Bioethics Paper

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

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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)

7917 Accesses 32 Citations 121 Altmetric Metrics

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,

a

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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 201,202 3 203 3 a 204 205,206 207, 208 25,28 26 29,30 31,32 33 34 35 1 36 4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology https://www.nature.com/articles/s41584-018-0133-2 8/66 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 b c a 3 3 b c 37 38,39,40,41,42,43,44,45,46,47,48 39 39 39,40,41,43 4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology https://www.nature.com/articles/s41584-018-0133-2 9/66 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, 49,50,51,52 51,52 44,46,47 39 40 53 54 39 40 40,47 43,46 4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology https://www.nature.com/articles/s41584-018-0133-2 10/66 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. 44,46,47 44 44 4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology https://www.nature.com/articles/s41584-018-0133-2 11/66 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). 41,42,43 https://www.nature.com/articles/s41584-018-0133-2/figures/2 4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology https://www.nature.com/articles/s41584-018-0133-2 12/66 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. 42 14,42,45,47 42 47 42,45,47 48 45 15 48 41 41 42 4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology https://www.nature.com/articles/s41584-018-0133-2 13/66 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. 39 42 39 42 39 42 4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology https://www.nature.com/articles/s41584-018-0133-2 14/66 Renal outcomes According to the EULAR/European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) …

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