systemic%20lupus%20erythematosus%20(pediatric)
SYSTEMIC LUPUS ERYTHEMATOSUS (PEDIATRIC)
Systemic lupus erythematosus (SLE) is a chronic, multisystem, inflammatory, autoimmune disorder characterized by formation of autoantibodies directed against self-antigens and immune-complex formation.
Clinical presentation varies in different patients and the disease activity varies over time in a single patient. Childhood-onset SLE has a greater disease severity and earlier disease damage than in adults with SLE.

Systemic%20lupus%20erythematosus%20(pediatric) Treatment

Principles of Therapy

Patients require individualized therapy depending on disease manifestations, activity and severity

Goals of Therapy

  • Control disease manifestations, ie aim for remission or low disease activity and flare prevention  
    • Complete remission is no clinical activity (SLEDAI = 0) without use of corticosteroids and immunosuppressants    
    • Low disease activity is SLEDAI ≤4, PGA ≤1, corticosteroid use of ≤7.5 mg/day of Prednisone, and well-tolerated immunosuppressants in stable doses
  • Allow the child to have a good quality of life without major exacerbations
  • Prevent serious organ damage that adversely affects function or life span
  • Prevent adverse effects of the drugs used

Pharmacotherapy

Corticosteroids

Oral Corticosteroids

  • Patients with mild SLE do not normally require use of systemic corticosteroids but there are patients whose quality of life is not improved if not given low-dose corticosteroids
    • Patients on remission or with low disease activity should be maintained with the lowest possible glucocorticoid dose
  • Decrease inflammation by suppressing the immune system  
    • Decrease lymphocyte volume and activity, PMN migration, capillary permeability
  • Used as initial therapy for severe discoid lupus erythematosus or lupus vasculitis
  • Low-dose corticosteroids may be added to Hydroxychloroquine for fatigue and fever
  • High-dose corticosteroids are necessary for refractory manifestations of SLE and for severe organ systems’ manifestations especially CNS, renal and hematologic manifestations
    • Show improved survival in patients with severe forms of SLE nephritis
    • May also be useful in severe, life-threatening thrombocytopenia and hemolytic anemia
    • May also be useful in pleuritis or pericarditis
  • Consider adding a steroid-sparing agent if a glucocorticoid dose of >0.35 mg/kg/day is required for >3 months
  • Corticosteroid use should be <7.5 mg/day (Prednisone equivalent) during chronic maintenance therapy and tapered (and if possible withdrawn) as soon as desired response is observed (control of inflammatory manifestations) to avoid toxicity
    • Tapering or withdrawing of corticosteroids may be hastened with the prompt initiation of immunosuppressants  
    • High doses over periods of >2-3 weeks suppress adrenal function
Topical Corticosteroids
  • Helpful for discoid lesions especially on the scalp
  • Use a less potent steroid on the face because it is more prone to atrophy
Parenteral Corticosteroids
  • IV pulse dosing of Methylprednisolone gives immediate therapeutic effect and allows the initiation of oral corticosteroids at a lower dose  
  • Pulse therapy with IV corticosteroids with or without immunosuppressive therapy can be given to patients with severe organ or life-threatening manifestations

Disease-Modifying Anti-Rheumatic Drug (DMARD)

Hydroxychloroquine
  • Inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions
  • Recommended for all SLE patients without contraindications 
  • Used for skin and joint manifestations
    • Useful for patients with skin disease that is unresponsive to topical corticosteroids and in patients with arthritis that does not respond to NSAID
  • Recommended as background treatment for class III/IV SLE patients with nephritis
    • Patients with continuing treatment with Hydroxychloroquine showed less renal damage as compared to those on placebo
  • Also used for preventing flares and other constitutional symptoms

Immunomodulatory Agents

Choice of immunomodulatory agent will depend on nature and severity of disease manifestation

  • These agents act as immunosuppressive, cytotoxic and anti-inflammatory agents
  • Consider the addition of immunosuppressants in patients unresponsive to Hydroxychloroquine therapy (with or without corticosteroids) or unable to decrease corticosteroid doses below that acceptable for chronic use
  • Can be included in the initial treatment of organ- or life-threatening SLE wherein an initial course of high-intensity immunosuppressive therapy is given followed by a longer course of less intensive treatment to consolidate patient’s response and prevent relapses
    • In the treatment of severe CNS and severe glomerulonephritis, thrombocytopenia and hemolytic anemia, high dose glucocorticoids and immunosuppressants are used
    • Concomitant use with corticosteroids allows lower doses of immunosuppressants
Azathioprine
  • Antagonizes purine metabolism and inhibits synthesis of DNA, RNA and proteins 
  • May decrease proliferation of immune cells resulting in lower autoimmune activity
  • A steroid-sparing agent in non-renal SLE and prevents flares
  • May be used as an immunosuppressant for SLE nephritis and hematologic and dermatologic manifestations

Methotrexate

  • Blocks purine synthesis and increases anti-inflammatory adenosine concentration at sites of inflammation
  • Used for mild to moderate non-renal SLE and prevents flares
  • May be used as the initial immunosuppressant for severe arthritis

Mycophenolic acid

  • A reversible inhibitor of inosine monophosphate dehydrogenase which is the rate-limiting step in de novo purine synthesis  
  • Effective for both renal and non-renal lupus and certain neuropsychiatric diseases  
    • Used for moderate to severe non-renal SLE and prevents flares   
    • Recommended as induction and maintenance therapy for patients with lupus nephritis and has shown better results (less adverse effects and infections) as compared to IV Cyclophosphamide  

Calcineurin Inhibitors

  • Eg Cyclosporine A, Tacrolimus
  • Can be considered in the treatment of class V lupus nephritis or select cases of refractory lupus nephritis
Cyclophosphamide
  •  As an alkylating agent, may involve cross-linking of DNA which may interfere with growth of normal and neoplastic cells
  • Used as the initial immunosuppressant for SLE nephritis
    • Concomitant use with Prednisone is the standard treatment for lupus nephritis as it helps preserve renal function
  • Given to children with moderate or severe SLE who cannot be maintained on a dose of Prednisone at <0.5 mg/kg/day and other steroid-sparing agents  
  • Useful for severe organ- or life-threatening SLE (eg severe CNS, cardiopulmonary or renal involvement) and as rescue therapy for non-major organ manifestations unresponsive to other immunosuppressants  
  • Prevents lupus flares
Intravenous Immunoglobulin (IVIg)
  • Neutralizes circulating myelin antibodies through anti-idiotypic antibodies
    • Down-regulates proinflammatory cytokines, including interferon-gamma
    • Blocks receptors on macrophages, suppresses inducer T and B cells and augments suppressor T cells
    • Blocks complement cascade, promotes remyelination and may increase colony stimulating factor IgG
  • Used in serious SLE flares and refractory severe lupus
  • May be considered in the acute phase of lupus thrombocytopenia if there is an inadequate response to high-dose corticosteroids or to prevent infectious complications from corticosteroid therapy

Biologic Therapies 

Belimumab

  • The first US FDA-approved biologic therapy for the treatment of SLE
  • A human monoclonal antibody that binds to soluble B-lymphocyte stimulator (BLyS/BAFF) to reduce disease activity 
  • Used for patients with active, autoantibody-positive SLE with a high degree of disease activity (eg positive anti-dsDNA and low complement) despite standard therapy (Hydroxychloroquine and corticosteroid combinations with or without immunosuppressants)  
  • Considered as an add-on therapy to extrarenal disease that is persistently active or flaring, or to patients with frequent relapses and/or residual disease activity preventing corticosteroid tapering
  • Studies have shown that patients on Belimumab therapy experienced reduced risk of severe flares, improved health-related quality of life and reduced steroid use as compared to those on placebo
  • Not recommended for patients with severe active lupus nephritis or severe active CNS lupus

Rituximab

  • A biologic, it is a chimeric monoclonal antibody to CD20 antigen which regulates cell cycle initiation  
  • Used as rescue therapy for SLE patients with organ-threatening disease refractory or with intolerance or contraindications to standard immunosuppressive therapy
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
  • Inhibit inflammatory reactions and pain by decreasing prostaglandin synthesis 
  • These drugs provide symptomatic relief of fever, arthritis and mild serositis, ie controls symptoms in mild non-renal lupus 
  • SLE patients have a high incidence of NSAID-induced hepatotoxicity

Specific Manifestations and Comorbidities of SLE

Specific Manifestations of SLE

Lupus Nephritis

  • Patients suspected to have lupus nephritis should immediately undergo renal biopsy to confirm diagnosis, evaluate severity, determine prognosis and therapy
  • Indications for renal biopsy in SLE patients:
    • Unexplained increase in serum creatinine in the absence of alternative causes (eg sepsis, hypovolemia, medications)
    • Confirmed proteinuria of ≥1 g/24 hr or reproducible proteinuria of ≥0.5 g/24 hr plus glomerular hematuria and/or cellular casts  
  • For induction of treatment, Mycophenolate or low-dose IV Cyclophosphamide are recommended  
    • Consider giving the same regimens or use high-dose IV Cyclophosphamide in those at high risk of renal failure or those with adverse prognostic factors   
  • Initial combination of treatment regimens with 3 consecutive pulses of IV Methylprednisolone then followed by oral Prednisone helps increase efficacy and decrease cumulative corticosteroid dose  
  • Azathioprine or Mycophenolate should be used for maintenance treatment  
  • Patients with severe nephrotic syndrome or incomplete renal response without a decreased GFR, uncontrolled hypertension and/or kidney biopsy with a high chronicity index can be given Mycophenolate combined with low-dose calcineurin inhibitor  
  • Rituximab can be given to refractory disease  
  • Monitoring of lupus nephritis includes a BP check and lab tests such as urinalysis, protein/creatinine ratio, serum creatinine, C3/C4 and anti-DNA levels

Neuropsychiatric SLE (NPSLE)

  • Monitor SLE patients for neurological and/or psychiatric manifestations as in non-NPSLE patients
  • Usually appears within 1 year from the time of diagnosis; may also appear before or at the time of diagnosis 
  • Diagnostic work-up may include the following: 
    • Lumbar puncture  
    • Nerve conduction studies (NCS)  
    • Neuropsychological assessment of cognitive function  
    • Cerebrospinal fluid analysis  
    • Electroencephalography (EEG)  
    • Neuroimaging: T1/T2 MRI, diffusion-weighted imaging, gadolinium-enhanced T1 sequences  
  • Manifestations indicating an inflammatory process are treated with corticosteroids and/or immunosuppressants while atherothrombotic or antiphospholipid-related manifestations are treated with antiplatelets/anticoagulants  
  • Patients found to have NPSLE should be referred to a team of psychiatrists, psychologists, neurologist and rheumatologist

Skin Disease

  • Initial management includes use of topical agents (corticosteroids, calcineurin inhibitors), antimalarials (Hydroxychloroquine, Quinacrine) with or without systemic corticosteroids  
  • Consider adding Methotrexate, Mycophenolate, Dapsone or retinoids to unresponsive patients or those who need high-dose corticosteroids  

Hematological Disease

  • Lupus thrombocytopenia can be acutely treated with moderate to high doses of corticosteroids (including IV pulse dosing of Methylprednisolone) in combination with immunosuppressants and/or IVIg  
  • Azathioprine, Mycophenolate or Cyclosporine can be used for maintenance therapy  
  • Refractory patients can be given Rituximab or Cyclophosphamide

Comorbidities of SLE

Cardiovascular Disease

  • Regularly evaluate SLE patients for traditional and disease-related risk factors for cardiovascular disease, eg persistently active disease, increased disease duration, chronic use of corticosteroids, persistent proteinuria and/or GFR <60 mL/min and medium/high titers of antiphospholipid  
  • SLE patients may be given low-dose Aspirin and/or lipid-lowering agents based on their individual cardiovascular risk profile  

Infectious Diseases

  • Evaluate SLE patients for general and disease-related risk factors for infection, eg frailty, renal disease, DM, use of corticosteroid and immunosuppressive therapy  
  • Early diagnosis and treatment of infection or sepsis and general preventive measures, eg immunizations, are recommended

Antiphospholipid Syndrome

  • Antiplatelet agents as primary prophylaxis may be given to SLE patients with a high-risk antiphospholipid profile, especially if with other atherosclerotic or thrombophilic factors, after considering potential for bleeding  
  • Management for secondary prevention (thrombosis, pregnancy loss/complication) should be the same as for primary antiphospholipid syndrome  

Malignancies    

  • May include non-Hodgkin's lymphoma, thyroid, lung, cervical and vulval cancer  
  • Perform cancer screening and manage according to established guidelines for the specific condition  

Macrophage Activation Syndrome (MAS)

  • A rare but severe and potentially life-threatening complication of cSLE  
  • In clinically unstable patients in whom MAS is suspected, treatment should be initiated immediately if a bone marrow aspirate cannot be performed
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