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7.5 mg/day (Prednisone equivalent) during chronic maintenance therapy and tapered (and if possible withdrawn) as soon as desired response is observed (control of inflammatory manifestations) to avoid toxicity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
- Helpful for discoid lesions especially on the scalp
- Use a less potent steroid on the face because it is more prone to atrophy
- 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
- 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
- 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
- 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
- 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