patients (35.6%), low-dose protocol in 4 patients (6.8%), and mycophenolate mofetil (MMF) in 41 patients (69.5%). Partial response, defined as the reduction of the 24-hour proteinuria by 25% at 3 months and 50% at 6 months, was achieved in 18 patients (33.3%) at 3 months and decreased to 13 patients (24.1%) at 6 months. Complete clinical response, defined as 24-hour urinary protein between 500 and 700 mg at 12 months, was achieved in 44 patients (81.5%). Complete remission was higher among patients with Class IV LN (64.4%). The achievement of partial clinical response at 3 months was significantly lower among patients with hypertension (P = .041). This study presented the LN remission rates in a single center in Saudi Arabia. Similar to previous studies, Class IV LN were the most common histopathological finding in this study. Complete remission at 12 months was achieved in 44 (81%) patients. Delayed remission is associated with hypertension at the time of LN diagnosis.

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease.

Introduction: Defective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present. Aim: We examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model. Methods: Using a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect. Results: Treatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced. Conclusion: Addition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.

Mycophenolate-induced colitis in a patient with lupus nephritis: a case report and review of the literature.

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressive drug that is frequently prescribed to patients with rheumatological diseases. MMF's side effects include abdominal discomfort, nausea, vomiting, and other gastro-intestinal side effects, which typically appear in the first few months of treatment. However, late-onset diarrhea does not rule out the presence of MMF-induced colitis, which can be misdiagnosed since it is linked to a broad range of histopathological characteristics, including alterations that resemble inflammatory bowel disease, graft-versus-host disease, and ischemia. The differences in treatment response may be explained by the complexity of the histopathologic characteristics. CASE PRESENTATION: Here we present a case of a 29-year-old Arabian female with lupus nephritis who started on MMF as induction therapy. In two months, the patient was presented to the Emergency Department with diarrhea and manifestations of severe dehydration. Infectious diseases and adverse drug events were suspected, so the patient was admitted for further workup, and MMF was stopped. The patient was diagnosed with MMF-induced colitis based on colonoscopy and histological findings. Fourteen days after stopping MMF, she was within her baseline. CONCLUSION: The purpose of this paper is to report a case of early-onset MMF-induced colitis in a patient with lupus nephritis who had started MMF as induction therapy. A review of the available literature on this uncommon immunosuppressive effect is also presented.

Longitudinal modeling of efficacy response in patients with lupus nephritis receiving belimumab.

Belimumab was approved for active lupus nephritis (LN) in adults in the European Union and patients ≥ 5 years of age in the USA based on a Phase 3, double-blind, placebo-controlled, 104-week study. The study evaluated the efficacy of belimumab plus background standard therapy in adults with active LN using an intravenous (IV) dose of 10 mg/kg. A longitudinal analysis of Primary Efficacy Renal Response (PERR) and Complete Renal Response (CRR) was performed to assess whether patients with high proteinuria at the start of belimumab treatment would benefit from a higher dose. Responder probability was modeled as a logistic regression with probability a function of time and treatment (belimumab or placebo). Dropout risk at each visit was incorporated into a joint model of efficacy response; only efficacy data prior to dropout events (belimumab discontinuation, treatment failure, or withdrawal) were included. Average belimumab concentration over the first 4 and 12 weeks and baseline proteinuria were considered as continuous covariates. In general, renal response (PERR and CRR) over time was higher in patients receiving belimumab than in those receiving placebo. Baseline proteinuria was considered the most relevant predictor of renal response, with reduced efficacy in patients with increased proteinuria for both belimumab or placebo treatment. For belimumab-treated patients, belimumab exposure was not found to be an important predictor of renal response. In conclusion, the 10 mg/kg IV dose was considered appropriate in all patients and there was no evidence to suggest a higher response would be achieved by increasing the dose.