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

Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype. METHODS: A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined. RESULTS: Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon. CONCLUSION: These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis

Practice advisory on the appropriate use of NSAIDs in primary care

Cyclo-oxygenase (COX)-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are important in managing acute and chronic pain secondary to inflammation. As a greater understanding of the risks of gastrointestinal (GI), cardiovascular (CV) and renal events with NSAIDs use has emerged, guidelines have evolved to reflect differences in risks among NSAIDs. Updated guidelines have yet to reflect new evidence from recent trials which showed similar CV event rates with celecoxib compared to naproxen and ibuprofen, and significantly better GI tolerability for celecoxib. This practice advisory paper aims to present consensus statements and associated guidance regarding appropriate NSAID use based on a review of current evidence by a multidisciplinary group of expert clinicians. This paper is especially intended to guide primary care practitioners within Asia in the appropriate use of NSAIDs in primary care. Following a literature review, group members used a modified Delphi consensus process to determine agreement with selected recommendations. Agreement with a statement by 75% of total voting members was defined a priori as consensus. For low GI risk patients, any nonselective NSAID plus proton pump inhibitor (PPI) or celecoxib alone is acceptable treatment when CV risk is low; for high CV risk patients, low-dose celecoxib or naproxen plus PPI is appropriate. For high GI risk patients, celecoxib plus PPI is acceptable for low CV risk patients; low-dose celecoxib plus PPI is appropriate for high CV risk patients, with the alternative to avoid NSAIDs and consider opioids instead. Appropriate NSAID prescription assumes that the patient has normal renal function at commencement, with ongoing monitoring recommended. In conclusion, appropriate NSAID use requires consideration of all risks

Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension.

OBJECTIVE: This extension study of the Phase III, randomized, placebo-controlled Belimumab International SLE Study (BLISS)-52 and BLISS-76 studies allowed non-US patients with SLE to continue belimumab treatment, in order to evaluate its long-term safety and tolerability including organ damage accrual. METHODS: In this multicentre, long-term extension study (GlaxoSmithKline Study BEL112234) patients received i.v. belimumab every 4 weeks plus standard therapy. Adverse events (AEs) were assessed monthly and safety-associated laboratory parameters were assessed at regular intervals. Organ damage (SLICC/ACR Damage Index) was assessed every 48 weeks. The study continued until belimumab was commercially available, with a subsequent 8-week follow-up period. RESULTS: A total of 738 patients entered the extension study and 735/738 (99.6%) received one or more doses of belimumab. Annual incidence of AEs, including serious and severe AEs, remained stable or declined over time. Sixty-nine (9.4%) patients experienced an AE resulting in discontinuation of belimumab or withdrawal from the study. Eleven deaths occurred (and two during post-treatment follow-up), including one (cardiogenic shock) considered possibly related to belimumab. Laboratory parameters generally remained stable. The mean (s.d.) SLICC/ACR Damage Index score was 0.6 (1.02) at baseline (prior to the first dose of belimumab) and remained stable. At study year 8, 57/65 (87.7%) patients had no change in SLICC/ACR Damage Index score from baseline, indicating low organ damage accrual. CONCLUSION: Belimumab displayed a stable safety profile with no new safety signals. There was minimal organ damage progression over 8 years. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00424476 (BLISS-52), NCT00410384 (BLISS-76), NCT00732940 (BEL112232), NCT00712933 (BEL112234)

Drivers of Satisfaction With Care for Patients With Lupus

Objective. Quality of life (QOL) and quality of care (QOC) in systemic lupus erythematosus (SLE) remains poor. Satisfaction with care (SC), a QOC surrogate, correlates with health behaviors and outcomes. This study aimed to determine correlates of SC in SLE. Methods. A total of 1262 patients with SLE were recruited from various countries. Demographics, disease activity (modified Systemic Lupus Erythematosus Disease Activity Index for the Safety of Estrogens in Lupus Erythematosus: National Assessment trial [SELENA-SLEDAI]), and QOL (LupusPRO version 1.7) were collected. SC was collected using LupusPRO version 1.7. Regression analyses were conducted using demographic, disease (duration, disease activity, damage, and medications), geographic (eg, China vs United States), and QOL factors as independent predictors. Results. The mean (SD) age was 41.7 (13.5) years; 93% of patients were women. On the univariate analysis, age, ethnicity, current steroid use, disease activity, and QOL (social support, coping) were associated with SC. On the multivariate analysis, Asian participants had worse SC, whereas African American and Hispanic patients had better SC. Greater disease activity, better coping, and social support remained independent correlates of better SC. Compared with US patients, patients from China and Canada had worse SC on the univariate analysis. In the multivariate models, Asian ethnicity remained independently associated with worse SC, even after we adjusted for geographic background (China). No associations between African American or Hispanic ethnicity and SC were retained when geographic location (Canada) was added to the multivariate model. Canadian patients had worse SC when compared with US patients. Higher disease activity, better social support, and coping remained associated with better SC. Conclusion. Greater social support, coping, and, paradoxically, SLE disease activity are associated with better SC. Social support and coping are modifiable factors that should be addressed by the provider, especially in the Asian population. Therefore, evaluation of a patient\u2019s external and internal resources using a biopsychosocial model is recommended. Higher disease activity correlated with better SC, suggesting that the latter may not be a good surrogate for QOC or health outcomes

Drivers of Satisfaction With Care for Patients With Lupus.

Quality of life (QOL) and quality of care (QOC) in systemic lupus erythematosus (SLE) remains poor. Satisfaction with care (SC), a QOC surrogate, correlates with health behaviors and outcomes. This study aimed to determine correlates of SC in SLE