Systemic Lupus Erythematosus Management

Evaluation

Specialist Referral 

It is essential to establish a good working relationship among the primary care physician, non-lupus specialist (eg general internist or pediatrician), lupus specialist (eg rheumatologist), nurse, pharmacist, other healthcare providers, the patient, and his/her family. A team approach will allow for earlier identification of disease flares and medication toxicity. 

The patient will initially present to a primary care physician or non-lupus specialist who is responsible for recognizing the signs and symptoms of systemic lupus erythematosus in their patients, making an initial diagnosis, treating and monitoring patients with mild disease, and referring the patient to a rheumatologist or other lupus specialist (eg nephrologist) and participating in further systemic lupus erythematosus diagnosis, management, and monitoring of patients with moderate to severe disease.

The lupus specialist is an integral part of the medical team managing a systemic lupus erythematosus patient. Referral to a lupus specialist especially a rheumatologist is indicated for confirmation of the diagnosis, formulation of a management plan for the patient, periodic evaluation of disease activity and severity, management of uncontrolled disease and complications, management of organ involvement or life-threatening diseases, prevention and/or management of treatment toxicities, and in special situations (eg pregnancy, antiphospholipid syndrome, concomitant infection, and surgery). 

Multidisciplinary care involves the referral of systemic lupus erythematosus patients to a psychologist, psychiatrist, physical and/or occupational therapist, ophthalmologist, dermatologist, cardiologist, orthopedic surgeon, and other specialists when necessary.

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Principles of Therapy

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

One of the goals of therapy is to control disease manifestations (ie aim for remission or low disease activity and flare prevention). Complete remission means there is no clinical activity (SLEDAI score of 0) without the use of corticosteroids and immunosuppressants. Low disease activity is SLEDAI 2000 of ≤4, PGA of ≤1, corticosteroid use of ≤7.5 mg/day of Prednisone, and well-tolerated immunosuppressants in stable doses. 

Other goals of therapy include allowing the patient to have a good quality of life without major exacerbations, preventing serious organ damage that adversely affects function or lifespan, preventing the adverse effects of the drugs used and minimizing, comorbidities.

In patients with lupus nephritis, the goal of treatment is to achieve proteinuria is <0.5-0.7 g/24 hr by 12 months, with improvement seen at 3 months and at least 50% reduction in proteinuria by 6 months.

Please see Lupus Nephritis disease management chart for further information.

Pharmacological therapy

Anti-inflammatory Agents

Corticosteroids

Oral Corticosteroids

Patients with mild systemic lupus erythematosus do not normally require the use of systemic corticosteroids, but there are patients whose quality of life is not improved if not given low-dose corticosteroids. Patients in remission or with low disease activity should be maintained with the lowest possible glucocorticoid dose. They are used as initial therapy for severe lupus erythematosus or lupus vasculitis. 

Corticosteroids decrease inflammation by suppressing the immune system. They decrease lymphocyte volume and activity, polymorphonuclear lymphocyte migration, and capillary permeability. 

Low-dose corticosteroids may be added to Hydroxychloroquine for fatigue and fever. High-dose corticosteroids are necessary for the refractory manifestations of systemic lupus erythematosus and for severe organ involvement especially central nervous system (CNS), renal, and hematologic manifestations. High-dose corticosteroids showed improved survival in patients with severe forms of systemic lupus erythematosus nephritis, may also be useful in severe, life-threatening thrombocytopenia, and hemolytic anemia, and in pleuritis or pericarditis. 

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

Topical corticosteroids are helpful for discoid lesions, especially on the scalp. Advise using a less potent steroid on the face because it is more prone to atrophy. 

Parenteral Corticosteroids

Intravenous pulse dosing of Methylprednisolone gives immediate therapeutic effect and allows the initiation of oral corticosteroids at a lower dose. Pulse therapy with intravenous corticosteroids with or without immunosuppressive therapy can be given to patients with severe organ or life-threatening manifestations. 

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)  

NSAIDs work by inhibiting inflammatory reactions and pain by decreasing prostaglandin synthesis. They provide symptomatic relief of fever, arthritis, and mild serositis (ie control symptoms in mild non-renal lupus). They are used in caution in patients with lupus nephritis or hypertension. SLE patients also have high incidence of NSAID-induced hepatotoxicity.

Disease-Modifying Anti-Rheumatic Drug (DMARD)

Hydroxychloroquine

Hydroxychloroquine is a 4-aminoquinolone antimalarial, it has immunomodulatory and anti-inflammatory effects in the treatment of systemic lupus erythematosus. It works by inhibiting the chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. 

It is recommended for all systemic lupus erythematosus patients unless intolerant or contraindicated. It is used for skin and joint manifestations and is useful for patients with a skin disease that is unresponsive to topical corticosteroids and in patients with arthritis that do not respond to non-steroidal anti-inflammatory drugs (NSAIDs). It is also used for preventing flares and sustaining remission, reducing cardiovascular risk, recurrent infection, and other constitutional symptoms. 

It is also recommended as background treatment for class III/IV systemic lupus erythematosus patients with nephritis. Patients with continuing treatment with Hydroxychloroquine showed less renal damage as compared to those on placebo. 

Immunosuppressants

The choice of immunosuppressant will depend on the nature and severity of the disease manifestation. These agents act as immunosuppressive, cytotoxic, and anti-inflammatory agents. Consider the addition of immunosuppressants in patients intolerant or unresponsive to Hydroxychloroquine therapy (with or without corticosteroids) or unable to decrease corticosteroid doses below that acceptable for chronic use. Immunosuppressants can be included in the initial treatment of organ- or life-threatening systemic lupus erythematosus wherein an initial course of high intensity immunosuppressive therapy is given followed by a longer course of less intensive treatment to consolidate the patient’s response and to 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

Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells resulting in lower autoimmune activity. 

It is used for mild to moderate systemic lupus erythematosus-related organ involvements (ie renal, neurological, hematological) and can also prevent flares. It may be used as the initial immunosuppressant for systemic lupus erythematosus nephritis. 

Calcineurin Inhibitors

Example drugs: Ciclosporin, Tacrolimus, Voclosporin

Calcineurin inhibitors can be considered in patients with moderate to severe systemic lupus erythematosus with arthritis, cutaneous disease, cytopenia, serositis, or vasculitis if Hydroxychloroquine treatment is insufficient. It can also be considered in the subsequent treatment of pure class V nephritis. 

Cyclophosphamide

Cyclophosphamide is an alkylating agent that may involve cross-linking of DNA which may interfere with the growth of normal and neoplastic cells. 

It is used as an initial immunosuppressant for severe systemic lupus erythematosus nephritis. Concomitant use with Prednisone is the standard treatment for lupus nephritis as it helps preserve renal function. It is also useful for induction therapy in severe organ- or life-threatening systemic lupus erythematosus (eg severe CNS, cardiopulmonary, or renal involvement) and as rescue therapy for non-major organ manifestations unresponsive to other immunosuppressants. It also prevents lupus flares. 

Methotrexate

Methotrexate works by blocking purine synthesis and increasing the anti-inflammatory adenosine concentration at the sites of inflammation. 

It is used for mild to moderate non-renal systemic lupus erythematosus and it can also prevent flares. It is often used as the initial immunosuppressant for musculoskeletal (eg severe arthritis) and cutaneous symptoms uncontrolled with corticosteroids and Hydroxychloroquine. Supplementation with folate is advised to decrease treatment-associated adverse effects and toxicity.

Mycophenolate mofetil

Mycophenolate mofetil is a reversible inhibitor of inosine monophosphate dehydrogenase which is the rate-limiting step in the de novo purine synthesis. 

It is effective for both renal and non-renal lupus and certain neuropsychiatric diseases. It is used for moderate to severe non-renal systemic lupus erythematosus and can also prevent flares. It is recommended as induction and maintenance therapy for patients with lupus nephritis and has shown better results (less adverse effects and infections) as compared to an intravenous Cyclophosphamide.

Biologic Agents

It is advised to consider giving monoclonal antibodies to patients who are unresponsive to treatment with corticosteroids and with maximum tolerable doses of immunosuppressants. They may also be considered in patients with intolerance or contraindications to standard treatment and/or in refractory diseases.  

Anifrolumab

Anifrolumab is a human IgG1 kappa monoclonal antibody that inhibits signaling of type I interferon by binding to subunit 1 of the type I interferon receptor resulting in the improvement of systemic lupus erythematosus symptoms. 

It is used for the treatment of moderate to severe systemic lupus erythematosus symptoms in adult patients who are receiving standard therapy (eg NSAIDs, corticosteroids, antimalarials, and/or immunosuppressants [Azathioprine, Methotrexate, or Mycophenolate]). It is not recommended for patients with severe active CNS lupus or severe active lupus nephritis.

Belimumab

Belimumab is a human monoclonal antibody that binds to a soluble B-lymphocyte stimulator (BLyS/B- cell activating factor [BAFF]) to reduce disease activity.   
It is used as an add-on therapy for patients with active, autoantibody positive systemic lupus erythematosus 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). It may be 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 a reduced risk of severe flares, improved health-related quality of life, and reduced steroid use as compared to those on placebo. It is not recommended for patients with severe active CNS lupus. 

Rituximab

Rituximab is a biologic agent and chimeric monoclonal antibody to CD20 antigen which regulates cell cycle initiation. 

It is used as rescue therapy for systemic lupus erythematosus patients with organ-threatening disease refractory or with intolerance or contraindications to standard immunosuppressive therapy. 

Intravenous Immunoglobulin (IVIg)

IVIg works by neutralizing circulating myelin antibodies through anti-idiotypic antibodies, therefore down-regulates proinflammatory cytokines, including interferon-gamma; blocks receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells; and blocks complement cascade, promotes remyelination and may increase colony stimulating factor lgG. 

It is used in serious systemic lupus erythematosus flares and refractory severe lupus. It 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. 

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Nonpharmacological

Patient Education

Patients should be provided with information, counseling, and support. It is important to involve all the family members in the counseling regarding the disease since the family must have a thorough understanding of the disease, its potential severity, and the complications of the disease and treatment.  

Patients must learn to cope with and monitor the disease. He or she should be able to distinguish the signs and symptoms that may precede a disease flare and consult with the physician immediately. Educate all patients regarding the prevention of cardiovascular complications, possible complications from unplanned pregnancy, poor compliance, recreational drug use, and infection. For married patients, contraception is important during the active phase of the disease. Advise patients to join other systemic lupus erythematosus patients in support groups.  

Patients must be advised to wear clothing with long sleeves, use an umbrella or sunscreen lotion and refrain from sunbathing to prevent exacerbation of dermatologic symptoms. Advise patients to use sunscreen with at least a sun-protection factor (SPF) of 15-75 to prevent dermal or systemic disease flares upon exposure to ultraviolet light.  

Patients must have an appropriate balanced diet to prevent obesity, osteoporosis, and dyslipidemia. Patients on corticosteroids should have a no-added-salt, low-fat, and calcium-sufficient diet.  

Advise patients to seek medical help when they have a fever. Exposure to immunosuppressive drugs used in systemic lupus erythematosus may predispose patients to infection.  

Encourage patients to maintain a normal lifestyle with regular exercise to maintain appropriate weight and bone density. Advise patients that fatigue and stress are associated with disease flares. Smoking cessation is recommended. The patient’s comorbidities should be managed; blood pressure, glucose, and lipid levels should be assessed and managed appropriately.   

Immunization should be updated for all patients. Patients should have appropriate immunizations (ie influenza, pneumococcal). Preferably given before the initiation of immunosuppressant therapy, or during remission or low disease activity.  

Antibiotic prophylaxis should be provided for all dental, genitourinary, and other invasive procedures for patients at high risk of infections (eg patients with valvular abnormalities, on immunosuppressive therapy). Patients should routinely undergo gynecologic assessments, dental care, and ophthalmologic examination, especially for patients taking corticosteroids and Hydroxychloroquine. Psychological support and interventions may also be necessary.

Plasma Exchange or Plasmapheresis  

In plasma exchange or plasmapheresis, high molecular weight substances involved in SLE pathogenesis undergo extracorporeal removal followed by return or exchange of blood plasma or components. It is an alternative therapeutic modality in select patients with acute life-threatening manifestations, rare complications, and severe refractory disease, in particular lupus nephritis and thrombotic thrombocytopenic purpura.  

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