Bioethics Paper 2

The management of systemic lupus erythematosus
(SLE) has evolved over the past few decades, leading
to improved patient survival in the mid- term; how-
ever, patients with SLE are still twice as likely to die as
age- matched individuals in the general population and
mostly die of long- term complications1–3.

Therapeutic strategies should aim to control disease
activity while minimizing damage accrual related to
both active disease and drug- related adverse effects4;
however, the management of SLE is highly variable,
possibly as a result of a lack of consensus on the con-
cepts 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 strategies5.
Nevertheless, scientific advances in diagnostics and dis-
ease monitoring are encouraging the discussion of early
diagnosis as well as personalized therapy. In this Review,
we discuss the available and emerging therap eutic
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.6) to 6–25
months since the year 2000 (refs7–9), 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 SLE10,11.
Furthermore, even when dealing with the interpreta-
tion 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 population12;
additionally, a diverse array of laboratory techniques
are used for their determination13. Hence, the search for
biomarkers of autoimmune abnormalities continues12.

Early diagnosis of SLE is important as it provides the
chance of a timely treatment to improve the patient out-
come and as the attainment of an early response damp-
ens the disease course by minimizing organ damage14–16.
Accordingly, in a retrospective 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 hos-
pitalization and SLE- related costs9. 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 death17–21.

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 settings22,23 and is

New therapeutic strategies in systemic
lupus erythematosus management
Mariele Gatto, Margherita Zen, Luca Iaccarino and Andrea Doria*

Abstract | The current treatment approach for systemic lupus erythematosus (SLE), as outlined
in the recommendations by international medical associations including EUL AR 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 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.

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

*e- mail: [email protected]

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

w w w.nature.com/nrrheum

R e v i e w s

30 | J A N UA RY 2 0 1 9 | v o l U m e 1 5

mailto:[email protected]

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

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

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)24 is paramount in the
early stages of disease (Table 1).

Preventive strategies
In addition to early diagnosis and treatment, preventive
strategies should be adopted as early as possible for indi-
viduals at risk of developing SLE (primary prevention)
or for patients who have already been diagnosed with
SLE to avoid disease exacerbations (secondary pre-
vention) 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 patients1.

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 progression8,25. 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)26. Evidence of the usefulness of pri-
mary 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 fea-
tures. Similarly, whether or not to screen asymptomatic
individuals who are potentially at risk of SLE is unclear27.

Preventive measures in SLE include the removal of
modifiable risk factors (such as exaggerated sunlight
exposure, smoking and drugs that can induce SLE)25,26;
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 immuno-
modulator y effects without notable drug adverse
events26,28. Although ANA positivity alone might not
necessitate hydroxychloroquine treatment, 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 pro-
gression is higher in these patients than in patients with
ANA positivity alone25,28.

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 population26, 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 posi-
tive for multiple aPL serological tests (double or triple
positive) are in turn at increased thrombotic risk29,30
and might benefit from low- dose aspirin; this recom-
mendation is supported by results from a meta- analysis
and expert opinion31,32, although, conversely, a previous
randomized controlled trial (RCT) has reported that this
treatment provided no additional protection in asymp-
tomatic aPL- positive individuals33. 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 irre-
versible damage (for example, to avoid the development
of conditions such as end- stage renal disease associ-
ated with persistently active lupus nephritis34, neuro-
psychiatric sequelae, scarring alopecia or skin atrophy
or dilatative myocardiopathy35).

Additionally, the occurrence of severe manifestations
can worsen disease prognosis1 and increase disease-
related medical costs36. In a 2018 observational study of
499 patients with lupus nephritis who were diagnosed
between 1970 and 2016 (median follow- up 10.6 years
(interquartile range (IQR) 4–18)), the patients had
a milder presentation of lupus nephritis over time37.
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 sur-
veillance 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.

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.

N AT U R e R e v I e W S | R h E u M ATO LO Gy

R e v i e w s

v o l U m e 1 5 | J A N UA RY 2 0 1 9 | 31

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 studies38–48. 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 outcomes39. 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 approach
Remission. An agreement on what principles should
guide the development of the definition of remis-
sion 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 speci-
alists and patient representatives who also put forward
a definition of remission in SLE39. In addition to this
proposed definition, at least three other different defi-
nitions of remission have been proposed in the past few
years39–41,43 (Table 2).

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

Compared with two decades ago, a greater propor-
tion of patients now achieve remission49–52, and yet
until a few years ago, prolonged remission was rarely
reported51,52. However, a number of studies in the past
few years have reported an increased prevalence of pro-
longed remission44,46,47. This increase could be because

Table 1 | Common mimickers of SLE

Type Mimicker Similarity to SLE Differences from SLE

Rheumatologic–
immunological
conditions209

• Undifferentiated connective tissue
diseases

• Undifferentiated polyarthritis
• Undifferentiated spondyloarthritis
• Antiphospholipid antibody syndrome
• Connective tissue diseases (early- stage)
• Vasculitis (early- stage)
• Fibromyalgia
• Sarcoidosis

• Generalized symptoms
• Skin manifestations
• Neurological manifestations
• Thrombosis
• Kidney involvement
• ANA positivity

• Different autoantibody profiles
• Additional clinical features and/or signs not

present in SLE (for example, Gottron papules in
early stage of dermatomyositis)

• Histological analysis of skin or kidney samples
might show lesions that are not typical for SLE
(for example, acute thrombotic microangiopathy ,
intrarenal vascular lesions and/or arterial
and arteriolar recanalizing thrombosis in
antiphospholipid- mediated nephropathy210)

Other
autoimmune
diseases209

• Autoimmune hepatitis
• Idiopathic thrombocytopenic purpura
• Autoimmune haemolytic anaemia
• TTP
• MAS

• Organ- specific presentation
might be clinically
indistinguishable

• ANA positivity

• Additional clinical manifestations might help
distinguish an SLE mimicker from SLE, but blood
and immunological investigations are necessary

• Anti- dsDNA antibodies are normally absent or low
in SLE mimickers

• Presence of schistocytes and anti- ADAMTS13
antibodies (in TTP)

• Typical histological pattern observed with
piecemeal necrosis (in autoimmune hepatitis)

Infections24 • Viral infections (for example, parvovirus
B19211, EBV212, CMV213 or HIV214
infection)

• Bacterial infections214 (for example,
Treponema pallidum or Borrelia
burgdorferi infection)

• Fungal infections (Trichophyton
infection)215

• Parasitic infections (for example,
Leishmania spp. or Toxoplasma
spp. infection)216

• Lymphadenopathy
• Blood cell count

abnormalities
• Arthritis
• Autoantibody positivity

(for example, seropositivity
for ANA , anti- dsDNA
anti bodies, anti- ENA
antibodies and/or ACA)

• Hypocomplementaemia
(occurs in >40% of individuals
with a parvovirus B19 virus
infection)

• Medical history (timing of symptoms and presence
of risk factors for specific infections such as
whether borreliosis is endemic in the area)

• High, rapid- onset fever with increased acute
phase reactants (CRP more reliable than ESR) a
feature of infections

• Hepatomegaly and splenomegaly more common
with infections

• Severe SLE features (for example, lupus nephritis
and NPSLE) and Raynaud phenomenon are
unlikely features of infection

• Complement consumption is uncommon with
infections

• Serological findings might help differentiate SLE
from mimickers

Neoplasms24 • Malignancies217 (for example, Burkitt
lymphoma, large B cell lymphoma,
plasmacytoid dendritic cell neoplasm
or T cell lymphoma)

• Benign conditions (for example, Kikuchi
disease218 or Castleman disease219)

• Systemic symptoms and
blood count alterations

• ANA positivity

• Specific manifestations of SLE and SLE- specific
antibodies usually absent

• Acute phase reactants are likely increased

Medication-
related or
vaccine related24

• Medication (for example, IFNα or
anti-TNF antibodies220)

• Vaccine (for example, HPV vaccine221)

• Shared clinical features (for
example, skin manifestations
and arthralgias)

• ANA positivity

• Medical history
• Anti- histone antibodies more frequent in

drug-induced SLE

ACA , anti- cardiolipin antibodies; ANA , antinuclear antibody ; CMV, cytomegalovirus; CRP, C- reactive protein; dsDNA , double- stranded DNA ; EBV Epstein–Barr
virus; ENA , extractable nuclear antigens; ESR , erythrocyte sedimentation rate; HPV, human papilloma virus; MAS, macrophage- activating syndrome; NPSLE,
neuropsychiatric SLE; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura.

w w w.nature.com/nrrheum

R e v i e w s

32 | J A N UA RY 2 0 1 9 | v o l U m e 1 5

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.39 and Zen et  al.40 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 variability53. Moreover, pre-
laboratory and post- laboratory PGA scores can differ54.
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 haemo-
lytic anaemia, myelitis and gastrointestinal activity)39.

However, it could be argued that the inclusion of a ‘treat-
ment’ criterion in the definition of remission (namely,
the threshold of prednisone equivalent of ≤5 mg/day
and a stable dose of immunosuppressive drugs) in addi-
tion to the SLEDAI-2K enables the exclusion of patients
with active disease, even in the domains not covered by
the SLEDAI-2K40.

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 Z en et  al. 40,47 or
van Vollenhoven et al.43,46, 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 find-
ings suggest that an achie vement of a clinical SLEDAI-2K
(that is, SLEDAI-2K score excluding serological

Subjects at risk of disease development
• Serology
• Abnormalities in the balance of
pro-inflammatory and anti-inflammatory mediators

Prevention of disease developmenta
• Smoking cessation
• Vitamin D
• HCQ
• Asymptomatic aPL-positive
individuals: low-dose aspirin31,32
• Tight follow-up

Prevention of disease flares
Primary strategies in addition to control of
disease activity using appropriate therapy68-70, 100
• Non-life-threatening: MTX, MMF, AZA or
belimumab120,121,132
• Life-threatening: CYC or RTX

Delay of disease progression and/or damage
• Primary and secondary strategies in
addition to steroid-sparing strategies86-91

Fu
n

ct
io

n
al

c
ap

ac
it

y Bu
rd

e
n

o
f d

ise
ase

Secondary
prevention

Primary
prevention

Tertiary
prevention

Patients with ILE or SLE
Diagnosis

Damage

Prevention and treatment of comorbidities

Primary prevention

Secondary prevention

Tertiary prevention

a

b

Fig. 1 | Levels of prevention in SLE. 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 erythematosus’ (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 antibody ; AZA ,
azathioprine; CYC, cyclophosphamide; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; MTX, methotrexate;
RTX, rituximab. aThe advice for drug measures is potentially useful, but this advice is mostly eminence- based and strong
evidence to support this advice is lacking.

N AT U R e R e v I e W S | R h E u M ATO LO Gy

R e v i e w s

v o l U m e 1 5 | J A N UA RY 2 0 1 9 | 33

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 damage44,46,47. 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 patients44. 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 accrual44. 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).

Low disease activity. The concept of using LDA as
a target has been applied to SLE in the past couple of
years41–43, and preliminary data suggest that the achieve-
ment of LDA is associated with better short- term out-
comes (Table 3), although data on long- term outcomes
are not available yet. Three definitions of LDA have been
proposed (Tables 2,3).

Although no agreed- upon definition of LDA in SLE
exists, an increasing number of studies have applied
the definition by Franklyn et al.42, referred to as the
lupus LDA state (LLDAS). The LLDAS was frequently
attained in different cohorts14,42,45,47 with a high propor-
tion of patients (ranging from 38.2%42 to 64.5%47) per-
sisting 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
accrual42,45,47, a finding also confirmed in a large cohort
of 1,356 patients48, and a ≥2-consecutive- year LLDAS is
an independent protective factor against new damage45.
Conversely, failure to achieve an LLDAS at 6 months is
an independent predictor of early damage15.

Notably, a similar protective effect on damage was
detected if patients spent <25% of follow- up time in clin- ical remission, which means that remission is superior to LLDAS in preventing damage progression48. The definition of LDA proposed by Polachek et al.41 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 defi- nition41. 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.42 has the limita- tion that SLEDAI-2K ≤4 and not clinical SLEDAI-2K ≤4 was used as an entry criterion, which means that both 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 factors200 - 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)101 - Steroid- sparing strategies Infections • 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 Sle201,202 • Prophylactic treatment with trimethoprim–sulfamethoxazole in patients with a low CD4 cell count (<200 cells/mm3)203 • 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/mm3)a, potentially combined with antifungal therapy (refer to a specialist in infectious diseases)204 • 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 common205,206 • 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) Osteoporosis207,208 • 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 - Bisphosphonatesb 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 monthsc aThe National Comprehensive Cancer Network considers the cut- off for severe neutropenia to be 100 cells/mm3, but the risk of opportunistic infections is already high for patients with <500 cells/mm3; the appropriate course should therefore be judged by the physician. bDrug holidays are recommended. cNot if pregnancy is planned. w w w.nature.com/nrrheum R e v i e w s 34 | J A N UA RY 2 0 1 9 | v o l U m e 1 5 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. 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 irrespec- tive of the type of manifestations (for example, low per- sistent 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 …