Systemic lupus erythematosus

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Systemic lupus erythematosus (SLE) requires multidisciplinary, individualised management including patient education and shared decision-making.[53] Management includes both non-pharmacological therapies and pharmacological therapies, the choice of which is dependent on symptoms and the severity of disease.

Early diagnosis of SLE (including serological assessment), regular screening for organ involvement (especially nephritis), prompt initiation of treatment aiming at remission (or low disease activity if this is not possible), and strict adherence to treatment are essential to prevent flares and organ damage, minimise drug toxicity, improve prognosis, and enhance quality of life.[53][54][55]

Routine care of patients with SLE should be managed by a rheumatologist with support from other specialists as required for specific components/complications (e.g., pleural effusion, pulmonary hypertension, and peritonitis).

Assessment of cardiovascular risk

Patients with SLE should be evaluated for cardiovascular risk. Preventive strategies based on their individual cardiovascular risk profile, as in the general population, may be appropriate (e.g., low-dose aspirin).[94] Although there are no specific interventions to lower the risk of cardiovascular events in patients with SLE, hydroxychloroquine plus the lowest possible corticosteroid dose to reduce disease or maintain low disease activity is recommended to minimise any potential cardiovascular harm.[94]

In patients with SLE, lower blood pressure is associated with lower rates of cardiovascular events and a blood pressure target of <130/80 mmHg should be considered.[94]

In patients with lupus nephritis, ACE inhibitors or angiotensin-II receptor antagonists are recommended for those with urine protein-to-creatinine ratio >500 mg/g or arterial hypertension.[94]

Patient education

Patient education is key, and people with SLE should be encouraged to take responsibility for management of their condition.[95] Guiding them to validated resources is an integral part of the treatment process:

Non-pharmacological treatment

Non-pharmacological management of SLE should be individualised to the patient’s needs, expectations and preferences, and directed at improving quality of life.[95]

Recommended interventions include sun protection (for the prevention of flares), smoking cessation, psychosocial interventions (for anxiety and/or depressive symptoms), and exercise (reducing fatigue and/or depressive symptoms).[95]

Sun protection

People with SLE should be advised to avoid excessive sun exposure and to use a broad-spectrum sunscreen because as exposure to ultraviolet light may exacerbate or induce systemic manifestations.[96][97]

Smoking cessation

In people with SLE, smoking habits should be assessed and cessation strategies implemented. Despite sparse evidence regarding smoking cessation for improving SLE disease activity, international guidelines emphasise the importance of this recommendation.[95] Evidence from clinical trials and meta-analyses suggests smoking is associated with more active disease, and a significant reduction in the therapeutic effect of hydroxychloroquine.[27][51][98][99] Smoking cessation reduces the risk of atherosclerotic vascular disease.

Diet and nutrition

No dietary measures have been shown to alter the course of SLE. However, adherence to a Mediterranean diet has been associated with lower cardiovascular risk, lower disease activity, and protection against organ damage.[95] General advice includes eating at least five 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 is also recommended.[100] 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.[101][102][103] Evidence regarding vitamin D supplementation in patients with SLE is conflicting. Some data suggest that vitamin D supplementation reduces disease activity; increases serum levels; and improves levels of inflammatory markers, fatigue, and endothelial function.[103][104][105] However, according to a subsequent systematic review vitamin D supplementation was not associated with a reduction in disease activity.[106]

Evidence demonstrates that omega-3 fatty acid supplementation may reduce SLE disease activity.[104][106][107][108] Herbal remedies should be avoided as 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.[100][109] In these patients, adherence to exercise guidelines should be encouraged to maintain optimum cardiovascular fitness. This will typically include ≥30 minutes of moderate physical activity ≥5 times per week; patients are advised to stop exercising if they experience pain or discomfort.

Psychosocial interventions

SLE has a significant impact on health-related quality of life, and has been shown to increase suicidal ideation and suicide attempts.[110][111] 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.[112][113]

Supportive care for SLE

People with SLE experience a wide range of symptoms, which extend beyond the manifestations that require immunosuppressive treatment. Symptoms such as fatigue, non-inflammatory pain, mood disturbance, and cognitive dysfunction are among the most commonly referred to by patients.[53] There is a lack of data to support specific recommendations to treat these symptoms.[53] Nevertheless, 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.[114][115][116] There is some evidence to suggest that patients with SLE suffer from poor sleep quality compared with the general population, and may be associated with feelings of depression.[117][118]

Fever can be a manifestation of active disease SLE, infection, or drug reaction.[119][120] Fever due to SLE often resolves with a non-steroidal anti-inflammatory drug (NSAID) or paracetamol. Persisting fever, despite treatment with these drugs, should raise suspicions of an infectious or drug-related aetiology.

Pharmacological treatment of non-renal SLE: general principles

Pharmacological interventions for non-renal SLE (which include constitutional symptoms, joint manifestations and serositis, mucocutaneous, neuropsychiatric, or haematological manifestations) are guided by symptoms, type and severity of organ involvement, treatment-related harms, comorbidities, risk for progressive organ damage, and patient preferences.[53] Specific treatments for each manifestation is covered later in this section.

Treatment should target complete remission (the absence of clinical activity with limited use of hydroxychloroquine and corticosteroids), but this is rarely achieved.[53] Therefore, low disease activity and prevention of flares in all organ systems is usually the aim.

Treat-to-target for non-renal SLE is defined as:[53]

Remission: clinical Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of 0; hydroxychloroquine and prednisolone (or equivalent) doses ≤5 mg/day; OR
Low disease activity: SLEDAI ≤4; hydroxychloroquine and prednisolone (or equivalent) doses ≤5 mg/day; immunosuppressants or biological agents at stable tolerated dose.

The recommended pharmacological treatment for non-renal SLE depends on the severity of symptoms at diagnosis.[53] Mild, moderate, and severe disease is defined as:[53]

Mild disease: constitutional symptoms; mild arthritis; rash ≤9% body surface area (BSA); platelet count (PLTs) 50-100 × 10⁹/L; SLEDAI ≤6; British Isles Lupus Assessment Group (BILAG) C or ≤1 BILAG B manifestation.
Moderate disease: moderate-to-severe arthritis (‘Rheumatoid Arthritis-like’); rash 9% to 18% BSA; PLTs 20-50 × 10⁹/L; serositis; SLEDAI 7-12; ≥2 BILAG B manifestations.
Severe disease: major organ-threatening disease (cerebritis, myelitis, pneumonitis, mesenteric vasculitis); thrombocytopenia with platelets <20 × 10⁹/L; thrombotic thrombocytopenic purpura like disease or acute haemophagocytic syndrome; rash>18% BSA; SLEDAI>12; ≥1 BILAG A manifestations.

For patients with mild-to-moderate disease, first-line treatment is hydroxychloroquine with or without an oral or intravenous corticosteroid.[53] For patients with symptoms that do not respond to first-line treatment, or those who are unable to reduce the corticosteroid dose below the acceptable use for chronic disease, the addition of an immunosuppressant (e.g., methotrexate, azathioprine, mycophenolate) and/or a biological agent (e.g., belimumab, anifrolumab) should be considered. The only difference between the recommended treatment options for mild and moderate disease is that patients with moderate disease may be treated with a calcineurin inhibitor (e.g., ciclosporin, tacrolimus) as the immunosuppressant.[53]

For patients with severe disease, first-line treatment is hydroxychloroquine with or without an oral or intravenous corticosteroid, in combination with either mycophenolate or intravenous cyclophosphamide. Belimumab and anifrolumab may be added on in cases of severe extrarenal disease with non-major organ involvement (e.g., extensive disease of skin or joints). Rituximab is reserved for those with disease that is refractory to other adjunct treatments.[53]

Hydroxychloroquine

The beneficial effects of hydroxychloroquine in SLE include the reduction of constitutional symptoms, and reduced musculoskeletal and mucocutaneous manifestations, as well as a reduced risk of mortality.[121][122]
Concerns exist regarding the development of retinal toxicity.[123][124] Risk factors include duration of treatment, higher dose, chronic kidney disease, and pre-existing retinal or macular disease.[124] Retrospective case-control study data suggest that risk of toxic retinopathy is low for doses <5.0 mg/kg (hydroxychloroquine base) for up to 10 years.[123] 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.[53]

Corticosteroids

Pulse doses of intravenous methylprednisolone may be considered in patients with moderate-to-severe disease to provide immediate therapeutic effect in SLE and enable the use of a lower starting dose of an oral corticosteroid.[53] However, the recommended dose and route of administration depends on the type and severity of organ involvement. For chronic maintenance treatment, the dose of oral corticosteroid should be minimised to ≤5 mg/day (prednisolone or equivalent) and, when possible, withdrawn.[53]
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).[125][126]
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.

Immunosuppressants

Early or appropriate initiation of immunosuppressants (e.g., methotrexate, azathioprine, mycophenolate, calcineurin inhibitors, cyclophosphamide) can expedite the tapering/discontinuation of corticosteroids.[53] The choice of drug depends on the prevailing disease manifestation(s), patient’s age and childbearing potential, and safety concerns.[53]

Biological agents such as belimumab and rituximab (monoclonal antibodies that target B cells) and anifrolumab (a type 1 interferon receptor antagonist monoclonal antibody) are beneficial for treating those whose condition is refractory to other drugs, and are used in addition to immunosuppressant therapy.[127][128][129][130]

Belimumab

Belimumab may be considered as an add-on treatment for patients whose symptoms do not respond to hydroxychloroquine (alone or in combination with a corticosteroid), or if they are unable to reduce the corticosteroid dose below an acceptable level for chronic use.[53] The use of conventional immunosuppressants is not mandatory for the initiation of belimumab.[53]
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:[131]
- 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.[132] Patients receiving the approved dose were found to have at lease at least a 4-point reduction in SELENA-SLEDAI score.[132]
Belimumab has been demonstrated to significantly reduce organ damage progression (5-year analysis), and significantly increase the risk of adverse effects compared with standard care for patients with SLE.[133][134]

Anifrolumab

Anifrolumab may be considered as an add-on treatment for patients whose symptoms do not respond to hydroxychloroquine (alone or in combination with a corticosteroid), or if they are unable to reduce the corticosteroid dose below an acceptable level for chronic use.[53] The use of conventional immunosuppressants is not mandatory for the initiation of anifrolumab.[53]
In randomised placebo-controlled phase 3 trials, anifrolumab reduced oral corticosteroid dose and severity of skin disease, and improved disease response at 52 weeks, in patients with moderate to severe SLE.[135][136]
Long-term treatment with anifrolumab suggests an acceptable safety profile with sustained improvement in SLE disease activity, health-related quality of life, and serological measures.[137] The most frequently seen adverse effects include upper respiratory tract infection, nasopharyngitis, bronchitis, and herpes zoster.[138]

Rituximab

Rituximab can be considered for patients with organ-threatening disease that is refractory to cyclophosphamide.[53]

Tapering of pharmacological treatment

Gradual tapering of corticosteroid and immunosuppressive treatment is recommended for patients who achieve sustained remission.[53]
Some evidence suggests that continuing low-dose corticosteroids may provide better disease control for patients with SLE with low disease activity, whereas discontinuation slightly increases the risk of disease flare.[139][140]
Hydroxychloroquine should not be discontinued, in the absence of intolerable adverse effects, due to the increased risk of flare.[53]

Pharmacological treatment of non-renal SLE: constitutional symptoms and joint manifestations

Constitutional symptoms

Constitutional symptoms are treated as mild disease (i.e., hydroxychloroquine with or without an oral or intravenous corticosteroid).[53]

Joint manifestations and serositis

Initial treatment for mild joint manifestations is hydroxychloroquine with or without a corticosteroid, in combination with an NSAID, if required to treat arthritis or arthralgia.[53][141][142] First-line interventions for moderate SLE (which includes moderate-to-severe arthritis and serositis), or second-line interventions for mild SLE, include the addition of methotrexate, azathioprine, or mycophenolate, and/or belimumab or anifrolumab.[142]

NSAIDs

NSAIDs are frequently used as a first-line measure in SLE to control joint stiffness as well as musculoskeletal and serosal pain. If an NSAID is required to control joint stiffness, naproxen may be the preferred first-line drug owing to the rare occurrence of aseptic meningitis with ibuprofen.[143][144][145]
Patients who require an NSAID 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.
NSAIDs are associated with an increased risk of cardiovascular thrombotic events and gastrointestinal toxicity (bleeding, ulceration, perforation). NSAIDs should be used at the lowest effective dose for the shortest effective treatment course.
Blood pressure should be monitored during treatment, 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.

Pharmacological treatment of non-renal SLE: mucocutaneous manifestations

First-line treatment of cutaneous disease should include hydroxychloroquine with or without an oral or intravenous corticosteroid, as well as topical therapies (e.g., corticosteroids, calcineurin inhibitors such as tacrolimus).[53][146]

The addition of methotrexate or mycophenolate and/or anifrolumab or belimumab should be considered as second-line therapy for patients who have symptoms that do not respond to first-line treatment, or patients with moderate severity cutaneous symptoms (i.e., rash on 9% to 18% of their body surface area).[53]

Other options for patients with symptoms that do not respond to first- or second-line treatments include retinoids (e.g., acitretin), dapsone, cyclophosphamide, azathioprine, or calcineurin inhibitors. These options should ideally be given with input from a dermatologist who is experienced in the treatment of cutaneous lupus.[53] Thalidomide and lenalidomide should be reserved for patients with symptoms that have not responded to multiple previous drugs, and with extreme caution in women of reproductive age.[53][146]

For patients with symptomatic mucocutaneous manifestations, such as aphthous ulcers, a thorough oral care regime is recommended.[147] Mouthwashes (e.g., chlorhexidine), basic oral hygiene, and regular attendance at a dental practitioner are helpful in the treatment of mouth ulceration. Topical lidocaine may be beneficial for the management of pain secondary to major oral aphthae.[148] Artificial saliva preparations may be required for those with dry mouth.[147] Dry eye disease may be present in up to 16% of patients with SLE, and lubricating eye drops are recommended for these patients.[149]

Pharmacological treatment of non-renal SLE: neuropsychiatric manifestations

The treatment of neuropsychiatric manifestations of SLE is challenging. Two pathological mechanisms have been demonstrated to contribute to these neuropsychiatric symptoms associated with SLE:[64]

Inflammatory: autoimmune or inflammatory pathway leading to NP manifestations due to inflammatory mediators or autoantibodies with either intrathecal immune complex formation or disrupted blood-brain barrier (BBB).
Atherothrombotic/anti-phospholipid-related: ischaemic or thrombotic pathway leading to cerebral microangiopathy, vascular occlusion, and haemorrhage. Accelerated atherosclerosis, immune complex deposition, and immune-mediated vascular injury interplay in this pathway.

Distinction between these two pathophysiological processes may be difficult in practice. The two processes could co-exist in the same patient.

In addition to hydroxychloroquine, in patients with active neuropsychiatric disease attributed to SLE, an immunosuppressant plus a corticosteroid is recommended for inflammatory manifestations, while antiplatelet/anticoagulant therapy is recommended for atherothrombotic/antiphospholipid antibodies (aPL)-related manifestations.[53] The combination of an immunosuppressant plus antiplatelet/anticoagulant therapy may be considered for patients with both inflammatory and atherothrombotic/antiphospholipid-related manifestations.[53]

The choice of immunosuppressant (e.g., azathioprine, mycophenolate, methotrexate) will depend on individual cases, as the neuropsychiatric manifestations can be varied. For severe inflammatory manifestations (e.g., myelopathy, acute confusional state), potent immunosuppressants (e.g., cyclophosphamide, rituximab) are preferred.[53]

For patients with severe neuropsychiatric disease, anifrolumab and belimumab are not recommended due to a paucity of evidence.[53]

SLE associated with thrombotic antiphospholipid syndrome (APS) should be managed with a long-term vitamin K antagonist (e.g., warfarin) after the first arterial or unprovoked venous thrombotic event. Low-dose aspirin should be considered in patients with SLE/without APS with a high-risk aPL profile. The treatment of SLE-a/APS should follow the same principles of therapy as primary APS. See Antiphospholipid syndrome.

Targeted symptomatic pharmacotherapy is indicated according to the type of neuropsychiatric manifestation.[53]

Antipsychotics can be used if required for psychotic symptoms in CNS lupus. Treatment regimes are the same as for patients without SLE. See Schizophrenia.
Antidepressants may be helpful in certain cases. Treatment regimes are the same as for patients without SLE. See Depression in adults.
Anti-migraine therapies may be helpful in certain cases. Treatment regimes are the same as for patients without SLE. See Migraine headache in adults.
Anticonvulsants may be used (e.g., for peripheral neuropathy).

Intravenous immunoglobulin (IVIG) may be used as an adjunctive therapy when initial treatment is inadequate, but the quality of evidence supporting its use is poor (small cohort studies).[150] IVIG can be effective in the treatment of SLE-associated peripheral neuropathies.

Plasmapheresis may also be considered as an adjunctive therapy.[150] The aim of the treatment is to remove circulating auto-antibodies. It is recommended if there are clinical and investigative findings consistent with cerebral vasculitis, and may be used when earlier treatments are inadequate.[150]

Pharmacological treatment of non-renal SLE: haematological manifestations

Haematological manifestations that require anti-inflammatory/immunosuppressive treatment in patients with SLE include thrombocytopenia and autoimmune haemolytic anaemia.[53] A platelet count of 20,000 to 30,000/mm³ is typically used as the cut-off; platelet counts below this number require treatment.[53]

In addition to hydroxychloroquine, recommended acute treatment of severe autoimmune thrombocytopenia includes an immunosuppressant (e.g., azathioprine, mycophenolate, ciclosporin) plus a high-dose systemic corticosteroid (including pulse doses of intravenous methylprednisolone) with or without IVIG. High-dose intravenous cyclophosphamide may be considered in patients with organ- or life-threatening disease. Rituxumab may be considered in refractory cases. Rituximab may also be used earlier in this setting. This is followed by maintenance therapy with azathioprine, mycophenolate, ciclosporin, or rituximab.[53]

For patients with symptoms that are refractory to initial treatments, a thrombopoietin receptor agonist (e.g., eltrombopag, romiplostim) or splenectomy can be considered.[53] It should be noted that thrombopoietin receptor agonists have been associated with a higher risk of thromboembolic events.[53]

With the exception of the use of thrombopoietin receptor agonists, similar treatment options apply to the management of autoimmune haemolytic anaemia.[53]

Pharmacological treatment of renal SLE (lupus nephritis): general principles

For renal manifestations of SLE, induction therapy is required to achieve complete or partial response, followed by maintenance immunosuppression to maintain the response.

Treat-to-target is defined as:

3 months: ≥25% reduction in urine protein (UPr)
6 months: ≥50 reduction in UPr to <3 gr/day
12-24 months: UPr <0.5 to 0.7 gr/day

(all with an estimated glomerular filtration rate (eGFR) within 10% of baseline).

Pharmacological treatment is based on levels of disease severity.

Class I/II

Patients with class I or II lupus nephritis have normal kidney function, or at most, low-grade proteinuria that is well below the nephrotic range, and sometimes microscopic haematuria. For these patients, immunosuppressive treatment should be guided by extrarenal manifestations of SLE.[87]
Nephrotic syndrome should be treated as minimal disease; a maintenance combination with a low-dose corticosteroid with another immunosuppressant should be considered.[87] See Glomerulonephritis.

Class III/IV

Proliferative lupus nephritis - see ‘Pharmacological treatment of renal SLE (lupus nephritis): induction therapy’.[87]

Class V or membranous lupus nephritis

Class V lupus nephritis involves thickening and scarring of the important structures within the kidney. Patients with class V disease will have high levels of blood, protein, or both in their urine as well as high blood pressure and should be treated with a renin-angiotensin system inhibitor to protect renal function, in addition to blood pressure control.[86] For those with low-level proteinuria, immunosuppressive treatment should be guided by extrarenal manifestations. For those with nephrotic range proteinuria, treatments listed for active disease class III/IV should be considered.[87]

Pharmacological treatment of renal SLE (lupus nephritis): induction therapy

Induction therapy is recommended for active renal SLE (class III/IV/V).

All patients with active lupus nephritis should be treated with hydroxychloroquine, unless contraindicated, plus an oral or intravenous corticosteroid. Consider pulse doses of an intravenous corticosteroid (with the dose dependent on the severity of disease), followed by oral corticosteroid therapy tapered to target at 6 months.[53][86][87] Evidence demonstrates that combination therapy significantly increases the rate of complete remission compared with monotherapy in patients with lupus nephritis.[151] Continued hydroxychloroquine is associated with increased remission rates in patients initially treated with mycophenolate for lupus nephritis.[152]

Immunosuppressant options for induction therapy in patients with active proliferative lupus nephritis include:[53][86][87]

Mycophenolate (with or without belimumab or a calcineurin inhibitor such as voclosporin or tacrolimus)
Low-dose intravenous cyclophosphamide (with or without belimumab)

The American College of Rheumatology (ACR) conditionally recommends mycophenolate-based regimens over cyclophosphamide-based regimens. Regimens that contain mycophenolate plus a calcineurin inhibitor may benefit patients with proteinuria ≥3 g/g, while regimens that include belimumab may be effective for patients with extrarenal manifestations.[86]

The ACR conditionally recommends that patients with active onset, new onset, or flare of pure class V lupus nephritis and proteinuria ≥1 g/g receive a triple regimen of a pulse-dose intravenous corticosteroid (followed by oral corticosteroids with taper) plus mycophenolate plus a calcineurin inhibitor.[86] For patients with proteinuria <1 g/g, treatment with a corticosteroid and/or immunosuppressant (i.e., mycophenolate, azathioprine, a calcineurin inhibitor) is conditionally recommended by the ACR.[86]

In the UK, NICE recommends voclosporin (plus mycophenolate) as treatment option for adults with class 3 to 5 (including mixed class 3 and 5, and 4 and 5) lupus nephritis.[153]

In patients at high risk for kidney failure (defined as reduced glomerular filtration rate, histological presence of cellular crescents or fibrinoid necrosis, or severe interstitial inflammation), high-dose intravenous cyclophosphamide in combination with a pulse-dose intravenous corticosteroid can be considered.[53]

Any of the treatments recommended for lupus nephritis should be considered for patients with active disease. The treating clinician has the option to decide if and when combination therapy should be used, based on individual patient factors.[53][87] Examples of individual patient factors that may guide initial treatment include:[53][86][87]

Intravenous cyclophosphamide can be used as the initial therapy for active class III and IV disease for patients who may have difficulty adhering to an oral regimen.
Mycophenolate-based regimens are the preferred initial therapy for patients at high risk of infertility, such as patients who have a moderate-to-high prior cyclophosphamide exposure.
Initial therapy with an immunosuppressive regimen that includes a calcineurin inhibitor may be preferred in patients with relatively preserved kidney function and nephrotic range proteinuria likely due to extensive podocyte injury, as well as patients who cannot tolerate standard-dose mycophenolate or who are unfit for, or will not use, cyclophosphamide-based regimens.
A triple regimen of a corticosteroid plus belimumab plus either mycophenolate or low-dose cyclophosphamide may be preferred in patients with repeated kidney flares or at high-risk for progression to kidney failure due to severe chronic kidney disease.
Other therapies such as azathioprine or leflunomide (combined with a corticosteroid) may be considered in lieu of the recommended initial drugs for proliferative lupus nephritis in situations of patient intolerance or lack of availability, but these alternatives may be associated with inferior efficacy, including increased rate of disease flares and/or increased incidence of drug toxicities.
Mycophenolate is considered to be a first choice option for treating patients with class V lupus nephritis with nephrotic-range proteinuria. If ineffective, cyclophosphamide for ≤6 months should be considered to help induce long-term remission. Long-term use of a calcineurin inhibitor or rituximab may also be tried if the patient has prior significant exposure to cyclophosphamide or is reluctant to take the drug because of associated toxicities.

Evidence from systematic reviews and meta-analyses suggest that mycophenolate is more effective for the initial treatment of lupus nephritis, significantly increasing the levels of serum complement C3 and complete remission, and the reduction of adverse effects compared with cyclophosphamide.[154]

Cyclophosphamide should be given with adequate fluid intake 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.

Compared with standard therapy alone, belimumab has been demonstrated to significantly increase the rate of renal response 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 for patients with lupus nephritis.[155]

In a phase 3 randomised controlled trial (RCT) of patients with lupus nephritis, voclosporin in combination with mycophenolate and a low-dose corticosteroid led to a clinically significant superior complete renal response at week 52 compared with mycophenolate and a low-dose corticosteroid alone (73 [41%] of 179 patients vs. 40 [23%] of 178 patients, respectively).[156] Long-term follow-up data from these patients demonstrated the continued efficacy and safety of voclosporin at 3 years.[157]

Non-responsive or refractory lupus nephritis

For patients with any class of lupus nephritis who have not achieved at least a partial renal response by 6-12 months, treatment escalation may be considered once doses and patient adherence have been assessed.[86] If treated initially with dual therapy, escalation to triple therapy is recommended. For patients treated with triple therapy initially, an alternative triple therapy regimen or the addition of rituximab as the second immunosuppressive drug should be considered.[86]

Rituximab is recommended especially after failure with cyclophosphamide-based regimens, or an extended course of intravenous cyclophosphamide may be considered for patients with persistent disease activity or inadequate response to initial treatment.[53][87]

For patients who experience treatment failure with two standard therapy courses, a more intensive regimen is recommended, including the addition of rituximab, or triple therapy with three non-corticosteroid immunosuppressive drugs (i.e., mycophonate, belimumab, and a calcineurin inhibitor), or patients can be referred for investigational therapy.[86]

Pharmacological treatment of renal SLE (lupus nephritis): maintenance therapy

On the condition that appropriate renal response has been achieved, maintenance immunosuppressant therapy depends on the initial treatment regimen used, for example:[53][86]

Patients initially treated with mycophenolate (alone or in combination with belimumab or a calcineurin inhibitor) should remain on these drugs for maintenance therapy
Patients initially treated with intravenous cyclophosphamide (alone or in combination with belimumab) should be switched to mycophenolate or azathioprine for maintenance therapy
Patients initially treated with triple therapy should remain on the same regimen for maintenance.

Corticosteroid dose should be tapered to the lowest possible dose during maintenance therapy. Discontinuation can be considered after patients have maintained a complete renal response for 12 months.[87]Maintenance treatment should continue for at least 3 years post renal response.[53][86][87]

If relapse of lupus nephritis occurs after a partial or complete response has been achieved, the patient should be treated with the same induction therapy used to achieve the original response, or an alternative recommended induction regimen.[87]

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