Special Considerations Needed for Kids

WASHINGTON — When the American College of Rheumatology (ACR) released its updated guideline for management of lupus nephritis (LN) at its 2024 Annual Meeting, they included recommendations for managing pediatric LN for the first time. 

The pediatric recommendations use the same classification criteria, outcome measures, and treatments as in adults — including the first-line triple therapy recommendation — but there remain important differences between pediatric and adult LN, Mary Beth Son, MD, clinical chief of immunology and section chief of rheumatology at Boston Children’s Hospital and an associate professor of pediatrics at Harvard Medical School, Boston, told attendees. 

“In general, kids and adolescents with lupus are sicker,” Son said. They are more likely to have renal manifestations and neuropsychiatric lupus at diagnosis, compared with adults. Further, “although the disease is the same, it’s happening to kids and adolescents who are undergoing critical periods of growth and development,” she said. 

Medication risk profiles also shift for younger patients, Son noted. 

“Importantly, they’re at risk for higher cumulative dosing of both glucocorticoids and cyclophosphamide,” Son said. “When we give an adolescent a course of cyclophosphamide, we have to be aware that this might be the first of a few courses over the course of the lifetime disease, and with increasing numbers of cyclophosphamide courses, you have increased risk for infertility and malignancy.” 

Son also acknowledged challenges of pediatric literature, including differences in definitions of pediatric lupus, very few randomized controlled trials, and fewer pediatric studies in general, with fewer participants. Given these research gaps, the guideline panels included pediatric rheumatologists and nephrologists, and the patient panel included several patients with childhood-onset disease.

Son also addressed differences in pediatric drug development. Dosing studies also do not always directly translate from adults to children because children have larger drug volume distribution and differences in drug clearance, and they may need different formulations, she said. Children tend to tolerate medications better than adults because they usually have fewer comorbidities, but the assessment of a drug’s safety must take its impact on growth and development into consideration.

During a press conference after the session where the guideline was presented, Linda Hiraki, MD, ScD, a clinician-scientist in rheumatology at the Hospital for Sick Children, Toronto, said the panel took into consideration that pediatric patients receive their diagnosis during a critical time of development, so considerations of medication risks include the fact that children “have much more life to live.”

Triple Therapy Recommended

As with adults, the pediatric LN guideline recommends a triple therapy approach: glucocorticoids plus mycophenolate mofetil and belimumab, in addition to the usual renin-angiotensin-aldosterone system inhibitors and hydroxychloroquine. But Son acknowledged limitations of applying the new guideline to children. For one, voclosporin has not been studied in or approved for pediatric patients, although there exists modest evidence for other calcineurin inhibitors, mainly tacrolimus, in children.

“The other important consideration is that the lower dose of prednisone that’s being offered by the guidelines of 40 mg per day as a starting dose has not been studied in pediatric lupus nephritis patients,” Son said. “However, I would offer that, given that we know that kids get higher doses and longer courses, it’s even more important to consider a lower dose to begin with in the setting of other immunosuppressants.”

Good Practice Statements for Pediatric LN

Son also reviewed three good practice statements for pediatric LN. First, “glucocorticoid regimens should use pediatric-appropriate doses for children, as reduction of human glucocorticoid dosing is critically important given the early age of pediatric lupus onset and attendant comorbidities,” she said.

That statement is based on both common sense and some literature, including awareness that children are more likely to receive higher doses of steroids and that children’s higher damage scores are driven in part by steroid-related toxicity, such as avascular necrosis and cataracts. In addition, glucocorticoids can have profound effects on body mass index, mood, and height attainment.

“This is during a period of emerging self-identity and struggles with appearance; steroids exacerbate that” as well as mood issues already associated with puberty, Son said.

The second good practice statement recommends that clinicians monitor patients “for delayed pubertal onset and decreased growth velocity that can result from disease activity and glucocorticoid treatment and consider referral to pediatric endocrinology if indicated.” The third states that “a structured, intentional transition from pediatric to adult rheumatology care is indicated to avoid poor outcomes during this vulnerable period.” 

During the press conference, Hiraki said that pediatric rheumatologists already recognize the need for discussions about transfer to adult care to begin very early, even years before patients are ready to transfer.

“The transition from being a pediatric patient to being an adult patient is very challenging for a number of reasons,” starting with loss of insurance coverage, added Bonnie Bermas, MD, a professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas. When adult rheumatologists take on these patients, they may not have had care for 2 or 3 years, she said. 

Rebecca Sadun, MD, PhD, an associate professor of pediatrics in rheumatology at Duke University School of Medicine, Durham, North Carolina, and vice-chair of the Systemic Lupus Erythematosus Committee for the Childhood Arthritis and Rheumatology Research Alliance, was not involved in the guideline development process but reviewed the new guideline. 

“We appreciate that the ACR took care to involve pediatric rheumatologists, pediatric nephrologists, and patients with childhood-onset lupus in the development of the newest lupus nephritis treatment guidelines,” she told Medscape Medical News. She also noted, however, that “the dearth of pediatric-specific clinical trial data means that we continue to wonder when it is appropriate to extrapolate from adult data regarding the efficacy, safety, and dosing of certain medications, including steroids and voclosporin.” She also noted that voclosporin use can increase pill burden and therefore be difficult to use in pediatrics.

“Children, adolescents, and young adults are a unique population with unique challenges, including significant struggles with adherence to complex medication regimens,” she said. Sadun drew attention to two themes from the guideline that she found particularly applicable to management of pediatric LN.

“First, we must remain wary of the serious consequences of long-term, high-dose glucocorticoids, and we should continue to look towards steroid-sparing strategies that will reduce reliance on glucocorticoids,” Sadun said. “Second, we are likely to see better outcomes, including better renal response, when we take advantage of combination immunosuppression earlier in the disease course.”

Son, Bermas, and Sadun had no disclosures. Hiraki has consulted for Janssen. The guideline development did not involve outside funding. 

Tara Haelle is a Dallas-based science/health journalist.