Childhood- and adult-onset lupus: an update of similarities and differences

Eva D Papadimitraki, MD, PhD; David A Isenberg, MD, FRCP, FACS

Disclosures

Expert Rev Clin Immunol. 2009;5(4):391-403. 

In This Article

Therapies

Lupus is associated with chronic morbidity and an increased risk of mortality, and has an unpredictable course. These features emphasize the need for long-term monitoring. Although broadly similar, some aspects of management have a different emphasis in children with lupus. As childhood-onset lupus is often an aggressive disease with a higher incidence of renal and CNS disease, the requirement for high-dose steroids may be more frequent than in adults. Aside from raising concerns for premature atherosclerosis, secondary osteoporosis and growth delay, this requirement may have a considerably negative impact on child and adolescent physical and psychosocial development. Data from adult studies cannot be safely extrapolated to juvenile patients.

Immunosuppressive agents are initiated when significant risks for organ damage (i.e., the presence of biopsy-proven diffuse glomerulonephritis or acute CNS disease) are met. As with adults, when prolonged steroid requirements with doses over 0.3 mg/kg/d are needed, immunosuppressive agents, most commonly azathioprine (for its favorable safety profile), are also recommended. Brunner and colleagues and Hersh and colleagues showed that steroids were used in 97–100% of children with lupus compared with 72–90% of adult lupus patients (p < 0.001), and that pediatric lupus patients required more immunosuppressive drugs compared with their adults counterparts.[7,8] Adherence to treatment is a frequent problem in pediatric lupus populations.[75] Obesity, stunted growth, striae and hirsuitism are the main fears of patients within these age groups, which not uncommonly lead to treatment withdrawals and thus treatment failures.

Lupus Nephritis It is now widely accepted that lupus nephritis treatment requires an initial phase of intensive induction therapy followed by a longer period of less intensive therapy (i.e., maintenance phase). The 10-year follow-up data of the Euro-Lupus Nephritis Trial demonstrated comparable efficacy of low- and high-dose cyclophosphamide (CYC) induction regimens, and the former may be favored as a less toxic, albeit an equally effective therapeutic, approach.[76–78] In adults, data from recent randomized clinical trials suggest that mycophenolate mofetil (MMF) as an induction regimen is at least as good as intravenous CYC in terms of efficacy and safety, and that it might be a better option for black patients with lupus nephropathy. There are preliminary data to suggest that the combination of MMF with tacrolimus may exhibit an added benefit over CYC; however, claims of efficacy superior to CYC need confirmation. Regarding remission maintenance, there is some evidence that suggests that MMF is superior to quarterly CYC and is equivalent to azathioprine, although the results of large randomized trials are awaited to clarify its role. The safety of MMF in patients with severely compromised renal function has not been documented.[77,78] It has been demonstrated recently that rituximab (RTX), a chimeric human/mouse monoclonal antibody against CD20+ B cells, may be effective in refractory cases of lupus nephritis or in cases of toxicity to conventional regimens in adult SLE.[79–82] The efficacy and safety of the combination of MMF with RTX for lupus nephritis relapses has yet to be documented in long-term randomized trials.[83]

Prospective, randomized control trials comparing the efficacy and safety of the aforementioned regimens in pediatric lupus nephritis are generally lacking. To date, there is no study documenting an increased rate of serious adverse effects, such as life- threatening infections, hemorrhagic cystitis or secondary neoplasia, in children compared with adults receiving monthly pulses of CYC. In fact, premature ovarian failure more commonly occurs in older women (>32 years old) exposed to CYC, and reduced progesterone levels accompanied by a reduced follicular reserve are mostly associated with the disease per se in juvenile patients.[84] However, fears of life-threatening infections, secondary neoplasia and ovarian failure may lead patients or their parents to refuse CYC-based regimens. In an attempt to overcome the obstacle of CYC-induced side effects, a quadruple therapy protocol may be employed, although, again, there are no randomized data to support its generalized use.[85] To date, the only study comparing MMF to CYC for induction of remission in childhood lupus nephritis showed superiority of the former for class III nephritis.[75–86] However, despite showing efficacy in membranous nephropathy, MMF failed to attenuate disease progression in pediatric patients with class IV nephritis.[87] No studies comparing MMF to azathioprine for the maintenance of remission in pediatric lupus populations have been conducted. Fujinaga et al. showed that MMF was beneficial in maintaining remission in Japanese pediatric lupus patients with all forms of nephritis who were followed up for 27.5 months.[88] Azathioprine or MMF may be used as maintenance treatments, but further studies are needed to document the superiority of one against the other. As in adults, RTX is a therapeutic option in pediatric patients with refractory lupus nephritis. After 3 years of follow-up, Nwobi and colleagues report clinical and laboratory improvement in 93% of 18 patients who had refractory to conventional regimens disease who received RTX; however randomized, controlled trials are required to establish its long-term efficacy and safety in pediatric populations.[80]

CNS Disease The recognition and treatment of CNS involvement is a major diagnostic and therapeutic challenge in patients with SLE. There are no adequate randomized, controlled data to guide the treatment of this heterogeneous component of lupus. In adults, mild NP manifestations may need symptomatic treatment only. Thrombotic manifestations, especially in the presence of APS require anticoagulant therapy. Severe diffuse CNS manifestations, such as generalized seizures, acute confusional states, mood disorders and psychosis, generally require high doses of pulsed intravenous corticosteroids, with the addition of intravenous pulsed CYC if the patient is refractory – that is, if an adequate response is not achieved within 3–5 days of treatment – although some experts advocate the ab initio use of pulsed intravenous CYC as a first-line regimen in this setting. Patients with diffuse or focal neurological syndromes, including, for example, demyelinating syndromes, transverse myelitis, chorea, seizures and cognitive dysfunction, may be helped by long-term anticoagulation if there is evidence of persistently raised levels of antiphospholipid antibodies.[89] There has not yet been any large, controlled study of the therapy of pediatric CNS disease. The case series suggest that steroids alone without concomitant use of immunosuppressive drugs (particularly CYC) may be associated with a worse outcome in pediatric neurolupus.[90,91] The results of these studies suggest that significant CNS involvement in children should be treated with a combination of high-dose steroids with an immunosuppressive agent, such as azathioprine of CYC, in the case of severe organic brain syndrome or psychosis requiring hospitalization, however, further studies and a generalized consensus are needed to establish the proper therapeutic approaches for NP involvement in children with lupus.[53] There is scant evidence to suggest the use of MMF in either adult of childhood NP lupus.

Other Disease Manifestations High-dose steroids represent the mainstay of treatment for hematological manifestations of both adult- and childhood-onset lupus, with azathioprine, MMF, ciclosporine and CYC proposed as second-line agents for refractory disease. Preliminary evidence suggests that B-cell depletion with RTX is safe and efficacious for autoimmune thrombocytopenia and autoimmune hemolytic anemia in pediatric SLE, comparably with adult-onset disease.[92] Severe refractory cardiorespiratory adult disease may also respond to RTX, although there are no data regarding its use in childhood disease in this context.[93] The EXPLORE study is a Phase II/III study that assessed the efficacy and safety of RTX versus placebo over 52 weeks in 257 patients from 16 to 75 years of age with moderate-to-severe active extrarenal SLE. Unfortunately, no statistically significant differences between RTX and placebo and no differences when analyzing the BILAG index results, with either area under the curve (AUC) of total activity or landmark analyses of clinical responses using different definitions, were observed.[94] However, there is a growing optimism for targeting B cells in the treatment of both childhood- and adult-onset SLE, despite the failure of the EXPLORER trial, which may well have failed due to the rather high doses of concomitant steroids that were allowed.

New tools are becoming available for immune modulation, for example, anti-B-cell targets, such as anti-CD22, anti-BAFF, toleragen molecules specific for autoreactive B cells (LJP394) and peptide vaccination, that have the prospective of increased efficacy and lower toxicity than currently used immunosuppressive treatments; however, their use in both adult and childhood SLE populations require further documentation.

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