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Lupus Nephritis: Diagnosis, Classification, Treatment, and The Role of The Pediatrician · Pediatrics Now: Cases Updates and Discussions for the Busy Pediatric Practitioner

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I'm Haolee Weyman, and this is Pediatrics Now, cases, updates,
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and discussions for the busy pediatric practitioner.
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Today, I'm bringing you Grand Rounds.
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It's my great pleasure to introduce today's two speakers we have.
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The first one is Dr. Ruby Patel, who is a Clinical Assistant Professor in the
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Division of Pediatric Nephrology at Stanford University.
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She was a pediatric resident and chief resident from 2018 to 2019 at Kaiser
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Permanente in Northern California in Oakland, California.
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She finished her fellowship training in nephrology at Stanford in 2022 and has
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remained at Stanford with a clinical focus in general nephrology and kidney transplantation.
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She is also Associate Program Director for a nephrology fellowship.
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She has presented on general nephrology topics as well as advanced dialysis
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in neonatal population and various topics related to transplant such as disparities,
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adolescent outcomes, and novel medication regimens in transplant patients internationally,
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nationally, and regionally.
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Our second speaker is Dr. Rajdeep Pooni, who is a clinical assistant professor
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in the Division of Pediatric Allergy, Immunology, and Rheumatology at Stanford
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University in California.
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She trained at Kaiser Permanente Northern California in Oakland.
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Where she was a pediatric resident and chief resident between 2016 and 2017.
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Following residency, she completed her fellowship in pediatric rheumatology
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and master's degree in health research and policy at Stanford in 2020.
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In addition to caring for general rheumatology patients, She has special research
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interest in clinical informatics and chronic non-bacterial osteomyelitis.
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So Dr. Patel and Dr. Puneet, thank you very much for accepting our invitation. The floor is yours.
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Thank you so much for that kind introduction. Dr. Patel and I are excited to be here today.
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I don't know if anyone had a chance to glean from the bios. Yes,
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I have known Dr. Patel since residency, and so we have had many mutual patients over the years.
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And more recently, as faculty, we share patients with lupus nephritis,
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and we're happy to share our experience.
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We have no disclosures.
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So we'll go over the objectives for our talk today.
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We will review and discuss clinical and laboratory features of lupus.
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We'll review the classification system as well.
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We'll review the general approach to therapies per the 2024 ACR guidelines.
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And after our talk, we hope that you understand some of the potential side effects
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of these therapies and how to approach the care of an immunocompromised patient.
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We'll also review how to monitor for certain clinical complications that can
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be associated with lupus nephritis. and we'll review the role of the pediatrician
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in the management of these complex patients.
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So we'll start with the case. This is actually a recent patient that we cared for in our hospital.
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She's a 12-year-old female. She presented with a one-week history of right lower
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quadrant abdominal pain and with daily emesis and chills.
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She also had diarrhea about one to two times in the past week.
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Her emesis is food content. Yellow in color occurs one to two times per day.
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She was seen by her PCP and appropriately counseled for precautions for appendicitis.
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And upon further discussion on review of systems, she maybe has had some darker
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urine for the past three months, which didn't change with hydration.
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A picture of her actual urine is in the bottom right of this slide.
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And then additionally, after starting her period three months ago,
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she mentions that her first period was really heavy.
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Eventually, the parents and patient presented to the ED because of the symptoms.
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In the ED, her vitals were as follows, a heart rate of 58, blood pressure 142
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over 86, temperature of 36.9, respiratory rate, and saturation normal.
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They did additional workup in the ED, which included an ultrasound because they
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were concerned for appendicitis.
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The ultrasound showed a small free fluid collection in the lower quadrant,
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some prominent dilated small bowel loops,
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also some prominent right lower quadrant lymph nodes as well,
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but the appendix wasn't visualized, so they proceeded with the CT.
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The CT scan also showed this free fluid in the pelvis, but commented on some
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body wall soft tissue anisarca and moderate pericardial effusion on the imaging.
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The appendix was normal.
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Interventions done in the ED included a dose of Tylenol, Zofran,
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and a bolus of 20 mLs per kilo, and the patient was started on some maintenance IV fluids.
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All right, so this was her exam documented in the ED.
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It was significant for moderate tenderness in the suprapubic,
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epigastric, right and left lower quadrants.
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Her extremities had pitting edema over both feet and legs. And these were her labs.
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So what is abnormal with these labs? We'll kind of go over that.
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So as you can see, she had pretty significant pancytopenia.
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Her serum laboratory results showed a low serum bicarbonate of 14 and an elevated
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serum creatinine of 3.03.
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Her urinalysis had protein, blood, as well as white cells and red blood cells
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under urine microscopy.
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When this patient was admitted, a few questions, you know, came up,
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the first of which being which additional labs were testing to obtain.
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And so given this patient's presentation, I would plan to repeat and trend the chemistries,
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repeat CBC with smear potentially if there's any indication of precipitous drop
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in your hemoglobin or thrombocytopenia, anything to suggest microangiopathic changes.
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In terms of further workup, at this point, the differential would be still broad,
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but you would consider additional workup for glomerular disease,
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evaluating for post-infectious etiologies,
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including your post-strep titers, so your ASO, your DNxV,
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complements for immune complex-mediated disease, specifically C3 and C4,
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thinking about lupus, the
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And then you would also think about vasculitis, so ANCA, so your C-ANCA,
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your P-ANCA, you'd want to check an ANA, I think, at this point,
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and by immunofluorescence, given possibility of lupus.
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And then, you know, trending inflammatory markers, including ESR and CRP.
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I think we'd also want to work up the anemia further, specifically,
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again, if there's any concern for autoimmune hemolytic anemia,
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and we would likely obtain a Coombs, haptoglobin, LDH.
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And if this patient's not already had imaging, which she has,
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you could have considered additional imaging, such as venal envelope bladder ultrasound.
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In terms of what needs to be monitored acutely, I think at this point,
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we're still concerned about AKI, possibly AKI in the setting of chronic kidney disease.
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So electrolytes, ins and outs,
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weight are all going to be critical in the management of this patient.
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This patient was also interestingly noted to be bradycardic,
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which is a little unusual given the presumed inflammatory state that she's in.
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So it would be key to keep this patient on monitors in addition to checking
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her blood pressure regularly.
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And then given the known edema in this patient with hypoalbuminemia,
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her clinical exam will also need to be monitored, particularly if there's any
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concern for new respiratory symptoms as she's at risk for pulmonary edema.
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And then lastly, the cytopenias are of concern.
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One, we're worried about clotting leading risk if we're at all concerned about
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thrombotic microangiopathy or even worsening thrombocytopenia.
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But we might also be worried about, again, acute hemolysis given anemia.
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And then kind of like with broader systemic involvement, you might be thinking
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about things like macrophage activation syndrome, given that all her cell lines are slightly down.
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So it'll be important to trend her CBC, at least initially.
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And so what are the emergent issues that could come up for this patient.
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She's at risk for fluid overload, so monitoring her I's and O's will be important.
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You may have to think about restricting her intensibles, monitoring her urine output.
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She's also at risk for electrolyte disturbances, specifically hyperkalemia.
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Again, she's also at risk for bleeding, infection.
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And then in terms of what is this affected diagnosis, we're worried about AKI,
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acute, acute and chronic.
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And so, you know, as a rheumatologist, the things I'm thinking about are lupus and vasculitis.
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And then who should we consult?
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So we consult, you know, general pediatrics for admission as the workup is pending.
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You consult Dr. Patel or your local nephrologist for their recommendations as
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well, given the AKI and the concern for AKI on CKD.
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And then likely consult rheumatology as well.
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Taking a step away from the case just for a minute, I wanted to review both
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the laboratory and clinical features of systemic lupus.
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Is this a patient's diagnosis to be determined?
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And what I'm actually sharing here is the 2019 classification criteria for lupus
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that was developed by the American College of Rheumatology and the European
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League Against Rheumatism, or ULAR.
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Although this criteria was developed with clinical research in mind,
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we do use this classification criteria to help diagnose lupus.
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As you can see here, having a positive ANA is an entry criterion,
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and there are both then clinical and immunologic domains. And you need both
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immunologic and clinical criteria to consider a diagnosis of lupus.
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Clinical criteria can include constitutional symptoms such as fever,
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immunologic symptoms, so leukopenia, mollusis, neuropsychiatric disease,
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so seizures, psychosis,
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eucocutaneous symptoms, and this is a number of clinical manifestations,
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so everything from oral ulcers to rashes consistent with acute cutaneous lupus, alopecia.
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Serosal involvement, so that could be having pericardial effusions,
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acute pericarditis, other signs of serocitis,
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MSK involvement, so arthritis, myositis, although that's a little bit more or
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not as common in lupus, and then certainly renal involvement.
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And then for the immunologic criteria, You'll see a whole host of laboratory tests here.
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Starting from the bottom, there's the lupus-specific antibody,
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so your anti-double-stranded DNA antibody or your anti-SMF antibody.
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There's low complement that would also earn you some points,
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the low C3 or C4, or having both that are low.
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And then the presence of some antiphospholipid antibodies, and specifically
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your anticargiolipin, your antibeta-2-glycoprotein antibody,
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and your lupus anticoagulant.
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And so, again, it's a combination of clinical factors, laboratory features that help us diagnose lupus.
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One question that sometimes I get is, you know, there's different types of testing
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for the ANA, specifically ANA by immunofluorescence versus ELISA. Yeah.
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In general, the IFA is better because the negative predictive value is better.
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The way that that test is done, it's labeled antibody to antigen.
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That's looked at under the microscope.
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ANA by ELISA is usually automated. It's more cost effective,
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but that's looking at antibody to antigen.
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And then that is an enzyme linked to antibody to detect color change.
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So, again, if there is an option, checking ANA by IFA or immunofluorescence is the better test.
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So prior to 2019, there were classification criteria used to define lupus,
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again, for research purposes.
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The reason that they developed the newer criteria in 2019, aside from having
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kind of a unified international consensus, was to improve upon the sensitivity
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of the criteria from 1997, but sustain its specificity.
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And then as you can see here, the 2019 ACR-ULAR criteria did just that with
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a sensitivity of 96.1%, specificity of 93.4% in the validation cohort,
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which demonstrated improved performance compared to the ACR-97 and LIF-2012 criteria.
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I'd point this out because you might be different rheumatologists refer to the
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more recent criteria as well as the prior criteria.
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And again, you know, I think keeping in mind how to diagnose lupus,
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you still need clinical and immunologic criteria for all of these criteria.
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You still must have a positive ANA.
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Some of the tests that we order, again, specifically like the antibodies,
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whether it's the ANA or the anti-DSDNA or Smith antibodies, can sometimes take
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several weeks or several days to a week to come back, depending on the lab.
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So it's important to get kind of other clinical domains and have high suspicion
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based on what else might be present.
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So this slide here highlights some of the clinical features you may see in patients
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with lupus. The top left photo shows a child with alopecia.
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Typically, alopecia is non-scarring in lupus. The bottom left photo shows polytol
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ulceration in a teen patient.
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And then the top right photos show a bilar rash.
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The one kind of the furthest top right has more significant involvement with
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some dermatitis and possibly even some baculitis. And then the bottom right
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photos here show changes associated with acute cutaneous lupus.
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So some common questions that I get regarding the diagnosis of lupus is,
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one, when should I get an ANA or other antibodies?
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And my answer to this is usually if there are concerns about the history,
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you know, if there's history of chronic unexplained fevers,
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arthritis, rash, or concerning laboratory features like leukopenia,
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anemia, AKI, those might be reasons, again, to kind of explore a diagnosis of
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lupus, and that's when I would get the ANA by immunofluorescence.
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The other question I commonly get is, in addition to rheumatology,
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who else should I consult?
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And I would say it really depends on the clinical manifestations of disease.
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Obviously, if there's concern about like AKI or CKD, then nephrology.
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If there are questions about skin changes, then obviously dermatology.
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It really just depends on the clinical manifestation. And then the other question
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I often get is, if there's a family history of autoimmunity,
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should any preemptive testing be done in a healthy child?
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And usually the answer to this is no, unless there's concerning symptoms.
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Lupus is likely both due to genetic and environmental factors,
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but we only know a small subset of the genes involved. So I would not do any
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preemptive testing unless there was some clinical concern.
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And then last question is how childhood lupus differs from adult lupus.
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And so we'll actually talk about that in the next slide.
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And so in terms of childhood versus adult lupus, it's generally worse.
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We tend to see more pulmonary, neurologic, thematologic involvement in childhood lupus.
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There's a higher prevalence of renal disease in children.
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Usually children present with more active disease as well.
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And kind of like with this, you may also see higher medication burden in children
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certainly at the start, but then also in time.
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And then the related toxicities with those therapies.
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About 20% or so of cases of lupus nephritis are diagnosed in childhood,
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and about 40 to 70% of children with lupus will potentially develop lupus nephritis at some point in time.
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Although the clinical manifestations of childhood lupus and related kind of
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medication toxicities tend to be worse, we have gotten much better at treating lupus.
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So as you can see here, back in 1945, five.
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The five-year survival of patients with lupus was only 28%, but by the 1990s,
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around 91%. So again, significantly improved.
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In terms of renal prognosis, this has also gotten much better in the 80s or 90s.
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We were anywhere from 85% to 90% renal survival to mid-90s by the early 2000s.
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And I'll hand this over back to Dr.
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Patel to discuss the prognosis of lupus nephritis in a little bit more detail.
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Yeah, so this is more about lupus nephritis in our pediatric patients.
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So lupus nephritis, you know, the numbers are very variable,
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but it can occur in close to half of patients with systemic lupus.
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So some of the numbers may be, say, 10 to 30.
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Other data says maybe closer to 32 to 55 percent of patients will have lupus nephritis.
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What's interesting is a majority present within the first couple years of diagnosis.
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So 88% of patients will present with lupus nephritis within the first year of
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their systemic lupus diagnosis, and 94% will present within two years.
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And of those with lupus nephritis, anywhere from 10% to maybe 22% will go on
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to develop end stage in their lifetime.
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Lupus nephritis carries a mortality rate of up to 30% at 10 years.
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Like we mentioned earlier, in the 1950s, death was pretty common within two
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years of having lupus nephritis.
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So outcomes are better, but it's still guarded.
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And now the mortality rate on dialysis is about 22% at five years,
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and this is pediatric and adult data.
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So who are the patients who are more at risk of developing this end stage from
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their lupus nephritis diagnosis? Well, it's the younger children.
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It's seen more in males and people of certain backgrounds, so African-Americans,
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Hispanics, American Indians, Alaskan Natives, and Asian, those with Asian ancestry.
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And in general, we know that this is not limited to just lupus nephritis,
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but patients who are socially disadvantaged and live in medically underserved
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areas have worse kidney outcomes as well.
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So going back to our case, these were the additional lab workup that was ordered.
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It showed a low C3, low C4, again, pancytopenia, Coombs negative.
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What was interesting is that the time the patient came to the ED,
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nephrology was actually consulted for admission, and we didn't have many of these labs back.
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So the concern was we have a patient who's presenting with GN.
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Ultimately, the patient was cared for by general pediatrics because there was
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such a high suspicion for lupus.
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And then once some of these serological tests resulted in the morning,
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she was transferred to the rheumatology service.
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Treatment was started, and we planned to do a renal biopsy later in her admission.
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All right, I think the next slide, perfect. So in case you were curious,
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we did get additional labs back, but again, and this took some time.
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She had a pretty high ANA. She had a positive anti-Rho and LAW and positive
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double-stranded DNA antibodies.
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Some of her antiphospholipid antibodies also were positive.
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And we'll talk about this in the coming slides, but biopsy showed class 4 lupus nephritis.
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So I do want to spend some time discussing when we do a biopsy in patients with
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suspected lupus nephritis.
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Of course, your nephrologist will help answer this question,
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but sometimes, you know, as the general pediatrician or maybe the hospitalist,
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you're the first provider that's coming face-to-face with this patient,
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and maybe family has questions about what are next steps.
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So in general, the guidelines say a biopsy should be performed in any new diagnosis
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lupus patient with proteinuria,
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and the cutoff is 0.5 grams per gram, or if the patient has abnormal renal function
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that's otherwise unexplained.
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Those are two kind of key reasons to do a biopsy.
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For patients with known systemic lupus, we consider biopsy in the setting of a nephritis flare,
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or if after six months of appropriate treatment, their proteinuria hematuria
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or renal function is not improving.
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And then there are certain cases where a biopsy may not be possible.
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There may be concerns around the procedure, such as maybe the patient's really
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inflamed and we're concerned about bleeding, or if the patient has positive
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titers that make them at risk for clotting,
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or sometimes these kids present with uncontrolled hypertension,
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and this would make doing a biopsy or anesthesia unsafe.
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The guidelines say if a patient mainly has hematuria as part of their presentation,
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you choose treatment for class 3 and 4 lupus nephritis, or if they have features
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that are more nephrotic, so more heavy proteinuria,
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you would treat according to class 5 recommendations if you can't do a biopsy.
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So what is lupus nephritis? Well, we consider it an immune complex-mediated glomerulonephritis.
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So you have a large amount of autoantibodies that react with self-antigen,
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creating these immune complexes, which then deposit in the glomerulus.
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These deposits result in activation of the classical complement pathway.
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It activates macrophages, neutrophils, as well as pro-inflammatory and pro-fibrotic cytokines.
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Basically, all of this results in podocyte injury, mesangial endocapillary,
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and epithelial hypercellularity, as well as extracellular matrix deposits.
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And eventually, all this will lead to renal injury and impairment.
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There are other features that you can also see in a kidney biopsy,
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such as TMA, immune complex tubulo-interstitial nephritis, amyloidosis,
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are all kind of other features as well that we can see.
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So we'll go back to the next slide, and this is kind of going back to medical
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school, where I'm sure we all looked at EM images and pathology.
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So this is a part of the glomerulus, where you have the podocyte and the foot processes.
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There's also a mesangial cell, which is marked with a black arrow,
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and the capillary loop is what kind of what we're zoomed in on.
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The red dot is where you would see mesangial hypercellularity,
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so more cells in the mesangium.
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The darker blue is where you would see subendothelial deposits,
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and the light blue is where you would see subepithelial deposits.
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So just to kind of get an idea of what we will be looking at.
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So this is a quick table describing the International Society of Nephrology
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and the Renal Pathology Society classifications of the various classes of lupus nephritis.
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So this was developed in 2004, and there have been revisions done in 2018.
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So it's probably not as applicable to know each type or each class of lupus,
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but it's interesting to kind of note the column on the right,
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which gives us an idea of how these patients may clinically present.
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So you have class 1 and class 2, lupus nephritis, which these patients will
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have mesangial hypercellularity.
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And the differentiating factor between 1 versus 2 is how many cells are present
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in a 3 micron thick histological section. So if there are three cells or less,
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it's classified as class one.
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If it's four cells or more, it's class two.
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And clinically, these patients have mild symptoms, maybe some hematuria,
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maybe some mild proteinuria, and overall, they'll present with normal kidney function.
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Then we have class 3 and 4 lupus nephritis. This is defined as having glomeruli
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that have hypercellularity in the capillaries.
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So this is due to like an influx of inflammatory cells.
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You may have heard the term endocapillary proliferation, which is kind of a misnomer.
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It's more endocapillary hypercellularity or too many inflammatory cells in the
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capillary. So if less than half the glomeruli show changes, it's class 3.
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If more than half of the glomeruli biopsies show changes, it's considered class 4.
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And these patients have a little more AKI on presentation.
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Perhaps they also have hematuria and mild to moderate proteinuria,
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and this is kind of like our patient.
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Class 5 is membranous lupus nephritis, where there are protein deposits in the subendothelial space.
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And what's characteristic of these patients is they have heavy proteinuria,
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so often nephrotic range.
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And if they have isolated class 5, they may present with normal kidney function,
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but it can decline over time if not treated.
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And then there is this entity called class 6 lupus nephritis.
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It still exists, although maybe future nomenclature may do away with it,
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but it's really a biopsy sample with very advanced sclerosis,
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so almost like an advanced CKD kidney or end-stage kidney.
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Again, this is a drawing differentiating the various classes of lupus nephritis
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and where the deposits are.
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I won't spend too much time on this, but it shows kind of what we talked about on the previous slide.
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And if you ever want to look at this for reference, the colors in the box on
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the left kind of indicate what we're looking at in the images on the right.
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So there are still other things you can see on biopsy for a patient with lupus
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just beyond the deposits. You can see crescents.
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There can be fibrous crescents. You can have epithelial proliferation,
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and the cellular crescents will have a lot of different types of white blood cells in them.
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This picture here shows a fibrocellular crescent, and the arrow shows where the crescent is.
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You can also describe a glomerulus as having global or segmental,
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which means partial necrosis, in the setting of having a crescent.
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And then sometimes with a crescent, you can get fibrinoid necrosis,
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which is basically like a rupture of the glomerular basement membrane.
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And sometimes you see these types of lesions also in Anka disease as well.
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And then there are some other definitions like cariorexis, which is basically
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fragmented apoptotic cells in the kidney.
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It's important to review and be familiar with some of these pathological findings
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because it's how we assign scores to the biopsy.
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So there is a modified NIH activity index used for lupus nephritis.
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And the activity score essentially is given based on characteristics that show inflammation.
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So, specifically, this is inflammation that can be treated and is reversible.
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This activity index also has a separate chronicity score, and these are assigned
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based on findings like global glomerulosclerosis,
28:14
fibrous crescents, or basically changes that show irreversible damage or lesions
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that are scars, and this will not respond to therapy.
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So, we'll go back to our patient's case. This is actually our patient's biopsy stain.
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The image on the left is a normal pink H&E stain, and the picture on the right
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is three of her glomeruli.
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And as you can see, these three glomeruli look very pink compared to the normal
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one, which probably indicates mesangial expansion.
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And there's just a lot of cells, a lot of little blue-purplish dots,
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which we call increased cellularity in each glomeruli.
28:57
We can go to the next slide. Thank you. And so this is her PAS stain.
29:02
The mesangial expansion looks magenta on PAS.
29:06
And again, these are the same three glomeruli we saw in the previous slide,
29:10
and there's increased cellularity as well.
29:13
This slide here is a trichrome stain on the left, and the blue shows fibrosis.
29:20
And then on the right, it's a separate glomerulus, but this is a Jones silver
29:25
stain, and these lacy black lines are the preserved glomerular basement membrane.
29:32
And you can see towards the top is where we have a fibrocellular crescent.
29:37
This is our patient's immunofluorescent slides.
29:41
So what was really interesting about this case is she actually had a lot of
29:45
crescents, almost like a patient with Anka disease rather than lupus.
29:51
So her immune deposits actually weren't that impressive.
29:55
She had positive staining for IgG, C3, and C1Q, which are all shown here.
30:01
And there are some lupus cases where you don't get the classic full house staining,
30:05
but just kind of these three stains come back positive.
30:09
We can go to the next slide. And this is not our patient, but this is the textbook,
30:15
you know, full house IF staining that you would see with C1Q, C3, IgG, IgM, and IgA.
30:22
And again, going back to our patient slide, this is an electron microscopy slide of the glomerulus.
30:29
You can see the gray deposits, which are highlighted by the red arrows,
30:34
showing subendothelial deposits within this capillary loop.
30:39
And then again, another electron microscopy image.
30:42
The red arrows, kind of more to the top of the slide show subendothelial deposits.
30:48
Some of them are rather quite large. And then the arrows on the bottom right
30:53
corner show some mesangial deposits.
30:57
So just to summarize, the pathology report diagnosed class 4 lupus nephritis with crescents.
31:03
So 74% of her 35 glomeruli showed some type of involvement, whether it was necrosis or crescents.
31:11
The activity index was very high. It was 18 out of 24, and the chronicity index was 3 out of 12.
31:20
All right. So now, big question, now that we've established that this patient
31:24
has lupus and lupus nephritis, is how do we treat these patients?
31:29
So in pediatric rheumatology, we have a research body called CARA,
31:33
and CARA has developed consensus treatment plans, or CTPs, for various conditions,
31:40
including childhood lupus nephritis.
31:43
And so this is from the KERAS ATP for lupus nephritis.
31:48
And you can see here that there's a few different treatment arms, but,
31:55
The main non-steroids, so there's steroids and then there's non-steroidal agents.
31:59
And so for the non-steroidal agents, you're using either cyclophosphamide or mycophenolate.
32:07
And then for the steroid component, it can be either oral steroids,
32:13
a combination of mixed oral and IV steroids with a long taper for the oral steroids.
32:19
However, last year at the American College of Rheumatology, new guidance for
32:26
the treatment of lupus nephritis in terms of medication approach and disease
32:31
monitoring were presented.
32:32
We don't have to go into significant detail for the various treatment arms,
32:38
but I wanted to make you aware that compared to prior and what differs from
32:43
the care of CTP is that there's actually a shift towards triple therapy or slightly
32:49
more medication at presentation of disease.
32:51
So typically, the immunosuppressants that we use include mycophenolate,
32:58
calcineurin inhibitors, so that vocal spore in adults or tacrolimus in children.
33:04
Bulimumab, which is a monoclonal antibody that inhibits B-cell activating factor
33:09
or BATH, and cyclophosphamide.
33:11
The mycophenolate-based regimens are conditionally recommended over cyclophosphamide-based
33:19
regimens in patients with class 3 or 4 lupus nephritis due to some of the toxicity
33:25
associated with cyclophosphamide.
33:27
But if cyclophosphamide is to be considered, then they actually recommend a lower-dose protocol.
33:36
Other recommendations that are not specifically highlighted in this table have
33:41
to do with updates for recommendations regarding when to consider kidney biopsy.
33:46
The new guidelines suggest that repeat kidney biopsy is conditionally recommended
33:51
in patients who previously were diagnosed with lupus nephritis and remission
33:57
who then present with suspected flare.
34:00
Kidney biopsy is also recommended for patients who've had the appropriate treatment
34:04
but have ongoing signs of disease, such as ongoing significant proteinuria or
34:09
hematuria or decreased kidney function.
34:12
So in terms of the therapies, there's kind of like a main commonality between
34:19
steroids, mycophenolate, cyclophosphamide, and then the T-cell agents and calcineurin
34:25
inhibitors, the top one being infection.
34:27
So patients who are undergoing induction therapy you for lupus nephritis,
34:33
certainly are immunocompromised and at increased risk for infection.
34:37
So that should always be top of mind.
34:40
With regards to steroids, they continue to be a man's day of treatment for the disease.
34:46
And although as a rheumatologist, I love them, I also kind of hate them at the same time.
34:51
And that's because there's lots of potential adverse side effects,
34:54
especially in a growing child.
34:56
So some of the side effects that we can C include hypertension,
35:00
which again, you can imagine that someone who already has AKI or a renal disease
35:07
is already at increased risk and then you add steroids on top of it.
35:11
Effects. So you can see hyperglycemia or even diabetes in these patients on high-dose steroids.
35:19
There are potentially psychiatric effects. I would say the most common are mood
35:23
changes, irritability, sleep disturbance that can be as severe as icosah.
35:29
And then with regards to bone health, chronic steroids increase your risk for osteoporosis.
35:34
Again, can impact growth in children as well.
35:38
With regards to mycophenolate, this is a very consolidated list,
35:43
but in addition to infection, it's terabogenic.
35:46
So someone who is trying to conceive or is pregnant should not be on this therapy.
35:52
And then with regards to GI side effects, it's not uncommon when starting mycophenolate
35:58
that people will have some cramping or even like diarrhea at the start.
36:04
So oftentimes will start at a lower dose and dose escalate over several weeks.
36:09
In terms of cyclophosphamide, we typically use doses lower than some of our
36:15
oncology colleagues use in the treatment of cancer, but there are still risks.
36:20
So there could still be GI side effects, including nausea, vomiting.
36:26
Obviously reproductive side effects.
36:29
As I say from terabogenicity, we think about effects on fertility,
36:33
which is dependent on cumulative dosing and where kids are in terms of their pubertal growth.
36:39
We also worry about secondary malignancy.
36:42
And then lastly, we think about hemorrhagic cystitis, which basically can happen
36:49
as a consequence of how the medication's metabolized and with the toxic metabolite
36:56
hanging out in the bladder.
36:57
And so these patients who receive cyclophosphamide, also receive essentially
37:02
super hydration to potentially clear that out.
37:05
And they also receive mesomet to bind the creolin.
37:08
In terms of B-cell agents and calcineurin inhibitors, just kind of, again, very broad.
37:14
We unfortunately don't have time to go into detail for all these therapies,
37:17
but we think about everything from allergic reactions with our B-cell agent
37:21
to AKI and hypertension with our calcineurin inhibitors, and then a whole host of other things.
37:28
One thing I will mention before we go on to the next slide is that,
37:32
again, patients are immunocompromised when they're on these agents.
37:35
And so when thinking about how to protect these patients, certainly vaccines
37:41
are something that come up and something that we're really all for,
37:45
except for live vaccines in these patients.
37:48
Those we would typically avoid.
37:51
This slide briefly lists common complications related with lupus nephritis,
37:56
and these are important to be aware of.
37:59
So when you see a patient with lupus nephritis, it's very important to review
38:02
their recent creatinine.
38:04
This will give you an idea of what their GFR is and their renal function is,
38:08
or if you notice that their creatinine is much higher from previous measurements,
38:12
this could lead to acutely a lower GFR.
38:15
Maybe you're concerned in that moment for AKI or a lupus flare on top of the
38:21
patient's baseline potential CKD.
38:25
Hypertension can also be an active issue. It can be a consequence of the lupus
38:28
nephritis or even a consequence of the steroid treatment that the patient's on.
38:34
If a patient with systemic lupus has hypertension, we often refer them to nephrology
38:40
for management of the blood pressure, even if they don't have lupus nephritis
38:43
at that time, or if the blood pressure is dangerously high,
38:47
I use a cutoff of the 95th percentile plus 30 millimeters of mercury.
38:52
That's kind of my indicator of should this patient go to the ED for dangerously high blood pressures.
38:58
Again, if the patient doesn't have as high of the measurements but has symptoms
39:04
of hypertensive urgency, another reason to call nephrology or refer to the ER.
39:09
There's always a risk of more commonly like fluid overload.
39:14
So always trending the patient's weight, especially with active lupus nephritis,
39:19
just to get an idea of fluid balance.
39:22
Blood pressure may also be elevated if the patient is fluid overloaded.
39:27
Many times ongoing fluid overload. These patients will be on daily diuretics
39:32
for management, which can also be adjusted if they have worsening fluid overload.
39:37
And sometimes many of my patients go to their pediatrician more often than they're seeing me.
39:42
And so I do have a lot of active discussion with their primary provider on how
39:48
to adjust some of these diuretics as things are getting better or worse.
39:52
Lupus nephritis patients, especially depending on what class of lupus nephritis
39:57
may have proteinuria, low serum albumin.
40:00
They're always at risk with heavy proteinuria for fluid shifts,
40:04
hypogammaglobulinemia, infection, and bleeding and clotting.
40:08
And of course, also related to renal function and also maybe medication side
40:14
effects, patients can have abnormal electrolytes.
40:16
So just looking at potassium, for example, especially if there's an AKI from their lupus nephritis.
40:22
And then also related to lupus nephritis, but also impacted by what antibodies the patient has.
40:29
For example, if a patient has a positive lupus anticoagulant or antiphospholipid
40:34
antibody or is very inflamed or proteuric, could there be a risk for bleeding or clotting?
40:41
So in terms of managing these patients outpatient, we really try to partner
40:46
with our general pediatrics colleagues.
40:48
And so this schematic is actually from Boston Children's and their model when
40:53
it comes to how specialists and pediatricians can work together to deliver care
40:58
to medically complex children and also, you know,
41:02
children with chronic disease, including those with lupus.
41:05
As you can see here, the majority of children are
41:09
care are healthy, and that's where the medical home is really with the primary care team.
41:16
However, once someone's diagnosed with a chronic condition, it is really a matter
41:21
of the primary care team collaborating with specialists and the family.
41:25
And then for those children who have both medically complex and chronic disease,
41:30
their model suggests that either the primary care team or specialty care team
41:35
can service a medical home, but collaboration as well as having support team
41:40
members such as the coordinator,
41:42
social worker, a nurse are really key.
41:45
I'm not sure what your current model looks like at your institution,
41:48
but I think what works best for our rheumatology group is really serving as
41:53
the medical home for these complex patients.
41:55
However, really relying on our general pediatrics colleagues for ongoing support
41:59
with general preventive care, including vaccination, well visits,
42:04
and then urgent sick visits for routine illnesses.
42:07
So that actually brings me to this slide, which gives a very broad overview
42:12
of vaccine recommendations for rheumatology patients in general.
42:16
And so this is actually family and patient-facing guidance that was put together
42:21
by one of our former and recently graduated fellows,
42:24
Amanda Moyer, who worked on this internally with considerations from rheumatology,
42:28
as well as our immunocompromised ID group.
42:31
We don't have to go into this in detail, but I wanted to share some general principles.
42:37
In general, we know that many of our patients are, again, at increased risk
42:41
of infection due to weakened, dysregulated immune systems.
42:46
Vaccination may be key in preventing some illnesses. In general,
42:50
patients with weakened immune systems should not receive live vaccines,
42:54
but may benefit from additional vaccinations, including pneumococcal,
42:59
shingles, hepatitis, B vaccines.
43:02
And so what I would encourage is that if there isn't already guidance between
43:07
pediatric and specialty groups at your institution,
43:10
it might be worth considering, you know, coming up with a plan so that these
43:14
patients can be screened and receive the appropriate vaccinations.
43:19
So in terms of the role of the pediatrician in long-term care,
43:23
we've already touched on some of this.
43:26
But in general, as specialists, we really rely, again, on our pediatrics colleagues
43:30
for helping to support our patients, certainly with lupus or other chronic conditions,
43:34
to evaluate for acute illness and anticipate prevented care.
43:38
Many of our patients don't live within close proximity to our clinics,
43:42
nor do we always have availability to do sick or urgent visits.
43:46
So in these cases, our pediatric colleagues are able to support these patients
43:51
for the initial assessment and determination for whether additional workup or
43:55
admission may be needed.
43:57
I think, again, in general, for these patients who are immunocompromised,
44:02
having a low threshold for, you know, workup for infectious illness is really key.
44:08
You might think about also opportunistic infections, fungal infections, atypical things.
44:14
So I would, again, also encourage not just reaching out to like your local emergency
44:19
room if needed and colleagues there and sending the patient there potentially,
44:23
but also reaching out to the subspecialist if there's questions.
44:27
And we're generally only a page away. And again, we're usually very happy to
44:31
partner with our general pediatrics colleagues to help provide the best care
44:35
for our patients. For our shared nephrology patients, Dr.
44:40
Patel already kind of went into this, but they're at risk for fluid overload, hypertension.
44:44
They need to be seen regularly for blood pressure monitoring and other general care.
44:50
And then for vaccinations, again, in addition to ensuring that these patients
44:56
are appropriately vaccinated,
44:58
we also have to keep in mind that these patients are at risk for more serious
45:02
sequela from certain infections and may need post-exposure treatment.
45:07
So if there's ever any question of exposure to things like measles,
45:11
varicella, in addition to connecting with the primary rheumatologist or potentially
45:16
nephrologist, discussing with your infectious disease colleagues may be required.
45:21
There may be some coordination needed for some of those therapies.
45:26
And this is a nice summary table for practice guidelines for adjuvant therapies
45:31
for patients with lupus nephritis.
45:33
It goes through diet, additional medications for proteinuria,
45:37
which those will probably be managed by nephrology, as well as managing blood pressure, bone health.
45:44
But a focus for a primary physician would be not only vaccinations,
45:48
but also discussing and aiding in reproductive health.
45:52
As you may deal with, you know, contraception and certain considerations,
45:56
usually in these patients, we do recommend using methods without high-dose estrogen.
46:02
So just a nice summary table to reference.
46:05
I think that might be all of our thoughts. Yeah.
46:11
Do we want to, oh, I will not share the questions because I think Maybe the
46:16
answer are highlighted, it looks like.
46:19
We don't see the highlights. Oh, if I click further, they will be highlighted.
46:25
So my apologies. But let me see if I can jump to our references slide.
46:29
After references. Thank you, everyone, for your time and for listening to our talk.
46:35
Thank you, Dr. Poonia and Dr. Patel for updating us on lupus and lupus nephritis.
46:42
Let's see if anybody has any questions or comments. You can always put your
46:47
questions in the chat box or raise a hand and you can ask the question directly
46:53
to our wonderful speakers.
46:55
Dr. Williams, go ahead and ask your question, please.
46:59
Good morning. Thank you. Both the speakers were wonderful.
47:05
Thank you for that information. And one just a side comment that's weird,
47:09
but, you know, quite a while ago, I saw the roof of the mouth ulcer like that
47:18
related to a patient we diagnosed with scurvy.
47:22
So just saying to put it in your differential. Of course, it's unusual, but it happens.
47:29
On the other hand, I wondered if you, and if I missed this, I'm sorry, relate more her,
47:35
her, is there a relationship, do you think, to her menstrual cycle, the menarche,
47:43
that type of part of her presentation to what you found, you know,
47:49
that anisarka or any of the other symptoms?
47:51
Was there a relationship or
47:53
just, it's just happened to be within three months? Like quenfoot and all?
47:58
I think like at least with lupus and some of our other autoimmune conditions in general,
48:05
it's not uncommon for us to see patients in their early teenage years,
48:09
kind of in the context of all these hormonal and pubertal changes.
48:15
I think kind of from that standpoint, could there, again, be a relationship? I think it's possible.
48:22
But I think in terms of the patient's
48:24
presentation, I think not anything specifically, except that maybe,
48:31
again, kind of like family perception or, you know, it can be confusing to patients,
48:37
you know, if they're seeing blood in their urine and, again,
48:41
like there's potentially menarche around the same time.
48:44
In this case, the patient had hematuria, so I think it just could have muddied
48:49
the picture kind of maybe initially for what the family was thinking or maybe
48:54
what their primary care doctor was thinking just because there are other factors.
48:58
Sure. Okay. Thank you so much. And Dr.
49:01
Williams, I wonder if your patient was scurvy, were they like autistic or had
49:07
certain eating behaviors? I just diagnosed a scurvy patient yesterday.
49:11
So we're seeing it a lot. Actually, they weren't.
49:14
It was amazing. It was a dietary issue, and the child got into a vicious cycle where the parents only,
49:26
you know, the child would only eat like three things, bean tacos,
49:31
nothing that had any kind of vegetable vitamin C,
49:36
any kind of vitamins I forgot what it was bean tacos there
49:39
were three things they would eat and and they
49:41
were so happy that the child would eat anything that that's
49:45
all they would give them it was just this vicious cycle it's
49:49
hard to believe but yeah no they we
49:52
did follow them for some learning issues
49:55
but I became a Linus Pauling you know follower because the minute we gave him
50:02
vitamin c I mean You could see a change from this crabby kid and couldn't really
50:10
walk and just to becoming human.
50:14
It was pretty amazing. That's incredible.
50:18
I do some research on chronic non-bacterial osteomyelitis or CNO or CRMO,
50:25
definitely on the differential.
50:27
I know this patient presented with the oral issues.
50:32
But it sounds like they also had some bone pain, so when you're thinking about
50:36
like arthralgias or limb pain, definitely I've diagnosed patients with vitamin
50:42
C deficiency as well. Check their vitamin C. Yeah, check their vitamin C level.
50:46
Yeah. Well, thank you so much. Yeah, that's a funny little segue,
50:51
but really it's important, so thank you.
50:54
Any other questions or comments for Dr. Patel and Dr. Kuni?
51:00
Quickly comment on use of biologics in lupus, pediatrics?
51:05
What are the indications and what is the current status?
51:11
Yeah, so there is this kind of, again, shift towards triple therapy at least
51:16
with lupus, lupus nephritis.
51:19
And so it depends on the class of disease for the patient.
51:26
But if we're thinking about class 3 or more commonly kind of class 4 lupus nephritis,
51:32
then we're thinking about high-dose steroids and mycophenolate,
51:35
which is a similar fire, but we're also thinking about things like blimumab
51:39
or if there is a severe refractory disease, things like rituximab, obinutuzumab.
51:45
So those are, you know, kind of like B-cell or B-cell depleting agents in kind
51:50
of different ways that we're thinking about.
51:52
We're kind of more of the class 5 disease. We're still thinking more about casinurin inhibitors.
51:58
But certainly, we have patients with overlap of class 4 and 5 lupus nephritis.
52:04
So, again, B-cell depleting agents might be considered for both.
52:08
And then also, you know, again, this has been primarily a lupus nephritis-focused
52:13
talk, but sometimes we use B-cell depleting agents also for kind of other clinical
52:19
manifestations of disease,
52:21
whether like severe hematologic kind of refractory disease, sometimes even kind
52:27
of the presence of other factors.
52:30
Like if we're thinking about like antiposylobid antibodies, you know,
52:33
syndrome in conjunction with lupus, if we're thinking about just other clinical
52:38
features in general, is, you know, severe rashes, eucutaneous findings.
52:42
So we are using biologics fairly frequently.
52:45
I would say, again, binlimumab being amongst the most common,
52:50
and it's kind of more recently approved for the treatment of lupus nephritis,
52:53
and even in children, which when I was in fellowship with not the case,
52:56
and then some of our anti-CV20 agents.
53:00
Yeah. Thank you. Dr. Hundon, please go ahead and ask your question, please.
53:06
Yeah. I was curious about the general overall epidemiology.
53:13
For example, I noticed that a lot of these young women.
53:19
Menarche and then they got involved in sports sports
53:23
that relied that relied on a lot of stress and
53:26
exposure to heat and you know elevated body
53:29
temperature and the other thing i was concerned about since i treated a lot
53:35
of adult patients is male male cases of sle and about they have Have you noticed
53:44
any changes there or any revelations?
53:48
Yeah, I think, you know, autoimmune disease in general has kind of the increasing
53:53
prevalence, probably due to a whole host of factors, some of which are,
53:59
as you're alluding to, you know, potentially environmental.
54:03
But I think that at least with regards to kind of when these patients present,
54:08
again, it's not uncommon for you to see patients with lupus kind of in their
54:14
teenage years or kind of entering or just having entered puberty.
54:18
It is far less common still to see really young patients with lupus.
54:24
I mean, do I have, have I seen it in, you know, a seven or eight year old?
54:28
Yes. But I would say that would be kind of like the exception.
54:32
And then certainly, we still, you know, the predominance is still female,
54:39
but we do have a fair number of patients who are male with lupus, with renal disease.
54:47
I don't know that I can say just anecdotally that there's increasing frequency
54:52
in the male population in general.
54:55
But again, I think that we're seeing more lupus, more like general autoimmune
55:00
disease in general. So I wouldn't be surprised if there had kind of been an
55:04
increase as well by gender.
55:07
I just got used to the idea that males presented gender.
55:14
With CNS symptoms, behavioral symptoms, pulmonary manifestation,
55:19
and perfectly good kidneys, and things like that, just getting a really,
55:23
you know, an entirely different constellation.
55:29
Of presentations. Yeah, I think it's, I mean, you feel like the whole host of presentations,
55:37
I mean, we have this thing in rheumatology that if you've seen one patient with
55:42
lupus, And I really can't think of like two patients that are alike,
55:46
but I agree with you about like, you know,
55:49
still have a higher suspicion and kind of like our teenage female patient,
55:53
again, higher suspicion for renal disease.
55:56
But I do have some male patients who also have renal involvement.
56:00
So, yeah, it just depends. And I feel like the male patients that I've taken
56:06
care of with renal involvement usually have a strong family history of lupus,
56:10
like a parent with lupus, something like that, almost always.
56:14
But again, what else? Dr. Brooks, quick, Ali.
56:20
Yeah, it's more of a comment that, as an immunologist, I find it helpful to
56:25
do an initial flow cytometry for teen B-cell subsets at diagnosis.
56:31
And part of the reason is the predisposing factor can become a variable immune deficiency.
56:37
And again, the symptoms at teenage years can be quite subtle.
56:40
And later with immunosuppression, we do see patients with T-cell deficiencies,
56:46
et cetera. And you wonder if it's chicken or the egg.
56:49
I have seen patients with suppression with high doses of mycophenolate and have
56:53
to back off those doses and see the CD4 T-cell counts increase after that.
56:58
So just a quick comment from an immunology standpoint.
57:03
Thank you for that learning point. No, definitely.
57:07
It's definitely something to think about.
57:11
Thank you, Dr. Pune. Thank you, Dr. Patel, for that wonderful presentation.
57:17
Thanks for listening to that fabulous talk. Don't forget to click on the link for free credit.
57:24
I'm Holly Weyman. I'll see you soon.