Autoimmune hemolytic anemia following SARS-COV- 2 vaccine in SLE nephritis with coexistent thymoma, complicated by severe COVID-19 infection

Background: We report a 40-year- old female with co-existent lupus nephritis and thymoma who developed severe lupus flare (worsening nephritis, new onset hemolytic anemia) following SARS-CoV- 2 vaccine. Case: This 40 year old female has had stable lupus nephritis (LN) while maintained on mycophenolate mofetil and hydroxychloroquine for several years. A co-existent thymoma was likewise stable and did not require any added therapy apart from the management of the LN. She received the first dose of inactivated vaccine for SARS-CoV- 2 without event. Two weeks following the second dose, she developed Coombs positive hemolytic anemia (hemoglobin 64 g/L) with leukopenia (WBC 2.3 x 109/L), worsening nephritis (3+ proteinuria with uPCR 1.0, active urine sediments), hypocomplementemia, and elevated anti-dsDNA. She received methylprednisolone pulse therapy then maintained on prednisone 40mg/day with clinical improvement. Two weeks thereafter, she was admitted due to severe COVID-19 pneumonia accompanied by severe anemia requiring blood transfusion;she received a regimen of bevacizumab, dexamethasone, and remdesivir and was discharged recovered, without overt sequelae at the time of this report. Discussion(s): Vaccines are highly effective in reducing hospitalization and death attributable to SARS-CoV- 2 infection. There are concerns however regarding autoimmune disease flares following SARS-CoV- 2 vaccine, reported to occur in about 4% patients with autoimmune disorders. It is also possible that this patient's reaction may have been further aggravated by the co-existent thymoma. While there was apparent sub-optimal protection of the vaccine against moderate to severe COVID-19 infection in this patient, it may be conjectured that her significant recovery and response to the anti-viral combined with immunosuppressive regimen may be due to the high dose steroid treatment given for the post-vaccine autoimmune reaction.

Infections in SLE

Infectious agents especially viruses e.g. Epstein Barr virus contribute to systemic lupus erythematosus (SLE) pathogenesis and can trigger lupus disease activity by driving autoimmunity through molecular mimicry, bystander activation and epitope spreading.1 This intricate relationship between viruses and autoimmunity is further substantiated by contemporary observations on the effects of dysregulated host immune response in severe COVID-19 infection resulting in development of autoantibodies and clinical manifestations simulating a lupus flare, albeit with distinguishing features.2Infections are a significant cause of morbidity and mortality in SLE, with infections and active lupus as the most frequent causes of death across various cohorts. Compared with the general population, SLE patients have a median 3-fold increased risk of severe infection and are more likely to die of an infection with standardised mortality ratio (SMR) of 5 specifically due to infections alone.3 The most common infections in SLE are pneumonia and bacterial sepsis, with Staphylococcus aureus, Streptococcus pneumoniae and Escherichia coli as the most common causative agents. There is also a 2.5-fold higher risk of herpes zoster in SLE, and a 6-fold risk of tuberculosis especially in endemic countries. There is a higher incidence of Hepatitis B infection especially in Asia usually triggered by B-cell depleting agents, as well as Pneumocystis jirovecii pneumonia and other opportunistic infections.The susceptibility to infections among lupus patients may be explained by several intrinsic and acquired defects in the immune system. Established risk factors for infection in SLE patients are disease activity including high anti-double-stranded DNA titres, low complement levels, active nephritis, leucopenia, and medications including prednisone or prednisone-equivalent dose greater than 7.5 mg/day, corticosteroid pulse therapy, and high-dose cyclophosphamide.4 Conversely, antimalarials particularly hydroxychloroquine not only control disease activity and prevent flares, but also prevent serious infections in SLE.5 6Although vaccination is essential in the prevention of infections, concerns regarding efficacy (lower immunogenicity and seroprotection), and safety (adverse events or disease flares), among physicians and patients are major deterrents for vaccination. In general, vaccinations against influenza, Streptococcus Pneumonia, Hepatitis A and B, and Human Papilloma Virus are recommended for SLE patients with clear benefit-risk/side-effect profile. Vaccinations should be administered during stable disease and before B cell depletion therapy. Conversely, live vaccines should be avoided in patients on immunosuppressive therapy.James JA, et al. Lupus and Infections. In Dubois Lupus Erythematosus and Related Syndromes. Eds DJ Wallace et al. Saunders Philadelphia 2019. ISBN: 978-0-323-47927-1, pp 543–555.Spihlman AP, Gadi N, Wu SC, Moulton VR. COVID-19 and Systemic Lupus Erythematosus: Focus on Immune Response and Therapeutics. Front Immunol 2020 Oct 30;11:589474. doi: 10.3389/fimmu.2020.589474. PMID: 33193418;PMCID: PMC7661632.Pego-Reigosa JM, Nicholson L, Pooley N, Langham S, Embleton N, Marjenberg Z, Barut V, Desta B, Wang X, Langham J, Hammond N1 -https://media.proquest.com/media/hms/PFT/1/fwm9N?_a=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&_s=dgJBG44RvtPhipiXzS1OCqh0ObE%3D ER. The risk of infections in adult patients with systemic lupus erythematosus: systematic review and meta-analysis. Rheumatology (Oxford) 2021 Jan 5;60(1):60–72. doi: 10.1093/rheumatology/keaa478. PMID: 33099651;PMCID: PMC7785308.Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, Martinez-Berriotxoa A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009;11(4):R109. doi:10.1186/ar2764. Epub 2009 Jul 15. PMID: 19604357;PMCID: PMC2745791.Jung JY, Yoon D, Choi Y, Kim HA, Suh CH. Associated clinical factors for serious infections in patients with systemic lupus erythematosus. Sci Rep 2019 Jul 4;9(1):9704. doi: 10.1038/s41598-019-46039-5. PMID: 31273256;PMCID: PMC6609713.Oku K, Hamijoyo L, Kasitanon N, Li MT, Navarra S, Morand E, Tanaka Y, Mok CC. Prevention of infective complications in systemic lupus erythematosus: A systematic literature review for the APLAR consensus statements. Int J Rheum Dis 2021 Jul;24(7):880–895. doi: 10.1111/1756-185X.14125. Epub 2021 May 17. PMID: 33999518.Learning ObjectivesExplain the role of infections in SLE pathogenesisDescribe the spectrum of infections in SLEDiscuss the risk factors for infectionsDiscuss strategies for prevention of infections in SLE

Rheumatoid arthritis management in the APLAR region: Perspectives from an expert panel of rheumatologists, patients and community oriented program for control of rheumatic diseases.

Rheumatoid arthritis (RA) is a major health burden in Asia Pacific affecting the quality of life of patients and consuming healthcare resources. According to recent estimates from the World Health Organization-International League Against Rheumatism-Community Oriented Program for Control of Rheumatic Diseases, prevalence is around 0.3%-0.5%. Management guidelines have helped to improve treatment across this diverse region. To gain better insight into current real-world management applications in view of these guidelines, virtual meetings were conducted in mid-2020 to explore perspectives of rheumatologists and patients, as well as discuss the impact of coronavirus disease 2019 on RA management. Patients and rheumatologists from Hong Kong, Malaysia, Singapore, the Philippines, Thailand, India, Pakistan, and Taiwan were included, representing a diverse mix of healthcare systems, wealth, ethnicity and culture. Despite many countries having prospered in recent years, similar challenges in RA diagnosis and treatment were identified. The daily impact and patient experience of RA were also similar across countries, marked by "silent" pain and disability, and universal misunderstanding of the disease. Late diagnosis and treatment, and barriers to access to appropriate treatment, remain problematic. The experience shared by Taiwan offers a glimmer of hope, however, wherein patient advocacy groups have succeeded in being included in policy-making decisions and securing access to advanced treatment. Real-world solutions that pay heed to the unique local needs and diversity of Asia Pacific are required to improve RA management, which will take time. In the interim, help can be sought from the trained, non-rheumatologist community to reduce some of the disease burden.

19 Lupus nephritis

Case 1: 35-year-old patient with lupus nephritis presents with anasarca, hypertension and renal insufficiency at her 18th week of pregnancyLiz Lightstone, and Sandra NavarraA 35-year-old female was diagnosed lupus nephritis (LN) 7 years earlier with kidney biopsy showing LN Class IV-G activity 7, chronicity 3. She received methylprednisolone pulse and was thereafter maintained on prednisone, hydroxychloroquine (HCQ), mycophenolate mofetil (MMF) and calcium plus vitamin D. Her condition was ‘stable’ despite erratic follow-up and poor adherence. Two months ago, while on prednisone 10 mg/day, she consulted at clinic because of anasarca and hypertension at Week 18 of her 4th pregnancy. Obstetric history included two spontaneous abortions at 2 months gestation in 2013, 2015 and a successful term pregnancy in 2018 with a healthy baby girl delivered by C-section. Laboratory tests showed: Hemoglobin 83 g/L, hematocrit 0.24, WBC 6.97, platelets 270, creatinine 2.29 mg/dL, ↓ C3 0.20 g/L, ↑anti-dsDNA 1152.12 IU/mL, urine albumin 4+, RBC 90–95/hpf with dysmorphic RBCs, WBC 10–12/hpf, hyaline and granular casts. Anticardiolipin, lupus anticoagulant, anti-Ro and anti-La were negative.Clinical coursePrednisone was increased to 40 mg/day and she was started on methyldopa, azathioprine, HCQ, calcium plus vitamin D, iron plus folate, and aspirin 80 mg/d. A week later, she was admitted due to cough, dyspnea, orthopnea and low-grade fever. Chest radiograph showed hazy densities on both lung fields. Laboratory tests showed: Hemoglobin 74 g/L, hematocrit 0.22, WBC 17.20, platelets 433. Urine albumin 4+, RBC 18–22/hpf, WBC 10–15/hpf, hyaline, granular and waxy casts, urine total protein 822.40 mg/dL, urine creatinine 151.08 mg/dL, urine protein-creatinine ratio 5.44;BUN 62.6 mg/dL, creatinine 2.90 mg/dL, total protein 5.01 mg/dL, albumin 2.66 g/dL, Na 132 mmol/L, K 5.69 mmol/L, phosphorus 6.07 mmol/L, and iCa 1.19 mmol/L;SARS-CoV2 test was negative. She was started on antibiotics and received red cell transfusions;regular hemodialysis was initiated due to pulmonary congestion and metabolic acidosis.Discussion PointsDistinguish pre-eclampsia from LN flareManagement of severe LN flare with renal insufficiency during pregnancy including the role of plasma exchangeCase 2: 22–year-old female with refractory LN despite immunosuppressive regimens and rituximabLiz Lightstone, Sandra NavarraClinical dataA 22-year-old female presented with anti-phospholipid syndrome (APS) and LN at age 8. She had completed cyclophosphamide induction therapy, had been adherent to MMF (plus tacrolimus for 18 months), and received eight doses of rituximab. Renal histopathology (2008, 2016, 2019) shows persistent lupus nephritis ISN/RPS Class IV, varying activity and chronicity indices. She would attain partial renal remission for a few months, but never achieved complete remission. Blood pressure and renal function remain within normal range.Discussion PointUpdates in the management of LNCase 3: 35-year-old male with LN presents with persistent hypokalemiaLiz Lightstone, Sandra NavarraClinical dataA 35-year-old male with LN ISN/RPS Class IV – S, activity 11 and chronicity 4, presented with nephrotic-range proteinuria, hypertension, and impaired renal function. Renal ultrasound was normal without calcinosis. He received prednisone, MMF, HCQ, anti-hypertensives, and calcium plus vitamin D. He had persistently low levels of serum potassium (K) 2.4–3.8 meqs/L, and serum bicarbonate (HCO3) 11–20 mmol/L despite K and HCO3 supplementation. Urine pH was 6.0, urine sodium (Na) 80 mmol/L, urine K 20.63 mmol/L, urine chloride (Cl) 97.90 mmol/L. Serum anion gap was normal, and urine anion gap positive at 2.73 meq/L, confirming the diagnosis of an underlying distal renal tubular acidosis (RTA).Discussion PointsClinical significance and management of RTA in LNCase 4: 31-year-old patient with LN and APS presents with fever, deteriorating kidney function and an ovarian massLiz Lightstone, Sandra NavarraClinical dataA 31-year-old female was diagnosed with L and APS 8 years ago presenting with Raynaud’s, mononeuritis multiplex, proteinuria, pancytopenia, and pericarditis. She was given methylprednisolone pulse, cyclophosphamide, and belimumab then maintained on hydroxychloroquine, MMF, aspirin, nifedipine, iron plus folate, and calcium plus vitamin D. She developed hematologic flare a year ago which responded well to methylprednisolone pulse and two doses of rituximab. Two months ago, she presented with intermittent fever, dysuria, and cough. Laboratory results were: Hemoglobin 97 g/L, WBC 8.4 x109/L, platelet 109 x109/L, BUN 52.1 mmol/L, creatinine 2.73 mg/dL (eGFR 22.3 ml/min) →3.26 mg/dL (eGFR 18.1 ml/min), urine protein 2+, RBC 40–50, pus >100;urine PCR by Gene Xpert® was positive for Mycobacterium tuberculosis (TB), no rifampicin resistance. Chest radiograph showed infiltrates suggestive of miliary TB. Abdominal ultrasound showed renal cysts with calcifications, mild left ureteropelvocaliectasia from a left adnexal cystic mass measuring 8.57 cm. Exploratory laparotomy with left salpingo-oophorectomy was performed;histopathology showed caseating granuloma. She was started on an anti-TB regimen.Discussion PointsCauses of renal insufficiency in a patient with LNRenal involvement in APSLearning ObjectivesDescribe management approach to LNExplain special considerations in the management of LN flare during pregnancyDiscuss further management options in refractory LNDiscuss clinical situations which significantly contribute to morbidity in LN