Highlights of upcoming 2023 APLAR guidelines on the LN management

03 Feb 2023

The Asia-Pacific League of Associations for Rheumatology (APLAR) published a consensus statement on the management of systemic lupus erythematosus (SLE) in 2021. However, it only contained 7 statements on managing lupus nephritis (LN), which is a very common complication of SLE.1 In the 24th APLAR Congress 2022, Dr. Mok, Chi-Chiu from the Tuen Mun Hospital, Hong Kong, highlighted the need for specific consensus statements for the LN management and the unaddressed issues regarding the previously published guidelines.1 He then elaborated on the new criteria and evidence that will be considered for formulating the 2023 consensus statements on the LN management.1 In the meantime, he also concluded with a glimpse of 80 new statements that have been prepared for the LN management under various headings.1

Reasons for developing special consensus statements for LN in the Asia-Pacific region:

  • LN has a more serious prognosis among the Asians as compared with the Caucasian population due to several factors: 
  • In Asian patients, the incidence of renal damage in SLE varied from 21%-65% at diagnosis to 40%-82% over time, which was greater than in Caucasian SLE patients.
  • Asian patients have lower medication tolerance [e.g., mycophenolate mofetil (MMF) 3g/day, ocrelizumab).
  • A meta-analysis found that MMF did not reduce the risk of infections in Asian LN patients when compared with cyclophosphamide (CYC).
  • Asian patients are less adherent to taking medication due to fears of toxicity.
  • There is less access to healthcare and medicine availability in certain Asia Pacific regions, leading to treatment delay.
  • Asians may be genetically predisposed to having more severe LN, particularly with certain genes [e.g., signal transducer and activator of transcription 4 (STAT4) risk alleles].
  • Renal disease and end-stage renal disease associated with SLE significantly increase the standardized mortality rate of SLE patients to 9 to >60 times, respectively, as compared with the general population.
  • Earlier renal biopsies and treatment, lower starting dose of glucocorticoids (GCs), and improved support care for chronic kidney disease (CKD) result in slightly better renal survival without dialysis in SLE patients diagnosed post-2005, as compared with those diagnosed before 2004.
  • LN treatment is split into 2 phases: The induction/consolidation phase, in which more aggressive immunosuppression is administered to minimize kidney inflammation; and the maintenance phase, which seeks to prevent or lessen the risk of renal flares.
  • The induction phase was defined as 6 months but may be prolonged to 12 months or longer as evidenced in more recent randomized controlled trials (RCTs).
  • A long induction/consolidation phase is required for the membranous type of LN. 
  • The maintenance phase requires a lower dose of immunosuppressant or switching to a less potent agent, and the optimal duration depends on individualized factors (e.g., high-risk patients require a longer maintenance phase).
  • Recent French trials found that for reducing renal flares over the next 2 years, withdrawal of methyl methacrylate/azathioprine (MMA/AZA) was non-inferior to continuation.
  • LN is a significant complication of SLE that warrants the development of additional consensus statements focusing on its management in SLE patients, given the general recommendations for SLE published in 2021 contain only 7 statements for the LN management, which are far from enough.

The overpassing controversies and details in the previous consensus

The revised guidelines, expected to be published in 2023, will address the following controversies or details of LN management that have been overpassed previously :

  • The optimal initial choice of induction regimen in LN is not known.
  • There is a lack of data on the role of repeat renal biopsy post-induction therapy.
  • The optimal choice and duration of maintenance therapy are unknown.
  • Management strategies for specific subgroups of patients, such as those with pure membranous LN and rapidly progressive LN, should be addressed.
  • The role of novel agents such as anti-B-cell activating factor (e.g., belimumab), new generation of calcineurin inhibitors (CNIs) (e.g., voclosporin), and anti-cluster of differentiation 20 (anti-CD 20) (e.g., obinutuzumab).
  • There is a lack of consensus on treatment strategy, e.g., whether an initial combination of multiple drugs should be used or an add-on therapy when treatment is suboptimal.
  • The timing of the add-on therapy is not clear.
  • Non-immunosuppressive therapies (renal protection) and renal replacement therapy for LN will be discussed.
  • Management of CKD and other risk factors, such as blood pressure and lipids, will be included.
  • Statements on pregnancy, assisted reproduction, and contraception will be incorporated.
  • The new recommendations will include prevention and treatment of comorbidities such as infections, vascular complications, osteoporosis, etc.
  • The expert panel for developing the new guidelines will comprise an equal number of rheumatologists and nephrologists to prevent biased viewpoints due to their specialties.

Updates on new LN treatment data:

The following studies emerged after the publication of the last APLAR SLE guidelines and will be taken into consideration for formulating the LN guidelines:

  • Asian subgroup data of the 2022 BLISS-LN (belimumab) study.
  • BLISS-52, BLISS-76, subcutaneous belimumab RCT, RCT in China, South Korea, and Japan for non-renal SLE.
  • Intravenous (IV) belimumab is licensed for adult and pediatric patients with autoantibody-positive SLE that fail the standard of care (SoC).
  • Subcutaneous belimumab is licensed for adult patients with the same indication.
  • Cost-effectiveness issues for the first-line use in LN will be explored.
  • Further discussion is needed to clarify the role of belimumab in LN (e.g., initial therapy to SoC or add-on therapy), and the duration of therapy to enhance response and prevent relapse.

Other novel therapies for LN:

The following novel drugs, regimens, and aspects will be discussed:

  • Voclosporin: This has been approved by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) but is not yet available in Asia.
  • Cost-effectiveness when compared with conventional CNIs such as tacrolimus.
  • Choice of induction therapy between CYC, MMF, and CNIs.
  • The anti-CD20 drug, e.g., obinutuzumab (awaiting the phase 3 results).
  • Anifrolumab (awaiting the phase 3 results).

Draft of new statements for the LN management:

A comprehensive draft of 80 statements under the following categories has already been developed:

  • Overarching principles
  • Screening and monitoring of renal disease in SLE
  • Indications of renal biopsy
  • Histopathological assessment of renal biopsy
  • Immunosuppressive treatment of LN
  • Initial therapy and options
  • Target of therapy
  • Specific subgroups of patients
  • Patients at the risk of renal deterioration 
  • Patients with pure membranous LN with significant proteinuria
  • Maintenance therapy for LN
  • Refractory LN
  • Non-immunosuppressive therapies
  • Management of comorbidities
  • Prevention of infection complications during immunosuppressive therapies
  • Renal replacement therapies in LN
  • Reproductive issues in LN patients
  • Pregnancy and assisted reproduction
  • Contraception
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