17 Fertility and pregnancy issues in patients with lupus nephritis

Case 1: Pre-pregnancy counselling for women with lupus nephritis Liz Lightstone An African Caribbean woman was diagnosed with systemic lupus erythematosus (SLE) in 2009 aged 21 years. At that time, she had severe Class IV lupus nephritis (LN) with crescents and acute kidney injury and was treated with steroids and cyclophosphamide. She achieved good clinical remission and was maintained for several years on low-dose prednisolone, mycophenolate mofetil (MMF), hydroxychloroquine (HCQ) and irbesartan. Antiphospholipid and lupus anticoagulant were negative, she was anti Ro positive with no extra renal manifestations. She attended for pre-pregnancy counselling in July 2017 aged 29 years. She was off steroids but still taking MMF and irbesartan. Her creatinine was 97 umol/l with eGFR 70.8 mls/min (59 mls/min not corrected for race) and she had no proteinuria. Her labs at that time were ANA 1:320; dsDNA titer 10 units/ml; C3 normal; and C4 low 0.13 g/l. The counselling addressed fertility (in light of previous cyclophosphamide), contraception, as well as medicines management; in particular, what to stop (i.e. MMF and irbesartan), what to continue (i.e. HCQ) and what treatments might be added (i.e. azathioprine, aspirin, folic acid). The evidence base for advice regarding timing, risks to her and to the baby came from the PROMISSE study, metanalyses and the Italian series (Moroni G et al). Her key risk factors for adverse pregnancy outcomes were being non-white, on an antihypertensive, and having anti Ro antibodies but she was in a good remission from her lupus. I advised her to continue to use contraception whilst weaning off her MMF and to consider trying to conceive, if all remained well, when off her MMF for at least 3 months. She presented pregnant in December 2017 but had not stopped either her MMF or irbesartan, despite the advice to do so back in July that year. We discussed the risks to the baby of first trimester exposure and she declined termination. Coincident with the pregnancy, she was serologically more active, and became symptomatic with joint pains, rising creatinine and hypertension and developed significant proteinuria. During the workshop we will discuss the pros and cons of renal biopsy in pregnancy and how we managed a really major flare. Also, the difficulty of diagnosing pre-eclampsia in a patient with active LN. The pregnancy was ultimately successful. She was treated with rituximab and MMF post-partum and again advised regarding contraception. The story continues in 2020! Case 2: Lupus nephritis in pregnancy Angela Tincani Maria is a 39-year-old woman who consulted at 21 weeks of gestation for the sudden occurrence of proteinuria (3.8 g) during a previously uncomplicated pregnancy with normal fetal growth. She had a history of undifferentiated connective tissue disease, diagnosed in 1997, because of thrombocytopenia (48,000 platelets per microliter) and Raynaud's; positive ANA, anti U1RNP. She was successfully treated with corticosteroids, which were stopped in 2000. She has had Hashimoto thyroiditis, treated with levothyroxine since 2000. In 2014 she had vaginal delivery of a female baby at 40 weeks of an uncomplicated pregnancy without any treatment. In 2016 and 2017 she had three early miscarriages at 8, 7 and 9 weeks. During our first evaluation (29th March 2019), she presented acrocyanosis and modest feet oedema. Proteinuria was 4 g with normal renal function; positive ANA and anti Sm/RNP; low titer anti ds DNA; positive anti-cardiolipin and anti β2 glycoproptein1 IgG. In the last week she was treated with prednisone 50 mg/day plus low dose aspirin (LDA) and low molecular weight heparin (LMWH). Azathioprine (AZA) was added, but because of increasing proteinuria (9.8 g) one week later she was admitted to the Obstetric Department. She was given three small pulses of methylprednisolone (250 mg), AZA shifted to tacrolimus (3 mg/bd) and HCQ started. When discharged, prednisone was reduced to 25 mg/day; LMWH, LDA, HCQ, vitamin D and levothyroxine unchanged. Proteinuria rapidly decreased (1.3 g on 15th May and 0.260 g on 10th July). On 23rd July she had vaginal delivery at 38 weeks' gestation, her baby was 3.390 kg and 51 cm high; APGAR 10/10. Tacrolimus was suspended on the delivery day and the patient continued with prednisone 5 mg every other day with LMWH during puerperium. A subsequent kidney biopsy confirmed Class V glomerulonephritis. At last evaluation (October 2019), the patient and the baby were fine, urinalysis did not show proteinuria. Discussion Points Pre-pregnancy counselling for women with a history of LN Management of acute flares of LN in pregnancy Diagnosing pre-eclampsia in women with active LN Discuss the use of immunosuppressive medications in pregnancy Learning Objectives Explain the importance of pre-pregnancy counselling in women with LN Discuss the best management of flares of LN in pregnant women Discuss how to recognise pre-eclampsia in women with LN Distinguish lupus nephritis from APS nephropath

Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy

Complement 3 glomerulopathy; Inflammatory kidney disease; IptacopanGlomerulopatia del complement 3; Malaltia inflamatòria del ronyó; IptacopanGlomerulopatía del complemento 3; Enfermedad inflamatoria del riñón; IptacopanIntroduction Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G. Methods In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recurrent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1–21: 10–100 mg; days 22–84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels. Results A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 (P = 0.0003). In the recurrent KT cohort, the median C3 deposit score decreased by 2.50 (scale: 0–12) on day 84 versus baseline (P = 0.03). Serum C3 levels were normalized in most patients; complement hyperactivity observed pretreatment was reduced. Severe adverse events (AEs) included post-biopsy hematuria and hyperkalemia. No deaths occurred during the study. Conclusion Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).The study was funded by Novartis Pharma AG, Basel, Switzerland

A multi-centre qualitative study exploring the experiences of UK South Asian and White Diabetic Patients referred for renal care

Background An exploration of renal complications of diabetes from the patient perspective is important for developing quality care through the diabetic renal disease care pathway. Methods Newly referred South Asian and White diabetic renal patients over 16 years were recruited from nephrology outpatient clinics in three UK centres - Luton, West London and Leicester – and their experiences of the diabetes and renal care recorded. A semi-structured qualitative interview was conducted with 48 patients. Interview transcripts were analysed thematically and comparisons made between the White and South Asian groups. Results 23 South Asian patients and 25 White patients were interviewed. Patient experience of diabetes ranged from a few months to 35 years with a mean time since diagnosis of 12.1 years and 17.1 years for the South Asian and White patients respectively. Confusion emerged as a response to referral shared by both groups. This sense of confusion was associated with reported lack of information at the time of referral, but also before referral. Language barriers exacerbated confusion for South Asian patients. Conclusions The diabetic renal patients who have been referred for specialist renal care and found the referral process confusing have poor of awareness of kidney complications of diabetes. Healthcare providers should be more aware of the ongoing information needs of long term diabetics as well as the context of any information exchange including language barriers

Lack of seroresponse to SARS-CoV-2 booster vaccines given early post-transplant in patients primed pre-transplantation

SARS-CoV-2 vaccines are recommended pre-transplantation, however, waning immunity and evolving variants mandate booster doses. Currently there no data to inform the optimal timing of booster doses post-transplant, in patients primed pre-transplant. We investigated serial serological samples in 204 transplant recipients who received 2 or 3 SARS-CoV-2 vaccines pre-transplant. Spike protein antibody concentrations, [anti-S], were measured on the day of transplantation and following booster doses post-transplant. In infection-naïve patients, post-booster [anti-S] did not change when V3 (1st booster) was given at 116(78-150) days post-transplant, falling from 122(32-574) to 111(34-682) BAU/ml, p=0.78. Similarly, in infection-experienced patients, [anti-S] on Day-0 and post-V3 were 1090(133-3667) and 2207(650-5618) BAU/ml respectively, p=0.26. In patients remaining infection-naïve, [anti-S] increased post-V4 (as 2nd booster) when given at 226(208-295) days post-transplant, rising from 97(34-1074) to 5134(229-5680) BAU/ml, p=0.0016. Whilst in patients who had 3 vaccines pre-transplant, who received V4 (as 1st booster) at 82(49-101) days post-transplant, [anti-S] did not change, falling from 981(396-2666) to 871(242-2092) BAU/ml, p=0.62. Overall, infection pre-transplant and [anti-S] at the time of transplantation predicted post-transplant infection risk. As [Anti-S] fail to respond to SARS-CoV-2 booster vaccines given early post-transplant, passive immunity may be beneficial to protect patients during this period

Antibody prevalence after three or more COVID-19 vaccine doses in individuals who are immunosuppressed in the UK: a cross-sectional study from MELODY

SummaryBackground In the UK, additional COVID-19 vaccine booster doses and treatments are offered to people who are immunosuppressed to protect against severe COVID-19, but how best to choose the individuals that receive these vaccine booster doses and treatments is unclear. We investigated the association between seropositivity to SARSCoV-2 spike protein with demographic, disease, and treatment- related characteristics after at least three COVID-19 vaccines in three cohorts of people who are immunosuppressed.Methods In a cross-sectional study using UK national disease registries, we identified, contacted, and recruited recipients of solid organ transplants, participants with rare autoimmune rheumatic diseases, and participants with lymphoid malignancies who were 18 years or older, resident in the UK, and who had received at least three doses of a COVID-19 vaccine. The study was open to recruitment from Dec 7, 2021, to June 26, 2022. Participants received a lateral flow immunoassay test for SARS-CoV-2 spike antibodies to complete at home, and an online questionnaire. Multivariable logistic regression was used to estimate the mutually adjusted odds of seropositivity against each characteristic.FindingsBetween Feb 14 and June 26, 2022, we screened 101 972 people (98 725 invited, 3247 self-enrolled) and recruited 28 411 (27·9%) to the study. 23 036 (81·1%) recruited individuals provided serological data. Of these, 9927 (43·1%) were recipients of solid organ transplants, 6516 (28·3%) had rare autoimmune rheumatic diseases, and 6593 (28·6%) had lymphoid malignancies. 10 485 (45·5%) participants were men and 12 535 (54·4%) were women (gender was not reported for 16 [<0·1%] participants), and 21661 (94·0%) participants were of White ethnicity. The median age of participants with solid organ transplants was 60 years (SD 50–67), with rare autoimmune rheumatic diseases was 65 years (54–73), and with lymphoid malignancy was 69 years (61–75). Of the 23 036 participants with serological data, 6583 (28·6%) had received three vaccine doses, 14 234 (61·8%) had received four vaccine doses, and 2219 (9·6%) had received five or more vaccine doses. IgG anti-spike antibodies were undetectable in 2310 (23·3%) of 9927 patients with solid organ transplants, 922 (14·1%) of 6516 patients with rare autoimmune rheumatic diseases, and 1366 (20·7%) of 6593 patients with lymphoid malignancies. In all groups, seropositivity was associated with younger age, higher number of vaccine doses (ie, five vs three), and previous COVID-19. Immunosuppressive medication reduced the likelihood of seropositivity: the lowest odds of seropositivity were found in recipients of solid organ transplants receiving a combination of an anti-proliferative agent, a calcineurin inhibitor, and steroids, and those with rare autoimmune rheumatic diseases or lymphoid malignancies treated with anti-CD20 therapies. InterpretationApproximately one in five recipients of solid organ transplants, individuals with rare autoimmune rheumatic diseases, and individuals with lymphoid malignancies have no detectable IgG anti-spike antibodies despite three or more vaccine doses, but this proportion decreases with sequential booster doses. Choice of immunosuppressant and disease type is strongly associated with serological response. Antibody testing using lateral flow immunoassay tests could enable rapid identification of individuals who are most likely to benefit from additional COVID-19 interventions

Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.

OBJECTIVES: To develop recommendations for the management of adult and paediatric lupus nephritis (LN). METHODS: The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus. RESULTS: Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III-IV(A) or (A/C) (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults. CONCLUSIONS: Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (&lt;380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies