Update on the treatment and outcome of systemic lupus erythematous in children

Abstract

Purpose of review

Provide an update of studies published in last 2 years on the outcomes and therapies in childhood-onset systemic lupus erythematous (cSLE).

Recent findings

Additional evidence has been provided about the benefits of universal hydroxychloroquine in SLE patients, although antimalarial maculopathy may be more prevalent than previously thought. Recent studies support lower glucocorticoid doses than used in the past may provide comparable therapeutic benefits, and cSLE patients can mount adequate immunogenic response and sustain long-term seroprotective titers when vaccinated. Long-term studies of adults with cSLE confirmed that damage accrual increases with disease duration. Cardiovascular disease, renal transplants, replacement arthroplasties, and myocardial infarctions occur between 20 and 40 years of age. Higher prednisone doses predicted higher damage trajectory and antimalarial exposure was protective. There were no prospective clinical trials published in pediatric patients with cSLE, but positive results from phase II trials with bariticinib and ustekinumab in adult SLE may raise the expectation that these drugs could be beneficial when used in cSLE.

Summary

The dire need for more clinical trials and licensed medications for cSLE persist as well as decreasing damage accrual.

INTRODUCTION

Systemic lupus erythematous (SLE) is a heterogeneous autoimmune disease driven by autoantibodies and proinflammatory cytokines with the potential to cause multisystem damage. Childhood-onset SLE (cSLE) occurs before the age of 18 years and typically has a more severe clinical course than adult-onset SLE (aSLE) [1]. Standard therapy includes glucocorticoids, antimalarials, and additional systemic immunosuppression when disease is severe or refractory. Most therapies in SLE are used off label [2]. Treatments for cSLE remain understudied, especially with respect to their impact on the physical, mental, and psychosocial development that occurs during childhood and adolescence. This review provides an update of publications over the preceding 2 years relevant to the treatment and outcome of cSLE.

TREATMENT

Glucocorticoid and antimalarials

Glucocorticoids, mainly prednisone and methylprednisolone, together with antimalarials continue to be the backbone therapies for SLE. Although most recent publications have studied adults, some of the reported findings appear applicable to cSLE. The use of high-dose glucocorticoids in SLE is increasingly being challenged. Ruiz-Arruza et al. [3] published a case–control study of aSLE patients treated with a restrictive regimen of oral prednisone (average 15 mg/day in year 1 and average of 2.8 mg/day in years 2–5 post diagnosis, mandatory hydroxychloroquine, and intravenous pulse methylprednisolone for flares) vs. a historic control group of aSLE patients treated with high-doses oral prednisone (average 36 mg/day in year 1 and average 9.4 mg/day in years 2–5), less strictly enforced use of hydroxychloroquine (100 vs. 52%), and fewer methylprednisolone pulses for flares (32 vs. 12%) [3]. The restrictive prednisone group accrued less glucocorticoid-related and cardiovascular disease, while experiencing similar overall SLE-related damage. This suggests that lower doses of oral steroids, when combined with hydroxychloroquine and intravenous methylprednisolone pulses provide similar disease control but can reduce overall damage with SLE.

Similar observations were made in the Lupus-Cruces and Bordeaux Study [4]. Herein lupus nephritis was treated with bi-weekly 125 mg pulse intravenous methylprednisolone and intravenous cyclophosphamide and low-dose oral prednisone. The latter was rapidly weaned for the Lupus-Cruces study. Comparison was made with the Lupus Bordeaux group where patients received less intravenous methylprednisolone pulses with higher doses and slower wean of oral prednisone. The Lupus-Cruces group achieved remission of lupus nephritis faster and at a higher rate. Thus, lower oral corticosteroid doses did not result in worse outcomes and had the added benefit of lessening glucocorticoid-related side effects. In addition, pulse methylprednisolone use, instead of higher steroid daily oral doses, may provide added therapeutic benefits.

Retinopathy from hydroxychloroquine is irreversible, and there is currently no treatment. Recent studies suggest that the prevalence of retinopathy with antimalarial use is higher (1.6–8.0%) than previously believed (0.4–1.9%) [5]. In part, these observations may be due to more sensitive screening modalities such as spectral-domain optical coherence tomography (SD-OCT). Risk factors for ocular toxicity with hydroxychloroquine use is a daily dose exceeding the recommended maximum weight-adjusted dose, exposure to hydroxychloroquine for over 5 years, impaired renal function, tamoxifen use, and macular disease [6▪▪]. The risk of ocular toxicity from hydroxychloroquine intake for up to 5 years is less than 1% and increases to less than 2% for up to 10 years. Ocular toxicity risk rises close to 20% with 20 years of daily hydroxychloroquine intake, and the incidence of ocular toxicity is 4% during each year thereafter [6▪▪]. The American Academy of Ophthalmology (AAO) published revised recommendations on screening for antimalarials in 2016 [7▪]. The recommended maximum daily dose of hydroxychloroquine is 5 mg/kg based on real weight, instead of ideal body weight as was suggested previously [8]. Screening includes SD-OCT with multifocal electroretinogram and fundus autofluorescence. The cSLE Quality Indicators [9] and the SHARE recommendations [10▪] suggest that children with cSLE should receive annual eye exams while on hydroxychloroquine therapy of any duration, high prevalence of renal disease, cotherapy of glucocorticoids, other ocular manifestation of cSLE, and anticipated long-term use of hydroxychloroquine. Despite heightened concerns, universal hydroxychloroquine therapy continues to be recommended for cSLE [9,10▪].

Given the profound benefits of antimalarial therapy, the AAO emphasized that questionable abnormalities on ocular screening should be verified using another validated testing method prior to discontinuing antimalarials with SLE [7▪]. This is because there is mounting evidence that continuing antimalarials has multiple benefits such as maintaining disease remission, decreasing SLE flare rates, protecting against thrombosis, and increasing survival. These benefits were reaffirmed by recent publications that confirmed that antimalarials provide protection against infections, decreases mortality, are steroid sparing, and decrease damage accrual [11,12]. A long-term clinical outcome study in adults with cSLE and a median disease duration of 20 years reported that monotherapy with hydroxychloroquine was associated with avoidance of damage as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI score; odd ratio = 0.16, 95% confidence interval (CI): 0.042–0.633, P = 0.009] [13▪▪]. This is in line with a longitudinal cSLE study which showed that antimalarials protected against an increase in damage trajectory even when high-dose prednisone therapy was deemed necessary [14▪]. Notably, these cSLE studies found benefits despite quite likely limited adherence to hydroxychloroquine in a sizable proportion of cSLE patients. The benefits of hydroxychloroquine are more pronounced in the setting of superior adherence [15].

Cytokine targeted therapies

Target-specific therapies against proinflammatory cytokines linked to the pathogenesis of lupus are underway. Since 2017, a few phase II, multicenter, randomized, double blind placebo controlled trials on aSLE showed promising results by targeting type 1 interferons, IL-12 and IL-23, and dual APRIL (a proliferation-inducing ligand)/B lymphocyte stimulator (Table 1) when added to the standard of care (SoC) treatment of aSLE [16▪,17▪▪,18]. Addition of baricitinib (4 mg/day) to SoC therapy was superior to placebo in achieving resolution of arthritis or rash and aSLE improvement as measured by the SLE responder index-4 (SRI-4). With these results, the US Food and Drug Administration (FDA) granted baricitinib fast-track status and a confirmatory phase III study is underway.

Table 1.

Adult-onset systemic lupus erythematosus multicenter, randomized, double-blind, placebo-controlled, 24-week phase II clinical trials with potential benefit in childhood-onset systemic lupus erythematosus

Drug and trial number	Mechanism of action	Intervention	Eligibility requirement	Organ	Primary outcome	Results	Reference
Baricitinib NCT02708095	JAK1/JAK2 inhibitor	Daily baricitinib 4mg or 2mg or PBL added to SoC	≥18 Years old with SLEDAI-2K score ≥4 and with active arthritis or rash. Steroids limited to ≤20mg Excluded were active severe lupus nephritis, CNS disease or recent serious infection	Joint and skin	Resolution of arthritis or rash defined by SLEDAI-2K	Resolution of SLEDAI-2K arthritis or rash was significantly higher with baricitinib 4mg than PBL (67 vs. 56%) No significant improvement in skin disease alone in SLEDAI-2K mucocutaneous domain or CLASI activity was found Only bariticinib 4mg compared with PBL achieved greater SRI-4 response, low disease activity score, and decrease flares	[16▪]
Ustekinumab NCT02349061	Fully humanized mAb directed at the p40 subunit shared by cytokines IL-12 and IL-23	IV infusion ustekinumab (260–520mg depending on weight) followed by SQ of ustekinumab 90mg every 8 weeks or IV infusion of PBL at week 0 followed by SQ injections of PBL every 8 weeks, both to SoC	18–75 Years old with SLEDAI-2K score ≥6 during screening and a SLEDAI-2K score ≥4 for clinical features at baseline. Steroids limited to ≤20mg Excluded those with rheumatoid and psoriatic arthritis, psoriasis, unstable, or progressive SLE (active class III or IV nephritis, systemic vasculitis, or active CNS involvement)	All except kidney and CNS	SLEDAI-2K Responder Index-4 (SRI-4) greater than PBL	Ustekinumab compared with PBL group achieved significantly greater SRI-4 SRI-5, and SRI 6 response Post-hoc analyses, ustekinumab had greater response than PBL group in improvement of joint disease (90 vs. 66%) and CLASI activity score (64 vs. 30%) also greater mean response on modified SLEDAI-2K (75 vs. 52%)	[17▪▪]
Atacicept NCT019722568	Dual BLyS and APRIL (a proliferation-inducing ligand) inhibitor	Once weekly SQ injection of 75 or 150mg atacicept or PBL to SoC	≥18 Years old with SLEDAI-2K score ≥6 during screening and a SLEDAI-2K score ≥4 for clinical features at baseline Excluded were lupus nephritis or major CNS involvement, received rituximab, ocrelizumab or other B cell directed biologics 1 year before screening visit	All except kidney and CNS	SLEDAI-2K Responder Index-4 (SRI-4) greater than PBL	No significant improvement in SRI-4 with atacicept 75 (58%) and 150mg (54%) compared with PBL (44%) A subgroup with high level of disease activity, serologically active disease or both at baseline had significant improvement in the SRI-4 (63 vs. 42%) and SRI-6 (55 vs. 29%) in the atacicept group than PBL	[18]

BLyS, B lymphocyte stimulator; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; CNS, central nervous system; IV, intravenous; PBL, placebo; SLE, systemic lupus erythematous; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; SoC, standard of care; SQ, subcutaneous; SRI, Systemic Lupus Erythematous Responder Index.

Anifrolumab, a monoclonal antibody (mAB) of the interferon alpha receptor, achieved greater response as measured by the SRI-4 with sustained reduction of oral steroids, greater improvement in organ-specific disease features, such as cutaneous and arthritis disease, and improved disease control compared with placebo [19]. However, one of the two phase III trials of anifrolumab failed to reach its primary endpoint. The second phase III trial of fixed dose of anifrolumab is still underway.

Compared to placebo, ustekinumab, mAb against p40 shared by IL-12 and IL-23, resulted in higher rates of achieving a SRI-4 response (33 vs. 62%; P = 0.006) [17▪▪]. Post-hoc analyses suggested a beneficial effect on cutaneous involvement with aSLE. Unlike the previously mentioned drugs, ustekinumab holds a pediatric indication from the FDA for the treatment of psoriasis in children more than 12 years.

The phase II trial with atacicept did not yield significantly greater SRI-4 response compared with the placebo. But a subgroup of patients with more severe or serologically active disease treated with 150 mg of atacicept experienced higher rates of SRI-4 response compared with placebo group [18].

Belimumab

Belimumab is approved for the treatment of active aSLE based on a series of clinical trials. A long-term extension study of belimumab of aSLE patients followed for 13 years revealed that adverse effects and infections rate remain stable over time [20▪]. Based on observed analysis, SRI response increased from 33% (88/268) at year 1 to 76% (68/90) at year 12. Low-SLE activity status (SELENA-SLEDAI score ≤2) increased from 8% (25/296) at baseline to 62% (46/ 74) at year 12, and 13% of patients were able to discontinue corticosteroids [20▪]. Another study compared organ damage in SLE patients enrolled in the BLISS long-term extension study of belimumab with matched control from a SLE Toronto Cohort not receiving belimumab [21]. Over a 5-year period, development of damage was significantly lower in the belimumab group vs. controls (difference in SDI change = −0.434; 95% CI −0.667 to −0.201; P < 0.0001). Intravenous belimumab has been approved for cSLE therapy by the FDA in 2019 [22].

Vaccines

Infections are a major source of SLE morbidity and mortality, with vaccines offering protection. Current vaccine guidelines recommend that SLE patients receive inactivated vaccines according to schedules for the general population, and receiving pneumococcal polysaccharide vaccine (PPSV23). If a patient has not received the 13 valent pneumococcal conjugate vaccine (PCV13), then the PCV13 should be administered at least 8 weeks prior to the PPSV23 vaccine. Generally, live or live-attenuated vaccines are contraindicated in immunocompromised patients. In SLE patients, live vaccines are recommended on a case-to-case basis given the variability in immunosuppressive treatments used for disease control [23]. Such vaccines include vaccines against varicella, live herpes zoster, measles, mumps, rubella, yellow fever, intranasal influenza, oral polio, and oral typhoid. No supporting evidence has been shown that vaccine administrations may cause lupus flares or newly initiate lupus features in susceptible individuals [24]. A recent review of vaccination practices, safety, and efficacy summarizes evidence that administration of pneumococcal, influenza, hepatitis B, diphtheria and tetanus toxoid, hemophilus influenzae Type B (HIB), and human papilloma virus (HPV) vaccines does not prompt SLE flares [25].

Despite lack of strong evidence, it is recommended to give vaccines when SLE is quiescent or has low activity because most information of vaccine efficacy stems from patients with stable, controlled SLE [23]. There is some evidence that high disease activity and immunosuppressive therapies (high cumulative dose of prednisone, mycophenolate, rituximab) can impact seroconversion rates and antibody titer levels to some vaccines [26,27,28▪]. Nonetheless, studies have shown that SLE patients can mount an adequate immunogenic response after vaccinations to protect against hepatitis A, hepatitis B, HPV, HIB, clostridium tetani, and diphtheria [23,29]. Sequential vaccination of PCV13 and PPSV23 protective serotype levels (>70% of serotypes >1.3 μg/dl) were reported in 65 and 59% of children with cSLE, as compared with healthy controls with rates of 100 and 95% of the cases [28▪]. A steeper decline of antibody titers was observed when rubella and hepatitis A titers were measured annually for 3 years postdiagnosis in cSLE patients compared with controls. Despite faster decline in titers, cSLE patients sustained adequate seroprotection rates for rubella (95% at diagnosis and 90% at 12 and 36 months) and hepatitis A (95% at diagnosis, 90% at 12 and 89% at 36 months), respectively [26,30].

HPV vaccination is important because SLE patients are at higher risks of abnormal pap smears and precancerous cervical lesions compared with healthy women [31,32]. In cSLE, HPV vaccination was reported to be safe, not increase lupus flares, result in high seroconversion rate more than 94% [33,34]. For quadrivalent HPV vaccine, antibodies persisted 5 years post vaccination (84–96%) in SLE patients, although titer levels for serotypes 6 and 16 were lower compared with controls [27].

Vaccines are an effective method to keep SLE patients healthy and decrease morbidity. The safety and efficacy of inactivated vaccines have been demonstrated by numerous studies. There is still need for large prospective studies on long-term immunity of vaccines in children past 5 years and if revaccination may be required if titers decline below seroprotective levels.

OUTCOME

Time to diagnosis and mortality rates of cSLE patients have improved. Most cSLE patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry were diagnosed by a pediatric rheumatology within 1.4 months of symptom onset [35]. However, delays in diagnosis of 3–12 months occurred in 23% and severe delay of over 1 year in 9% of patients, respectively. There were no significant differences in disease activity among children with rapid as compared with moderately or severely delayed cSLE diagnosis. A family history of lupus and residence in a state with higher density of pediatric rheumatologists were associated with earlier diagnoses while low family income and younger age at symptom onset was associated with severe delay, suggesting health disparities in diagnosing cSLE in North America.

Despite lower mortality with cSLE, morbidity remains high [13▪▪,14▪,35,36]. An international multicenter study of 1048 cSLE patients with mean disease durations of 3.8 years, showed that almost half the patients had disease-related damage measured by SDI [37]. Two studies addressed the long-term outcomes of adults diagnosed with cSLE. One was a cohort of 111 adult patients with cSLE in the Netherlands with median disease duration of 20 years [13▪▪] and the second in Canada assessing the damage trajectory in 473 cSLE patients with median follow-up 5.6 years (with maximum follow-up of 26 years) [14▪]. Both studies reaffirmed that damage accrual increases with disease duration, and often affects the musculoskeletal (i.e., avascular necrosis and osteoporosis) and neuropsychiatric system (i.e., cognitive impairment). Premature cardiovascular damage remains a concern. Hydroxychloroquine use was associated with lower damage accrual. In a long-term study of Dutch cSLE patients with median disease durations of 20 years, where 65% had a low disease score (SLEDAI-2K score ≤4) at the time of the study, most types of cSLE manifestations developed during the initial 2-years post diagnosis. However, 68% of the patient still needed steroid therapy, and drug free remission was rare [13▪▪]. Cardiovascular disease, renal transplants, arthroplasties, and myocardial infarction occurred early, that is, at median ages of 20, 24, 34, and 39 years, respectively. Lim et al. [14▪] reported steady damage accrual throughout the disease course. Predictors of damage acquisition were treatment with high doses of prednisone, cyclophosphamide use, lupus headache, acute confusion, and threatening major organ manifestations (lupus nephritis class III–V, stroke, vasculitis, and myocarditis). African-Caribbean patients with SLE had more organ damage and persistently steeper damage trajectory than Whites and Asians.

A prospective international multicenter cohort of 467 patients showed that cSLE often impacts emotional health and is associated with marked worries about well being. The least impacted domains of health-related quality of life (HRQoL) were social and physical aspects, activities of daily living, and social functioning [38]. Lower HRQoL was associated with female sex, high disease activity, presence of damage, non-White ethnicity, and the need for cyclophosphamide or rituximab therapy. For reasons not entirely clear, European and Asian patients had the highest HRQoL and North and South American patients had the lowest HRQoL.

The latest outcome studies confirm that there is a deep lasting impact of cSLE into adult life. Disease durations beyond 30 years were associated with significantly worse physical and mental health (SF36) compared with patients with a disease duration of less than 10 years [13▪▪]. As may be expected, adults with cSLE have lower HRQoL compared with the general population. Particularly cSLE-associated altered physical appearance, that is, rash or alopecia, negatively impacted HRQoL, irrespective of overall disease activity [13▪▪]. On average, active renal disease had no acute negative impact on HRQoL. Adults with cSLE with or without organ damage (SDI > 0 vs. SDI = 0) only differed importantly in their physical function.

CONCLUSION

There remains a great need for research in and approval of drugs for cSLE. Profound morbidity from cSLE continues, making research in better treatment strategies mandatory. Despite recent data of more common retinotoxicity from antimalarial long-term use, steroid-related ocular side effects are currently more common than hydroxychloroquine retinopathy. Thus, research in the evidence-driven use of intravenous and oral corticosteroids seems of utmost importance and better insights about optimal use of antimalarials are needed given their steroid sparing effects and other beneficial impact on cSLE. Future needs include rigorous studies of medicine for cSLE in tested in clinical trials, development of treatment strategies targeted to improve HRQoL.

KEY POINTS.

• Recent studies have reaffirmed that hydroxychloroquine has steroid-sparing affects, decreases flares, damage accrual, infections, and increases survival.

• Reduced glucocorticoids doses have equal or better therapeutic benefits than higher doses of glucocorticoids.

• Phase II trials with baricitinab and ustekinumab in adult-onset SLE patients have been shown that these drugs are likely safe and efficacious with the potential beneficial use in cSLE.

• Outcome studies in adults with cSLE show renal, neuropsychiatric, and musculoskeletal are the most prevalent damaged organs, cardiovascular disease continues to occur early, and most patients remain on glucocorticoid therapy.