Lupus management

Treatment goals for lupus

Overall aims of treatment

In the following video, Professor Petri provides an overview of the relevant therapeutic goals in systemic lupus erythematosus (SLE), with a particular focus on the benefits of the Lupus Low Disease Activity State (LLDAS).

SLE is associated with high morbidity and a much-reduced quality of life¹. Irreversible damage accrual is a key driver of morbidity in SLE and increases risk of mortality¹. Treatment of SLE therefore focuses on improving patients’ long-term survival, preventing organ damage and optimising health-related quality of life². Managing comorbidities and addressing debilitating but frequently overlooked symptoms, such as fatigue and pain, are also important aspects of SLE care³.

Prevention of flares is also considered an important goal and can be achieved through careful pharmacological management and avoidance of specific triggers^2,4. In addition, physicians should aim to maintain patients who require ongoing treatment with glucocorticoids on the lowest effective dose, as long-term use of these drugs can contribute to further irreversible organ damage².

Treat-to-target in SLE

Treat-to-target is a therapeutic approach in which the response to treatment is closely monitored and therapy adjusted in patients who do not meet predefined goals¹. This concept has been applied across a range of disciplines and has proved particularly successful in patients with rheumatoid arthritis^4,5. As a result, the first recommendations regarding the use of a treat-to-target strategy for SLE were published in 2014⁶. 

Identifying appropriate treatment targets has been relatively straightforward for other diseases, but has proved more challenging in SLE, given its heterogeneity and the limited understanding of its underlying pathophysiology¹. The 2014 recommendations identified remission as a potential treatment target but highlighted the lack of a universally accepted definition of remission⁶. The development of a treat-to-target approach in SLE has also been complicated by the fact that some of the therapies currently used to treat this disease may also contribute to poorer patient outcomes⁷.

Definitions of Remission in Systemic Lupus Erythematosus

The Definitions of Remission in Systemic Lupus Erythematosus (DORIS), an international task force consisting of patient representatives, rheumatologists, nephrologists, dermatologists and immunologists, was convened in 2015 to provide a framework for the definition of remission in SLE⁸. The task force recommended a definition based on a validated disease activity index, supplemented by a Physician’s Global Assessment (PGA) of disease activity, which includes the patient’s perspective in the assessment⁸. The three most widely used disease activity indices are the SLE Disease Activity Index (SLEDAI), the British Isles Lupus Activity Group (BILAG) index and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI PGA⁹. In 2021, after considerable research, the DORIS task force arrived at an evidence-based, on-treatment definition of remission. This definition, based on the SLEDAI, allows patients to be on some medications, including antimalarials, low-dose glucocorticoids (prednisolone <5 mg/day) and/or stable immunosuppressives, including biologics¹⁰. The rationale for opting for an on-treatment definition was that remission off-treatment, though ideal, is rare and an off-treatment definition would therefore be impractical.¹⁰

In 2021 the DORIS task force defined remission in SLE as a clinical SLEDAI of 0 and PGA of <0.5 (0–3), irrespective of serology or treatment with some medications¹⁰

Lupus Low Disease Activity State (LLDAS)

Low disease activity (LDA) is an alternative to remission as a treatment target. Specifically, the Low Lupus Disease Activity State (LLDAS), a less stringent target than remission, allows a SLEDAI of ≤4, without disease activity in the major organ systems¹¹. It also stipulates that patients must have no new SLE disease activity, compared with previous assessment, and have a SELENA-SLEDAI of ≤1¹¹. In addition, current glucocorticoid dose must not exceed 7.5 mg per day and only maintenance doses of well-tolerated, approved medications are acceptable¹¹.

Evidence suggests that low disease activity represents an achievable goal for a large proportion of patients with SLE; lower rates of organ damage accrual have been reported among patients who spend more than half of their observed time in LLDAS, compared with those who do not (P=0.0007)¹¹. Furthermore, the likelihood of these patients having an increase in a damage index score of ≥1 was lower than in those who spent <50% of their observed time in LLDAS (relative risk, 0.47; 95% CI 0.28–0.79; P=0.005)¹¹.

The LLDAS and 2021 DORIS definitions serve important purposes and both should be used in clinical practice and research settings¹⁰

Lupus treatment options

Overview

In the video below, Professor Daniel Wallace summarises the strategies that are currently used in the management of patients with systemic lupus erythematosus (SLE).

The following section will focus on the pharmacological agents that are recommended for the treatment of SLE. It should be noted that the only drugs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for patients with SLE are corticosteroids, hydroxychloroquine, belimumab and anifrolumab^12,13. In Europe, azathioprine is also licensed for the treatment of SLE, and cyclophosphamide is indicated in cases of life-threatening autoimmune disease such as severe progressive forms of lupus nephritis¹⁴.

Antimalarials

The use of antimalarials for the treatment of rheumatic diseases dates back more than 50 years and today, hydroxychloroquine is recommended for all patients with SLE^2,15. Hydroxychloroquine is a 4-aminoquinoline with demonstrated efficacy across a wide range of different diseases, including various autoimmune diseases¹⁶.

Hydroxychloroquine is recommended for all patients with SLE, except where contraindicated²

The immunomodulatory properties of hydroxychloroquine are well established and although research into its precise mechanism of action in SLE is ongoing, it is thought to involve inhibition of both innate and adaptive immunity^16,17. To date, proposed mechanisms include lysosomal alkalinisation, inhibition of toll-like receptor (TLR) signalling and interference with B- and T-cell receptor calcium signalling^16,18. 

The beneficial effects of hydroxychloroquine include reduced risk of flares and organ damage^16,18. In some patients, hydroxychloroquine use may facilitate a reduction glucocorticoid dose and it also has antithrombotic effects². In addition, hydroxychloroquine is associated with improved patient survival and reduced utilisation of acute care services¹⁹. However, hydroxychloroquine has a slow onset of action, generally only reaching optimum efficacy after 3–6 months of treatment²⁰.

Hydroxychloroquine has a favourable safety profile, though ideally the dose should not exceed 5 mg/kg of real body weight^16,21. Nausea, vomiting, diarrhoea and abdominal discomfort are the most frequent adverse effects associated with hydroxychloroquine and it is not thought to increase risk of infection or malignancy²¹. Retinopathy is considered the most serious complication of long-term hydroxychloroquine treatment, but risk of retinal toxicity can generally be mitigated through appropriate dosing and implementation of modern screening techniques¹⁶. Of note, patients should also be monitored for signs of hydroxychloroquine-induced cardiomyopathy and arrhythmias^16,21. Chloroquine is also licenced for the treatment of SLE and in some cases may be used as an alternative to hydroxychloroquine, though hydroxychloroquine is generally preferred due to concerns of higher retinal toxicity associated with chloroquine²².

Hydroxychloroquine is the antimalarial agent of choice in SLE as chloroquine is associated with increased retinal toxicity²²

Drug–drug interactions are an important consideration when treating patients with antimalarial drugs^16,21. Both hydroxychloroquine and chloroquine may interfere with the metabolism of various drugs through their interaction with cytochrome P450 enzymes¹⁶. Conversely, certain drugs, such as proton pump inhibitors, may reduce the efficacy of hydroxychloroquine²⁰. Similarly, smoking is thought to reduce the efficacy of antimalarials and smoking cessation is recommended in all patients with SLE²⁰. In addition, in patients with decreased renal function, reduced drug clearance can result in dangerously high hydroxychloroquine concentrations²³.

Despite convincing evidence of the safety and efficacy of hydroxychloroquine in patients with SLE, poor treatment adherence remains a major issue¹⁹. Though rates of non-adherence vary between different patient groups, some estimates suggest that up to 85% of patients with SLE do not adhere to their hydroxychloroquine treatment²⁴. The reasons for this are not fully understood; however, possible explanations include concerns over the possibility of adverse effects, doubts surrounding the efficacy of hydroxychloroquine, poor mental health and confusing drug regimens¹⁹. The importance of adherence to treatment with hydroxychloroquine is highlighted by studies demonstrating that non-adherence is associated with worse long-term survival and increased utilisation of healthcare resources^25–27.

Glucocorticoids

Glucocorticoids have been used in the management of SLE for over 50 years and remain a therapeutic cornerstone, despite an extensive list of adverse effects including²⁸:

• cataracts
• cardiovascular disease
• changes in appearance
• infection
• osteonecrosis
• osteoporosis
• weight gain

Several synthetic glucocorticoids have been developed, including prednisone, prednisolone, methylprednisolone and triamcinolone, and various formulations are available for administration via different routes²⁹.

The appeal of glucocorticoids lies in their ability to provide rapid symptomatic relief for patients with SLE³⁰. These potent anti-inflammatory drugs act systemically, exerting their effects via two distinct pathways: genomic and non-genomic^30,31. In the genomic pathway, glucocorticoids bind the cytosolic glucocorticoid receptor and the resultant complex is translocated into the nucleus, where it binds glucocorticoid response elements^31,32. The complex inhibits transcription of genes in the synthesis of cytokines via a process called transrepression^31,32. In addition, high levels of glucocorticoid in the nucleus upregulate transcription of anti-inflammatory genes (transactivation)^31,32. The process of transactivation is the main driver of adverse effects associated with glucocorticoid use^31,32. The effects of the non-genomic pathway become apparent more rapidly than the effects of the genomic pathway^31,32. The non-genomic pathway ultimately results in reduced immune cell activity and proliferation, which occurs via three different mechanisms^31,32. First, this may be mediated by cytosolic glucocorticoid receptors. The second mechanism involves activation of membrane-bound glucocorticoid receptors and the third involves nonspecific interactions of glucocorticoids with cell membranes^31,32.

Despite the apparent necessity of glucocorticoids for some patients, these drugs should be used sparingly and avoided altogether where possible. It has previously been reported that 80% of organ damage in SLE occurs as a direct or indirect result of prednisone use³. Current guidelines recommend that the daily dose should not exceed 7.5 mg (prednisone equivalent), though any dose over 6 mg/day is associated with a 50% increase in long-term organ damage^3,9. 

Long-term use of glucocorticoids is associated with significant toxicity and these drugs should be used sparingly in patients with SLE³

Pulse therapy involves the administration of high doses of glucocorticoids over a short period of time and is highly effective in inducing remission in life-threatening or organ-threatening disease². A common example is high-dose intravenous methylprednisolone at 250–1000 mg/day for three days². The efficacy of pulse therapy can be explained primarily by the rapid non-genomic effects of glucocorticoids^29,31. Adopting a glucocorticoid pulsing strategy or earlier introduction of immunosuppressive drugs into a patient’s treatment regimen may be used to facilitate faster tapering of glucocorticoid therapy².

Immunosuppressants

Various immunosuppressive agents are available for the treatment of SLE, the most appropriate choice of which varies among patients².

Cyclophosphamide

Cyclophosphamide is one of a wide range of alkylating agents, which are commonly used in the treatment of cancer as well as in life-threatening cases of autoimmune diseases, such as SLE^33,34. The immunomodulatory properties of cyclophosphamide can be attributed to its ability to decrease B cell and T cell numbers and reduce autoantibody production³³.

Cyclophosphamide may be used in organ-threatening cases of SLE, particularly in patients with severe renal, cardiopulmonary or neuropsychiatric manifestations. In treatment-refractory non-major organ manifestations, cyclophosphamide should only be used as rescue therapy².

Fertility is an important consideration in patients treated with cyclophosphamide, owing to the gonadotoxic effects of this drug². In premenopausal women, use of gonadotrophin-releasing hormone (GnRH) analogues alongside cyclophosphamide is recommended to help preserve function². In addition, counselling on the potential use of ovarian cryopreservation services should be provided to women prior to treatment with cyclophosphamide². Further risks associated with cyclophosphamide include malignancy and infections and should not be overlooked during the clinical decision-making process².

Azathioprine

Azathioprine exerts its effect through inhibition of purine synthesis³⁵. Use of azathioprine results in reduced lymphocyte proliferation and production of antibodies, as well as a decrease in natural killer cell activity³⁶. In patients with SLE who fail to achieve satisfactory symptomatic control following treatment with glucocorticoids and hydroxychloroquine, or those for whom hydroxychloroquine alone is likely to be inadequate, azathioprine is considered a suitable treatment option².

Common adverse effects associated with azathioprine use include gastrointestinal toxicity, oral ulcers, nausea, vomiting, diarrhoea and epigastric pain. Bone marrow toxicity resulting in leucopenia or thrombocytopenia and anaemia may also occur in some patients³⁷. However, aside from tacrolimus, azathioprine is the only immunosuppressive drug that is considered suitable for pregnant patients³⁸. This is because azathioprine cannot be metabolised by fetuses³⁶.

Methotrexate

Methotrexate is a folate analogue. It exerts its therapeutic effects via the inhibition of dihydrofolate reductase (DHFR), which is involved in the synthesis of purines and pyrimidines^37,39. This interrupts DNA replication, preventing T cell division and proliferation^37,39. In SLE, this steroid-sparing agent is used to treat patients without major organ involvement³⁷. 

Like azathioprine, methotrexate may be used to treat patients who fail to achieve satisfactory symptomatic control following treatment with glucocorticoids and hydroxychloroquine, or those for whom hydroxychloroquine alone is likely to be inadequate². Evidence for the use of methotrexate in this group of patients is considered stronger than the evidence for azathioprine; however, methotrexate is contraindicated in pregnancy². In addition, gastrointestinal side effects are common, and patients should be monitored to minimise the risk of hepatotoxicity¹⁴.

Mycophenolate mofetil

Mycophenolate mofetil selectively inhibits the activity of inosine monophosphate dehydrogenase (IMPDH), which interferes with the de novo synthesis of purines⁴⁰. It is thought that its efficacy in patients with SLE can be explained primarily by its ability to prevent the proliferation of B cells and T cells and the generation of autoantibodies⁴⁰. It can be used to treat renal and nonrenal cases of SLE². In patients with class III-IV lupus nephritis, induction therapy with mycophenolate mofetil/mycophenolic acid or cyclophosphamide plus glucocorticoids is followed by maintenance therapy with mycophenolate mofetil/mycophenolic acid or azathioprine².

The ALMS trial compared the efficacy of mycophenolate mofetil and azathioprine for the maintenance of remission in patients with lupus nephritis⁴¹. This study found that mycophenolate mofetil was superior to azathioprine in terms of maintaining a renal response and preventing relapse in patients who had responded to induction therapy⁴¹. In the MAINTAIN Nephritis trial, however, mycophenolate mofetil was not significantly superior to azathioprine in reducing the number of renal flares in patients with proliferative lupus nephritis^41,42.

Bone marrow cell line toxicity is lower with mycophenolate mofetil, compared with other immunosuppressants used to treat SLE; however, it is associated with a range of adverse effects including infection and diarrhoea⁴³. 

Interestingly, there is some evidence to suggest that race, ethnicity and geographical region may influence response to treatment⁴⁴. In the ALMS study, for example, more Black and Hispanic patients responded to mycophenolate mofetil than to intravenous cyclophosphamide⁴⁴. It is also worth noting that like many other immunomodulatory medications, mycophenolate mofetil is unsuitable for pregnant women and should be discontinued at least 6 weeks before conception².

Calcineurin inhibitors

Calcineurin is a calcium and calmodulin-dependent phosphatase, which prevents activation of T cells. Calcineurin inhibitors include tacrolimus and cyclosporine A⁴⁵.

Calcineurin inhibitors may be used in renal or non-renal disease. In non-renal SLE, these drugs are used in patients with moderate disease, either as a first-line therapy or to treat refractory disease². For example, in cutaneous disease glucocorticoids or calcineurin inhibitors plus hydroxychloroquine, with or without glucocorticoids may be considered as fist-line therapy².

In patients with lupus nephritis, calcineurin inhibitors are currently used as induction or maintenance therapy in second-line treatment². These drugs may be used alone or in combination with other agents, such as mycophenolate mofetil, in certain cases². They are particularly useful in patients with membranous lupus nephritis, podocytopathy or proliferative disease with refractory nephrotic syndrome who have responded inadequately to standard of care after a period of 3–6 months². The benefits of a multitarget approach whereby patients are treated with more than one immunosuppressive agent with differing mechanisms of action has been demonstrated in some studies, but this requires further investigation².

In 2021, voclosporin became the first oral agent to receive FDA approval for the treatment of lupus nephritis, on the basis of results from the AURORA 1 phase III and AURA-LV phase II clinical trials^46,47. The key results from the AURORA study are summarised in Table 1⁴⁶.

Table 1. Key results from the AURORA 1 study investigating the safety and efficacy of voclosporin vs placebo in patients with lupus nephritis who also received mycophenolate mofetil and rapidly tapered methylprednisolone (Adapted⁴⁶). CI, confidence interval; HR, hazard ratio; OR odds ratio; UPCR, urinary protein:creatinine ratio

In general, it is important that drug levels in patients receiving calcineurin inhibitors are monitored appropriately as these drugs have a narrow therapeutic window⁴⁸. Adverse effects associated with calcineurin inhibitor use include new-onset hypertension, renal toxicity and hyperglycaemia⁴⁹. An important advantage of voclosporin is that it requires less therapeutic monitoring than other calcineurin inhibitors⁴⁶.

Biologics

Belimumab

In 2011, belimumab became the first biologic agent to receive FDA and EMA approval for the treatment of SLE. This followed a period of more than 50 years during which no new drugs had been approved specifically for patients with SLE⁵⁰. Belimumab was also the first agent to receive FDA approval, in 2020, and EMA approval soon after, in 2021, for treatment of lupus nephritis⁵¹.

Belimumab is a recombinant human IgG-1λ monoclonal antibody that targets B lymphocyte stimulator, also known as BLyS or BAFF^50,52. BLyS plays a key role in B cell differentiation⁵³. Its other biological activities include promotion of B cell survival and inhibition of B cell apoptosis⁵³. By binding BLyS, belimumab blocks its interaction with each of its three receptors located on B cells resulting in inhibition of its activity (Figure 1)⁵⁰. It is used as an add-on therapy in patients with autoantibody-positive SLE, whose disease activity remains high despite treatment with standard therapy^2,14.

Figure 1. Belimumab mechanism of action (Adapted⁵⁰). BLyS is able to bind three receptors expressed on B cells, T cells and plasma cells (A), belimumab blocks the interaction between BLyS and its receptors, but not the interaction between APRIL and BCMA or TACI (B). APRIL, a proliferation-inducing ligand; BCMA, B cell maturation antigen; BLyS, B lymphocyte stimulator; BR3, BLyS receptor 3; TACI, transmembrane activator and calcium modulator and cytophilin ligand interactor.

The approval of belimumab for treatment of SLE was based on the results of two phase III double-blind randomised controlled clinical trials, BLISS-52 and BLISS-76, which included a total of 1,684 patients with autoantibody-positive disease and a SELENA-SLEDAI score of at least 6, who were being treated with stable standard SLE therapy^54,55. Patients with severe active lupus nephritis or severe active CNS SLE were not included in these trials^54,55. The key results of BLISS-52 and BLISS-76 are summarised in Table 2 and Table 3 respectively.

Table 2. Key results from the BLISS-52 clinical trial at Week 52 (Adapted⁵⁴). BILAG, British Isles Lupus Assessment Group; OR, odds ratio; PGA, Physician’s Global Assessment; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment – Systemic Lupus Erythematosus Disease Activity Index; SRI, Systemic Lupus Erythematosus Responder Index.

BLISS-52

Table 3. Key results from the BLISS-76 clinical trial at Week 52 (Adapted⁵⁵). BILAG, British Isles Lupus Assessment Group; OR, odds ratio; PGA, Physician’s Global Assessment; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment – Systemic Lupus Erythematosus Disease Activity Index; SRI, Systemic Lupus Erythematosus Responder Index.

BLISS-76

More recently, BLISS-LN, a phase III randomised, double-blind, placebo-controlled trial investigated the safety and efficacy of belimumab for the treatment of patients with active lupus nephritis⁵². This study found rates of primary efficacy renal response (ratio of urinary protein:creatinine of ≤0.7, estimated glomerular filtration rate that was no more than 20% below the pre-flare value or ≥60 ml per minute per 1.73 m² of body-surface area, and no use of rescue therapy) were significantly higher in the belimumab group, compared with the placebo group at week 104 (43% vs 32%; odds ratio [OR], 1.6; 95% confidence interval [CI], 1.0–2.3; P=0.03; Figure 2)⁵². Similarly, a complete renal response was reported in a significantly higher proportion of patients treated with belimumab as compared with placebo (30% vs. 20%; OR, 1.7; 95% CI, 1.–2.7; P=0.02)⁵². Furthermore, among patients receiving belimumab, risk of renal-related events or death was significantly lower than in the placebo group (hazard ratio, 0.51; 95% CI, 0.34–0.77; P=0.001)⁵². The results of BLISS-LN were the basis for approval of belimumab for the treatment of lupus nephritis⁵¹.

Figure 2. Primary efficacy renal responses over time in receiving belimumab or a placebo in the BLISS-LN trial (Adapted⁵²).

In terms of safety, the available data suggests that belimumab is generally well tolerated by patients with SLE⁵⁶. The most common adverse events associated with belimumab use are viral upper respiratory tract infections, bronchitis and diarrhoea¹⁴. Given the immunomodulatory properties of belimumab, it is possible that this drug could increase the risk of malignancy¹⁴. Psychiatric status may also be an important consideration when prescribing belimumab as there is some evidence suggesting that psychiatric disorders are more common among patients treated with this drug¹⁴. 

To date, long-term safety data appear reassuring⁵⁷. A 2019 study reporting on the safety and efficacy of belimumab plus standard therapy for up to 13 years found that the most common adverse events were arthralgia, upper respiratory tract infections, sinusitis, urinary tract infection and headache⁵⁷. Meanwhile, the most frequent serious adverse events included pneumonia, osteoarthritis, noncardiac chest pain, pyrexia, cellulitis, chronic obstructive pulmonary disease, abdominal pain, viral gastroenteritis and vomiting⁵⁷. Overall, this study revealed no new safety concerns and rates of adverse events did not appear to increase over time⁵⁷.

Anifrolumab

In July 2021, the FDA approved anifrolumab as the second targeted therapy for adults with SLE¹³. Anifrolumab is a human IgG monoclonal antibody that binds type 1 interferon (IFN) receptor subunit 1 (IFNAR1) and blocks type 1 interferon signalling (Figure 3).

Figure 3. Anifrolumab mechanism of action (Adapted⁵⁸). BDCA-2, blood dendritic cell antigen-2; DC, dendritic cell; GAS, gamma-activated sequence; IFN, interferon; IFNAR1; type 1 interferon receptor subunit 1; IFNAR2; type 1 interferon receptor subunit 2; IRF9, interferon regulatory factor 9; ISREs, interferon-sensitive response elements; JAK1, Janus kinase 1; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2

Approval for anifrolumab was based on two phase 3 clinical trials. In the first of these clinical trials, TULIP-1, anifrolumab did not have a significant effect on the primary end-point; however, in the second trial, TULIP-2, a secondary end-point from TULIP-1 was evaluated as the primary end-point⁵⁹.

In the TULIP-2 trial, patients were randomly assigned to receive either placebo or anifrolumab (300 mg) intravenously every 4 weeks for 48 weeks. The primary end-point was a response at 52 weeks defined by a British Isles Lupus Activity Group (BILAG)-based Composite Lupus Assessment (BICLA). This response required⁵⁹:

• a reduction in any moderate-to-severe baseline disease activity
• no worsening in any of nine organ systems in the BILAG index
• no worsening on the SLEDAI
• no increase of 0.3 points or more in the PGA
• no discontinuation of the trial intervention
• no use of medications restricted by the protocol.

Secondary end-points in the TULIP-2 trial included⁵⁹:

• a BICLA response in patients with a high interferon gene signature at baseline
• reductions in the glucocorticoid dose
• reductions in the severity of skin disease, counts of swollen and tender joints, and the annualised flare rate.

The results of the TULIP-2 trial are summarised in Table 4.

Table 4. Key results from the TULIP-2 clinical trial (Adapted⁵⁹). BICLA, British Isles Lupus Activity Group (BILAG)-based Composite Lupus Assessment; CI, confidence intervals; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; ^*Glucocorticoid dose reduction from ≥10 mg/day to ≤7.5 mg/day; ^†CLASI ≥10 at baseline

Anifrolumab was generally well tolerated. Adverse events that occurred more frequently in the anifrolumab group, compared with placebo, included bronchitis, upper respiratory tract infection and herpes zoster. The latter infection was cutaneous and resolved without discontinuation of treatment⁵⁹.

Other biologics may be used off-label in the treatment of patients with SLE². For example, although rituximab failed to meet the primary endpoints in the EXPLORER and LUNAR clinical trial programmes, it is commonly used off-label to treat patients with treatment-refractory, organ-threatening disease^2,60,61. Other molecules of interest include the anti-TNFs abatacept and tocilizumab.

Treating comorbidities

Patients with SLE are at increased risk of developing a range of different comorbidities including cardiovascular disease, malignancies, infections and osteoporosis^62,63. These comorbidities contribute significantly to the burden of SLE and onset can occur in either earlier or later stages of disease⁶⁴. Multimorbidity is also common among patients with SLE and other rheumatic diseases and may affect health-related quality of life, work productivity and mortality^65,66. Ensuring early diagnosis and effective treatment of comorbidities can help promote better health-related outcomes, however managing these comorbid conditions can be complex and they are associated with an increased risk of hospitalisation^66,67.

In patients diagnosed with SLE, comorbidities should be considered from the outset. Preventive measures such as smoking cessation, physical activity and maintenance of a healthy weight should be encouraged in all patients, particularly those at high risk of developing cardiovascular disease⁶⁶. Vaccinations are also strongly recommended, except where contraindicated, as a means of mitigating infection risk⁶⁶. Furthermore, minimising patient exposure to certain drugs, particularly glucocorticoids, should also be encouraged to reduce the risk of developing treatment-associated comorbidities⁶⁶.

Treatment sequencing

In the following video, Professor Daniel Wallace explains the factors that influence choice of treatment in patients with systemic lupus erythematosus (SLE).

The 2019 European League Against Rheumatism (EULAR) guidelines for the management of SLE recommend remission where possible as the aim of treatment or low disease activity where this is not achievable, as well as prevention of flares².

Hydroxychloroquine remains a cornerstone of SLE therapy and is recommended at a dose of 5 mg/kg real body weight for all patients². Glucocorticoids, such as prednisone, are introduced for the treatment of acute disease and maintained at a dose of ≤7.5 mg where required². Given the adverse effects of long-term glucocorticoid use, efforts should be made to taper glucocorticoid dose and withdraw them altogether where possible². Steroid-sparing immunosuppressive agents including azathioprine, mycophenolate mofetil and methotrexate are used in cases of active, flaring, non-renal disease; the choice of agent depends on various patient- and disease-specific factors².

Belimumab may be introduced as an add-on treatment in patients with persistent extrarenal disease who have not responded to first-line therapies². Anifrolumab is the second biologic agent to have been approved as add-on treatment for patients with moderate-severe SLE who are receiving standard therapy^68,69. Off-label use of another biologic, rituximab, is also recommended for severe, organ-threatening cases of SLE in patients whose disease has proven refractory to all other lines of treatment². The 2019 EULAR recommendations for treatment sequencing in patients with non-renal SLE are shown in Figure 4. Note that anifrolumab is not included in the treatment algorithm as it was approved for use in SLE in 2021, after publication of the EULAR recommendations.

Figure 4. Treatment algorithm for patients with non-renal SLE (Adapted²). aPL, antiphospholipid antibodies; AZA, azathioprine; BEL, belimumab; BILAG, British Isles Lupus Assessment Group disease activity index; CNI, calcineurin inhibitor; CYC, cyclophosphamide; GC, glucocorticoids; HCQ, hydroxychloroquine; IM, intramuscular; MMF, mycophenolate mofetil; MTX, methotrexate; Pre, prednisone; PO, per os; RTX, rituximab; PLTs, platelets; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

Specific recommendations regarding the treatment of cutaneous, neuropsychiatric, haematological and renal disease have also been made². In the case of renal disease, patients who develop lupus nephritis should, ideally, receive induction treatment with mycophenolate mofetil or low-dose cyclophosphamide². High-dose cyclophosphamide or mycophenolate mofetil may be used in cases of severe lupus nephritis². As in non-renal disease, off-label rituximab may be deemed appropriate in refractory or relapsing disease². Belimumab and voclosporin were approved in 2020 and 2021, respectively, as add-on treatment of lupus nephritis, but their place in the treatment sequence is yet to be clarified⁷⁰.

In patients with lupus nephritis, calcineurin inhibitors are currently used as induction or maintenance therapy in the second line of treatment². These drugs may be used alone or in combination with other agents such as mycophenolate mofetil in certain cases². They are particularly useful in patients with membranous lupus nephritis, podocytopathy, or proliferative disease with refractory nephrotic syndrome who have responded inadequately to standard of care after a period of 3–6 months².

Lupus treatment burden

In the video below, Professor Wallace summarises the social and economic burden associated with treatment of SLE.

The burden of treatment in systemic lupus erythematosus (SLE) should not be underestimated. Upon diagnosis of any chronic disease, patients are faced with the challenge of learning how to manage their medications, which may involve getting to grips with complicated treatment regimens and engaging with a multidisciplinary team of healthcare professionals⁷¹. Multimorbidity is common among patients with SLE and learning how to manage the different aspects of their illness may be overwhelming and increases risk of developing further psychological comorbidities^65,71. The economic cost of SLE therapies is also high, representing a significant personal and societal burden⁷².

Though appropriate treatment is crucial for management of SLE, many of the pharmacological agents used are associated with burdensome adverse effects^73,74

Despite its association with favourable disease outcomes, adherence to hydroxychloroquine treatment remains low⁷⁴. The reasons for this are not well understood, and though blood tests can be used to monitor compliance, this is not always practical in a clinical setting⁷⁴. In addition, the risk of retinal toxicity from long-term hydroxychloroquine use is an important consideration, particularly in high-risk patient groups⁷⁴. Striking a balance between the relative benefits and risks associated with hydroxychloroquine is important and requires regular monitoring for signs of retinal damage and limiting hydroxychloroquine dose while maintaining its efficacy⁷⁴.

Similarly, the importance of reducing glucocorticoid use in patients with SLE is increasingly recognised⁷³. Though glucocorticoids represent an effective therapeutic option when it comes to gaining rapid control in SLE, their long-term use is associated with a plethora of unpleasant complications including severe irreversible organ damage⁷⁵. Nevertheless, up to 86% of patients are maintained on long-term glucocorticoid therapy, including those who have achieved remission⁷⁶.

Dose reduction and, where possible, complete withdrawal of glucocorticoids is recommended for patients receiving long-term treatment with these drugs. Recent evidence suggests that this is a realistic goal in patients in long-term remission or LLDAS⁷⁶.

Use of steroid-sparing immunosuppressive agents such as azathioprine, mycophenolate mofetil, methotrexate, cyclosporine A and cyclophosphamide may offer a solution to this problem in some cases but these drugs are not without drawbacks^2,77. Adverse effects associated with the use of immunosuppressants include infections, haematological and ovarian toxicities, and gastrointestinal issues, which may lead to discontinuation in some patients⁷⁸. Selecting which immunosuppressant is best suited to an individual patient requires careful consideration of a number of factors but, overall, there is a movement towards earlier introduction of any immunosuppressant into the treatment regimen of patients with SLE in order to facilitate tapering or discontinuation of glucocorticoid therapy^2,74.

Though belimumab has a favourable safety profile, its high cost currently limits its use to patients in whom standard of care therapy, usually including an immunosuppressive agent, has been inadequate⁷⁴. Further research regarding whether or not belimumab can be tapered in patients who respond well to this drug is still needed, though long-term use does not appear to be associated with an increased risk of adverse effects⁷⁴. Rituximab is similarly costly and is therefore currently used as an off-label treatment in severe, organ-threatening cases of SLE that have not responded to alternative therapeutic options⁷⁴.

Lupus patient management

Patient-reported outcome measures in SLE

In the video below, Professor Petri highlights the importance of patient-reported outcome evaluation, particularly when it comes to assessing the impact of type 2 symptoms.

Patient-reported outcome measures (PROMs) are tools used to assess various aspects of health status, including health-related quality of life, and can be a useful means of increasing patient engagement in their treatment plan and encouraging better patient-physician communication⁷⁹. Examples of some of the generic and disease-specific PROMs that are currently used in systemic lupus erythematosus (SLE) are listed below.

Generic PROMs

Medical Outcomes Study Short-Form 36 (SF-36) – the SF-36 is a 36-item questionnaire in which questions are divided into eight different domains with a final transition question. The questions are also separated into a physical component summary and a mental component summary. Scores range from 1–100, with higher scores indicating better health^80,81.

EuroQol-5D (EQ5D) – EQ5D is used to assess HRQoL based on five different dimensions. These include mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Scores range from 1, indicating full health to –0.594, with scores of <0 indicating a state of health that is worse than death^80,82.

Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) – FACIT-Fatigue is a 13-item PROM which assess different aspects of fatigue including physical fatigue, functional fatigue, emotional fatigue and social consequences of fatigue. Questions take the form of Likert scales and total scores range from 0–52, with higher scores indicating less fatigue^80,83.

Patient Reported Outcomes Measurement Information System Item-bank (PROMIS) Short Forms – various versions are available each of which cover one domain comprising 4–10 items. Total scores range from 1–100, with higher scores indicating greater impact of that domain on the patient⁸⁰.

Patient Reported Outcomes Measurement Information System Item-bank Computer Adaptive Tests (PROMIS CATs) - various versions are available each of which cover one domain comprising 4–12 items. In PROMIS CATs a computer selects the most appropriate questions based on previous responses, reducing the number of questions a patient is required to complete in order to establish their status with respect to the relevant domain^80,84.

SLE-specific PROMs

Lupus Quality of Life questionnaire (LupusQoL) – LupusQoL is a 34-item questionnaire comprising 8 different domains. Questions take the form of a Likert scales, with total scores ranging for 0–100, with higher scores indicating better health^80,81,85.

LupusPRO – LupusPRO is a 43-item PROM used to assess both HRQoL and non-HRQoL. Questions take the form of a Likert scales, with total scores ranging for 0–100, with higher scores indicating better health. The most recent version of LupusPRO comprises 14 domains^80,86.

Lupus Impact Tracker (LIT) – LIT is a 10-item PROM that was derived from LupusPRO as a means of rapidly assessing impact of disease on the daily functioning and well-being of patients with SLE. Scores range from 0–100, with higher scores indicating a greater impact on the patient’s life^80,87.

Understanding patients' goals in SLE

Shared decision-making is considered an important aspect of patient-centred care in SLE and is thought to be associated with better treatment compliance and outcomes for patients⁸⁸. Understanding patients’ needs and expectations is crucial and providing patients with access to appropriate educational resources enables them to make informed decisions regarding their treatment plan and personal goals^89,90.

Recently, Pietsky and colleagues proposed a new classification system in which the symptoms of SLE are grouped into two broad categories: type 1 manifestations and type 2 manifestations⁹¹. The former encompasses the classical inflammatory symptoms of SLE, which are typically the focus of clinical assessment tools such as the SLEDAI⁹¹. These include nephritis, arthritis and vasculitis⁹¹. Type 2 symptoms differ in that they do not tend to fluctuate with disease activity and generally do not respond to treatment with immunosuppressants⁹¹. Examples of type 2 manifestations of SLE include fatigue, pain throughout the body, cognitive dysfunction, sleep disturbance, brain fog and mental health disorders such as anxiety and depression⁹¹. Despite uncertainty as to where type 2 manifestations fit into our current understanding of SLE, they are among the most common and debilitating symptoms reported by patients with this disease⁹¹. Recognition of the profound impact that type 2 manifestations can have on health-related quality of life (HRQoL) is important to patients and this is often reflected in patient-reported outcome assessments⁹¹.

Patient education in lupus

Download this insightful infographic that you can share with your patients to provide education about lupus and guidance for self-management.

Living with lupus

Despite the advances in treatments and overall improvements in survival rates, systemic lupus erythematosus (SLE) continues to place a major burden on patients through increased morbidity and reduced self-esteem and quality of life⁹². A systematic review of qualitative studies exploring patients’ experiences and perspectives of living with SLE found that many patients felt their condition was trivialised, misunderstood and stigmatised⁹². This study highlighted the need for information and educational support to promote self-care and treatment adherence, and thereby improve health outcomes, including mental resilience, self-advocacy and positive coping strategies⁹².

Another study found that a sense of insecurity and mistrust in patients were associated with negative healthcare behaviours, including under-reporting of symptoms and healthcare avoidance. This can be harmful for patients if they feel insecure about reporting potentially life-threatening or organ-threatening symptoms⁹³. Patients have also reported a reluctance to report mental health and cognitive concerns for reasons including embarrassment and fear of stigma⁹³. Clinicians can help to allay such fears and insecurities by validating patients’ symptoms and, where appropriate, sensitively asking about mental health concerns and providing resources or referrals to relevant services⁹³.

Understanding the needs of patients living with lupus

Understanding patients’ needs is key to patient engagement, which in turn is essential for optimal management of chronic diseases such as SLE^89,94. Effective communication and good rapport with clinicians have been found to lessen self-doubt and increase self-efficacy in patients with SLE⁹³. Self-efficacy refers to patients’ perception of their capacity to manage their illness in partnership with carers and health professionals, and has been associated with increased treatment compliance and improved health outcomes for patients with chronic diseases⁹⁵.

Patients living with SLE value comprehensive information about SLE, risks and benefits of available treatments, advances in treatments, and ongoing research about SLE⁹²

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