Approach

The goals of treatment for patients with SLE are to ensure long-term survival, achieve the lowest possible disease activity, prevent organ damage, minimise drug toxicity, improve quality of life, and educate patients about their role in disease management.[81][82]

Treatment should target complete remission (the absence of clinical activity with no use of corticosteroids), but this is rarely achieved.[47] Therefore, low disease activity and prevention of flares in all organ systems may be the aim. Low disease activity is considered to be Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≤3 on antimalarials, or alternatively SLEDAI ≤4, physician global assessment (PGA) ≤1 with ≤7.5 mg of prednisolone, and well-tolerated immunosuppressive agents. 

SLE is a multisystem disease and certain components/complications of the disease (e.g., pleural effusion, pulmonary hypertension, and peritonitis) are managed by other specialists in addition to routine rheumatology care.

Patient education

Patient education involves encouraging the patient to take responsibility for their disease management. Guiding patients to validated resources is an important part of the treatment process.

Non-pharmacological treatment

Potential non-pharmacological interventions for SLE include sun protection, diet and nutrition, exercise, psychological treatment, and smoking cessation.

Sun protection

Exposure to ultraviolet light may exacerbate or induce systemic manifestations of SLE.[83] Patients with SLE should be advised to avoid excessive sun exposure and to use a broad-spectrum sunscreen.[84]

Diet and nutrition

No dietary measures have been shown to alter the course of SLE. However, the late complications of premature cardiovascular disease should be borne in mind. Patients should be advised to maintain an ideal body weight for their height and reduce salt intake if hypertension due to renal disease is present. General advice includes eating at least 5 servings of fruit or vegetables per day, replacing saturated fats with monounsaturates and polyunsaturates, and increasing the amount of oily fish eaten; a diet rich in polyunsaturated fatty acids should be recommended.[85] Standard advice for the amount of alcohol per week for men and women should be given.

SLE is associated with inadequate levels of serum vitamin D compared with the general population.[86][87][88] In patients with SLE, vitamin D supplements reduce disease activity; increase serum levels; and improve levels of inflammatory markers, fatigue, and endothelial function.[88][89][90] 

Some evidence suggests omega-3 fatty acid supplementation may reduce SLE disease activity.[89][91]

Herbal preparations should be avoided. They can interact adversely with pharmacological agents and may cause harm.

Exercise

Patients with stable SLE should be advised to avoid a sedentary lifestyle and to undertake supervised exercise.[85] In these patients, adherence to exercise guidelines should be encouraged to maintain optimum cardiovascular fitness. This should include ≥30 minutes of moderate physical activity ≥5 times per week; patients are advised to stop exercising if they experience pain or discomfort.

Psychological intervention

SLE has a significant impact on health-related quality of life, and has been shown to increase suicidal ideation and suicide attempts.[92][93] Literature reviews suggest that psychological interventions such as psychotherapy, cognitive behavioural therapies (CBT), psychoeducation, and mindfulness-based CBT, as adjuncts to medical therapy, improve fatigue, depression, pain, and quality of life for patients with SLE.[94][95] 

Smoking cessation

Patients who smoke should be encouraged to stop. Evidence suggests smoking is associated with more active disease, and a significant reduction in the therapeutic effect of hydroxychloroquine.[44][96][97] Smoking cessation reduces the risk of atherosclerotic vascular disease.

Pharmacological treatment

Common pharmacological treatment for SLE includes non-steroidal anti-inflammatory drugs (NSAIDs), antimalarial therapy, corticosteroids, immunosuppressive agents, and biological agents.

NSAIDs

NSAIDs are frequently used as a first-line measure in SLE to control joint stiffness as well as musculoskeletal and serosal pain. Naproxen may be the preferred first-line agent owing to the rare occurrence of aseptic meningitis with ibuprofen.[98][99][100]

Patients who require an anti-inflammatory and who are at high risk of gastrointestinal ulceration should be given a cyclo-oxygenase-2 (COX-2) inhibitor (e.g., celecoxib) if they are at low cardiovascular risk.

Blood pressure should be monitored and NSAIDs should be avoided in patients with hypertension or renal disease.

If long-term NSAID therapy is indicated, Helicobacter pylori eradication and the need for gastroprotection should be considered.

Hydroxychloroquine

Hydroxychloroquine is recommended for all patients with SLE (unless contraindicated).[47]

The beneficial effects of hydroxychloroquine in SLE include the reduction of constitutional symptoms, and reduced musculoskeletal and mucocutaneous manifestations.[101] Guidance recommends that patients who are in long-standing remission may lower their dose, although no studies have formally addressed this strategy.[47]

Concerns exist regarding the development of retinal toxicity with hydroxychloroquine therapy.[102][103] Risk factors include duration of treatment, dose, chronic kidney disease, and pre-existing retinal or macular disease.[103] Retrospective case-control study data suggest that risk of toxic retinopathy is low for doses below 5.0 mg/kg of real body weight for up to 10 years.[102]

Ophthalmological screening (by visual field examination and/or spectral domain-optical coherence tomography) is recommended at baseline, after 5 years, and yearly thereafter in the absence of risk factors for retinal toxicity.[47]

Corticosteroids

Pulse doses of intravenous methylprednisolone are recommended to provide immediate therapeutic effect in SLE and enable the use of a lower starting dose of oral corticosteroid.[47]

The recommended dose and route of administration depends on the type and severity of organ involvement. For chronic maintenance treatment, the dose of oral corticosteroids should be minimised to <7.5 mg/day and, when possible, withdrawn.[47]

The long-term adverse effects of corticosteroid therapy are well documented, and patients should be counselled regarding risk of hypertension and atherosclerotic disease, hyperglycaemia, potential skin changes, infection, mood disorders, disorders of bone and muscle (e.g., osteoporosis, osteonecrosis, myopathy), and ophthalmological effects (e.g., cataracts, increased ocular pressure, exophthalmos). Caution is advised with corticosteroid use in patients with upper gastrointestinal symptoms, especially if also taking NSAIDs. The lowest possible dose to control symptoms should be used for the shortest period of time.

Immunosuppressive agents

The addition of immunosuppressive agents (such as methotrexate, azathioprine, or mycophenolate) should be considered for the treatment of patients:[47]

  • with organ-threatening disease

  • not responding to hydroxychloroquine (alone or in combination with corticosteroid)

  • unable to reduce the corticosteroid dose below the acceptable dose for chronic use.

Early initiation of immunosuppressive agents can expedite the tapering/discontinuation of corticosteroids.[47]

The choice of agent depends on prevailing disease manifestation(s) of SLE, the patient’s age, childbearing potential, and safety concerns.[47] 

Cyclophosphamide can be used for severe organ-threatening or life-threatening SLE as well as rescue therapy in patients not responding to other immunosuppressive agents.[47]

Biological agents

B-cell targeting agents such as belimumab and rituximab are beneficial for treating patients with SLE who are refractory to other agents.[104][105][106][107]

Belimumab should be considered as an add-on treatment for patients who have an inadequate response to combination treatment with hydroxychloroquine and corticosteroids with or without immunosuppressive agents (where inadequate response constitutes residual disease activity not allowing tapering of corticosteroids and/or frequent relapses).[47]

In the UK, the National Institute for Health and Care Excellence (NICE) recommends belimumab as an add-on treatment for patients with active autoantibody-positive SLE with high disease activity despite standard treatment, only if:[108]​​

  • high disease activity is defined as at least 1 serological biomarker (positive anti-double-stranded DNA or low component) and a SELENA-SLEDAI (Safety of Estrogen in Lupus National Assessment - Systemic Lupus Erythematosus Disease Activity Index) score of greater than or equal to 10

  • treatment is continued beyond 24 weeks only if the SELENA-SLEDAI score has improved by 4 points or more.

One Cochrane review concluded that there is moderate- to high-quality evidence that belimumab is associated with clinically meaningful benefit for patients with SLE at 52 weeks compared with placebo.[109] Patients receiving the approved dose were found to have at lease at least a 4-point reduction in SELENA-SLEDAI score.[109]

Belimumab significantly reduced organ damage progression compared with standard care in a long-term study (5-year analysis) of patients with SLE.[110]

Rituximab can be considered for patients with organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents.[47]

Other treatments

Other pharmacological treatments for SLE include dapsone, thalidomide, retinoids, and intravenous immunoglobulin, depending on clinical circumstances.[47]

Constitutional symptoms

Fatigue is the most common constitutional symptom associated with SLE, occurring in 80% to 100% of patients, but it does not correlate with disease activity.[48][49] It is important to determine whether there is any evidence of anaemia, renal impairment, hypothyroidism, depression, interrupted sleep pattern, or deconditioning and treat each symptom accordingly.[111][112][113] Anaemia is usually secondary to chronic disease and improves with controlling disease activity.

Fever can be a manifestation of active disease, infection, or drug reaction.[77][114] Fever due to SLE often resolves with an NSAID or paracetamol. Persisting fever, despite treatment with these agents, should raise suspicions of an infectious or drug-related aetiology. 

Joint manifestations and serositis

Hydroxychloroquine can be used in combination with NSAIDs and/or corticosteroids if required to treat arthritis or arthralgia.[115][116]

If an NSAID is required to control joint stiffness, naproxen may be the preferred first-line agent owing to the rare occurrence of aseptic meningitis with ibuprofen.[98][99][100] Patients at high risk of gastrointestinal ulceration should be given a COX-2 inhibitor (e.g., celecoxib) if they are at low cardiovascular risk. If long-term NSAID therapy is indicated, Helicobacter pylori eradication and the need for gastroprotection should be considered.

Corticosteroids may be used when NSAIDs and hydroxychloroquine are inadequate. The recommended dose and route of administration of corticosteroids depends on the type and severity of organ involvement.[47]

Additional treatment for joint manifestations and serositis

Early initiation of immunosuppressive agents such as methotrexate or azathioprine can expedite the tapering/discontinuation of corticosteroids.[47]

Methotrexate can be a helpful addition in patients taking oral corticosteroids for arthritis/arthralgia.[117] Patients taking methotrexate should have regular haematological and liver function testing. Methotrexate use may increase the risk of infection. Abnormal haematological and/or liver function results may necessitate reduction in prescribed dose.[117]

Belimumab should be considered as an add-on treatment for patients who have an inadequate response to combination treatment with hydroxychloroquine and corticosteroids with or without immunosuppressive agents (where inadequate response constitutes residual disease activity not allowing tapering of corticosteroids and/or frequent relapses).[47]

Rituximab can be considered for patients with organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents.[47]

Mucocutaneous manifestations

For patients with mucocutaneous manifestations, effective protection from ultraviolet exposure with broad-spectrum sunscreens and smoking cessation are strongly recommended.[47] 

A thorough oral care regime is recommended for all symptomatic patients.[118] Mouthwashes (e.g., chlorhexidine), basic oral hygiene, and regular attendance at a dental practitioner are helpful in the treatment of mouth ulceration. 

Lidocaine ointment may be beneficial for the management of pain secondary to major oral aphthae.[119] 

Artificial saliva preparations may be required for those with dry mouth.[118]

Hypromellose eye drops are recommended for dry eyes.

Pharmacological treatment for mucocutaneous manifestations

First-line treatment of skin disease in SLE includes topical agents (e.g., corticosteroids, calcineurin inhibitors), and oral antimalarials (e.g., hydroxychloroquine) with or without systemic corticosteroids (starting dose dependent on the severity of skin involvement).[47]

One Cochrane review found evidence to support the use of hydroxychloroquine (or chloroquine) and methotrexate for treating cutaneous SLE, but for most key outcomes this was of low or moderate quality.[120] More studies are being evaluated and may change the conclusions of this review. 

Topical corticosteroids of different potencies may be used in combination depending on the patient’s symptoms. Potent corticosteroids (e.g., betamethasone valerate 0.1%) and very potent corticosteroids (e.g., clobetasol propionate 0.05%) are often used to treat the trunk and limbs including the hands, as well as the scalp. Moderate-potency corticosteroids (e.g., triamcinolone acetonide 0.1% or betamethasone valerate 0.025%) are used in areas more prone to atrophy such as the face and neck. Mild-potency corticosteroids (e.g., hydrocortisone 1%) are typically reserved for the eyelids, although may prove insufficient. Scalp involvement may be treated with foam or lotion formulations.

Additional treatment for refractory mucocutaneous manifestations

Methotrexate, retinoid (e.g., acitretin), dapsone, or mycophenolate can be added for patients who do not respond to first-line treatment (approximately 40%) or who require high-dose corticosteroid.[47]

Belimumab and rituximab also have demonstrated efficacy in mucocutaneous manifestations of SLE, although rituximab may be less efficacious in chronic forms of skin lupus.[47] 

Thalidomide should be considered only as a rescue therapy for patients who have failed multiple previous agents due to its strict contraindication in pregnancy, the risk for irreversible polyneuropathy, and the frequent relapses on drug discontinuation.[47]

Lupus nephritis

For renal manifestations of SLE, induction therapy is required to achieve complete or partial response, followed by immunosuppression to maintain the response. An early significant drop in proteinuria (to ≤1 g/day at 6 months or ≤0.8 g/day at 12 months) is a predictor of favourable long-term renal outcome.[47]

Induction therapy for lupus nephritis

Mycophenolate or low-dose intravenous cyclophosphamide are recommended as initial induction treatment, as they have the best efficacy/toxicity ratio.[47][121][122] [ Cochrane Clinical Answers logo ] [Evidence C] Therapeutic regimens considered for patients at high risk for renal failure are similar, but high-dose intravenous cyclophosphamide can be used.[47]

One systematic review and meta-analysis found that mycophenolate significantly increased the level of serum complement C3 compared with cyclophosphamide.[123] Mycophenolate was also superior to cyclophosphamide with respect to secondary end points of complete remission and adverse reactions. 

Corticosteroids are also given as part of the induction regimen in addition to background treatment with hydroxychloroquine.[124][125] Continued hydroxychloroquine is associated with increased remission rates in patients initially treated with mycophenolate for lupus nephritis.[126] 

Belimumab is approved for the treatment of adults with lupus nephritis. In a randomised double-blind trial, significantly more patients who received belimumab plus standard therapy had a renal response (43% vs. 32%; defined as ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate that was no worse than 20% below the pre-flare value or at least 60 mL/minute/1.73 m², and no use of rescue therapy for treatment failure) compared with standard therapy alone.[127]

Cyclophosphamide should be given with adequate fluid and mesna (a uroprotective agent) as there is a risk of uro-epithelial toxicity (e.g., haemorrhagic cystitis). Young women should be advised about the risks of amenorrhoea or premature ovarian failure with cyclophosphamide; gynaecological referral may be required for further in-depth discussion. Male patients should also be counselled regarding possible risk of infertility. The risk of amenorrhoea is lower with mycophenolate, although there are concerns about congenital malformations if it is given during pregnancy.

Second-line treatment for renal manifestations

Calcineurin inhibitors (e.g., ciclosporin) may be considered as second-line agents for induction therapy in membranous lupus nephritis, podocytopathy, or proliferative disease with refractory nephrotic syndrome despite standard-of-care within 3 to 6 months.[47] Calcineurin inhibitors may be used alone, or in combination with mycophenolate, to treat proliferative lupus nephritis.[128][129][130][131][132][133]

For patients with refractory nephrotic syndrome, tacrolimus may be used alone or in combination with mycophenolate, as this combination is effective in disease refractory to standard therapy.[47][134] 

Monitoring serum creatinine and blood levels of patients being treated with calcineurin inhibitors is essential to avoid chronic drug toxicity.[47]

Maintenance therapy for lupus nephritis

Once a patient has attained complete or partial response, immunosuppression is continued to maintain the response.

First-line maintenance therapy for renal manifestations

For maintenance therapy, mycophenolate or azathioprine should be used in combination with corticosteroids.[47] Either treatment can be used for maintenance therapy after induction with cyclophosphamide or mycophenolate, and is more effective in preserving renal function than corticosteroids alone.[135]

Second-line maintenance therapy for renal manifestations

Calcineurin inhibitors may be considered as second-line agents for maintenance therapy in membranous lupus nephritis, podocytopathy, or proliferative disease with refractory nephrotic syndrome despite standard-of-care within 3 to 6 months.[47]

One systematic review and meta-analysis of the effect of calcineurin inhibitors for the induction and maintenance treatment of lupus nephritis found that calcineurin inhibitor treatment during the maintenance period was as effective as azathioprine treatment, with a much lower risk of adverse effects.[130] 

Monitoring serum creatinine and blood levels of patients being treated with calcineurin inhibitors to avoid chronic drug toxicity is essential.[47]

Neuropsychiatric manifestations

Attribution of neuropsychiatric manifestations to SLE (by neuroimaging, investigation of cerebrospinal fluid, and consideration of risk factors), as opposed to non SLE, is essential.[47]

First-line treatment for neuropsychiatric manifestations

Treatment of SLE-related neuropsychiatric disease includes immunosuppressive agents and corticosteroids for manifestations considered to reflect an inflammatory process, and antiplatelet agents/anticoagulants for atherothrombotic/antiphospholipid-related manifestations.[47] The choice of immunosuppressive agent (e.g., azathioprine, mycophenolate, methotrexate) will depend on individual cases, as the neuropsychiatric manifestations can be varied. 

Distinction between the two pathophysiological processes may be difficult in practice. The two processes could co-exist in the same patient. Combination of an immunosuppressive agent and antiplatelet agent/anticoagulant therapy may be considered in these patients.[47]

Patients with SLE with cerebrovascular disease should be managed like the general population in the acute phase; in addition to controlling extra-central nervous system lupus activity, immunosuppressive therapy may be considered in the absence of antiphospholipid antibodies and other atherosclerotic risk factors or in recurrent cerebrovascular events.[47]

In this context, neuroimaging and/or cerebrospinal fluid studies may provide additional supporting evidence for immunosuppressive therapy.[47]

Ancillary therapies for neuropsychiatric manifestations

Targeted symptomatic therapy is indicated according to the type of manifestation.[47] 

  • Antipsychotics can be used if required for psychotic symptoms in central nervous system lupus.

  • Antidepressants may be helpful in certain cases. Treatment regimes as per patients without SLE.

  • Migraine treatments may be helpful in certain cases. Treatment regimes as per patients without SLE.

  • Anticonvulsants may be used (e.g., for peripheral neuropathy).

Alternative or additional treatment for refractory neuropsychiatric manifestations

Cyclophosphamide can be used for severe organ-threatening or life-threatening SLE as well as ‘rescue’ therapy in patients not responding to other immunosuppressive agents.[47] Rituximab can be considered for patients with organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents. Evidence of benefit in severe refractory neuropsychiatric SLE is limited to case reports. 

Intravenous immunoglobulin (IVIG) may be used as adjunctive therapy when initial treatment is inadequate, but the quality of evidence supporting its use is poor (small cohort studies).[136] IVIG can be effective in the treatment of SLE-associated peripheral neuropathies. 

Plasmapheresis may also be considered as an adjunctive treatment.[136] The aim of the treatment is to remove circulating auto-antibodies. Recommended if there are clinical and investigative findings consistent with cerebral vasculitis, and may be used when earlier treatments are inadequate.[136]

Haematological manifestations

Haematological manifestations that require anti-inflammatory/immunosuppressive treatment in patients with SLE include thrombocytopenia and autoimmune haemolytic anaemia.[47] 

Evidence suggests that patients with SLE and thrombocytopenia have an increased risk of mortality and end-organ damage.[137] 

First-line treatment for haematological manifestations

Treatment of significant lupus thrombocytopenia (platelet count below 30,000/mm³) and autoimmune haemolytic anaemia consists of moderate/high doses of corticosteroids in combination with an immunosuppressive agent (e.g., azathioprine, mycophenolate, ciclosporin) as a corticosteroid-sparing agent.

Initial therapy with pulse dose of intravenous methylprednisolone is encouraged.[47]

Additional treatment for haematological manifestations

IVIG may be considered in the acute phase, in cases of inadequate response to high-dose corticosteroids or to avoid corticosteroid-related infectious complications.[47]

Alternative treatment for refractory for haematological manifestations

Rituximab or cyclophosphamide should be considered in patients with no response to corticosteroids or patients who have relapsed.[47] 

Thrombopoietin agonists or splenectomy should be reserved as last options.[47] 

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