Systemic lupus erythematosus (SLE) in children: Treatment, complications, and prognosisAuthorThomas JA Lehman, MDSection EditorMarisa Klein-Gitelman, MD, MPHDeputy EditorElizabeth TePas, MD, MSAll topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Sep 2015. | This topic last updated: Aug 28, 2015.

INTRODUCTION — Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect the skin, joints, kidneys, lungs, nervous system, serous membranes, and/or other organs of the body. SLE in children is fundamentally the same disease as in adults, with similar etiology, pathogenesis, clinical manifestations, and laboratory findings. However, the care of children and adolescents with SLE is different from that of adults because of the impact of the disease and its therapy on physical and psychologic growth and development. (See "Overview of the clinical manifestations of systemic lupus erythematosus in adults".)

The treatment, complications, and prognosis of SLE in children are reviewed here. The epidemiology, clinical features, diagnosis, and classification of SLE in children are discussed separately. (See "Systemic lupus erythematosus (SLE) in children: Clinical manifestations and diagnosis".)

TREATMENT — The goals of therapy for patients with SLE are to ensure long-term survival, achieve the lowest possible disease activity, prevent organ damage, minimize drug toxicity, improve quality of life, and educate patients and their families about their role in disease management [1,2].

Treatment of SLE is individualized based upon patient preferences, disease activity and severity, and comorbidities [3,4]. Patients require monitoring at regular intervals by a rheumatologist to optimize both nonpharmacologic and pharmacologic therapies and achieve treatment goals. Patients often have multiorgan system involvement and may require multidisciplinary care. Assessment of disease activity and severity and nonpharmacologic interventions are reviewed in detail separately. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Assessment of disease activity and severity' and "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Nonpharmacologic and preventive interventions'.)

Clinicians caring for children must be especially conscious of the effects of medications, such as glucocorticoids, on growth and physical appearance in children and adolescents. The unique problems related to growth and development effect both the need for and the impact of aggressive therapy [5-7]. Failure of therapy of childhood SLE frequently results from efforts to care for a child or adolescent with a complex and chronic disease without considering the special needs of the growing individual and his or her family. As a result, clinicians who are unprepared to deal with these needs should refer these patients to a pediatric rheumatology center. (See 'General considerations' below.)

General considerations — Clinicians caring for children with SLE must remember that normal laboratory values for children differ from those for adults. As an example, a "normal" serum creatinine concentration in a child younger than 10 years of age is 0.5 mg/dL (44 micromol/L). As a result, a level of 1.1 mg/dL (97 micromol/L), while "normal" in an adult, represents substantial

renal failure in a young child. In addition, levels of compromised renal function that may have no clear adverse effect among adults may be sufficient to affect normal growth and development in a child or adolescent.

The emotional impact of SLE and its treatment also makes the care of children and adolescents distinct. Adolescence is a period of substantial psychologic stress associated with evolving self identity. It is very difficult for these children to internalize the concept of chronic illness. The resultant sense of being different is markedly intensified by changes in their appearance, whether directly caused by the illness or as a result of therapy (eg, glucocorticoids). Failure to deal appropriately with these issues often leads to noncompliance and a poor outcome.

In particular, high dose glucocorticoids have a profound impact on growth and appearance in children and adolescents. This impact is often associated with both physical impairment (ie, short stature and/or osteonecrosis) and psychologic devastation. For many adolescents with SLE, their current cushingoid appearance is of greater significance than any potential future event. Thus, both overt and covert suicide attempts (eg, surreptitious refusal to take necessary medications) are well recognized in centers caring for large numbers of adolescents. The treating clinician must do everything possible to minimize glucocorticoid toxicity and maximize compliance with the treatment regimen (including the use of other immunosuppressive agents). (See "Suicidal behavior in children and adolescents: Epidemiology and risk factors" and "Major side effects of systemic glucocorticoids" and "Causes of short stature", section on 'Glucocorticoid therapy'.)

Initial therapy — The agent that best combines safety and efficacy for the treatment of SLE is hydroxychloroquine. Additional agents are also used and vary depending upon disease severity and response to treatment. The most common additional agent used is glucocorticoids. (See 'Mild SLE' below and 'Moderate SLE' below and 'Severe SLE' below.)

There is general agreement among adult and pediatric rheumatologists that all patients with SLE should receive hydroxychloroquine during the entire course of the disease, including during pregnancy. In order to minimize the risk of irreversible visual damage, the hydroxychloroquine dose in children should be ≤7 mg/kg/day, and these children should have regular ophthalmic evaluations, including color vision and visual field testing. Ophthalmic monitoring is reviewed in greater detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)

A review of 95 studies examining the effects of hydroxychloroquine and chloroquine on SLE found strong evidence of a beneficial effect on disease activity and survival, and convincing, though weaker, evidence of improvements in irreversible organ damage, thromboses, atherosclerosis, bone mineral density (BMD), and lipid profile [8]. Adverse events from these agents were uncommon and tended to be mild, although in rare cases use was associated with irreversible retinal toxicity. However, this agent works slowly and should not be expected to remedy more significant disease manifestations in a timely manner. Thus, it is best used as an addition to other agents rather than alone.

Most children with SLE are treated with glucocorticoids in addition to hydroxychloroquine. While glucocorticoids are known to be effective in treating childhood SLE based upon extensive clinical experience and observational studies, there are no data regarding optimal dosing. Thus, dosing and duration of glucocorticoids is decided on an individual basis and depends upon the clinical severity, combination of disease manifestations, and response to treatment [9]. As examples, a lower initial dose (eg, prednisone 0.25 mg/kg/day) and more rapid taper are suitable for a patient with milder disease who responds quickly to treatment, whereas a child with severe lupus nephritis or

neuropsychiatric involvement may be treated with pulse intravenous methylprednisolone (10 to 30 mg/kg/day for up to three doses) followed by oral prednisone (2 mg/kg/day) that is tapered over many months. (See 'Mild SLE' below and 'Moderate SLE' below and 'Severe SLE' below.)

Mild SLE — Conservative care is indicated for the child with mild SLE who does not have renal or other life-threatening organ system involvement. The use of nonsteroidal antiinflammatory drugs (NSAIDs) (to control musculoskeletal manifestations) and hydroxychloroquine (≤7 mg/kg per day up to 200 mg in most children with an adult maximum of 400 mg per day) is often sufficient in this setting. NSAIDs that have a sulfa component, such as sulindac, should be avoided, since sulfa antibiotic allergy is more common in patients with SLE [10,11]. Any other NSAID is suitable. NSAIDs should be discontinued once musculoskeletal manifestations have resolved. Dapsone may be helpful for the occasional child with primarily dermatologic manifestations [12]. Patients on hydroxychloroquine must have regular ophthalmologic screenings. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)

Low dose glucocorticoids (less than 0.35 mg/kg per day of prednisone) are often necessary to attain adequate disease control in children with mild SLE. However, long-term use of even such low amounts should be avoided if possible, since doses above 0.2 mg/kg per day may adversely affect longitudinal growth [12]. We suggest adding a second-line agent, typically mycophenolate mofetil, whether or not renal disease is present if glucocorticoids in a dose of greater than 0.35 mg/kg/day are required for more than three months.

Children with mild disease are increasingly common in large centers as more pediatricians identify such patients through appropriate screening for SLE. These patients should be followed closely, since apparently mild cases may progress in severity over time.

Moderate SLE — The approach in children and adolescents with moderate SLE (eg, clinically significant, but not life-threatening involvement of the kidneys or other vital organs/systems) is similar to that for mild SLE, except that these patients often require the continued use of high dose glucocorticoids to control disease activity in addition to hydroxychloroquine. Options for managing glucocorticoid toxicity include higher dose alternate day oral therapy, intermittent intravenous high dose therapy, or addition of a steroid-sparing agent. At the author's institution, children whose disease does not quickly come under control with a combination of hydroxychloroquine and glucocorticoids are promptly advanced to mycophenolate mofetil. If there are persistent disease manifestations, they may be advanced to intravenous cyclophosphamide and rituximab. (See 'Mild SLE' above and 'Initial therapy' above and 'Severe SLE' below.)

Many centers attempt to manage glucocorticoid toxicity by using higher dose alternate day oral therapy (prednisone or prednisolone), but the benefits of this regimen remain uncertain. An alternative regimen is intermittent intravenous high dose methylprednisolone, which has the advantage of shutting down the lupus interferon signature (ie, decrease expression of particular interferon genes that are upregulated in SLE), an effect that is not seen with oral glucocorticoids [13]. Some centers use mycophenolate mofetil, azathioprine, and/or methotrexate as steroid-sparing agents in these children because of the concerns noted above about glucocorticoid toxicity, but clinicians must be aware of the possible renal toxicity of methotrexate and the risk of reaching toxic methotrexate levels if renal function deteriorates.

There is extensive experience with azathioprine and increasing experience with mycophenolate mofetil [14]. Reports of the usefulness of methotrexate in SLE are less conclusive, although it appears to be helpful with musculoskeletal disease [15]. The author does not use methotrexate, because it is potentially nephrotoxic and may unexpectedly reach toxic levels if kidney function

deteriorates since it is excreted in the urine. Monitoring for methotrexate toxicity is reviewed in the specific drug topic.

Severe SLE — Children and adolescents with severe SLE (eg, substantial renal or neurologic disease) require more aggressive therapy [9]. As in adults, children with the diffuse proliferative type of lupus nephritis have the worst prognosis [16]. Initial treatment is the same as is used for moderate SLE. Cyclophosphamide is used in patients with life-threatening lupus nephritis immediately upon diagnosis in most institutions, and in patients unable to taper the prednisone dose sufficiently. Mycophenolate mofetil is the most commonly used alternative to cyclophosphamide in patients with severe SLE. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus" and 'Moderate SLE' above and "Therapy of diffuse or focal proliferative lupus nephritis".)

The use of intravenous cyclophosphamide was initially restricted to children with life-threatening diffuse proliferative glomerulonephritis. It has since been used routinely in children with moderate to severe SLE who cannot be maintained on an acceptable level of glucocorticoids and other glucocorticoid-sparing agents. It is also increasingly used as an additional induction agent in children who do not respond to initial therapy with hydroxychloroquine and glucocorticoids, before trying another steroid-sparing agent.

With extensive use, monthly intravenous cyclophosphamide was found to permit a reduction in daily glucocorticoid use to a minimal level and was associated with acceptable long-term safety [17]. Thus, its use has broadened to include all children with moderate or severe SLE who cannot be adequately controlled on a lower dose of glucocorticoid and another steroid-sparing agent. Specifically, we use intravenous cyclophosphamide in children who cannot otherwise be maintained on a prednisone dose of less than 0.5 mg/kg per day despite use of steroid-sparing agents. The length of immunosuppressive therapy varies based upon organ involvement. In children with nephritis, for example, there is an unacceptable frequency of disease flare when cyclophosphamide is discontinued after the initial seven doses without substitution with an alternative immunosuppressive agent. In contrast, a one-year course may be sufficient for those with extrarenal disease only.

Intravenous cyclophosphamide appears to have the best documented long-term success rate in children and adults with severe SLE [17-19], despite scattered studies suggesting comparable outcomes with agents such as mycophenolate mofetil [20]. The regimen we prefer is based upon the National Institutes of Health (NIH) protocol developed during the 1980s and 1990s [21]. It consists of monthly intravenous pulses of cyclophosphamide (500 mg/m2 increasing to 1 g/m2 as tolerated) for six months (seven doses), followed by maintenance therapy with mofetil mycophenolate or azathioprine. Patients who have a history of poor adherence should be maintained on cyclophosphamide every three months for an additional 30 months instead. However, one study suggested the addition of rituximab with cyclophosphamide may obviate the need for continued administration of cyclophosphamide, mycophenolate mofetil, or azathioprine [22]. (See "Therapy of diffuse or focal proliferative lupus nephritis".)

An intravenous cyclophosphamide regimen is effective in treating children with SLE who have diffuse proliferative glomerulonephritis. In one study, intravenous cyclophosphamide was given to 16 children, 8 with steroid-unresponsive lupus nephritis and eight with either steroid-dependent nephrosis or active lupus nephritis and unacceptable glucocorticoid-induced side effects [18]. Cyclophosphamide therapy significantly reduced proteinuria (1 versus 3.2 g per day) and increased creatinine clearance among those with decreased function prior to therapy (121 versus 57.5 mL/min per 1.73 m2). Prevention of progression of renal scarring using this program of cyclophosphamide

administration in another study of 16 children with renal biopsies performed before and following three years of cyclophosphamide therapy [19].

Cyclophosphamide is increasingly used as an induction agent in a variety of rheumatologic conditions in patients who are unresponsive to an initial course of hydroxychloroquine and glucocorticoids. This involves a seven-infusion course of monthly pulsed doses followed by conversion to a less toxic maintenance medication, such as mofetil mycophenolate or azathioprine. In one small study, lower doses of glucocorticoids were needed when rituximab was added to the initial regimen [22]. In adult studies of vasculitis [23] and SLE [24], this has appeared to optimize benefits of the more potent drug while minimizing exposure and long-term toxicity. An absence of data precludes favoring one approach over another.

The long-term safety of intravenous pulse cyclophosphamide in children is not well defined. With respect to gonadal toxicity, data from oral therapy suggest that the risk is greatest in sexually mature males and lowest in prepubertal children. Girls rarely become infertile. The clinician should consider sperm banking or ovarian protection to reduce the risk of infertility when cyclophosphamide is needed if the family is concerned, but the author has many female patients who have successfully begun families following completion of intravenous cyclophosphamide therapy without taking any specific protective measures during therapy. The risk of bladder toxicity is markedly reduced with the use of mesna, but the effect on other toxicities is not yet known. (See "General toxicity of cyclophosphamide in inflammatory diseases" and "Fertility preservation in patients undergoing gonadotoxic treatment or gonadal resection".)

Some centers use mycophenolate mofetil instead of cyclophosphamide, particularly where there is significant risk to future gonadal function. In addition, and there are no efficacy data to support the use of a specific steroid-sparing agent. However, mycophenolate mofetil is associated with a significant incidence of stomach upset and requires consistent twice or three times daily dosing to be effective. As a result, compliance can become problematic, particularly in adolescents. Gastrointestinal side effects are reduced with an enteric coated formulation. Mycophenolate levels can be monitored and some patients may need alteration of usual dosing due to personal pharmacokinetics and pharmacogenetics. Cyclophosphamide may be no more effective than mycophenolate mofetil in controlled studies, but it is easier to ascertain compliance with a monthly intravenous medication than with a daily oral medication.

Some children develop recurrent disease following withdrawal of intravenous cyclophosphamide therapy. There is no consensus on how to treat such patients. Options include a multidrug regimen consisting of intravenous cyclophosphamide and intravenous methotrexate monthly for one year [25], one to two doses of rituximab with or without cyclophosphamide, and other biologic or immunosuppressive agents [26]. (See 'Refractory disease' below.)

Refractory disease — Children with renal disease resistant to other immunosuppressive agents may benefit from treatment with mycophenolate mofetil. Rituximab is a therapeutic option in children with severe SLE refractory to conventional therapy.

Mycophenolate — Data from uncontrolled retrospective studies suggest that children with renal disease resistant to other immunosuppressive agents may benefit from treatment with mycophenolate mofetil [14,27,28].

In one study of 11 children with lupus nephritis, all four with membranous glomerulonephritis improved on mycophenolate, although those with proliferative glomerulonephritis had little renal benefit [14]. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was reduced in 10

of the children and mean glucocorticoid dose was decreased in 6. Adverse effects were common (infection, leukopenia, nausea, pruritus, headache, and fatigue).

In another study, 16 children with severe proliferative lupus nephritis were treated with mycophenolate mofetil [27]. Thirteen patients were also treated with cyclosporine. Significant improvement was seen in the SLEDAI score, proteinuria, and serologic markers (C3, C4, and anti-double stranded deoxyribonucleic acid [anti-dsDNA]). Complete remission was attained by 44 and 75 percent at 6 and 12 months, respectively. The remaining patients achieved partial remission. The most common side effect reported was infection. No serious adverse effects were noted.

Biologic agents — Rituximab, a chimeric anti-CD20 monoclonal antibody, and belimumab, an immunoglobulin G1-lambda monoclonal antibody are under study for refractory SLE.

In several uncontrolled retrospective studies, rituximab, a chimeric anti-CD20 monoclonal antibody often used in combination with cyclophosphamide, was effective in the treatment of children with severe SLE refractory to conventional therapy [29-34]. In addition, children treated with a combination of rituximab and cyclophosphamide in small open label trials had improved clinical responses and decreased need for cyclophosphamide and glucocorticoids [22,35]. Controlled clinical trials in adults have failed to show efficacy of rituximab alone [36]. Caution is particularly warranted in view of the rare reports of severe, and often fatal, complications in some adults treated with rituximab [22,37,38]. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Rituximab'.)

In the largest of the retrospective studies, 63 children (median age 14.4 years) were treated with two doses of rituximab (750 mg/m2) given two weeks apart [32]. Nineteen patients received more than one course of rituximab. About three-quarters of the patients were also treated with cyclophosphamide, and nearly all of the patients were on oral glucocorticoids. All patients had received prior immunosuppressive therapy. The oral glucocorticoid dose was significantly reduced and clinical biomarkers improved after rituximab treatment. However, there was no significant reduction in SLE disease activity assessed by the British Isle Lupus Assessment Group (BILAG) index in the subset of 25 patients with this data available. Adverse events occurred in 19 of the 104 total courses of rituximab and included neutropenia (n = 1), decreased immunoglobulin levels requiring replacement therapy (n = 2), infection (cytomegalovirus and adenovirus infections in one patient and herpes zoster infection in another), and anaphylaxis (n = 2).

Hematopoietic cell transplantation — Some have advocated autologous hematopoietic cell transplantation (HCT) for children with severe SLE [39,40], while others feel that "conventional" therapy is adequate. Thus, the use of HCT is most likely to remain largely theoretical, until the morbidity and mortality of this intervention can be reduced.

Assessment of response to therapy — The Pediatric Rheumatology International Trials Organization (PRINTO) has developed and validated a set of criteria to measure clinical response to therapy in children with SLE [41]. These criteria are similar to those used in patients with juvenile idiopathic arthritis. They include questionnaire-based assessments by the clinician, patient, and parents on disease activity, patient well being, and quality of life, as well as clinical assessment of the patient using a global disease activity index (eg, European Consensus Lupus Activity Measurement [ECLAM]). Global disease activity indices use a combination of history, examination, and laboratory data. These indices were designed to monitor response to therapy in adults with SLE. However, none have been universally adopted. They are hampered by the enormous variability of disease manifestations in different cases of lupus, rendering meaningful

comparison difficult. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Assessment of disease activity and severity'.)

Continued efforts are needed to establish a universally accepted set of criteria for assessment of response to therapy in juvenile SLE. This work is ongoing and consensus to define lupus disease flare, remission, and response to therapy are forthcoming [42-44].

Monitoring disease activity — Disease activity in children is monitored in a similar fashion to disease activity in adults. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Monitoring frequency'.)

Treatment of disease flares — The management of disease flares in children with SLE is highly individualized. Fortunately, they are rare in those treated with systematic cyclophosphamide with or without rituximab. When they occur, an increased dose of glucocorticoids followed by mycophenolate mofetil is often required. For those already receiving mycophenolate or azathioprine, cyclophosphamide can be used if there is no response to a short-term increase in glucocorticoids. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Flares'.)

Treatment of specific organ system involvement — Patients with specific disease manifestations may require additional therapy beyond the usual treatment for SLE. Treatment for hematologic, pulmonary, and cardiac manifestations in children is reviewed here. Treatment for SLE manifestations in other systems (eg, renal, neurologic) is discussed in detail separately in the following topic reviews:

●(See "Mucocutaneous manifestations of systemic lupus erythematosus" and "Initial management of discoid lupus and subacute cutaneous lupus" and "Management of refractory discoid lupus and subacute cutaneous lupus".)

●(See "Musculoskeletal manifestations of systemic lupus erythematosus".)

●(See "Therapy of diffuse or focal proliferative lupus nephritis" and "Therapy of resistant or relapsing diffuse or focal proliferative lupus nephritis" and "Clinical features and therapy of membranous lupus nephritis" and "Clinical trials of immunosuppressive therapy in proliferative lupus nephritis" and "End-stage renal disease due to lupus nephritis".)

●(See "Gastrointestinal manifestations of systemic lupus erythematosus".)

●(See "Neurologic manifestations of systemic lupus erythematosus" and "Neuropsychiatric manifestations of systemic lupus erythematosus".)

Hematologic abnormalities — Hematologic abnormalities that may require additional therapy include neutropenia, iron deficiency anemia, autoimmune hemolytic anemia (AIHA), and thrombocytopenia.

●Leukopenia – Leukopenia in children with SLE usually resolves as disease activity is brought under control. Neutropenia is the exception. Granulocyte colony-stimulating factor (G-CSF) may be used to increase the neutrophil count when granulocytopenia is secondary to infection [45]. Neutropenia secondary to drug toxicity typically responds to lowering the drug dose or temporarily discontinuing the relevant drug. (See "Drug-induced neutropenia and agranulocytosis".)

●Anemia – Similar to leukopenia, anemia of chronic disease in children with SLE typically resolves as the disease is brought under control. Iron therapy is not helpful if there are adequate iron stores. The treatment for iron deficiency anemia in children and adolescents with SLE is the same as it is for those without SLE: 3 to 4 mg/kg per day of elemental iron orally. The efficacy of this therapy is demonstrated by an increase in the reticulocyte count within three days of initiating therapy. Parenteral iron is rarely required [46]. (See "Iron requirements and iron deficiency in adolescents" and "Iron deficiency in infants and young children: Treatment".)

Systemic glucocorticoids are the first-line therapy for AIHA in children with SLE. Mild to moderate cases are treated with prednisone. Cases of severe rapidly progressive anemia may respond to intravenous methylprednisolone administered as a bolus of 30 mg/kg per day for three days (maximum daily dose 1 g), followed by tapering daily oral doses of prednisone as the response to therapy allows. Children with hemolytic anemia may benefit from supplemental vitamins, especially folate, in view of their increased metabolic synthesis of red cells.

Second-line therapies reserved for those patients who do not respond to glucocorticoids include danazol [47], intravenous immune globulin [48], and plasmapheresis [49]. Rituximab has proven useful in adults with SLE who failed other therapies [50] and in children in the author's experience. Splenectomy should be used only in life-threatening circumstances [51]. (See "Autoimmune hemolytic anemia in children and adolescents", section on 'Treatment'.)

●Thrombocytopenia – Glucocorticoids, usually prednisone, are the first-line therapy for thrombocytopenia in SLE. Refractory cases, and those in which there is active hemorrhage, are treated with intravenous methylprednisolone administered as a bolus of 30 mg/kg per day for three days (maximum daily dose 1 g). Intravenous immune globulin also may be used, but is usually reserved for severe, life-threatening bleeding and should be used with caution in patients with renal compromise. An alternative is rituximab [52,53]. Hydroxychloroquine or danazol are used in patients who fail to respond to glucocorticoids [54]. Splenectomy should be avoided unless absolutely necessary.

Thrombotic thrombocytopenic purpura (TTP) is an extremely serious cause of thrombocytopenia and rapidly causes death in a majority of untreated patients. The prompt institution of therapy with plasmapheresis greatly improves prognosis in these patients [55]. Rituximab is an additional treatment option in patients with SLE and TTP [56]. (See "Acquired TTP: Initial treatment".)

●Antiphospholipid antibodies – The management of children and adolescents with SLE and antiphospholipid antibodies (aPL) remains controversial. These patients are often treated with low dose aspirin if they have not had thrombosis. If thrombosis has occurred, warfarin should be added. The dose of warfarin must be titrated for the individual patient, with a goal of maintaining an international normalized ratio (INR) of 2 to 3. The usual dose is between 2 and 10 mg/day. Enoxaparin 0.5 to 1 mg/kg, titrating to an antifactor-Xa level of 0.5 to 1 units/mL, is an alternative if warfarin is not tolerated. (See "Clinical use of coagulation tests".)

Pulmonary disease — Pulmonary manifestations of SLE that often require additional therapy include pleuritis, acute pulmonary hemorrhage, pulmonary hypertension, and acute pneumonitis.

●Pleuritis – The treatment of pleuritis in SLE depends upon its severity. Patients who are tachypneic and in severe pain may require oxygen, analgesia, and pulsed intravenous doses of methylprednisolone (30 mg/kg, not to exceed 1 g). Most patients will improve dramatically within 24 hours of instituting this therapy. Thereafter, glucocorticoids may be given orally. Milder cases can be managed with oral glucocorticoid doses and the mildest cases with NSAIDs.

In the rare child with chronic painful pleuritis, talc poudrage [57] or tetracycline pleurodesis [58] may be helpful. However, these are rarely necessary. Pleuritis alone should not require systemic treatment with cytotoxic agents, but chronic recurrence suggests inadequate overall disease control. (See "Management of refractory nonmalignant pleural effusions".)

●Acute pulmonary hemorrhage – The therapy for acute pulmonary hemorrhage often requires ventilation and high dose intravenous glucocorticoids. Delay in therapy may result in a fatal outcome. (See "Hemoptysis in children".)

Once the child's cardiorespiratory status has been stabilized, management should be directed towards improving the control of the patient's underlying disease. Cyclophosphamide and mycophenolate mofetil have been used to improve control of SLE complicated by pulmonary hemorrhage [59,60]. In the author's personal experience, the addition of rituximab is helpful in reducing the frequency of recurrences, but not in treating the acute phase of bleeding.

●Pulmonary hypertension – Epoprostenol, bosentan [61], and a small number of other medications are available to treat this form of pulmonary disease. (See "Treatment of pulmonary hypertension in adults".)

●Acute pneumonitis — Pneumonitis usually is treated successfully with glucocorticoids. If glucocorticoids are insufficient, other immunosuppressants are required [62]. Acute pneumonitis is not associated with long-term problems unless complicated by pneumothorax, pulmonary hemorrhage, or infection.

Cardiac abnormalities — Cardiac manifestations that can require additional therapy include pericardial effusion, myocarditis, coronary artery disease (CAD), and heart failure.

●Pericardial disease – Subclinical pericarditis usually does not require specific therapy [63]. Symptomatic pericarditis is typically treated with NSAIDs or glucocorticoids. Indomethacin (3 to 4 mg/kg per day divided in two doses) or other NSAIDs are often effective in milder cases [64]. Large doses of glucocorticoids are rarely necessary, but pulse doses of intravenous methylprednisolone (30 mg/kg per dose, not to exceed 1 g) may be used acutely in the setting of severe constrictive pericarditis. Children with rapid accumulation of large pericardial effusions may develop tamponade and require prompt pericardiocentesis. (See "Diagnosis and treatment of pericardial effusion" and "Cardiac tamponade" and "Emergency pericardiocentesis".)

Activity is self-restricted during acute episodes of pericarditis because of the pain. Clinical status should be monitored by follow-up echocardiography, and activities may be resumed as is appropriate.

●Myocarditis – Significant myocarditis in children and adolescents with SLE typically is treated with glucocorticoids, usually in the form of prednisone. The dose of prednisone is decreased as the patient responds to therapy. Activity should be restricted as appropriate to the compromise in cardiac function determined by echocardiography. (See "Treatment and prognosis of myocarditis in children".)

●Endocarditis – Children with a prior history of infective endocarditis should receive antibiotic prophylaxis as recommended by the American Heart Association (AHA) when undergoing procedures with a risk of bacteremia. Periodic echocardiography provides the best assessment of valvular function over time and helps determine whether further intervention is needed. (See "Antimicrobial prophylaxis for bacterial endocarditis".)

●Coronary artery disease – Guidelines for reducing the risk of CAD are based upon risk assessment and the presence of other CAD risk factors, such as hypertension. Suggested therapeutic interventions include nonpharmacologic measures (eg, a diet low in saturated fat and cholesterol, supplementation with omega-3 fatty acids, and routine exercise) and pharmacologic measures including statins and antihypertensive medications, as needed. However, a study of the use of statins in children with SLE found that their routine use was not justified. Atorvastatin was not significantly more effective than placebo in preventing subclinical atherosclerosis progression, as measured by carotid intima-media thickening, in a 36-month randomized trial of 221 patients aged 10 to 21 with pediatric-onset SLE [65]. Hydroxychloroquine, a treatment recommended for children with SLE, can improve lipid profiles and minimize the likelihood of a disease flare [66]. Management to reduce the risk of atherosclerosis is discussed in greater detail separately. (See "Overview of the management of the child at risk for atherosclerosis".)

●Heart failure – Treatment must address the underlying comorbid conditions while supporting the myocardium appropriately. Angiotensin-converting enzyme (ACE) inhibitors should be used where appropriate because they are not only effective antihypertensives, but have antithrombotic and antiatherogenic actions as well [67]. (See "Management of heart failure in infants and children".)

COMPLICATIONS — The most common complications of childhood SLE include medication toxicities and infections.

Medication toxicity — Long-term use of glucocorticoids is associated with a variety of significant side effects, which are commonly seen in children with SLE [68,69]. Ocular toxicity is the greatest concern with hydroxychloroquine therapy. These side effects are discussed in greater detail separately. (See "Major side effects of systemic glucocorticoids" and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects'.)

Infection — Infection, particularly pneumonia, is the most common complication in children with SLE [70]. The child's ability to handle bacterial infections is significantly compromised in the face of active SLE with neutropenia and hypocomplementemia.

Pneumonia in patients with SLE may be caused by viruses, bacteria, or opportunistic organisms [71-73]. Cytomegalovirus and aspergillosis are particular problems in children who have received immunosuppressive therapy [59,74]. (See "Pneumococcal pneumonia in children" and "Pneumonia in children: Epidemiology, pathogenesis, and etiology", section on 'Special populations'.)

Broad-spectrum antibiotics should be used to treat pulmonary infections until a specific organism can be isolated. Those children receiving glucocorticoids and other immunosuppressants are at highest risk. (See "Pneumonia in children: Inpatient treatment" and "Community-acquired pneumonia in children: Outpatient treatment".)

Both pneumococcal and influenza vaccine should be administered to children who have SLE, particularly if they are receiving high doses of glucocorticoids or have a history of pulmonary disease. (See "Pneumococcal (Streptococcus pneumoniae) polysaccharide vaccines in children", section on 'Indications' and "Seasonal influenza in children: Prevention with vaccines", section on 'Indications' and "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Indications'.)

Macrophage activation syndrome — Macrophage activation syndrome (MAS), a form of hemophagocytic lymphohistiocytosis (HLH), is a rare, but serious and potentially life-threatening complication of all rheumatic diseases in childhood, including SLE [75]. Although data are limited,

the reported incidence ranges from 1 to 4.6 percent [76]. MAS is caused by an activation of T cells and macrophages resulting in a massive release of proinflammatory cytokines (eg, interleukin-1-beta [[IL-1-beta], interleukin-6 [IL-6], interferon-gamma [IFN-gamma], and tumor necrosis factor [TNF]). Clinical manifestations include persistent high fever, pancytopenia, hepatosplenomegaly, hepatic dysfunction, coagulation abnormalities, encephalopathy, and markedly elevated levels of ferritin. The pathognomonic bone marrow finding is the active phagocytosis of hematopoietic cells by benign looking macrophages. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Pathophysiology'.)

In one case series of 38 patients (20 with definite MAS and 18 with probable MAS), most episodes of MAS occurred within one to six months after the initial diagnosis with SLE [75]. There were apparent triggers for MAS in about three-quarters of the patients, which included disease flare, infection, or change in medication. There were four deaths attributed to MAS.

MAS is discussed in detail separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders/MAS' and "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'MAS/rheumatologic conditions'.)

PROGNOSIS — The prognosis of children and adolescents with SLE who receive appropriate care is generally good. Most centers find children with SLE do well [77], but some centers believe morbidity is worse in pediatric-onset SLE compared with adult-onset SLE [78]. Survival rates are high despite the fact that about one-half of patients have chronic active disease.

The primary causes of an unsatisfactory outcome are [16,79,80]:

●Poor compliance secondary to poor patient and family education

●Neurologic complications

●Intercurrent infections

●Renal disease, especially diffuse proliferative glomerulonephritis

●Failure to refer the child to an experienced center in a timely fashion

In a series of 35 patients followed for a median of 2.8 years (range 0.7 to 14.3 years), the following disease activity patterns were seen: chronic active (49 percent), relapse remitting (14 percent), and long quiescence (37 percent) [81]. Chronic active disease was associated with positive anti-Smith (anti-Sm) autoantibodies. Early aggressive treatment in patients with severe symptoms was associated with a more favorable disease course. Delayed recognition of SLE that occurs when the patient presents with clinical features associated with SLE, but that are not included in the classification criteria, is associated with delayed initiation of therapy and hence greater cumulative organ damage [79].

The overall survival rate for children and adolescents with SLE receiving the treatment approaches discussed above is unknown. Published data from the early 1980s documented survival rates of nearly 100 percent at 5 years and 85 percent at 10 years [82,83]. In children as well as adults, increased mortality rates are associated with lower socioeconomic status of the family, increased disease activity, and central nervous system (CNS) or renal involvement.

Renal disease — The degree of renal involvement affects the mortality and morbidity of children with SLE. This was illustrated in a retrospective study of 66 Canadian children, all of whom had renal biopsy documented disease [84]. The results are as follows:

●The 10- and 19-year mortality rates were 9 and 12 percent, respectively, among patients with diffuse proliferative disease (World Health Organization [WHO] class IV), all of whom received glucocorticoids and the majority of whom received either azathioprine or cyclophosphamide. End-stage renal disease had developed in approximately 25 and 40 percent, respectively, by the same time points. Caucasian children fared better than others. Fourteen of 16 such children (87 percent) were alive without end-stage renal disease at the last follow-up visit versus 9 of 16 (56 percent) of non-Caucasian patients.

●For patients with mesangial (15 patients) or focal proliferative (8 patients) nephritis, there were no deaths and no child with these types (WHO class II and III) developed end-stage renal disease at follow-up of up to 21 years (mean 11 years).

These results also highlight the importance of carefully assessing the ethnic characteristics of the population when comparing clinical outcome by varying institutions. Non-Caucasian children, particularly those of African-American ethnicity, have a poorer clinical outcome [85]. Thus, the relatively higher percentage of Caucasian children in this Canadian study must be considered when comparing these results with those of American centers.

Children with kidney failure resulting from lupus nephritis appear to do as well after renal transplantation as do children with other causes of end-stage renal disease [86]. (See "Outcomes of renal transplantation in children".)

Long-term outcome — The obligation in caring for a child or adolescent with SLE extends beyond the narrow view of providing adequate 5- or 10-year survival rates. For a 15-year-old, for example, surviving for this period of time means to live to an age of only 20 or 25 years. The goal should therefore be to seek optimal 50-year survivals if adolescent patients are to achieve normal lifespans. For this to be accomplished, both the morbidity of the disease and also the adverse effects of the medications used to treat the disease need to be minimized. In addition, further work is needed to ensure improved survival for non-Caucasian children that is equivalent to that achieved by Caucasian patients.

There are no published studies on the 10- to 15-year survival rate for adolescents treated with systematic intravenous cyclophosphamide pulses. However, clinical experience has taught us that this regimen is associated with a profound improvement in the quality of life with a dramatic reduction in total glucocorticoid dose and related complications, decreased school absence, decreased infections, and decreased emergency hospitalizations. (See 'Severe SLE' above.)

In adults with SLE, long-term cardiovascular disease (CVD) is a major cause of death. Cardiac disease in children with SLE is often silent and therefore may be underestimated. In addition, children with SLE are at increased risk for early atherosclerosis and coronary artery disease (CAD) [87]. Continued endeavors to identify the prevalence and risk factors of cardiac disease in children with SLE are needed and ultimately will aid in improving long-term survival. (See "Systemic lupus erythematosus (SLE) in children: Clinical manifestations and diagnosis", section on 'Cardiac abnormalities'.)

SUMMARY AND RECOMMENDATIONS

●Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect the skin, joints, kidneys, lungs, nervous system, serous membranes, and/or other organs of the body. The care of children and adolescents with SLE differs from that of adults, because of the impact of the disease and its therapy on physical and psychologic growth and development. (See 'Introduction' above.)

●The treatment for most manifestations of SLE does not differ among adults, children, and adolescents. However, children and adolescents with SLE have unique problems related to growth and development that affect both the need for and the impact of aggressive therapy. The profound negative effects of glucocorticoids during physical and psychologic growth and development necessitate minimizing the dose whenever possible. (See 'Treatment' above.)

•We recommend treating all children with SLE with hydroxychloroquine at a dose ≤7 mg/kg/day (up to a maximum of 400 mg per day) (Grade 1B). (See 'Initial therapy' above.)

•We typically use a nonsteroidal antiinflammatory drug (NSAID) in conjunction with hydroxychloroquine to control musculoskeletal manifestations in the child with mild SLE who does not require glucocorticoids, has renal or other life-threatening organ system involvement, or has poor compliance. (See 'Mild SLE' above.)

•We suggest treating all children with moderate to severe SLE with glucocorticoids in addition to hydroxychloroquine (Grade 2C). Dosing and duration of glucocorticoids is decided on an individual basis and depends upon the clinical severity, combination of disease manifestations, and response to treatment. (See 'Moderate SLE' above and 'Severe SLE' above.)

•Prolonged use of high dose glucocorticoids is associated with significant toxicity. Thus, we suggest adding mycophenolate mofetil or another steroid-sparing agent in children with moderate SLE that require continued use of high dose glucocorticoids to control disease activity (Grade 2C). (See 'Moderate SLE' above.)

•Children and adolescents with severe SLE (eg, substantial renal or neurologic disease), or those with moderate disease that does not quickly come under control, require more aggressive therapy. We suggest monthly intravenous cyclophosphamide in children with moderate or severe SLE who cannot be maintained on a prednisone dose of less than 0.5 mg/kg per day (Grade 2C). Extended immunosuppressive therapy is often required for patients with renal disease, but a one-year course may be sufficient for those with extrarenal disease only. (See 'Severe SLE' above.)

●Patients with specific disease manifestations may require additional therapy beyond the usual treatment for SLE. These treatments are reviewed above and in separate topic reviews. (See 'Treatment of specific organ system involvement' above.)

●Complications of SLE include macrophage activation syndrome (MAS), a form of hemophagocytic lymphohistiocytosis (HLH), and infections such as pneumonia. (See 'Complications' above.)

●The survival rate for children and adolescents with SLE is nearly 100 percent at 5 years and at least 85 percent at 10 years. Higher mortality rates are associated with lower socioeconomic status of the family, increased disease activity, and central nervous system (CNS) or renal involvement. (See 'Prognosis' above.)

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