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

A proposal of an effective platelet-rich plasma protocol for the treatment of androgenetic alopecia

Background: Platelet-rich plasma (PRP) has emerged as a promising treatment for androgenetic alopecia (AGA). In spite of the several studies previously reported, to date, a standardized protocol for PRP preparation and application, as well as a standard method for evaluating results has not been established. Aims: The aim of this study is to propose a standardized method for preparation and application of PRP for male AGA (MAGA) and female AGA (FAGA) and assess its safety and efficacy as a co-adjuvant therapy. Materials and Methods: Seventy-eight patients, 19 men and 59 women with AGA Grades II-IV in Ebling's scale, currently on treatment with topical minoxidil and/or oral finasteride for more than a year without improvement, were included in this study. PRP was prepared using a single spin method, and injected in affected areas for 3 monthly sessions, followed by 3 bimonthly sessions. A decrease of at least one grade in Ebling's scale was considered a successful result. Results: After the 6° session, 71.4% of MAGA and 73.4% of FAGA patients reached a successful outcome while 21.4% and 16.3%, respectively, remained without changes. Only 7.1% of MAGA and 10.2% of FAGA presented worsening of their condition. Conclusions: PRP together with a periodical application protocol can be considered effective as a coadjuvant therapy in patients who no longer respond to pharmacological treatments. Ebling's scale was a practical and reliable parameter to allow a better evaluation in both MAGA and FAGA

Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study.

OBJECTIVES: To evaluate the effect of subcutaneous (s.c.) secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic progression in patients with psoriatic arthritis (PsA). METHODS: Adults (n=996) with active PsA were randomised 2:2:2:3 to s.c. secukinumab 300 mg or 150 mg with loading dose (LD), 150 mg without LD or placebo. All groups received secukinumab or placebo at baseline, weeks 1, 2 and 3 and then every 4 weeks from week 4. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 16. RESULTS: Significantly more patients achieved an ACR20 response at week 16 with secukinumab 300 mg with LD (62.6%), 150 mg with LD (55.5%) or 150 mg without LD (59.5%) than placebo (27.4%) (p CONCLUSION: S.c. secukinumab 300 mg and 150 mg with and without LD significantly improved clinical signs and symptoms and inhibited radiographic structural progression versus placebo at week 24 in patients with PsA. TRIAL REGISTRATION NUMBER: NCT02404350; Results

Secukinumab provides sustained low rates of radiographic progression in psoriatic arthritis: 52-week results from a phase 3 study, FUTURE 5.

OBJECTIVE: To evaluate the effect of secukinumab on radiographic progression through 52 weeks in patients with PsA from the FUTURE 5 study. METHODS: Patients with active PsA, stratified by prior anti-TNF use (naïve or inadequate response), were randomized to s.c. secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load regimens or placebo at baseline, at weeks 1, 2 and 3 and every 4 weeks starting at week 4. Radiographic progression was assessed by change in van der Heijde-modified total Sharp score (vdH-mTSS; mean of two readers). Statistical analysis used a linear mixed-effects model (random slope) at weeks 24 and 52, and observed data at week 52. Assessments at week 52 included additional efficacy endpoints (non-responders imputation and mixed-effects models for repeated measures) and safety. RESULTS: The majority (86.6%) of patients completed 52 weeks of treatment. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS ⩽0.5) was 91.8, 85.2 and 87.2% in 300, 150 and 150 mg no load groups, respectively, at week 52. The change in vdH-mTSS from baseline to week 52 using random slope [mean change (s.e.)] was -0.18 (0.17), 0.11 (0.18) and -0.20 (0.18) in 300, 150 and 150 mg no load groups, respectively; the corresponding observed data [mean change (s.d.)] was -0.09 (1.02), 0.13 (1.39) and 0.21 (1.15). Clinical efficacy endpoints were sustained, and no new or unexpected safety signals were reported through 52 weeks. CONCLUSION: Secukinumab 300 and 150 mg with or without s.c. loading regimen provided sustained low rates of radiographic progression through 52 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02404350

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

Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: An across-study comparison

OBJECTIVE: To assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE). METHODS: We performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score; anti-dsDNA/C3/C4 levels); Week 52 SRI-6 response rate; and time to first severe flare (SELENA-SLEDAI Flare Index) over 52 weeks. Safety data were compared for all aforementioned studies along with adult LBSL02 (phase II) and BLISS-SC (phase III). RESULTS: SRI-4 response rates were similar across the paediatric and adult studies; more belimumab-treated patients achieved SRI-4 responses versus placebo (PLUTO: 52.8% vs 43.6%; BLISS-52: 57.6% vs 43.6%; BLISS-76: 43.2% vs 33.8%; BLISS-NEA: 53.8% vs 40.1%; EMBRACE: 48.7% vs 41.6%). Across all studies, SRI-4 response rates were generally greater in patients with baseline SELENA-SLEDAI scores ≥10 than in patients with baseline SELENA-SLEDAI scores ≤9. A similar proportion of belimumab-treated patients achieved SRI-6 across all studies (PLUTO: 41.2%; BLISS-52: 46.2%; BLISS-76: 33.1%; BLISS-NEA: 43.9%; EMBRACE: 37.5%). Belimumab reduced the risk of severe flare versus placebo in all studies. The incidence of adverse events was similar across all studies. CONCLUSIONS: These analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE. TRIAL REGISTRATION NUMBERS: PLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487)

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force.

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE