Pediatric Systemic Lupus Erythematosus Medication

Updated: Nov 02, 2015
  • Author: Marisa S Klein-Gitelman, MD, MPH; Chief Editor: Lawrence K Jung, MD  more...
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Medication

Medication Summary

Therapeutic interventions for pediatric lupus should occur under the direction or with the advice of an experienced physician. Many medications are used to treat lupus and are chosen depending on disease manifestations. The goal of therapy is to control disease manifestations, allowing the child to have a good quality of life without major disease exacerbations, while preventing serious organ damage that adversely affects function or life span. At the same time, the physician is challenged to prevent intolerable adverse effects from the therapeutic regimen.

Before treatment, identify organ system involvement and exclude other possible diagnoses. Many of the therapeutic options have serious adverse effects, contraindications, and drug interactions. A high risk for infection, infertility, and future cardiovascular disease is noted. Most medications are considered a high risk during pregnancy. Patients with lupus who are pregnant should seek the expertise of an obstetrician and rheumatologist with experience in treating other patients with similar conditions.

The most important management tool in the treatment of systemic lupus erythematosus (SLE) is meticulous and frequent reevaluation of patients. Reevaluation includes clinical and laboratory evaluation, allowing prompt recognition and treatment of disease flare that is essential to patient outcome.

Patients with hypertension should be aggressively treated. If hypertension is a consequence of corticosteroid therapy, consider immunomodulating medications as steroid-sparing agents to help control hypertension. (For more information, see Pediatric Hypertension.)

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Antimalarial agents

Class Summary

Rash and other minor symptoms, including musculoskeletal symptoms, can be treated with hydroxychloroquine 3-7 mg/kg/d, usually no more than 400 mg/d orally. Evidence indicates that the long-term use of antimalarial drugs is steroid sparing. Hydroxychloroquine may also decrease the risk of thrombotic events. Understanding that antimalarials hinder TLR 7/9 induction of interferon-alpha and tumor necrosis factor underscore the importance of this class of drugs in the treatment of lupus. The long-term use of this medication requires monitoring for retinal pigment changes every 6 months. Adverse effects are infrequent and include eye changes, GI symptoms (of which diarrhea is most prominent), and CNS changes.

Hydroxychloroquine (Plaquenil)

Antimalarial drugs inhibit the synthesis of DNA, ribonucleic acid (RNA), and proteins by interacting with nucleic acids. Antimalarial drugs have various immunosuppressive effects, can act as antioxidants, and interfere with prostaglandins. Two hundred milligrams of the sulfate salt equals 155 mg of the base.

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Corticosteroids

Class Summary

These agents elicit anti-inflammatory and immunosuppressive properties, cause profound and varied metabolic effects, and modify the body's immune response to diverse stimuli.

Treat children who have evidence of severe renal, CNS, or hematologic disease with corticosteroids. The dose varies with the intensity of SLE on the organ system involved and in select individuals with serologic disease activity. Consider initiating therapy with daily prednisone (1 mg/kg/d) or higher-dose alternate-day prednisone (5 mg/kg/d, not to exceed 150-250 mg, depending on the size of the patient). Alternatively, lower-dose daily prednisone (0.5 mg/kg) may be used in conjunction with intermittent high-dose IV methylprednisolone (30 mg/kg/dose, not to exceed 1 g) on a weekly basis.

Intermittent high-dose IV methylprednisolone is now known to extinguish the interferon signature of systemic lupus for up to 7 days, which oral therapy cannot accomplish, and should be considered for patients with significant disease activity. Patients must be monitored for high blood pressure or arrhythmia, especially if there is heart disease or electrolyte abnormalities.

Children who are systemically ill with renal, neurologic, severe hematologic, cardiac, or pulmonary disease are begun on high-dose daily prednisone 2 mg/kg/d (not to exceed 80 mg/d) in divided doses, which are consolidated after serologic disease activity is controlled and finally switched to alternate-day prednisone.

Alternatively, the patient may be treated with IV pulse methylprednisolone therapy (3 d of high-dose IV corticosteroids) and then switched to intermittent high-dose IV corticosteroids with lower daily prednisone doses, depending on disease severity. Obtain skin testing for tuberculosis (purified protein derivative [PPD]) and candidal infection before commencement of medical therapy in patients who require steroids. Consider further evaluation for mycobacterial disease in patients who are anergic to both tests.

Prednisone

Prednisone decreases inflammation by suppression of the immune system, which it does by (1) decreasing lymphocyte volume and activity, (2) decreasing polymorphonuclear (PMN) leukocyte migration, and (3) decreasing or reversing capillary permeability. High doses, especially over periods of more than 2-3 weeks, suppress adrenal function.

Methylprednisolone (Solu-Medrol, A-Methapred, Depo-Medrol)

Methylprednisolone decreases inflammation by suppression of the immune system in much the same manner as prednisone, but it has less mineralocorticoid effects. Intravenous high-dose steroids can be given in a hospital setting but also by home health teams.

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Immunosuppressive agents

Class Summary

Evaluate children with signs of active nephritis to determine the WHO classification category of their nephritis. Patients with class IV nephritis and some patients with class III nephritis should be treated with corticosteroids and cyclophosphamide. Mycophenolate mofetil has become an alternative therapy for lupus nephritis. Azathioprine is used for more mild nephritis. Consider cyclophosphamide for severe systemic involvement of other vital organs, especially the brain. Other agents (eg, mycophenolate mofetil, cyclosporine, methotrexate) are considered when standard therapies have failed.

Other treatments under study include hormonal therapy and biologic agents that target cytokine production and anti-DNA antibodies. Clinical trials using autologous stem cell transplantation are in progress for severe persistent disease. Most recently, anti-CD19 monoclonal antibodies (ie, rituximab) initially developed for treatment of B-cell malignancies have shown promise in the treatment of lupus, in particular cytopenias and kidney disease resistant to other forms of therapy.

Cyclophosphamide

Cyclophosphamide, which is chemically related to nitrogen mustards, interferes with the normal function of DNA by alkylation and cross-linking the strands of DNA and by possible protein modification. As an alkylating agent, the mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Mycophenolate (CellCept, Myfortic)

Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, inhibiting their proliferation. It inhibits antibody production by inhibiting T-cell and B-cell proliferation, cytotoxic T-cell generation, and antibody secretion.

Two formulations are available and are not interchangeable. The original formulation, mycophenolate mofetil (MMF, CellCept), is a prodrug that, once hydrolyzed in vivo, releases active moiety mycophenolic acid. A newer formulation, mycophenolic acid (MPA, Myfortic), is an enteric-coated product that delivers the active moiety.

Azathioprine (Imuran, Azasan)

Azathioprine is an imidazolyl derivative of 6-mercaptopurine. Many of its biological effects are similar to those of its parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in the erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 hours after it has been taken.

Azathioprine antagonizes purine metabolism and may inhibit the synthesis of proteins, RNA, and DNA. It may interfere with mitosis and cellular metabolism. The mechanism through which azathioprine affects autoimmune diseases unknown. The drug works primarily on T cells. It suppresses hypersensitivities of cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests are suppressed to a greater degree than are antibody responses.

Azathioprine works very slowly; it may require 6-12 months of trial prior to having an effect. Up to 10% of patients may have an idiosyncratic reaction, which results in disallowance of its use. Do not allow the WBC count to drop below 3000/mL or the lymphocyte count to drop below 1000/mL. Azathioprine is available in tablet form for oral administration or in 100-mg vials for IV injection.

Methotrexate (Rheumatrex, Trexall)

Methotrexate is an antimetabolite that binds to dihydrofolate reductase, blocking the reduction of dihydrofolate to tetrahydrofolic acid; depletion of tetrahydrofolic acid leads to depletion of DNA precursors and inhibition of DNA and purine synthesis. This reduces the metabolism of activated T and B cells, reducing the inflammatory response. Adjust the dose gradually to attain a satisfactory response. Consider SC route for patients who do not respond to PO methotrexate or who have GI intolerance to PO dosing.

Cyclosporine (Neoral, Gengraf)

Cyclosporine is an 11-amino acid cyclic peptide and a natural product of fungi. It acts on T-cell replication and activity.

It is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of the cell cycle is suggested.

Cyclosporine binds to cyclophilin, an intracellular protein, which in turn prevents formation of interleukin 2 and the subsequent recruitment of activated T cells.

It has about 30% bioavailability, but there is marked interindividual and brand variability. Patients should stay with one manufacturer of the drug. Some manufacturers have varying bioavailability within their own processing of the medication. It specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that the drug be present during first 24 hours of antigenic exposure.

This agent suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.

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Calcium and vitamin D supplements

Class Summary

All patients with systemic lupus erythematosus (SLE) who are on corticosteroids or who have arthritis are at increased risk for osteopenia and its complications. Diet and appropriate supplementation with vitamin D and calcium are important tools for bone health in these patients. Of note, natural production of vitamin D involves skin exposure to sun, which is discouraged in the SLE population, increasing the risk of vitamin D deficiency.

Calcium carbonate (Oystercal, Caltrate, Alcalak, Florical)

This is used as an antacid and for the prevention of calcium depletion. Calcium carbonate 1 g equals 400 mg of elemental calcium.

Vitamin D

Many different vitamin D3 (ie, cholecalciferol) supplements are available. Patients may use 400-2000 IU daily, depending on the size of the patient. Vitamin D levels, as well as calcium metabolism, should be monitored when supplements are being given.

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Nonsteroidal anti-inflammatory drugs (NSAIDs)

Class Summary

A child who presents with mild disease with no evidence of nephritis, hypocomplementemia, and elevated anti–double-stranded DNA antibodies is treated symptomatically and is monitored closely for signs of disease progression. Arthritis is treated with NSAIDs. Select a specific agent based on patient response to medication, history of previous drug allergy or reaction, and ease of use.

Administer NSAIDs with caution in any patient with renal or liver disease and avoid administering NSAIDs during pregnancy. NSAIDs have various adverse effects that should be monitored, including gastritis, bone marrow suppression, hepatitis, interstitial nephritis, and CNS changes. Occasionally, a patient with systemic lupus erythematosus (SLE) has a hypersensitivity reaction to NSAIDs; this is most often characterized by hepatotoxicity, but the reaction can include other symptoms and must be kept in mind.

There are many NSAIDs; the 3 listed are in common use but are certainly not exclusive in the treatment of lupus.

Naproxen (Aleve, Naprelan, Naprosyn, Anaprox)

Naproxen is used for analgesic and anti-inflammatory properties to treat arthralgia and arthritis. It is available with slightly different safety and efficacy profiles. The drug inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis. It is available in SR formulation (Naprelan) for once daily dosing.

Tolmetin

Tolmetin is used for its analgesic and anti-inflammatory properties in the treatment of arthralgia and arthritis. It is available with slightly different safety and efficacy profiles. Tolmetin inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Diclofenac (Voltaren, Cataflam, Cambia, Zipsor)

Diclofenac inhibits prostaglandin synthesis by decreasing the activity of the enzyme cyclo-oxygenase, which, in turn, decreases the formation of prostaglandin precursors. It is also available in SR formulation (Voltaren-XR [100 mg]) that allows once or twice daily dosing.

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Monoclonal antibodies

Class Summary

This agent is used investigationally for systemic lupus erythematosus (SLE).

Rituximab (Rituxan)

Rituximab is an anti-CD20 monoclonal antibody. Originally used to treat B-cell lymphoma, the monoclonal antibody is now used to treat persisting immune thrombocytopenia in children and rheumatoid arthritis. Rituximab's use in SLE is investigational.

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Rheumatologics, other

Class Summary

This agent is FDA approved for SLE in adults.

Belimumab (Benlysta)

Belimumab is an IgG1-lambda monoclonal antibody that prevents the survival of B lymphocytes by blocking the binding of soluble human B lymphocyte stimulator protein (BLyS) to receptors on B lymphocytes. This reduces the activity of B-cell mediated immunity and the autoimmune response.

Approved by the FDA in March 2011 for adults with active, autoantibody-positive lupus who are receiving standard therapy, including corticosteroids, antimalarials, immunosuppressives, and NSAIDs. Safety and efficacy is not yet established for children younger than 18 years.

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Anticoagulant

Class Summary

Chronic warfarin therapy is required for lupus-associated APS.

Warfarin (Coumadin)

Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. Long-term warfarin is the drug of choice for APS in patients with recurrent thrombotic events. A titrated dose is suggested to maintain an international normalized ratio (INR) of approximately 2.5-3.5.

Therapeutic agents are based on anticoagulant properties, and benefits are weighed carefully against their significant morbidities. Life-long treatment with moderately high-intensity warfarin (INR 2.5–3.5) is standard for recurrent thrombotic events.

Enoxaparin (Lovenox)

This is an alternative therapy for APS in the setting of lupus. It is necessary should a female patient with APS become pregnant during the treatment period.

Enoxaparin is produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). It binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin).

Enoxaparin does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis.

Advantages include intermittent dosing and decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing.

Low molecular weight heparin differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa compared with UFH.

Enoxaparin prevents deep vein thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. It is used for prevention in hip replacement surgery (during and following hospitalization), knee replacement surgery, or abdominal surgery in those at risk of thromboembolic complications or in nonsurgical patients at risk of thromboembolic complications secondary to severely restricted mobility during acute illness.

Enoxaparin is used to treat DVT or pulmonary embolism (PE) in conjunction with warfarin for inpatient treatment of acute DVT with or without PE or for outpatient treatment of acute DVT without PE.

Checking the activated partial thromboplastin time (aPTT) is not useful because the drug has a wide therapeutic window and aPTT does not correlate with anticoagulant effect.

The average duration of treatment is 7-14 days.

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