Review One year in review 2021: systemic lupus erythematosus
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Review
One year in review 2021: systemic lupus erythematosus
F. Trentin1, D. Zucchi1, V. Signorini1, E. Elefante1,2, A. Bortoluzzi3, C. Tani1
1
Rheumatology Unit, Department of ABSTRACT nese SLE patients and 9.451 healthy
Clinical and Experimental Medicine, In 2020 many contributions have been controls (4) showed an association be-
University of Pisa, Italy; produced on SLE. Our critical digest of tween the A>G variation at rs13259960
2
Department of Medical Biotechnologies,
the recent literature will be focused on in SLEAR, a long non-coding RNA,
University of Siena, Italy;
3
Rheumatology Unit, Department of genetic factors that contribute to the de- and susceptibility to SLE. In particular,
Medical Sciences, University of Ferrara velopment of the disease, novel potential this polymorphism leads to a down-
and Azienda Ospedaliero-Universitaria therapeutic targets (including IL-23, IL- regulation of SLEAR expression and
S. Anna, Ferrara, Italy. 17, interferons and JAKs), diagnostic enhances the apoptosis of peripheral
Francesca Trentin, MD and prognostic biomarkers, classifica- blood mononuclear cells.
Dina Zucchi, MD tion criteria, clinical manifestations and New data are emerging also on the im-
Viola Signorini, MD comorbidities. We will then present new munological abnormalities that are im-
Elena Elefante, MD treatment options (with a special focus plicated in the pathogenesis of SLE.
Alessandra Bortoluzzi, MD, PhD
on belimumab, anifrolumab, tacrolimus, Recently, Lee et al. (5) investigated the
Chiara Tani, MD, PhD
voclosporin and EULAR/ERA-EDTA mechanisms of T helper (Th)17 dif-
Please address correspondence to:
Francesca Trentin,
recommendations for the management ferentiation and their association with
U.O. di Reumatologia, of LN) and treat-to-target strategy. Last- SLE. Naïve CD4+ T cells were cultured
Diparimento di Medicina ly, we will concentrate on some of the in Th17 polarising conditions and then
Clinica e Sperimentale, aspects that influence patients’ disease treated with different cytokines; the re-
Università di Pisa, perception and quality of life. sults showed that Th17 differentiation
Via Roma 67, was promoted by IL-23 through the
56126 Pisa, Italy Introduction phosphorylation of Signal Transduc-
E-mail: francesca3ntin@gmail.com
Systemic lupus erythematosus (SLE) ers and Activators of Transcription 3
Received on March 26, 2021; accepted in is a complex autoimmune condition (pSTAT3), which regulates epigenetic
revised form on April 2, 2021.
characterised by heterogeneous clinical modifications. Interestingly, in patients
Clin Exp Rheumatol 2021; 39: 231-241. manifestations and immunological ab- with SLE (n=28), resting Th17 memo-
© Copyright Clinical and normalities. The purpose of this review ry cells were characterised by a higher
Experimental Rheumatology 2021.
is to summarise the recent literature on expression of IL-23R and pSTAT3;
pathogenesis, clinical manifestations moreover, stimulation with IL-23 sig-
Key words: systemic lupus
and disease management in SLE. As nificantly increased pSTAT3 expression
erythematosus, pathogenesis,
in the previous annual reviews of this in patients with SLE but not in healthy
comorbidities, treatment
series (1-3), we performed a Medline controls.
search of English language articles on Another recent study (6) investigated
SLE published between January 1st and the role of IL-17 on plasma cells from
December 31st, 2020. We selected the patients with active SLE, inactive SLE
most relevant papers, excluding case and healthy controls. Researchers iden-
reports and reviews. tified a subset of IL-17RA/RC+ plasma
cells that, upon IL-17 stimulation, re-
Pathogenesis and emerging acted with a potent anti-dsDNA anti-
therapeutic targets body production. This was positively
The pathogenesis of SLE is still poorly correlated to increased circulating Th17
understood and multiple factors are as- cell levels, serum autoantibody levels,
sociated with the development of the and disease activity both in SLE pa-
disease, including genetic, epigenetic, tients and murine models. Furthermore,
immunoregulatory, ethnic, hormonal, mice deficient for IL-17 or IL-17 recep-
and environmental factors. tor C exhibited a diminished plasma
As identified in several studies, the ma- cell response and attenuated renal dam-
jority of SLE susceptibility genes are age upon lupus induction.
located in non-coding regions. A recent Among other factors that could con-
Competing interests: none declared. genome-wide analysis in 4.556 Chi- tribute to the pathogenesis of SLE, it is
231One year in review 2021: SLE / F. Trentin et al.
worth mentioning Y-box binding pro- antibody to BLyS specifically approved ising anti-IFN-α2b serum antibodies in
tein 1 (YB-1), a cold-shock protein in- for seropositive and refractory SLE 91% of treated patients and a reduction
volved in the regulation of survival in – and (with an off-label prescription) of IFN gene signature in blood; moreo-
activated T cells. Meltendorf et al. (7) rituximab (RTX)- a monoclonal anti- ver, there was a significant reduction of
analysed its expression in 25 SLE pa- body to CD20 indicated for the treat- steroid-dose and an increased attain-
tients and 25 healthy controls, finding ment of haematological malignancies, ment of LLDAS in the IFN-K group,
significantly lower levels in apoptosis- ANCA-associated vasculitides, pem- with an acceptable safety profile.
prone and activated T cells from SLE phigus, Rheumatoid Arthritis (RA). Novelties regarding anifrolumab, a mo-
patients compared to non-apoptotic and Recently, some researchers proposed a noclonal antibody to type I interferon
activated T cells from healthy subjects. combined therapy with RTX and BEL receptor subunit 1, will be further de-
Interesting findings were also de- to prevent B-cell repopulation and clin- scribed in detail below.
scribed in the study by De Groof et ical relapses. In this regard, the results Among the biotechnological products
al. (8), in which researchers analysed of a long-term follow-up of a phase II recently proposed for SLE, it is worth
Toll-like receptor 3 (TLR3) expres- study (9) involving 15 SLE patients mentioning ustekinumab, a monoclo-
sion in HEK293 cells, myeloid-derived showed encouraging results, with 67% nal antibody already approved for the
dendritic cells (moDCs) and SLE of patients achieving lupus low disease treatment of moderate to severe plaque
skin lesions. TLR3 overexpression activity (LLDAS); furthermore, 75% psoriasis, psoriatic arthritis and Crohn’s
in HEK293 cells amplified apoptotic of patients with lupus nephritis (LN) disease. Ustekinumab targets the p40
responses, production of the Ro/SSA achieved a renal response and all pa- subunit of IL-12 and IL-23 cytokines,
autoantigen and increased maturation tients with anti-dsDNA positivity con- which are implicated in SLE pathogen-
of moDCs after exposure to UV irra- verted to negative throughout the study. esis. A phase II multicenter prospective
diation; moreover, TLR3 resulted over- Another B-cell directed therapy under randomised double-blind placebo-con-
expressed in skin biopsies, suggesting investigation is atacicept, a human re- trolled crossover study (12) evaluated
an active role of this molecule in SLE combinant fusion protein directed both the role of ustekinumab in 102 patients
inflammatory skin manifestations. The to BLyS and APRIL. Last year, Morand with active SLE despite conventional
analysis of single nucleotide polymor- et al. (10) performed a post hoc analysis therapy. Patients were randomly as-
phisms in TLR3 gene, however, ex- on the results of a phase II study (AD- signed (3:2) to receive either usteki-
cluded an association with an increased DRESS IIo), to evaluate the attainment numab (intravenous loading dose of
susceptibility to SLE both in a discov- of three treat-to-target endpoints (LDA, 260, 390 or 520 mg depending on body
ery cohort of 153 patients and 105 con- LLDAS, remission). The original study weight followed by 90 mg subcutaneous
trols and in a confirmation cohort of included 306 SLE patients who re- injections every 8 weeks) or placebo in
1.380 patients and 2.104 controls. ceived weekly atacicept (75 or 150 mg) addition to standard therapy. After 24
or placebo plus standard-of-care for 24 weeks, placebo group was switched to
Take home messages on pathogenesis weeks. LDA (SLEDAI-2K≤2), LLDAS subcutaneous 90 mg ustekinumab every
• Genetic variations in long noncoding and clinical remission at week 24 result- 8 weeks, while the original ustekinum-
RNAs and low levels of YB-1 seem ed more stringent than SLE Responder ab group continued to receive the same
to predispose to SLE by influencing Index (SRI)-4 and SRI-6 response, but therapy until week 40. A sustained re-
the apoptosis of mononuclear cells were able to discriminate active treat- sponse was observed in those patients
in the peripheral blood. (4, 7); ment (150 mg) from placebo, suggest- who received ustekinumab from base-
• Growing evidence suggests that IL- ing that these endpoints may be mean- line through week 40. Interestingly, in-
23 and IL-17 are involved in SLE ingful outcome measures in future SLE creased response rates were also noted
pathogenesis, since they have a role clinical trials. in patients from the placebo group who
in differentiation and in survival of Since there is growing evidence that crossed over to ustekinumab.
T cells (5, 6). interferons (IFNs) play an important Also kinase inhibitors are under inves-
role in the pathogenesis of SLE, many tigation for the treatment of SLE. Dörn-
Emerging potential therapeutic IFN-directed agents are currently under er et al. (13) analysed the results of a
targets: phase I and II studies evaluation for clinical use. Recently, a phase II, 24-week, randomised, placebo
Despite recent advances in under- 36-week phase IIb, randomised, dou- controlled double-blind study trial with
standing the molecular pathways that ble-blind, placebo-controlled trial was baricitib (BAR), a JAK1 and JAK2
contribute to the development of the performed to evaluate the efficacy and inhibitor. Blood samples from 274 pa-
disease, the complex immune dysregu- safety of the immunotherapeutic vac- tients were processed to characterise
lation and the heterogeneous clinical cine IFN-α kinoid (IFN-K) in 185 pa- gene expression and serum cytokines.
manifestations of SLE are still a chal- tients with active refractory SLE and The results confirmed that, also in
lenge for targeted treatment. positive IFN gene signature (11). Pa- SLE, JAK/STAT pathways have a cru-
Among B-cell-directed therapies cur- tients were randomised to receive intra- cial role in the pharmacological effect
rently used for SLE management we muscular injections of IFN-K or place- of BAR: changes in the expression of
find belimumab (BEL) – a monoclonal bo. At week 36, IFN-K induced neutral- STAT1/STAT2 target genes were linked
232 Clinical and Experimental Rheumatology 2021One year in review 2021: SLE / F. Trentin et al.
with response to treatment and serum Although many biomarkers have been and hsa_circ_0008675 serum levels
IL-12p40 and IL-6 decrease. discovered, only few are validated and were significantly higher in patients
A randomised, double-blind clinical trial used in the clinical practice. The latest with LN respect to SLE patients with-
was recently conducted to assess safety studies on this topic are enlisted in this out renal involvement, patients with
and efficacy of two selective kinase section. non-SLE nephritis and healthy controls.
inhibitors in patients with lupus mem- A cross-sectional Japanese (16) study Other interesting new data emerged on
branous nephropathy, a subtype of LN demonstrated that serum levels of Ga- proinflammatory cytokines/chemokines
that generally does not respond well to lectine-9 (Gal-9) were significantly in- such as TNF-like weak inducer of ap-
conventional immunosuppressive treat- creased in patients with SLE compared optosis (TWEAK) and neutrophil ge-
ment. Five patients were treated with with the control group. Moreover, Gal- latinase-associated lipocalin (NGAL);
filgotinib, a JAK1 inhibitor approved for 9 levels were correlated with disease their serum (s) and urine (u) levels cor-
RA, while 4 patients were treated with activity and with SLE-related organ related with disease activity in SLE.
lanraplenib, a spleen tyrosine kinase involvement. Li et al. (17) showed that Moreover, higher levels of (s)TWEAK
(SYK) inhibitor. After 16 weeks, a re- two serum exosomal microRNA, miR- were found in patients with active renal
duction of 24-hour urine protein excre- 21 and miR-155 were higher in SLE SLE (23).
tion was recorded in the filgotinib group, patients, compared to healthy controls; An interesting study (24) showed that
while no improvement was seen in pa- miR-21 and miR-155 were positively the absolute number and proportion
tients treated with lanraplenib (14). correlated with proteinuria. Similarly, of Milk fat globule epidermal growth
Lastly, clopidogrel was proposed as hsa_circ_0000479 (a circular RNA) factor 8 (MFG-E8) positive monocytes
add-on strategy in SLE, following the in peripheral blood mononuclear cells to total monocytes were significantly
observation that soluble CD40L ligand was increased in SLE patients, proving higher in patients with active SLE; the
(sCD40L) concentrations in blood are a possible diagnostic role. proportion was also significantly cor-
correlated with disease activity in SLE. Two studies analysed the possible role related with known disease activity
sCD40L is a cleaved form of CD40L, of long non-coding RNA (lncRNAs) parameters such as SLEDAI-2K score,
shed by activated T lymphocytes and as biomarkers for SLE diagnosis. The serum levels of anti-ds-DNA antibod-
platelets. In this study, 18 stable SLE first (18) found that the expression of ies, complement and C1q.
patients were enrolled in a single-arm, lnc-FOSB-1:1 was significantly de- Another study (25) analysed genetic
open-label, monocentric phase I/II trial creased in neutrophils of SLE patients variants of Tissue factor (TF) and Hu-
and received clopidogrel for 12 weeks compared to other connective tissue man apolipoprotein H (APOH) and
in addition to standard SLE therapies diseases or healthy controls; more im- demonstrated that TF rs3917615 and
(15). Clopidogrel was well tolerated, portantly, decreased lnc-FOSB-1:1 rs958587 and APOH rs4581 might pre-
but the primary endpoint (a significant expression was associated with lupus dispose to joint involvement in SLE.
change in sCD40L plasmatic concen- nephritis. The second study (19) iden- Finally, as shown by Schaier et al. (26),
tration after 12 weeks) was not statisti- tified TCONS_00483150 as diagnostic an imbalance between CD4+-regulato-
cally met, although a temporal relation- biomarker as it could be able to distin- ry T-cells (Tregs) and CD4+-responder
ship between clopidogrel exposure and guish patients with SLE (active or sta- T-cells (Tresps) seems to correlate with
sCD40L levels was recorded, suggest- ble disease) from healthy controls and occurrence of disease flares in SLE
ing that this drug could decrease plate- those with rheumatoid arthritis. patients.
let activation by interfering with plate- Another recent study (20) demonstrated Regarding potential biomarkers of re-
let CD40L and CD62 expression. that both anti-α-enolase Ab and RDW nal involvement, a Mexican study (27)
were significantly higher in SLE pa- demonstrated that urinary CD163 lev-
Take home messages on emerging tients than in the healthy control and els were higher in patients with active
therapeutic targets their presence correlated with disease LN than in patients with active extrare-
• Phase II trials of JAK inhibitors, activity. nal SLE, inactive SLE, and other glo-
ustekinumab and IFN-directed Also glycoprotein acetylation (GlycA) merular diseases, and correlated with
agents have shown preliminary pos- could be a good marker of disease ac- disease clinical severity, histologic
itive results (11-13); tivity, as highlighted in the study by Di- class, and the histologic activity index.
• A combined therapy with RTX and erckx et al. (21): GlycA levels, which Another study (28) measured urinary
BEL could be useful in refractory were found to be increased in several levels of transferrin and ceruloplasmin
cases (9). inflammatory disorders, had a positive in 120 patients with SLE. Urinary lev-
correlation with SLE disease activity els of these two biomarkers were sig-
Biomarkers and their value was higher in prolifera- nificantly higher in patients with LN
During the last decades, there has been tive nephritis than in non-proliferative compared to those without LN. Simi-
an increasing interest in biomarkers nephritis. larly, urinary levels of both biomarkers
not only for lupus diagnosis but also Another study (22) investigated the role were significantly higher in patients
for monitoring and predicting upcom- of circular RNAs as biomarkers of LN: with active LN compared to those with
ing flares and response to therapies. hsa_circ_0082688, hsa_circ_0082689 inactive LN.
Clinical and Experimental Rheumatology 2021 233One year in review 2021: SLE / F. Trentin et al. An American study (29) screened the Republic of Korea. The results showed as an obligatory entry criterion, and the presence of 1000 proteins from urine that complete remission at 1 year was additive, weighted multicriteria system samples of SLE patients, using a novel, less frequent in the higher uric acid (37). Over the past year, several studies quantitative planar protein microarray. (UA) group, whereas CKD and end- evaluated the accuracy of the new crite- 64 urinary proteins were significantly stage renal disease were more preva- ria among wider and diversified popu- elevated in the samples obtained by lent; levels of UA >7 mg/dL seemed to lations. An international multicentre SLE patients. Among these proteins be a significant predictor of progression study evaluated the performance of the Angptl4, L-selectin and TGFβ1 seemed to CKD in patients with LN. new EULAR/ACR and the Systemic to be potential biomarkers for tracking Since SLE patients are prone to accel- Lupus International Collaborating Clin- disease activity in LN. Davies et al. (30) erated atherosclerosis and increased ics (SLICC) 2012 and ACR 1982/1997 also analysed a urinary protein panel to incidence of cardiovascular (CV) dis- criteria with regard to disease dura- identify potential LN biomarkers. The ease, several studies tried to identify tion, sex and race/ethnicity (38). The results showed that levels of transfer- potential biomarkers that correlate with EULAR/ACR 2019 criteria performed rin, AGP-1, ceruloplasmin, MCP-1 and this risk. A possible useful biomarker is well in both genders and across differ- sVCAM-1 were higher in SLE patients serum sCD163, whose levels are posi- ent ethnic groups (White, Black, His- with active LN when compared with pa- tively correlated with the progression of panic, and Asian patients). Additional- tients without active LN; furthermore, a carotid plaque in SLE patients (35). ly, the new criteria performed well also combined model of five urine proteins, Considering that leptin and TWEAK among patients with early disease (less namely LPGDS, transferrin, AGP-1, have been correlated to subclini- than 3 years from disease onset) (39), ceruloplasmin, MCP-1 and sVCAM-1 cal atherosclerosis and that galectin- with a 97% sensitivity and a 96% speci- predicted response to rituximab treat- 3-binding protein (G3BP) is linked to ficity. The sensitivity of the EULAR/ ment at 12 months (AUC 0.818). a pro-thrombotic environment through ACR and previous classification crite- Also immunoglobulin binding protein type I interferon activation, Peretz et al. ria was assessed against physician diag- 1(IGBP1) plasma levels could be use- (36) measured serum levels of G3BP, nosis in a cohort of patients diagnosed ful LN biomarkers. In particular, Kwon interferon gamma-induced protein 10 with SLE (n=690) or control diseases et al. (31) observed that IGBP1 plasma (IP-10), sCD163, TWEAK and lep- (n=401) both at the time of diagnosis levels were higher in patients who de- tin in 162 patients affected by SLE. and at the last patient visit assessment. veloped LN, compared with patients The results of a univariable regression Both the EULAR/ACR and SLICC cri- who did not develop LN; interestingly, analysis showed that only G3BP levels teria had higher sensitivity (88.6% and the combination of plasma IGBP1 and were significantly associated with an 91.3%, respectively) than the ACR cri- anti-dsDNA antibodies was a highly increased risk of venous thromboembo- teria (85.7%), with the EULAR/ACR specific (97%) composite predictor for lism in SLE patients. having higher specificity than the other the development of LN. two sets (97.3% vs. 93.0–93.8%). By Some biomarkers are not only predic- Take home messages on biomarkers analysing patients with disease duration tive of LN development but can also • Gal-9, miR-21, miR-155, lnc-
One year in review 2021: SLE / F. Trentin et al.
the most common clinical criterion was al. (44) expanded the knowledge on College of Cardiology/American Heart
synovitis. These data suggest that im- peripheral nervous system (PNS) mani- Association (ACC/AHA) score and the
munologic abnormalities, cytopenias festations by analysing a large, multi- QRISK3 (46). The study demonstrated
and arthritis are common as initial pres- ethnic/multiracial, prospective, incep- that the QRISK3 – a validated algo-
entation in paediatric lupus patients. tion cohort of SLE patients. The overall rithm that in addition to traditional risk
For these patients, both the 2019 EU- frequency of PNS events in the study factors considers specific items such as
LAR/ACR criteria and the 2012 SLICC was 7.6%, with a rising trend over the the presence of SLE and the regular in-
criteria were more sensitive than the last decade. Peripheral neuropathy take of steroids – was able to classify a
1997 ACR criteria, with similar speci- (41.0% of PNS events), mononeuropa- greater number of patients at high risk
ficity. thy (27.3% of PNS events), and cra- of developing CV disease in the fol-
Lastly, Carneiro et al. (41) performed nial neuropathy (24.2% of PNS events) lowing 10 years in comparison with
a direct comparison of the three clas- were the most frequent events. Longer the other two classical algorithms. The
sification criteria sets in a cohort of time to resolution was associated with superiority of QRISK3 algorithm was
adult patients to investigate their pre- a previous history of neuropathy, pe- observed especially in the younger age
dictive role regarding organ damage ripheral nerve involvement, older age group (patients with less than 40 years),
and mortality over a 10-year follow-up at SLE diagnosis, and higher SLEDAI- in presence of CKD and in patients with
period. The analysis showed that in pa- 2K scores. The outcome, however, was chronic intake of glucocorticoids.
tients with higher EULAR/ACR scores favourable for most patients and resolu- Regarding specific risk factors, Tzelios
at the time of diagnosis, there was an tion occurred in 51% of patients by the et al. (47) evaluated the impact of hy-
increased incidence of organ damage end of the study. pertension - defined with the new ACC/
that persisted after adjustment for age AHA criteria (blood pressure ≥130/80
and sex. No associations were found Comorbidities mm Hg)- in a cohort of 1532 SLE pa-
between the ACR and SLICC sets and Comorbidities contribute substantially tients from the Toronto Lupus Clinic.
outcomes. to the disease burden in patients with Patients- with at least 2 years of fol-
SLE; over the past year special attention low-up and no prior CV- were divided
Clinical manifestations was paid to cardiovascular (CV) and into three groups according to their
In 2020, EULAR published the update atherosclerotic vascular (AV) domains. mean blood pressure over that period
of the joint EULAR and European Re- For example, Urowitz et al. (45) evalu- (≥140/90 mm Hg, 130–139/80–89 mm
nal Association–European Dialysis and ated the prevalence and the accrual of Hg andOne year in review 2021: SLE / F. Trentin et al. available for adult patients with active, belimumab was consistent with previ- The most recent ERA-EDTA recom- seropositive SLE. ous studies on adult patients, allowing mendations (42) confirmed for class III The recently published long-term open- an extension of the indication also to and IV LN a first-line induction treat- label extension study of the phase III childhood-onset SLE. ment with MMF 2–3 g/day or low-dose trials (BLISS-52 and BLISS-76) (48) Another promising biological drug is IV CY (500 mg x 6 biweekly doses) confirmed good efficacy and safety pro- anifrolumab, a monoclonal antibody in combination with glucocorticoids file of the drug, with a retention rate af- to type I interferon receptor subunit 1. (GCs); CNI/MMF combination and ter 8 years of 49.9% (368/738 patients). After a partial failure of TULIP-1 (50), high-dose CY are alternative options Similarly to the phase II continuation AstraZeneca published the results of a for nephrotic-range proteinuria and study, the incidence of adverse events second phase III trial (TULIP-2) (51), adverse prognostic factors, while RTX (AEs), severe AEs (SAEs) and AEs considering as primary endpoint the should be reserved for refractory cases. leading to discontinuation was higher response rate at week 52, defined us- Particular attention was paid to GC use: in the first year, with a subsequent ing the BILAG-based Composite Lu- the experts recommended administra- stabilisation or decline through the re- pus Assessment. A total of 362 patients tion of IV methylprednisolone pulses mainder of the study. Headache was the received the randomised intervention followed by lower doses of daily GCs most frequently reported AE, followed (IV monthly infusion of anifrolumab (oral prednisone 0.3–0.5 mg/kg/day) to by upper tract infections, diarrhoea 300 mg or placebo) for 48 weeks. The decrease the cumulative dose. and arthralgias; in both phase II and primary endpoint was met in 47.8% of MMF, in combination with GCs, was phase III extension studies, cellulitis patients in the anifrolumab group (vs. also the first-line choice for pure mem- and pneumonia were among the most 31.5% in the placebo group), with a branous LN. frequently reported SAEs. 1.1% of pa- positive impact on the severity of skin Notably, the recommendations re- tients experienced malignancies, peak- manifestations and a significant de- marked the importance of angiotensin- ing at study year 3-4. 12.9% of patients crease in the glucocorticoid dose. Con- converting enzyme inhibitors and an- developed an opportunistic infection, versely, there were no significant dif- giotensin receptor blockers as adjunct peaking in study year 0-1. Depression ferences in the annualised rate of SLE treatment for LN, as well as anticoagu- was reported in 11.7% of patients (95% flares and in the number of tender and lation in patients with antiphospholipid with mild symptoms), with incidence swollen joints. Notably, the drug was syndrome. decreasing over the course of the study. well tolerated, with a retention rate of Among CNI, tacrolimus (TAC) is a rel- Throughout the study, there were 1 sui- 85% at 48 weeks (vs. 71.4% in the pla- atively old drug widely used in neph- cidal ideation and 2 suicidal attempts cebo group). Adverse events that oc- rology for the prevention of transplant (not completed), providing evidence to curred at a frequency at least twice that rejection. A recently published long- alleviate concerns regarding suicidality of the placebo group were bronchitis, term randomised controlled study (53) while receiving belimumab. Death oc- upper respiratory infection and herpes compared the 10-year outcome of LN curred in 11 patients during the study, zoster; one patient died from pneu- in 150 Chinese patients treated with but only in one case (cardiac failure) monia. MMF or TAC followed by azathioprine the AE was considered as possibly re- Long-term safety and tolerability of IV maintenance. Renal response rate and lated to belimumab. Laboratory param- anifrolumab were recently confirmed renal flare rate were similar between eters and mean SLICC/ACR Damage by the three-year open-label extension MMF and TAC-treated patients, with Index score generally remained stable of MUSE, a phase IIb randomised con- no significant differences in the cumu- over time, indicating low drug toxicity trolled trial. This study (52) confirmed lative incidence of end-stage renal dis- and no organ damage accrual. an acceptable safety profile of anifrol- ease and death. Recently, the European Commission umab, with sustained improvement in During the drafting of this year’s re- and the FDA extended the indication of disease activity, quality of life and se- view, a novel calcineurin inhibitor – belimumab also to children 5 years and rology in patients with moderately-to- voclosporin (Lupkynis®, Aurinia Phar- older. This approval was based on the severely active SLE, with a retention maceuticals) – was approved by the US results of PLUTO (Pediatric Lupus Trial rate of 63.8% at three years. Food and Drug Administration (FDA), of Belimumab Plus Background Stand- making it the first oral treatment li- ard Therapy) (49), an ongoing phase New therapeutic options censed for active lupus nephritis (LN) II multicentre, double-blind, placebo- in lupus nephritis treatment in the US (54). This approval was based controlled trial in which 93 patients (13 For many years, mycophenolate on the results of a 52-week Phase III children and 80 adolescents) were ran- (MMF) and cyclophosphamide (CY) multicentre, randomised, double-blind, domised to receive either intravenous in monotherapy have been considered placebo-controlled study (AURORA), belimumab (10 mg/kg) or placebo every cornerstones for the induction therapy which included 357 patients with biop- 4 weeks, plus standard SLE therapy. of LN, but there is increasing evidence sy-proven active class III, IV and V LN Within the limits of the short period of that calcineurin inhibitors (CNI) and (55). observation (52 weeks) and the small multitargeted therapy are valid alterna- Patients were randomised to voclo- sample size, the benefit-risk profile of tive options. sporin (VCS) or placebo in combina- 236 Clinical and Experimental Rheumatology 2021
One year in review 2021: SLE / F. Trentin et al. tion with MMF (1 g BID) and rapidly body to type I interferon receptor lead to damage accrual in the longer run. tapered oral steroids. The combination subunit 1. Data at 54 weeks show If clinical remission seems to be an therapy with MMF and low-dose VCS good tolerability, amelioration of achievable target, remission off treatment (23.7 mg twice daily) was more effec- skin manifestations and steroid-spar- seems to be a more difficult and contro- tive than placebo in inducing renal re- ing effect (51); versial goal to achieve and maintain. mission (40.8% for the VCS arm and • TAC and MMF in monotherapy Jakez-Ocampo et al. (61) retrospec- 22.5% for the control arm (OR: 2.65; had similar efficacy at 10 year; tively described the clinical character- 95% CI: 1.64, 4.27; p
One year in review 2021: SLE / F. Trentin et al. rather than disease activity (PGA or A recent meta-analysis (67) explored the patient perception of disease status, fa- SLEDAI), was the key obstacle for pa- relationship between disease activity, tigue represents one of the most promi- tients who achieved LLDAS to further organ damage and HRQoL – assessed nent symptoms of SLE and a major achieve remission. by both generic and disease-specific contributor to QoL, although is only Babaoǧlu et al. (64) evaluated time scales – in SLE. In all eight domains of addressed in a few instruments used in to LLDAS in the Hopkins Lupus Co- SF-36, disease activity showed modest clinical practice to monitor the disease. hort. Compared to the Chinese cohort, correlation with HRQoL, with bodily In recent years, a great amount of lit- Babaoǧlu reported a shorter median pain being highest and physical func- erature has been focusing on fatigue in time to LLDAS (1.1 vs. 1.4 years), tioning being the lowest. Lupus-specific lupus. maybe due to the lower baseline disease QoL measurements, like the LupusPRO Obviously, it is important to distin- activity. Though different time needed questionnaire, was relatively sensitive guish between fatigue in patients with for LLDAS achievement, the cumula- to the changes of disease activity and high disease activity, in whom remis- tive probability of LLDAS achievement organ damage compared with generic sion or at least low disease activity in the first 5 years was similar between SF-36 scale. should be targeted, and fatigue in inac- the Chinese cohort and the Caucasian According to this work, mental health- tive patients, with a very high load of patients from Hopkins Lupus Cohort related domains showed less relation- anxiety and depression, for whom psy- (93% of patients), indicating that the ship with clinical outcomes, such as or- chological and behavioural assessment majority of patients can achieve LL- gan damage and remission status, when represents a key step (69). DAS. However, in the Hopkins Lupus compared to SF-36 domains related to In a large Italian cohort of SLE pa- Cohort the time to LLDAS was found physical well-being. tients, fatigue revealed to have a strong to be longer in African-American SLE The authors also wanted to further ex- negative impact on HRQoL and patient patients, even after adjustment for re- amine the effect of geographical differ- perception of the disease burden. Im- nal activity, and the probability of LL- ences of SLE patients on the correlation portantly, in this study (70), fatigue DAS achievement in the first 5 years between disease activity and HRQoL. A was irrespective of disease activity but was lower in African-American (82%) subgroup analysis was then conducted significantly influenced by the pres- compared to Caucasian patients. These in patients enrolled from various re- ence of fibromyalgia. findings point to the need to include gions including Africa, Europe, Asia, Clinical manifestations with an impact African-American SLE patients in both and America. Correlation coefficients on daily activities, although not severe, clinical and pharmaceutical research, between disease activity and bodily represent the most important patient as it is not possible to generalise from pain, general health, vitality, and so- concern, while they are often over- studies from Europe and Asia. cial functioning were statistically sig- looked by the treating physician. Recent data from the Tromsø Lupus nificant in African and European SLE According to a recent study (71), past Cohort, which includes patients with patients. Organ damage had stronger and ongoing joint involvement, a con- SLE in the two northernmost coun- negative correlations with SF-36 do- comitant diagnosis of fibromyalgia and ties in Norway, showed that 33.5% of mains in Asian SLE patients compared ongoing glucocorticoid treatment may patients spent at least half of their fol- with American and European patients. represent the most important variables low-up time in LLDAS (LLDAS-50). However, SDI was significantly corre- determining the poor concordance be- In this longitudinal population-based lated with physical functioning in SLE tween patient and physician perspec- study (65), the authors demonstrated patients from all regions. These results tive on the disease. that achievement of LLDAS-50 was as- seem to suggest that it is less likely to Actually, chronic pain represents a per- sociated with a significant reduction in optimising the mental health-related vasive symptom in SLE patients. severe damage and also with a reduc- quality of life by only controlling dis- A cross-sectional analysis (72) of pa- tion in mortality. ease activity and damage accrual. tient-reported data from a population- Among the unmet needs of T2T strat- It is well known in the literature that based registry including 766 individu- egy in SLE, studying non-inflammatory mood disorders are very frequent als with SLE, examined predictors of factors influencing patients’ Health Re- among SLE patients. This is also con- pain intensity and interference, defined lated Quality of Life (HRQoL) and de- firmed in a recent study by Cui et al. as pain that hinders major life activi- veloping interventions to improve such (68): in their cohort, they found a high ties. Patients reporting increased dis- factors represent some of the most im- prevalence of depression and anxiety ease activity also reported higher pain portant issues to be addressed. symptoms (79.5% and 86.8%, respec- intensity and interference. However, A lack of concordance between physi- tively). Interestingly, they found that disease activity and organ damage ex- cians’ evaluation of disease activity illness uncertainty was positively as- plained only 32–33% of the variance and damage and patients’ HRQoL is sociated with psychological distress in pain intensity and interference. So- commonly found in SLE. Some physi- and may contribute to the development ciodemographic factors accounted for cians even fear looking at the patient’s of depression and anxiety symptoms in an additional 4–9% of variance in pain perspective, because of uncertainties of women with SLE. outcomes, with older age and black how to face and treat it. (66). Among subjective factors influencing race being associated with increased 238 Clinical and Experimental Rheumatology 2021
One year in review 2021: SLE / F. Trentin et al.
pain intensity and higher socioeco- scare in recognising changes of dis- munomodulation with rituximab and beli-
mumab in severe, refractory systemic lupus
nomic status being protective for pain ease activity and organ damage (67);
erythematosus: 2-year results. Nephrol Dial
outcomes. Finally, psychosocial/be- • Anxiety, depression, chronic pain Transplant 2020 Jun 27 PMID: 32591783
havioural factors accounted for the fi- and fatigue have a negative impact [Online ahead of print].
nal 4% of variance. These findings sug- on patients’ quality of life and should 10. MORAND EF, ISENBERG DA, WALLACE DJ
et al.: Attainment of treat-to-target endpoints
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be needed to tackle the negative impact treated; patients should be educated the atacicept phase 2b ADDRESS II study.
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