4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology
https://www.nature.com/articles/s41584-018-0133-2 1/66
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
nature nature reviews rheumatology review articles article
View all journals Search Login
content Journal info Publish Sign up for alerts RSS feed
Download PDF
https://www.nature.com/nrrheum
https://www.nature.com/articles/s41584-018-0133-2/metrics
https://www.nature.com/
https://www.nature.com/nrrheum
https://www.nature.com/nrrheum/articles?type=review-article
https://www.nature.com/nrrheum
https://www.nature.com/siteindex
javascript:;
https://idp.nature.com/authorize/natureuser?client_id=grover&redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41584-018-0133-2
javascript:;
javascript:;
javascript:;
https://www.nature.com/my-account/alerts/subscribe-journal?list-id=114
http://feeds.nature.com/nrrheum/rss/current
https://www.nature.com/articles/s41584-018-0133-2.pdf
4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology
https://www.nature.com/articles/s41584-018-0133-2 2/66
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.
You have full access to this article via GW Libraries
Download PDF
Introduction
https://www.nature.com/articles/s41584-018-0133-2.pdf
4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology
https://www.nature.com/articles/s41584-018-0133-2 3/66
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
1,2,3
4
5
6 7,8,9
10,11
12
13
12
14,15,16
4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology
https://www.nature.com/articles/s41584-018-0133-2 4/66
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.
9
17,18,19,20,21
22,23
24
1
4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology
https://www.nature.com/articles/s41584-018-0133-2 5/66
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
https://www.nature.com/articles/s41584-018-0133-2/figures/1
4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology
https://www.nature.com/articles/s41584-018-0133-2 6/66
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
200
101
8,25
26
27
25,26
26,28
4/22/2021 New therapeutic strategies in systemic lupus erythematosus management | Nature Reviews Rheumatology
https://www.nature.com/articles/s41584-018-0133-2 7/66
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) …
Delivering a high-quality product at a reasonable price is not enough anymore.
That’s why we have developed 5 beneficial guarantees that will make your experience with our service enjoyable, easy, and safe.
You have to be 100% sure of the quality of your product to give a money-back guarantee. This describes us perfectly. Make sure that this guarantee is totally transparent.
Read moreEach paper is composed from scratch, according to your instructions. It is then checked by our plagiarism-detection software. There is no gap where plagiarism could squeeze in.
Read moreThanks to our free revisions, there is no way for you to be unsatisfied. We will work on your paper until you are completely happy with the result.
Read moreYour email is safe, as we store it according to international data protection rules. Your bank details are secure, as we use only reliable payment systems.
Read moreBy sending us your money, you buy the service we provide. Check out our terms and conditions if you prefer business talks to be laid out in official language.
Read more