Bioethics Paper

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Review Article Published: 11 December 2018

New therapeutic strategies in systemic lupus erythematosus management

Mariele Gatto, Margherita Zen, Luca Iaccarino & Andrea Doria  

Nature Reviews Rheumatology  15, 30–48(2019)

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Abstract

The current treatment approach for systemic lupus erythematosus (SLE), as outlined in the recommendations by international medical associations including EULAR and the ACR, is mostly eminence-based rather than evidence-based. However, knowledge on SLE is growing quickly, and such new advances need to be translated into clinical practice. Questions remain regarding the choice and timing of drug administration and tapering until withdrawal, which both can affect the balance between the control of disease activity and damage to organs triggered by long-standing and/or disproportionate immunosuppression. Currently, the treating physicians of patients with SLE are required to weigh the present with the future situation of their patients in an optimized balance between therapeutic harm and benefit. In this Review, the available therapeutic strategies and main challenges in the approach to SLE treatment are discussed. Remission and low disease activity are desirable therapeutic goals. Although

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the drug armamentarium for SLE has not expanded much in the past few decades, there are nonetheless opportunities to make better choices and explore combination therapies; such opportunities offer the potential of a personalized medicine strategy.

Key points

Early diagnosis and early treatment are required for a better outcome in systemic lupus erythematosus (SLE).

Preventive strategies should be applied at any stage of the disease course to minimize disease evolution or worsening; potential comorbidities should be prevented from the start of SLE treatment.

The achievement of clinical remission and subsequent tapering of glucocorticoids until withdrawal are desirable subsequent steps in SLE management.

Even when remission cannot be attained, the treatment of patients with SLE should be optimized to achieve the lowest stable level of disease activity.

Tapering of treatment should be initiated once there is a stable response and requires careful monitoring.

Patient-tailored therapeutic strategies should consider the immunological background, clinical features, realistic potential for recovery and the expectations of each patient.

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Introduction

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The management of systemic lupus erythematosus (SLE) has evolved over the past few decades, leading to improved patient survival in the mid-term; however, patients with SLE are still twice as likely to die as age-matched individuals in the general population and mostly die of long-term complications .

Therapeutic strategies should aim to control disease activity while minimizing damage accrual related to both active disease and drug-related adverse effects ; however, the management of SLE is highly variable, possibly as a result of a lack of consensus on the concepts of remission and/or low disease activity (LDA) and on how SLE should be handled in the long term. These caveats could lead to suboptimal therapeutic strategies . Nevertheless, scientific advances in diagnostics and disease monitoring are encouraging the discussion of early diagnosis as well as personalized therapy. In this Review, we discuss the available and emerging therapeutic strategies in SLE and how such strategies can exploit currently available drugs to improve patient prognosis in the long term.

Importance of early diagnosis

The median lag time from SLE onset to diagnosis has decreased from ~50 months before 1980 (ref. ) to 6–25 months since the year 2000 (refs ), largely because of the availability of antinuclear antibody (ANA) assays that enable an early diagnosis of SLE. However, this lag time is unsatisfactory as autoimmune abnormalities can occur up to 10 years before clinical onset of SLE . Furthermore, even when dealing with the interpretation of well-characterized antibodies (for example, anti-double-stranded DNA (dsDNA) antibodies), caution is required as false-positive results can occur in cases of infection or malignancy and in the elderly population ; additionally, a diverse array of laboratory techniques are used for their determination . Hence, the search for biomarkers of autoimmune abnormalities continues .

Early diagnosis of SLE is important as it provides the chance of a timely treatment to improve the patient outcome and as the attainment of an early response dampens the disease course by minimizing organ damage . Accordingly, in a retrospective

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longitudinal matched-cohort study of >9,000 patients with SLE, the frequency of flares was lower in the group of patients diagnosed within 6 months of symptom onset than in the group of patients with a later diagnosis, as was the rate of hospitalization and SLE- related costs . Furthermore, data on lupus nephritis indicate that a delayed renal biopsy and consequently a delayed initiation of treatment are strongly associated with an increased risk of adverse renal outcomes, including renal failure and death .

The measurement of potential biomarkers that change before clinical SLE, such as a rise in serum levels of pro-inflammatory mediators such as IL-5, IL-6, IFNγ and IFNα, has been limited to research settings and is not currently used to predict future disease development in asymptomatic individuals. Importantly, patients often present with fewer disease-specific elements the earlier they are diagnosed. Thus, a means of excluding diseases that mimic SLE (SLE mimickers) is paramount in the early stages of disease (Table 1).

Table 1 Common mimickers of SLE

Preventive strategies

In addition to early diagnosis and treatment, preventive strategies should be adopted as early as possible for individuals at risk of developing SLE (primary prevention) or for patients who have already been diagnosed with SLE to avoid disease exacerbations (secondary prevention) and disease progression (tertiary prevention) (Fig. 1). The treatment of comorbidities is also paramount (Box 1) as these conditions are the ultimate cause of death in a proportion of patients .

Fig. 1: Levels of prevention in SLE.

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a | Therapeutic strategies in systemic lupus erythematosus (SLE) should aim to

prevent disease development in predisposed individuals (primary prevention) and to

prevent disease flares and progression in patients already affected (secondary and

tertiary prevention). Secondary and tertiary preventive strategies also apply to those

individuals who do not fit the SLE classification criteria but fulfil the diagnostic

criteria for so-called ‘incomplete lupus erythematosusʼ (ILE). The prevention of

comorbidities should start at the time of diagnosis. Applying preventive strategies

early during the disease course can help to avoid the establishment of organ

damage, which is a major trigger of further damage and functional decline. b |

Preventive measures, including pharmacological and behavioural strategies, can be

implemented during the various stages of prevention. aPL, antiphospholipid

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antibody; AZA, azathioprine; CYC, cyclophosphamide; HCQ, hydroxychloroquine;

MMF, mycophenolate mofetil; MTX, methotrexate; RTX, rituximab. The advice for

drug measures is potentially useful, but this advice is mostly eminence-based and

strong evidence to support this advice is lacking.

Box 1 Prevention of SLE comorbidities

The prevention of systemic lupus erythematosus (SLE) comorbidities should start from the time of diagnosis. Major complications are mostly related to long-standing immunosuppression and glucocorticoid therapy.

Cardiovascular disease

Managing traditional risk factors

Control lipid levels in patients with dyslipidaemia with statins (or ezetimibe if there is a risk of myotoxicity)

High blood pressure (<130/80 mm/Hg): angiotensin converting enzyme inhibitors indicated

Smoking cessation

Managing disease activity

Hydroxychloroquine (protective against thrombosis and accelerated atherosclerosis)

Steroid-sparing strategies

Infections

Show more

Primary prevention

Stratification of asymptomatic autoantibody-positive individuals according to other risk factors (such as whether patients have hypergammaglobulinaemia, reduced levels of C3 and/or C4 or a family history of SLE) might be useful for characterizing the likelihood of disease progression . Indeed, although the presence of a low ANA titre on an isolated occasion might not require further investigation, a persistent high ANA titre (>1:80) and/or the presence of select autoantibodies (such as antibodies against dsDNA, U1RNP, ribosomal P or Sm) should be closely monitored, especially for patients who are at an increased risk of developing SLE (for example, pregnant women) . Evidence of the usefulness of primary preventive measures in asymptomatic individuals with serological abnormalities is mostly eminence-based; thus, the physician must base the decision on whether to implement such measures on patient-specific features. Similarly, whether or not to screen asymptomatic individuals who are potentially at risk of SLE is unclear .

Preventive measures in SLE include the removal of modifiable risk factors (such as exaggerated sunlight exposure, smoking and drugs that can induce SLE) ; however, there remains a lack of consensus on what preventive pharmacological interventions can be used. Vitamin D supplementation might be advisable in asymptomatic individuals to provide potential immunomodulatory effects without notable drug adverse events . Although ANA positivity alone might not necessitate hydroxychloroquine treatment,

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Screening for latent infections (tuberculosis, hepatitis C virus, hepatitis B virus and HIV)

Immunization with the inactivated influenza vaccine and the 23-valent pneumococcal polysaccharide vaccine (23-PPV) is strongly advised whereas immunization with the human papilloma virus (HPV) vaccine should be considered in young women with stable or inactive SLE

Prophylactic treatment with trimethoprim–sulfamethoxazole in patients with a low CD4 cell count (<200 cells/mm )

Prophylactic treatment with a quinolone antibiotic (such as levofloxacin (500 mg, daily) or ciprofloxacin (500 mg, twice daily)) in patients with chronic neutropenia (<500 cells/mm ) , potentially combined with antifungal therapy (refer to a specialist in infectious diseases)

Modulation of immunosuppressive therapy

Cancer

Most neoplasms that are more common in SLE than in the general population are haematological (such as non-Hodgkin lymphoma), but solid neoplasms (such as lung, hepatocellular or cervical tumours) are also more common

Screening according to age-related and sex-related recommendations

HPV vaccination and regular gynaecological screening in female patients, including the Papanicolaou (PAP) test (for women aged 21–30 years, repeated every 3 years) or the PAP test and the HPV test (for women aged 30–65 years, repeated every 5 years)

Osteoporosis

this therapy might be used for individuals who have a composite serology (such as positivity for anti-dsDNA or specific anti-extractable nuclear antigen (ENA) antibodies) and/or low complement levels because the risk of progression is higher in these patients than in patients with ANA positivity alone .

Another aspect of primary prevention concerns the risk of thromboembolic events in patients with SLE who are positive for antiphospholipid antibodies (aPLs) and have no history of thrombosis. Importantly, patients with SLE have an increased risk of thrombosis, compared with the general population , that might be worsened by pro- thrombotic risk factors such as smoking, genetic hypercoagulability, renal disease or glucocorticoid use; these factors should be assessed at diagnosis and removed whenever possible. Second, asymptomatic aPL-positive individuals who are positive for multiple aPL serological tests (double or triple positive) are in turn at increased thrombotic risk and might benefit from low-dose aspirin; this recommendation is supported by results from a meta-analysis and expert opinion , although, conversely, a previous randomized controlled trial (RCT) has reported that this treatment provided no additional protection in asymptomatic aPL-positive individuals . The occurrence of potentially precipitating conditions, such as pregnancy, prolonged immobilization or surgery, also requires, in our view, a temporary thrombosis prevention strategy, even in patients bearing a single yet persistent and high level of aPL specificity.

Secondary and tertiary prevention

In SLE, the prevention of disease progression and flares is important to preserve organ function and avoid irreversible damage (for example, to avoid the development of conditions such as end-stage renal disease associated with persistently active lupus nephritis , neuropsychiatric sequelae, scarring alopecia or skin atrophy or dilatative myocardiopathy ).

Additionally, the occurrence of severe manifestations can worsen disease prognosis and increase disease-related medical costs . In a 2018 observational study of 499 patients with lupus nephritis who were diagnosed between 1970 and 2016 (median follow-up

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Non-pharmacological approaches

Reduce caffeine and alcohol intake

Smoking cessation

Weight-bearing exercise for at least 30 minutes daily

Adequate protein intake

Use of hip protectors in patients at risk of falls

Physical or occupational therapy

Pharmacological approaches

Vitamin D and calcium supplementation

Bisphosphonates or denosumab in patients at risk of fractures. Teriparatide if fracture occurs under bisphosphonate therapy

Glucocorticoid-induced osteoporosis

Bisphosphonates in patients receiving prednisone equivalent ≥7.5 mg/day for at least 3 months

The National Comprehensive Cancer Network considers the cut-off for severe neutropenia to be 100 cells/mm , but the risk of opportunistic infections is already high for patients with <500 cells/mm ; the appropriate course should therefore be judged by the physician. Drug holidays are recommended. Not if pregnancy is planned.

10.6 years (interquartile range (IQR) 4–18)), the patients had a milder presentation of lupus nephritis over time . Interestingly, the time between SLE onset and the occurrence of lupus nephritis increased between 1970 and 2016 (from 1.3 ± 1.3 to 4.6 ± 6.3 years). The global improvement in presenting phenotypes might be the result of an earlier SLE diagnosis leading to a closer surveillance of patients and earlier and more appropriate therapeutic interventions, including the extensive use of antimalarial drugs, mycophenolate mofetil (MMF) and biologic drugs that can hinder the development of lupus nephritis. The question remains open as to whether more intensive immunosuppression at the time of SLE diagnosis might prevent the occurrence lupus nephritis.

Treat-to-target approach

In the wake of the treat-to-target (T2T) approach in rheumatoid arthritis (RA), remission and LDA have been proposed as targets for treatment in SLE and have been the subject of a number of studies . The validity of a definition of remission and LDA should be on the basis of its ability to enable the identification of patients who achieve better outcomes . Importantly, for patients who achieve remission or LDA, the target progresses to the maintenance of remission (such as the avoidance of disease flares, which should be the aim of maintenance treatment strategies).

Best outcomes of the T2T approachRemission

An agreement on what principles should guide the development of the definition of remission in SLE was achieved in 2016 in the context of the Definition Of Remission In SLE (DORIS) project, which involved a large international task force of 60 specialists and patient representatives who also put forward a definition of remission in SLE . In addition to this proposed definition, at least three other different definitions of remission have been proposed in the past few years (Table 2).

Table 2 Different definitions of remission and LDA

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All four definitions distinguish two subtypes of remission — namely, complete (no serological or clinical activity) and clinical (clinically quiescent disease with serological activity permitted) remission. The definitions differ in terms of the therapies allowed and the disease activity indices used (Table 2).

Compared with two decades ago, a greater proportion of patients now achieve remission , and yet until a few years ago, prolonged remission was rarely reported . However, a number of studies in the past few years have reported an increased prevalence of prolonged remission . This increase could be because of the application of new definitions of remission, together with improved knowledge and management of the disease.

The definitions of remission put forward by van Vollenhoven et al. and Zen et al. are similar, but unlike the definition by van Vollenhoven et al., the Zen et al. definition does not include the Physician Global Assessment (PGA), which has the known limitation of a relevant interobserver variability . Moreover, pre-laboratory and post-laboratory PGA scores can differ . Some researchers have pointed out that, despite these limitations, maintaining the inclusion of the PGA in the definition of remission could compensate for gaps in the SLE Disease Activity Index-2000 (SLEDAI-2K) (that is, the SLEDAI-2K does not consider haemolytic anaemia, myelitis and gastrointestinal activity) . However, it could be argued that the inclusion of a ‘treatment’ criterion in the definition of remission (namely, the threshold of prednisone equivalent of ≤5 mg/day and a stable dose of immunosuppressive drugs) in addition to the SLEDAI-2K enables the exclusion of patients with active disease, even in the domains not covered by the SLEDAI-2K .

Interestingly, comparable results in terms of the prevalence of remission and the protective effect of remission on damage progression can be achieved using either the definition by Zen et al. or van Vollenhoven et al. , although it should be noted that these definitions were tested in different cohorts and were not tested side by side in the same cohort. Such findings suggest that an achievement of a clinical SLEDAI-2K (that is,

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SLEDAI-2K score excluding serological activity) = 0 is probably the main driver of the protective effect of remission. Thus, the PGA is useful in grading clinical disease activity, but under conditions in which an instrument exists to determine the absence of activity (that is, clinical SLEDAI-2K = 0), studies to determine whether the PGA is redundant could be proposed.

All the newly reported definitions of remission (Table 2) have succeeded in identifying patients who achieved a better outcome in various studies, although differences in the design of the study, duration of follow-up and the type of cohort might explain some of the discrepancies between results.

A threshold for a durable remission has not yet been unanimously defined; however, the available studies suggest that the longer the remission, the better the protective effect against damage . In this regard, a remission lasting 2 consecutive years proved to be the shortest duration associated with protection from damage in a cohort of 293 patients . Importantly, the effect of long-standing glucocorticoid therapy, which is required to maintain clinical remission, should be considered. Indeed, in the long term, even a low daily prednisone dosage (≤5 mg/day) can contribute to damage accrual . Thus, two major sequential steps in the SLE T2T approach can be identified: first, achieve clinical remission; and second, minimize or withdraw prednisone whenever possible (Fig. 2).

Fig. 2: Proposed treat-to-target algorithm in SLE.

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The main target in the treatment of systemic lupus erythematosus (SLE) should be

the attainment and maintenance of clinical remission. If the main target cannot be

achieved, clinical low disease activity (LDA; without considering serology) could be a

suitable alternative target. The first step (which is common for the two threads) is to

treat the patient according to disease manifestations, following available guidelines

and recommendations and taking into consideration comorbidities and other patient

factors (see Fig. 3). If the target is achieved, the second step would be to reduce

and/or minimize and stop glucocorticoids. In patients in sustained clinical remission,

the third and last step would be the de-escalation of immunosuppressive therapy,

and, in selected cases, the complete discontinuation of immunosuppressants. In

patients in sustained LDA, the third step would be to decrease immunosuppressive

therapy.

Low disease activity

The concept of using LDA as a target has been applied to SLE in the past couple of years , and preliminary data suggest that the achievement of LDA is associated with better short-term outcomes (Table 3), although data on long-term outcomes are not available yet. Three definitions of LDA have been proposed (Tables 2,3).

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Table 3 Minimum requirement for fulfilling definitions of remission and LDA

Although no agreed-upon definition of LDA in SLE exists, an increasing number of studies have applied the definition by Franklyn et al. , referred to as the lupus LDA state (LLDAS). The LLDAS was frequently attained in different cohorts with a high proportion of patients (ranging from 38.2% to 64.5% ) persisting in the LLDAS for ≥50% of the follow-up period. Importantly, a persistent LLDAS (that is, LLDAS in ≥50% of observations) is associated with a lower risk of damage accrual , a finding also confirmed in a large cohort of 1,356 patients , and a ≥2-consecutive-year LLDAS is an independent protective factor against new damage . Conversely, failure to achieve an LLDAS at 6 months is an independent predictor of early damage .

Notably, a similar protective effect on damage was detected if patients spent <25% of follow-up time in clinical remission, which means that remission is superior to LLDAS in preventing damage progression .

The definition of LDA proposed by Polachek et al. is different from the two other new LDA definitions as it considers clinical SLEDAI-2K instead of SLEDAI-2K. The use of any medications for SLE, with the exception of antimalarial drugs, prevents the fulfilment of this definition . As such, this definition of LDA was associated with better disease outcomes after 2 years of follow-up. No external validation has been published.

In our opinion, LDA is primarily a clinical concept; therefore, clinical features should be considered over serological features for its definition, similar to what has been done for the definition of remission. In this regard, the LLDAS definition by Franklyn et al. has the limitation that SLEDAI-2K ≤4 and not clinical SLEDAI-2K ≤4 was used as an entry criterion, which means that both anti-dsDNA antibody positivity and the presence of low complement serum levels would preclude attainment of LLDAS irrespective of the type of clinical manifestation present, even if scored as 1 or 2 by the SLEDAI-2K.

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Notably, to capture low-intermediate disease activity, the measurement of disease activity incorporated into the LDA definition should be continuous and not categorical (that is, the presence or absence of an item; as it is in the SLEDAI-2K and SELENA- SLEDAI). In fact, LDA not only should correspond to milder lupus manifestations but also should identify individuals with LDA irrespective of the type of manifestations (for example, low persistent proteinuria or mild arthritis). As a dichotomic score, SLEDAI-2K does not capture the level of disease activity inside a given organ or domain (for example, the score does not change according to the number of joints involved or according to the severity of leukopenia or thrombocytopenia). In other words, SLEDAI- 2K is able to discriminate between mild and severe lupus on the basis of the type of organ involvement but is unable to discriminate between low, moderate and severe disease activity inside a given domain. In this regard, the PGA, despite its limitations, could complement the SLEDAI.

The PGA threshold differs in the definition of remission by van Vollenhoven et al. and the definition of LLDAS by Franklyn et al. (0.5 and ≤1.0, respectively); however, the SLEDAI thresholds are not necessarily different because a clinical SLEDAI of 0 in the definition of remission by van Vollenhoven et al. can coincide with an SLEDAI of ≤4 in the definition of LLDAS by Franklyn et al. . Thus, remission and LDA should be taken as two different levels of remission rather than two conceptually different targets (that is, the ‘absence of disease activity’ versus the ‘persistence of a low level of disease activity’). However, if these two targets, currently named ‘remission’ and ‘LDA’, are defined using the same instruments (as they are for the van Vollenhoven et al. definition of remission and the Franklyn et al. definition of LLDAS), they can be regarded as sequential steps of an improved treatment response.

What is still missing in the SLE armamentarium is a single, simple instrument for measuring disease activity that is able to clearly separate remission from LDA and from high disease activity on a continuum, similar to the Disease Activity Score 28 (DAS28) in RA.

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Renal outcomes

According to the EULAR/European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis , the goal of immunosuppressive treatment should be a complete renal response (CRR; that is, a urinary protein–creatinine ratio (UPCR) <0.5 and a normal or near-normal glomerular filtration rate (GFR) (±10%)) or, at least, a partial renal response (PRR; that is, a reduction in UPCR ≥50% (subnephrotic) and a normal or near-normal GFR (±10%)). PRR has a worse prognosis than CRR but might be an acceptable outcome when all treatment options have been exhausted or cannot be used because of a high risk of adverse effects. However, a PRR must be achieved preferably within the first 6 months of treatment and no later than 12 months after treatment initiation .

The UPCR measures the amount of protein in urine at a definite time point in relation to urinary creatinine and is commonly used as a suboptimal means of approximating 24- hour proteinuria in clinical studies . In extension studies of the Euro-Lupus Nephritis Trial , the threshold of proteinuria (with preserved renal function) that can predict a favourable renal outcome was reported to be 0.7–0.8 g/day ; the assessment of renal outcome was not improved by the addition of other parameters such as serum creatinine or urinary sediment . This proteinuria threshold was associated with a good long-term outcome (defined as serum creatinine concentration ≤1 mg/dl at 7 years after entry into the trial) . However, 7 years might not provide sufficient reassurance for the preservation of renal function in young patients. Moreover, some data have highlighted the detrimental contribution of silent active kidney lesions , thus raising the question of whether treating to histological targets rather than to clinical remission would be valuable. However, treating to histological targets would require repeated biopsies, the applicability of which is still debated and which are not currently recommended in the absence of clinical worsening.

Hence, it is reasonable to assume that patients with active lupus nephritis should be brought to the clinical target of proteinuria of ≤0.7 g/day, and treatment should preferably be started within 3–5 months of clinical onset (that is, within the ‘window of

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opportunity’), as longer intervals between clinical onset and treatment initiation are associated with worse outcomes . The evaluation of a renal response might require several months of follow-up to provide enough time for proteinuria normalization (for example, in proliferative lupus nephritis ); thus, an adequate follow-up period is important for making treatment decisions, which should be neither delayed nor premature .

Best treatment for T2T approaches

In SLE, treating ‘right the first time’ is an important concept; that is, an adequate intensity of treatment should be provided to control disease activity as early as possible. In fact, evidence suggests that earlier achievement of remission is associated with a better long-term outcome and early responders are likely to maintain a good treatment response in the long term . Unfortunately, a proportion of treated patients still fall outside the desired ‘control zone’, reaching a suboptimal level of disease control that would theoretically require a stronger treatment to reach a desirable target.

Indications for what treatment to use are available among international recommendations . In this section, we discuss strategies that make good use of the available drugs and aim to achieve treatment targets without exposing patients to overtreatment.

Glucocorticoids

Glucocorticoids have been a mainstay of treatment of patients with SLE for 60 years , and a boost in glucocorticoid treatment is commonly used to treat small spikes of disease activity despite there being no evidence that boosting steroids provides any stable benefit in the long term .

The adverse effects of glucocorticoids, such as the association of treatment with damage accrual, have been clearly established , and immunological mechanisms accounting at least in part for the occurrence of suboptimal response to glucocorticoids in SLE have been proposed . Interestingly, a number of studies have reported no differences in the

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outcome of diverse SLE manifestations, including lupus nephritis, when omitting high- dose glucocorticoids in induction or maintenance therapy . Notably, although glucocorticoids are indicated for severe manifestations such as lupus nephritis and neuropsychiatric SLE (NPSLE), the duration and dosage of treatment that are used in clinical practice have not been established in an RCT .

Data on lupus nephritis exemplify the unresolved issue of whether glucocorticoid minimization during induction or maintenance treatment is safe . In several cohort studies and in one small RCT , researchers compared the use of high versus low doses of glucocorticoids (ranging from 3 g/day to <20 mg/day ) during induction treatment; both approaches had comparable rates of renal responses by the end of follow-up (that is, at 6 to 12 months), but low-dose glucocorticoid therapy was associated with a better safety profile . Long-term data on the effects of a steroid-free maintenance regimen are available from the RITUXILUP (Trial of Rituximab and Mycophenolate Mofetil Without Oral Steroids for Lupus Nephritis) RCT, in which an induction treatment (comprising rituximab 1 g and intravenous methylprednisolone 500 mg fortnightly) followed by a maintenance treatment that included MMF but not glucocorticoids resulted in 52% of patients in complete remission and 34% of patients in partial renal remission at 1 year . At 5 years, more than 80% of patients were still in remission (complete or partial) and 77% were still glucocorticoid-free .

The RituxiRescue study used a similar therapeutic protocol to that of the RITUXILUP trial (in terms of the rituximab and MMF treatment) but involved patients who were already on glucocorticoid maintenance and who did not uniformly receive intravenous methylprednisolone during their induction therapy. In this study, glucocorticoids were actively decreased over time according to clinical practice . Notably, 76.3% of patients treated with this regimen reached a renal response (either complete or partial) at 5 years and 63.2% of individuals were off steroids or were receiving a minimal glucocorticoid daily dosage by this time . However, controlled studies of the feasibility of oral glucocorticoid-free regimens for patients with lupus nephritis or SLE are currently lacking. In light of the available and upcoming therapeutics , an

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advisable approach to glucocorticoid tapering and decreasing the long-term glucocorticoid daily dosage is to use combination therapy (for example, MMF and calcineurin inhibitors in lupus nephritis ) or to add a biologic drug to standard-of-care therapy .

Low-dose oral glucocorticoids can be as effective as higher dosages (≥30 mg/day) in treating systemic active extrarenal disease , suggesting that the intervening dosage could be routinely lowered. Hence, during disease reactivation, glucocorticoids should be used at the lowest effective dosage and with a clear indication and duration of treatment. Physicians should perform a careful patient evaluation to ensure they are really treating the manifestations related to active disease. The dosage of glucocorticoids should be reassessed at every patient evaluation, which should fall at intervals of no longer than 4 months, even if the patient responds to treatment . Finally, and most importantly, physicians should consider modifying the background treatment, especially when the patient has a relapsing–remitting disease course or is on long-term treatment with prednisone ≥5 mg/day or an equivalent, and progressively abandon the tendency to correct disease activity by adjusting the glucocorticoid dosage alone.

Antimalarial drugs

Antimalarial drugs (for example, hydroxychloroquine and chloroquine) were initially recommended for the treatment of mild-to-moderate SLE manifestations, especially skin rashes and arthritis. In more recent studies, these drugs were shown to decrease disease activity and thrombophilia and improve patient survival , and they are currently recommended for the treatment of active SLE .

Two major aspects of antimalarial therapy have resulted in modifications to their recommended use. First, non-adherence to treatment can affect the disease outcome , and non-adherence to antimalarial drugs might indicate poor adherence to all medication in general . A number of factors can contribute to treatment non- adherence (including young age ), and non-adherence can lead to a worse disease course, misinterpretation of disease activity and consequent unnecessary therapeutic

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changes . Thus, counselling strategies are recommended for increasing patient compliance , and blood hydroxychloroquine levels should be monitored in cases of adherence concerns .

The second update on the use of antimalarial drugs concerns the new inclusion of hydroxychloroquine to the drugs recommended by the EULAR/ERA–EDTA international task force for the management of lupus nephritis . Indeed, data from previous studies suggested that patients with lupus nephritis already being treated with hydroxychloroquine had a reduced likelihood of renal damage compared with those patients not receiving hydroxychloroquine treatment. Interestingly, some evidence suggests that administration of hydroxychloroquine in lupus nephritis is inversely associated with tubulo-interstitial inflammation and therefore is likely also inversely associated with a reduction in interstitial fibrosis.

In summary, antimalarial drugs have gained increased attention for the treatment of mild as well as severe SLE manifestations and should be regularly advised. Monitoring of hydroxychloroquine serum levels is not a common practice but might be considered in cases in which poor adherence is suspected before any therapeutic modifications are performed.

Immunosuppressive drugs

The traditional immunosuppressive drugs used for the treatment of SLE include alkylating agents (cyclophosphamide), inosine monophosphate dehydrogenase (IMPDH) inhibitors (MMF and mycophenolic acid), selective inhibitors of purine and/or pyrimidine synthesis (azathioprine and methotrexate, respectively) and calcineurin inhibitors (cyclosporine and tacrolimus) . Although these drugs do not target specific molecules and non-selectively suppress various cellular processes, lymphocytes (excluding plasma cells) are the major cell type affected as these cells are highly proliferative and preferentially use metabolic pathways that are targeted by immunosuppressive drugs such as IMPDH inhibitors .

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The use of single immunosuppressive drugs is discussed in international recommendations elsewhere . In this section, we discuss potential combination therapies. The purpose of combining different therapeutics is to exploit different mechanisms of action of the drugs and to lower the effective dosage of either drug. Interestingly, the effectiveness of combination therapies is usually superior to that expected from the sum of the single drugs, suggesting a synergy.

The effectiveness of combination therapies (such as combining a calcineurin inhibitor with MMF either as an induction or maintenance treatment) in SLE, and especially in lupus nephritis, has been explored in various studies . Most data regarding the combination of tacrolimus and MMF in lupus nephritis are limited to its effectiveness during 6-month induction therapy, for which renal remission was attained more quickly and by a greater proportion of patients receiving tacrolimus–MMF combination therapy than those receiving intravenous cyclophosphamide (46% versus 26% at 6 months) . In an extension study, patients who achieved renal remission with either regimen in the induction phase were monitored for an additional 18 months ; in the maintenance phase, the patients who had received combination therapy of MMF and tacrolimus during the induction phase continued with this treatment, whereas patients who had received intravenous cyclophosphamide were switched to azathioprine. Both groups had similar rates of renal relapse by the end of follow-up , in keeping with earlier data . However, combination therapy was associated with a decreased incidence of adverse events compared with azathioprine alone, especially in terms of leukopenia and liver dysfunction . Conversely, the induction trial showed an increased rate of adverse events in the group of patients receiving combination therapy (namely, serious infections and varicella zoster reactivation ), thus raising questions on the actual safety profile of this combination therapy. The apparent discrepancies between the two studies might result from the higher dosages required during the induction phase than during the maintenance phase; however, as the pharmacokinetics of tacrolimus has a high interindividual variability, the plasma levels of this therapy should be carefully monitored and usually maintained around 4–6 ng/ml in SLE .

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The efficacy of low-dose or high-dose voclosporin (a calcineurin inhibitor) in combination with MMF for the treatment of active lupus nephritis has been compared with that of MMF alone . The primary end point (complete response) was defined as preserved efficacy (UPCR ≤0.5 mg/mmol and estimated GFR ≥60 ml/min/1.73 m without a decrease ≥20% from baseline) together with a steroid-sparing effect and no administration of rescue medications. Notably, the rate of complete (and partial) remission was higher in the voclosporin group at 6 months and maintained higher at 12 months than in the group of patients receiving MMF alone . However, it should be mentioned that some drug safety concerns have been raised following the higher number of deaths occurring in the voclosporin group (ten in the low-dose group), which is expected to be addressed in the ongoing phase III trial of this treatment in patients with lupus nephritis .

Synergy between calcineurin inhibition and MMF in lupus nephritis has also been documented at the transcriptional level in samples of human renal biopsies and in a mouse model of lupus-like nephritis; for example, the expression of some pro- inflammatory genes was inhibited following treatment with both drugs but not following treatment with either drug alone . These observations, together with the finding that tacrolimus treatment in patients with lupus nephritis results in a lowered activity index after 6 months (as assessed by repeated renal biopsies) , implicate the anti-inflammatory potential of calcineurin inhibition in lupus nephritis, despite existing concerns around its mechanism of action .

Biologic drugs

Although a number of promising biologic therapies are in development , those currently available and most often used in clinical SLE management are belimumab (an anti-B lymphocyte stimulator (BLyS, also known as TNFSF13B) antibody, which is thus far the only licensed biologic drug for SLE ) and rituximab (an anti-CD20 antibody).

Despite the failure of rituximab treatment in SLE RCTs , rituximab is prescribed in clinical practice and is included in the European and US recommendations for

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the treatment of refractory lupus nephritis as well as NPSLE . Moreover, on the basis of expert opinion, rituximab has also been suggested for the treatment of refractory and glucocorticoid-dependent disease with severe manifestations, including severe thrombocytopenia and recalcitrant skin disease , although chronic lesions are unlikely to respond .

Overall, the effect of improved adherence to standard-of-care therapy following enrolment into a study or the effect of commencing standard-of-care therapy for treatment-naive patients (in both the placebo and the rituximab group) is speculated to have masked any marginal efficacy rituximab had in past RCTs . Most investigations of rituximab administration in SLE before the commencement of immunosuppressive drugs have been carried out in patients with lupus nephritis and seldom in patients with non-renal SLE . In such studies, rituximab consistently provided a relevant steroid-sparing effect , whereas the ability of rituximab to maintain the clinical response varied among different cohorts .

Belimumab can be efficacious in real-life settings, with increasing evidence suggesting that this biologic drug (as either an intravenous or subcutaneous formulation) can reduce disease activity and prevent flares . Importantly, damage accrual was hindered after belimumab administration, with no substantial change in the SLICC/ACR Damage Index (SDI) at 2 years . As these results come from uncontrolled studies, caution is needed in interpreting these findings; however, the consistency of these findings across different cohorts makes this observation promising. Belimumab is currently being tested for the treatment of lupus nephritis ; notably, the use of belimumab resulted in a long-term reduction in proteinuria both in a trial extension and in real-life observational studies .

Researchers have tested the coordinated strategy of using rituximab followed by belimumab in the treatment of refractory SLE . The rationale for this approach resides in the peak in serum BLyS levels that follow B cell depletion . An ongoing phase III RCT is currently testing this approach for the treatment of non-renal SLE .

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Drug costs and cost-effectiveness might limit the accessibility that patients have to biologic therapies. Indeed, studies of economic simulation models suggest that belimumab treatment could be cost-effective in several countries in Europe, including Italy, Spain, Portugal and Greece , mostly because of the gain in life-years and quality of life and the abatement of indirect costs associated with treatment . Conversely, the local costs of this treatment might hamper its cost-effectiveness in countries such as the United Kingdom, Germany and France , thus increasing the disparities in drug utilization. Indeed, several unapproved treatments often might fail for a patient before they have access to belimumab , likely because the incremental benefit of belimumab is not perceived as being large enough.

Deciding what timing and reasons are necessary for a patient to commence biologic therapy (that is, biologic accessibility) remains a relevant point as patients often must first demonstrate refractoriness to standard-of-care therapy including a traditional immunosuppressant before they can commence treatment with a biologic drug, limiting the accessibility of patients to belimumab in the early stages of disease, despite it being the only drug approved for SLE. In this regard, it should be mentioned that in recent RCTs of biologic therapies for the treatment of non-renal SLE , eligible patients often did not need to have failed a previous immunosuppressive drug. Accordingly, up to 50% of patients enrolled in two RCTs of belimumab (BLISS-52 and BLISS-76) were not taking immunosuppressants, and consistently official indications for belimumab do not necessarily require the failure of previous immunosuppressive drugs before use .

Hence, for moderate SLE, glucocorticoids and antimalarial drugs might be considered as the standard-of-care therapy, on top of which additional therapies are advised . For patients with severe manifestations of SLE that are refractory to cyclophosphamide or MMF, biologic drugs (namely, rituximab) can also be advocated as, although B cell- depleting therapies can take longer to exert their therapeutic effects than alkylating or antimetabolite agents, B cell depletion might still provide marginal benefits for refractory manifestations . Finally, the prompt use of belimumab is advisable, at least in countries

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where this treatment is cost-effective, for the treatment of SLE and especially for patients with active disease and non-life-threatening manifestations .

Despite the limited evidence available supporting the use of biologic therapies in SLE, maximizing the benefits of their use is paramount, taking into account the accessibility of these drugs and the additional benefit they can provide for patients with severe as well as refractory SLE. Indeed, it is common for patients to have residual disease activity (such as inflammatory arthralgias with prolonged stiffness or suboptimal control of proteinuria after a nephritis flare) despite receiving full standard treatment, and such patients are likely to benefit from additional interventions to help stabilize the treatment response while rendering glucocorticoid tapering feasible.

Critical aspects in T2T trial design

A suitable therapeutic strategy that clarifies which medications should be given or switched if the treatment goal is not reached has not yet been defined in SLE. This issue could be investigated in dedicated RCTs of T2T strategies, but such trials are in turn difficult to set up because of the heterogeneity in patient management. Several issues would arise when setting up a T2T trial, among which the method of patient selection, the type of treatment assessed and the included outcome measures seem the most critical. Such aspects have been extensively debated in the field and are deemed at least partially responsible for the failure of diverse SLE trials .

Advances in the management of lupus nephritis might inform the design of T2T strategies for SLE. In fact, a strategy for reaching the desired target (that is, CRR or PRR) in patients with lupus nephritis has already been proposed in the 2012 EULAR/ERA– EDTA recommendations , which advise to change the type of induction therapy treatment in the absence of any improvement after 3–4 months or in the absence of (at least) a partial response after 6–12 months or complete response after 24 months. In patients with lupus nephritis for whom treatment with MMF or cyclophosphamide failed either because of lack of efficacy or adverse events, the treatment should be switched from MMF to cyclophosphamide, or from cyclophosphamide to MMF, or

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rituximab should be given . The agreement on an overarching strategy is of relevance as thus far no therapeutic approach is universally accepted to reach remission or LDA in non-renal SLE. Moreover, the EULAR/ERA–EDTA recommendations include set time points for the evaluation of the renal response (6 and 12 months) and, most importantly, for the theoretical amount of time needed before tapering of maintenance therapy can be considered (3 years) . Hence, in lupus nephritis, some key aspects have been clearly defined, including quantifiable targets, drugs to be used, how to modify the therapeutic approach in cases of a lack of response at definite time points and how long (at least) to continue maintenance therapy before considering tapering.

Transferring the procedure for lupus nephritis to non-renal SLE might be tricky for several reasons. First, remission and LDA, unlike renal response, are composite targets that incorporate aspects of disease activity, therapy and physician assessment. In other words, these targets are a qualitative rather than a quantitative measure of improvement. Second, improvements in organ-specific targets (for example, resolution of arthritis or skin rash) might not guarantee the attainment of systemic remission. Third, even when remission or LDA is achieved, its maintenance should be evaluated over a long time period (for example, at least 2 years is needed to evaluate whether damage progression has been hindered ), thus rendering these targets unsuitable for an RCT. Given these caveats, a number of aspects need to be addressed before proposing a T2T trial in non- renal SLE, including the choices of which patients to recruit, when to periodically assess the patients and how to assess the patients.

The method of patient recruitment could differ according to what aspect of T2T is under investigation; for example, whether the aim is to assess patients with active disease who need to reach remission or patients who are in remission and need to maintain the treatment target. Medication-naive patients with new-onset SLE are the best patients to recruit for trials assessing the best strategy for reaching remission. Conversely, for trials evaluating maintenance strategies, for which the primary outcome would be relapse, patients in remission are the appropriate choice; such trials would be helpful for determining long-term therapeutic strategies. The two different trial types cover two

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relevant aspects of T2T (that is, how to reach the target and how to maintain it), the latter of which might be a major problem in the face of a relapsing–remitting disease course, a common feature of SLE . Other issues relating to the selection of patients in T2T trials include which type and severity of the clinical phenotype to include or exclude, which requires a dedicated discussion outside the topic of this Review.

To adequately evaluate the treatment response of patients, a suitable frequency of reassessment is necessary. Notably, for RA, the tight control of disease activity through regular assessment (every 1–3 months) can result in a notably higher treatment response rate than a lower frequency of visits (every 6–12 months) . In SLE, a similar strategy for tightly controlling disease activity might be suitable, as indirectly suggested in one study that compared the outcomes of patients with SLE being treated in community clinics with those being treated in a specialty clinic . In this study, the patients with SLE who attended a community clinic had, on average, a higher level of disease activity, a higher cumulative glucocorticoid dosage and a lower hydroxychloroquine intake at 5 years than the patients who attended a specialty clinic, suggesting that an expert-based management of SLE results in better outcomes in terms of disease control and treatment handling. Although not directly compared, the factors responsible for this difference are likely a higher frequency of visits (every 2–6 months) and more consistent assessment of disease activity, damage and comorbidities in the specialized care setting compared with the community care setting.

The method of patient assessment is an important consideration for T2T trials; ascertaining partial improvements in disease activity, including improvements not captured by current global disease activity scores, is necessary as such changes might be clinically relevant and affect therapeutic decisions. Further unresolved issues include defining the standard-of-care therapy on which the additional therapies are tested and the type of intervention that should be given when the pre-specified treatment target is missed within a given time frame, which would probably require a switch to a different drug.

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Once the issues highlighted in this section have been resolved, trials can be performed that compare different T2T strategies. The design of RCTs will need to be further tailored to different patient subsets (such as subsets with different levels of disease activity, types of disease manifestations, ethnicities and/or other clinical or immunological features).

Treatment tapering and withdrawal

The recommended treatment approach for patients with inactive disease, particularly for patients in prolonged remission, is a matter of debate (Fig. 3). The benefits of drug tapering and discontinuation have been proved for glucocorticoids , but insufficient evidence is available regarding the tapering and eventual withdrawal of antimalarial drugs and immunosuppressive drugs. As a general consideration, during the tapering and withdrawal of treatment, close surveillance is necessary to detect early signs or symptoms of disease relapse, and the patients should be informed that, although they have inactive disease, routine laboratory tests and regular clinical evaluations are still needed.

Fig. 3: Proposed algorithm for the management of patients with SLE in remission.

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Presented is one approach that could be used for the management of patients with

systemic lupus erythematosus (SLE) in remission. The first step in the management

of patients with SLE who are in remission is to evaluate whether the patient has

obtained the easier-to-achieve type of remission (that is, clinical remission rather

than complete remission). If the patient is in clinical remission, a progressive

reduction in therapy should be carefully undertaken, maintaining regular follow-up.

Eventually, discontinuation of therapy might be considered. The term ‘sustained

remissionʼ refers to a durable state of remission, which ideally should be associated

with a lower likelihood of flare. Any clinical decision should be based on patient

characteristics and the clinical observations of the treating physician. Notably, the

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time needed to achieve remission is a relevant prognostic factor as the shorter the

duration of active disease (meaning a rapid achievement of remission), the easier it

is to maintain the remission status. dsDNA, double-stranded DNA.

Glucocorticoids

SLE maintenance treatment should include the lowest glucocorticoid dosage needed to control the disease, and glucocorticoids should be completely withdrawn whenever possible ; however, further studies are needed to clarify when complete withdrawal of glucocorticoids can be done safely.

In a retrospective study of patients with SLE who were receiving 5 mg/day of prednisone, the prednisone dose could successfully be tapered to <5 mg/day for at least 1 year in 377 out of 688 patients (55%) . Successful tapering was most common in patients with a fairly low level of disease activity, in patients without cutaneous or musculoskeletal activity or in patients diagnosed after the year 2000. Some data are available on the effects of glucocorticoid tapering in lupus nephritis, as discussed in a previous section; in this subset of patients, researchers have even attempted to decrease glucocorticoid dosage during the induction treatment (and thus, before the achievement of a renal response).

Whether the complete withdrawal of glucocorticoids requires the achievement of complete remission or whether clinical remission or LDA can be sufficient has not been elucidated, and no trial has specifically addressed this issue. Frequently, patients who have been receiving long-term glucocorticoid therapy experience subjective difficulties following the withdrawal of glucocorticoids, despite persistent SLE inactivity; in these cases, an ‘alternate-day’ glucocorticoid regimen or a slower taper might be feasible .

Antimalarial drugs

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Few data are available on the contribution of antimalarial drugs to the maintenance of remission, and the actual protective effect of antimalarial drugs against SLE flares is not clear . The only RCT on the effect of tapering hydroxychloroquine was conducted in 1991 by the Canadian Hydroxychloroquine Study Group . The discontinuation of hydroxychloroquine in patients with stable disease was associated with a considerable increase in the risk of new clinical manifestations, exacerbation of previous manifestations and a 2.5-fold higher relative risk of flare. Studies of adherence to antimalarial drugs can provide indirect evidence of the effects of antimalarial withdrawal, as non-adherence might resemble an unplanned drug withdrawal.

In one study investigating the relationship between serum hydroxychloroquine levels and SLE activity, a higher serum concentration of hydroxychloroquine was associated with lower disease activity at baseline and a reduced likelihood of disease flares during follow-up . In a longitudinal subgroup analysis of 73 patients in remission, there was a trend towards having lower levels of disease activity and number of flares over time for the group of patients who had therapeutic hydroxychloroquine levels ( > 500 ng/ml) at baseline than for the groups of patients with lower baseline hydroxychloroquine levels, although the difference between the groups did not reach statistical significance . Similarly, in a 7-month multicentre RCT of 171 patients with SLE who were randomly allocated either to stay on stable pre-study dose of 100–750 ng/ml hydroxychloroquine or to increase the hydroxychloroquine dose to achieve a target blood level of >1,000  ng/ml, the rate of SLE flares was not notably different between the two groups; nonetheless, it should be pointed out that an increase in hydroxychloroquine blood levels in the control group was detected, meaning that patient adherence improved after inclusion in the study, and this better compliance might have biased the results of the study . Regarding lupus nephritis, maintenance of a hydroxychloroquine serum concentration of ≥600 ng/ml is suggested to be protective against renal flares ; however, this notion is on the basis of retrospective observations.

Additional aspects should be considered when evaluating the long-term use of antimalarial drugs in SLE remission, including that these drugs have favourable lipid-

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lowering and glucose-lowering effects , might contribute to the prevention of thrombotic and thromboembolic events , are safe and effective during pregnancy and might contribute to the preservation of renal function .

Thus, taking into consideration the cumulative beneficial effects of antimalarial drugs, clinical experience suggests that their use is a safe therapeutic and preventive strategy that should be considered for all patients in remission and that could be continued as long-term therapy. Nevertheless, for patients in complete, durable remission, the withdrawal of antimalarial drugs could be feasible, although no studies on the effects of antimalarial withdrawal are available to date. The decision of whether to discontinue antimalarial drugs during clinical remission should be on the basis of the patient clinical history, the presence of any comorbidities, the existence of damage, the duration of remission and patient preference.

Immunosuppressive drugs

Few data are available on the effects of withdrawing immunosuppressive drugs from patients with SLE who are in remission, especially for patients with non-renal SLE. In one study, 156 out of 667 patients with non-renal SLE achieved at least one period lasting ≥1 year of drug-free clinical remission . However, different results were obtained in a small controlled trial of azathioprine withdrawal in nine patients with stable non-renal SLE. In this study, disease flares occurred in seven patients after a mean interval of 10.5 weeks after drug withdrawal . Furthermore, data from the Toronto Lupus Cohort showed that immunosuppressive drug-free prolonged remission (>2 years) was rare .

Nevertheless, the results of these studies should be critically considered given the subsequent improvements that have been made in strategies for SLE management, including attempts at diagnosing SLE earlier, developments in the tailoring of treatments to different manifestations and the availability of evidence-based and expert-based recommendations; thus, the scenario depicted by the aforementioned studies might be outdated. Further studies aimed at identifying predictive factors of disease quiescence after drug discontinuation (for example, the type and duration of remission, the

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manifestations that require immunosuppressive therapy and the pattern of disease activity) would be timely.

Some data are available on the effect of immunosuppressive drug discontinuation in lupus nephritis. In a study of 11 patients with class IV lupus nephritis , the withdrawal of cyclophosphamide 2 years after complete renal remission resulted in a relapse in 36% of patients. In another study, 15 out of 33 patients (45%) with class IV lupus nephritis who withdrew immunosuppressive therapy after treatment with intravenous cyclophosphamide and glucocorticoids experienced a renal flare .

Researchers have tested a progressive approach of discontinuation of therapy in 52 patients with lupus nephritis in durable renal remission. Immunosuppressive drugs were first de-escalated and withdrawn, and glucocorticoid tapering was subsequently started: 32 out of 52 patients did not experience any flare during a median follow-up time of 101.8 months after drug discontinuation. The patients who did not flare had a longer duration of treatment and remission before withdrawal and were concomitantly treated with chloroquine. Ten patients who experience a flare after the first drug withdrawal could later withdraw therapies and were free of immunosuppressive and glucocorticoid therapy after a median follow-up time of 286 months . Importantly, the researchers recommended a tight follow-up during therapy de-escalation and an even closer follow-up after complete withdrawal of immunosuppressive agents and glucocorticoids (that is, every 15 days for the first 2 months, then every month for 6 months and then every 2–3 months).

Thus, immunosuppressive drug withdrawal requires careful evaluation tailored to each patient, taking into consideration the medical history, type and severity of organ involvement, the response to therapy (in particular, whether remission was rapidly achieved or not), the number of previous relapses, the number of immunosuppressive drugs and the duration of immunosuppression needed to achieve remission. A reasonable duration of remission is required before considering drug discontinuation, and progressive dose reduction, together with a close follow-up, could be a good option.

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Patients should be informed of the importance of continuing a regular follow-up after complete drug withdrawal.

Personalized medicine

Personalized (or precision) medicine broadly involves tailoring therapy to the clinical features of a given patient to provide a customized approach for improving their disease; given the developments in omics techniques over the years, such an approach could ideally be used to tailor treatment to the underlying molecular pathways .

Clinical predictors of drug response and effective methods of patient stratification are needed in SLE , as demonstrated by the differences in drug responses of patients with diverging clinical features. For example, although a trial of epratuzumab (an anti- CD22 antibody) for the treatment of patients with SLE failed, post hoc analysis indicated that those patients with both SLE and Sjögren syndrome had a better BILAG (British Isles Lupus Assessment Group) and BICLA (BILAG-Based Composite Lupus Assessment) response over time than the patients with SLE without secondary Sjögren syndrome . Furthermore, two phase II trials that stratified patients with SLE according to their manifestations had promising results .

One of the latest aspects of personalized medicine concerns the incorporation of omics data (such as genomic, transcriptomic, proteomic and metabolomic data). Such integrated information can provide insights into the mechanisms of disease, which can lead to specific treatments . Indeed, using omics data, autoimmune diseases can be dissected on the basis of molecular patterns and their resulting clinical manifestations, thus potentially providing a means of upstream stratification to indicate the most appropriate therapeutic approach. In 2017, a large omics-based project was initiated (PRECISESADS) to define a new molecular-based classification of systemic autoimmune diseases on the basis of shared composite biomarkers .

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Several levels of stratification can be used in SLE to take into account susceptibility genes , epigenomic data , transcriptomic data and proteomic data ; however, limited metabolomic data are available for SLE . The genetic variability in SLE is large and gene microarray studies have implicated a number of therapeutic targets in SLE ; however, the global clinical applicability of genetic stratification is still limited . Epigenetic mechanisms involved in the regulation of gene expression are greatly altered in SLE , accounting for the detrimental yet unclear role of environmental factors in SLE. In patients with SLE, several genetic regions are often extensively hypomethylated, which results in the overexpression of normally regulated genes, particularly genes involved in interferon pathways and B cell activation . Moreover, abnormalities in histone acetylation patterns are associated with disease development via the upregulated expression of survival factors and interferon regulatory factors in (mostly) T cells and monocytes . Interestingly, the presence of some epigenetic abnormalities, such as reduced activity of the epigenetic regulator miR-146a or hypomethylation of the gene encoding interferon regulatory factor 7 (IRF7), correspond with increased disease activity or specific manifestations . Notably, commonly available drugs such as antimalarial drugs or the immunosuppressive drug mycophenolic acid can modulate epigenetic mechanisms in vitro (for example, by affecting microRNA expression or histone acetylation patterns) , and treatment of mice with the epigenetic modifier trichostatin A (a histone deacetylase inhibitor) can result in increased regulatory T cell numbers, modulating autoimmunity in a mouse lupus model . These results suggest that modulating mechanisms that alter gene expression might be a feasible approach.

Most evidence regarding the stratification of patients with SLE concerns grouping patients according to their interferon signature (although this signature is not only present in SLE but also in other autoimmune diseases) . For example, T cells in patients with SLE have an abnormal expression of interferon-related genes . In 2016, the first longitudinal analysis of the blood transcriptomic profiles of patients with SLE was performed: 158 paediatric patients with SLE were stratified according to their transcriptional profile, and the analysis identified 5 immune signatures and 7 subgroups

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of patients . Among the five immune signatures identified, the presence of an interferon signature or a neutrophil signature (that is, the expression of neutrophil- specific transcripts in the blood or a given tissue) strongly correlated with disease activity and the development of lupus nephritis. Notably, an enrichment of neutrophil transcripts was detected during progression to active nephritis, and both the interferon and neutrophil signatures could be reduced with MMF treatment, especially in patients with proliferative lupus nephritis.

Notably, researchers have reported differences in the amount and type of transcripts that are upregulated in the affected glomeruli of patients with lupus nephritis, which might have a wide intersubject and intrasubject variability. Such heterogeneity suggests that any potential personalized treatment strategy will have to take into account this high complexity that requires further study . In the past few years, T cell abnormalities such as altered gene expression of signalling lymphocyte activation molecule receptors or enrichment of urinary CD4 cells have been identified in patients with lupus nephritis, which might be associated with a more refractory disease phenotype . Interestingly, increased expression of neutrophil-related genes in the blood of patients with SLE is associated with renal inflammation , in keeping with previous findings suggesting the involvement of neutrophil-driven processes in the development of lupus nephritis .

In the past couple of years, the stratification of patients with SLE has been attempted in clinical trials of type I interferon inhibition, in which patients were grouped according to the level of interferon-dependent genes . Notably, in the genomic and proteomic studies that identified IFNα as a potential therapeutic target, other potential therapeutic biomarkers were also identified, such as BLyS, TWEAK (TNF-related weak inducer of apoptosis) and APRIL (a proliferation-inducing ligand) . Despite the failure of treatment with atacicept, a drug that targets both BLyS and APRIL, in patients with SLE , a subgroup analysis performed on data from the ADDRESS II trial showed that higher baseline levels of BLyS or APRIL are associated with a greater treatment response to atacicept (as assessed by a decrease in flare rate) at 52 weeks , thus re-

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enforcing the importance of patient subgrouping in the design of RCTs and eventually in deciding on an approach to therapy in the clinic.

Conclusions

The treatment of patients with SLE should be multilayered and take into account the prevention of disease progression, relapse, damage and comorbidities from the time of diagnosis. Indeed, the more timely the treatment, the greater the likelihood of achieving control of disease with a governable drug regimen in a reasonable time span.

From the clinical point of view, validating the optimal dosages and administration protocols for the available drugs, including glucocorticoids, through RCTs would be opportune, as the drawbacks of overtreatment are widely acknowledged. Accordingly, trials that investigate the usefulness of modifying and/or tapering therapy following the achievement of treatment targets are needed, and the resulting strategies must be agreed upon before the concept of treating patients to a target can be implemented in clinical practice, without which patients might be subjected to unnecessary long-standing exposure to toxic drugs. In this view, patient-tailored outcomes should be used in clinical trials whenever possible.

Alongside the need to agree upon a shared definition of treatment targets, including remission and LDA, it is important to precisely define the concept of refractoriness to standard-of-care therapy, which is often required for access to biologic therapies. The judgement of the physician and economic considerations will always be involved in treatment decisions; nevertheless, we should realize that patients with mild to moderate SLE who do not respond to treatment with glucocorticoids and antimalarial drugs might already be considered refractory to standard-of-care therapy and as such might be elected for biologic therapy to benefit from early treatment. Additionally, the view of preventing disease-related or treatment-related flares and damage in the long term should always be factored into the choice of therapeutic strategy.

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1.

2.

3.

4.

5.

6.

7.

Although personalized medicine on the basis of molecular stratification is not yet widespread, treatments should be tailored to the patient to increase the likelihood of controlling disease and promote patient adherence. In this regard, studies aimed at evaluating the real effect of patient stratification on treatment efficacy are truly necessary.

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Acknowledgements

The authors thank T. Manning for help with revising the English language of the manuscript.

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1. Unit of Rheumatology, Department of Medicine, University of Padova, Padova, Italy

Mariele Gatto, Margherita Zen, Luca Iaccarino & Andrea Doria

4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology

https://www.nature.com/articles/s41584-018-0133-2 64/66

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All the authors researched data for the article, wrote the article, reviewed and/or edited the manuscript before submission and provided substantial contributions to discussions of its content.

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Correspondence to Andrea Doria.

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4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology

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Gatto, M., Zen, M., Iaccarino, L. et al. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol 15, 30–48 (2019). https://doi.org/10.1038/s41584-018-0133-2

Published 11 December 2018 Issue Date January 2019

DOI https://doi.org/10.1038/s41584-018-0133-2

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Subjects Systemic lupus erythematosus• Therapeutics

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