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The current treatment of lupus nephritis (LN) is not satisfactory, only 20-30% of patients achieve complete renal remission within 6-12 months, and 5-20% of patients develop end-stage renal disease
Relationship between LN and SLE: LN is the most common and important visceral complication of systemic lupus erythematosus (SLE) and is the leading cause of death in patients with SLE
Clinical Practice Guidelines and Recommended Medications for LNs: In 2012, the European Union of Rheumatology-European Kidney Association-European Association for Dialysis and Transplantation (EULAR/ERA-EDTA) developed joint recommendations for LNs
Six pathological classifications of LN: class I LN does not require special treatment, only the basic drug hydroxychloroquine is administered, small doses of prednisone (prednisone, PED) can be considered; Guidelines for type II with persistent/severe proteinuria consistently recommend the combination of immunosuppressants; The treatment of type III.
Overview of the pathophysiology of LN: LN is considered not only a glomerular disease (glomerulonephritis), but also a disease that affects all renal chambers (pan-nephritis
Multiple studies have reported that the long-term prognosis of LN is largely influenced by the degree of inflammation, fibrosis, and atrophy of TI
Treatment strategies for LN, as shown in Table 1, begin to lose podocytes (and corresponding renals) around the age of 40, resulting in an average decrease in eGFR of 0.
Based on these principles, the Association (EULAR/ERA-EDTA) jointly developed and updated the treatment recommendations
Once there is remission, maintenance immunosuppressive therapy
According to several retrospective studies, the use of rituximab, a B-cell consumable anti-CD20 monoclonal antibody
In LN, repeated measurement of whole blood HCQ titers is very helpful in identifying patients who do not comply otherwise will be considered refractory cases, exposed to treatment escalation, accompanied by more immunosuppression and possible additional adverse events
LN should be diagnosed
Although patient and kidney survival rates have improved considerably compared to the last century, due to the use of steroids and other immunosuppressants, only 20-30% of patients achieve complete renal remission (CRR), defined as proteinuria ≤0.
Treat-to-Target concept: This concept stems from the assumption that achieving a given goal early after the onset of the disease and initial treatment will ensure good long-term results
Is proteinuria reduction appropriate as a clinical goal? After 12 months of treatment, proteinuria is reduced to ≤ 0.
Renal biopsy versus clinicopathological remission: a recent study conducted three different groups revealed a mismatch between clinical and pathological remission to induce therapy
Renal biopsy is more reliable than proteinuria: in general, we recommend a systematic repeat renal biopsy
of the LN after one year of treatment.
Understanding how biopsy results and subsequent treatment change can be increased under international agreements (http:// www.
rebiolup.
com), thereby improving long-term outcomes
.
The results of two recent phase III randomized controlled trials open up a new avenue for treatment strategies for LN
.
Two drugs (Belimumab and voclosporin) have been listed by medical institutions as a combination therapy
for LN.
Belimumab (BEL) is superior to steroids: BEL is an anti-BLyS/BAFF monoclonal antibody that was originally registered more than 10 years ago for additional treatment in patients with non-renal SLE, based on 6 randomized controlled trials
.
A phase III LN trial (BLISS-LN) was designed based on retrospective analysis of patients randomized to some degree of proteinuria (no complete LN) and BEL improvement in two key trials
.
Patients receive BEL or placebo (PBO) therapy on the basis of standard care (SOC), i.
e.
steroids and MMF or Euro-Lupus IV CYC
.
After 104 weeks, the primary endpoint (predominantly effective renal remission) driven primarily by proteinuria (≤0.
7 g/day) was reached
in 32% and 20% of patients with BEL and PBO, respectively.
43% and 30% of BEL and PBO patients achieve CRR (proteinuria ≤0.
5 g/day
).
These differences are statistically significant
.
Importantly, the eGFR slope in BEL patients at 6 to 24 months was statistically reduced
.
The mechanism of this action can be elucidated
by repeated renal biopsy studies after BEL treatment.
More patients in the BEL group took ≤ 7.
5 mg/day of prednisone
at week 104.
Statistically, BEL patients take longer
from week 24 to their first kidney transplant.
BEL significantly improves serum markers such as anti-DNA antibodies and complement levels
.
That is, there is no statistically significant benefit
in IV CYC, Class V LN, and African patients.
Adverse events were also uncommon
in the BEL group.
The mode of action of CNI rapidly reduces proteinuria: Voclosporin (VOC) is a calcineurin inhibitor (CNI), similar
to tacrolimus and cyclosporine.
These drugs have an immunosuppressive effect and have a unique ability to stabilize the actin cytoskeleton of podocytes (by preventing synaptic peptide dephosphorylation), thereby reducing proteinuria
.
Compared with other CNIs, Voclosporin has good pharmacokinetic properties (without the need for drug monitoring) and a neutral effect
on lipid and glucose metabolism.
CNI has been used in LN for many years, especially in Asian patients, and is often used
in combination with MMF.
After the successful Phase II AURA-LV trial, VOC was tested in another positive Phase III trial (AURORA
).
Patients are given VOC (23.
7 mg bid or PBO) therapy on a steroid and MMF basis
.
It is worth noting that the steroid tapering regimen is very strict, with a target dose of 2.
5 mg/day for prednisone at 16 weeks
.
41% of patients with VOC and 23% of patients with PBO reached the primary endpoint (52-week CRR
).
As expected by the CNI's mode of action, the decrease in proteinuria
is very rapid.
VOCs have shown results in different racial groups, including people with African Americans and Hispanic/Hispanic Americans
.
The eGFR remained stable
in both groups.
There was no significant effect
on serum biologic markers.
Adverse events were not common
in the VOC group.
VOC is the first FDA-approved oral therapy for lupus nephritis, and on September 19, 2022, the European Commission also approved a marketing authorization for the VOC for the treatment of active lupus nephritis
.
Table 2 compares
the two newly approved drugs.
After a good initial signal was obtained in the Phase II study, other targeted therapies are currently being conducted in conjunction with SOC, such as obinutuzumab (OBI) and anifrolumab (ANI).
OBI is in Phase III clinical evaluation of the effects on LN: OBI is an anti-cd20 monoclonal antibody that has been approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma
.
In the NOBILITY Phase II trial, patients (predominantly Hispanic) were treated
with OBI or PBO on the basis of MMF and steroids.
At week 52 (primary endpoint), week 76, and week 104, CRR rates were 23%, 18%, and 23%, respectively, in the PBO group, and 35% (p=0.
11), 38% (p=0.
011), and 41% (p=0.
026)
in the OBI group, respectively.
In OBI-treated patients, peripheral blood B cells (CD19+ count≤5 cells/μl) reached 94%
at week 52.
Adverse events were rare in the OBI group
.
In the currently recruited Phase III trial (REGENCY), patients received OBI at weeks 0, 2, 24, 26, 50 and 52 and assessed for primary endpoints (CRRs)
at week 76.
anifrolumab is in Phase III clinical evaluation of the effects on LN: ANI is an anti-IFN-α and β receptor subunit 1 (IFNAR1) monoclonal antibody that blocks the activity
of all type 1 IFN (α, β, ε, κ, ω).
Based on the key role these cytokines play in SLE pathophysiology, ANI was successfully tested in two non-renal trials: TULIP-1 and TULIP-2
.
These results led to the FDA's recent approval of ANI for non-renal SLE and facilitated a Phase II controlled study
of LN (TULIP-LN).
In this trial, patients were treated with PBO or ANI, the latter following either a basal (lower) or enhanced (higher) regimen with both MMF and steroids
.
Only patients who received the intensive regimen showed more clinical remission than patients with PBO
.
A phase III clinical trial is underway using intensive ANI therapy
.
Drugs that target complement, such as C5aR antagonists or factor B inhibitors, may have a significant effect on
LN.
These drugs, through their action downstream in the cascade, may show a rapid effect, allowing for strict reduction or even avoidance of steroids, as recently demonstrated in ANCA-related vasculitis
.
Another example is Novartis's LNP023, which is an oral, specific, FIC complement factor B inhibitor that can block intravascular and intervascular hemolysis by targeting complement instead of signaling pathways, and is currently evaluating the effectiveness and safety of C3G patients in Phase III clinical trials, and its LN indications are in clinical phase
II.
Although specific data on LN are lacking, the results of a recent trial of patients with CKD with dapagliflozin (DAPA) (SGLT-2 inhibitor) deserve our attention
.
In the DAPA-CKD trial, 4304 patients with eGFR received DAPA (10 mg/day) or PBO in a body surface area of 25 to 75 ml/min/1.
73 m2 and proteinuria
.
The majority of patients (67%) have diabetes
.
Although patients with LN and vasculitis were excluded, other glomerular diseases, such as patients with
IgA nephropathy, were included.
The endpoint of the trial was a composite endpoint that included a sustained decline of at least 50% eGFR, end-stage renal disease, and cardiorenal death
.
The trial was discontinued after 32 months, and an intermediate analysis showed a 34%
reduction in primary outcomes in the DAPA group.
SGLT-2 inhibitors have a role to play in glomerular disease, just as
RAS inhibitors did 30 years ago.
The mode of action of SGLT-2 inhibitors is complex and leaves much unsolved
.
In chronic glomerular disease, there is excessive filtration of the unaffected kidneys, which increases sodium reabsorption of the proximal tubules, thereby reducing sodium levels
in the distal tubules and dense plaques.
This leads to further vasodilation (vicious circle)
of the afferent arterioles through tubule-glomerular feedback.
By blocking sodium (and glucose) reabsorption of proximal tubules and increasing the sodium content of distal tubules and dense plaques, SGLT-2 inhibitors induce vasoconstriction of afferent arterioles, reduce overfiltration and restore tubuloglomerular feedback
.
Current combination treatments can only bring up to 41% of LN patients to CRR, suggesting that there is still room for
improvement.
How can we push these numbers further? To achieve this, more attention should be paid to adherence to treatment and non-immunosuppressive therapy
.
With a CRR of 10-20% at 12-24 months, does this translate into fewer CKD/ESKD in the long term? The data suggest that patients who have never achieved CRR have a poorer
renal prognosis.
In this regard, improving CRR rates should have a positive impact on long-term prognosis, but only further follow-up will provide answers
.
Should we prescribe these drugs (in clinical trials discussed above) or wait two to three months before patients with no early signs of early remission of SOC begin to use these drugs? In a recent review [5], the latter recommendation targeted patients who did not have at least a 25% reduction in proteinuria compared to baseline after 8 to 12 weeks of induction therapy and were at risk of missing the window of
opportunity.
At least in Caucasian patients, most patients with rapid early remission (25% reduction in proteinuria >) may be associated
with the rapid efficacy of intravenous MP pulses.
If such rules are applied, these patients will not be able to benefit
from the new treatment.
Will it overtreat the patient? Unless we have effective tissue, blood, or urine biomarkers that can identify patients who do not respond to SOC at baseline, we are likely to overtreat a significant proportion of patients
.
On the other hand, pharmacoeconomic approaches should assess the economic burden of combination therapy versus the possible cost savings of
renal replacement therapy.
How effective is BEL or VOC in patients with severe renal impairment? Patients with eGFR< 30 ml/min/m2 were indeed excluded from BLISS-LN, AURA-LV, and AURORA
.
For patients with severe impairment of renal function, the use of CNIs is not recommended, at least until the improvement of renal function, such as after
intravenous MP pulses.
On the other hand, when several drugs that block different pathways are available, the next urgent problem to be solved will be how to choose the best treatment for a particular patient, because "one method cannot be applied to everyone"
.
Our selection will be guided
by the patient's extrarenal disease (BEL may be more indicative in the case of systemic manifestations), the patient's specific toxicity profile, the availability of the drug, etc.
Precision medicine and treatment will replace the use of indirect biomarkers, such as proteinuria, although it also reflects inflammation and chronic injury
.
Transcriptomics [6] and genetic variants may play a role in assessing individual risk of CKD and allow for a tailored approach
.
After decades of unregistered drug use and multiple failed clinical trials, it is foreseeable that the future for LN patients will be better
.