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• Correspondance to "EULAR recommendations for the management of systemic lupus erythematosus: 2023 update"
  Benoit Suzon, Aurore Abel, Fabienne Louis-Sidney, Alexandre Karras, Florence Moinet, Cédric Aglaé, Cédric Aglaé and Christophe Deligny
  Published on: 2 January 2024
• Correspondence on "EULAR recommendations for the management of systemic lupus erythematosus: 2023 update" by "Antonis Fanouriakis, et al”"
  Zhuochao Zhou, Jingyi Wu, Chengde Yang and Junna Ye
  Published on: 2 January 2024
• Comment on the 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus by Fanouriakis, et al
  Naoto Yokogawa
  Published on: 2 January 2024
• Correspondence on “EULAR recommendations for the management of systemic lupus erythematosus: 2023 update” by “Fanouriakis A, et al”
  Hiroshi Oiwa
  Published on: 2 January 2024

• Published on: 2 January 2024

  Correspondance to "EULAR recommendations for the management of systemic lupus erythematosus: 2023 update"

  • Benoit Suzon, Internal Medicine physician Department of Internal Medicine, Martinique University Hospital
  • Other Contributors:
    • Aurore Abel, Internal Medicine physician
    • Fabienne Louis-Sidney, Rheumatology physician
    • Alexandre Karras, Nephrology physician
    • Florence Moinet, Internal Medicine physician
    • Cédric Aglaé, Nephrology physician
    • Cédric Aglaé, Nephrologist
    • Christophe Deligny, Internist

  The EULAR 2023 recommendations for the management of systemic lupus erythematosus (SLE) outline a number of principles and approaches, most of which are based on high-level evidence [1]. Indeed, numerous studies, meta-analyses and double-blind randomized controlled trials have been conducted in recent years, leading to the approval or consolidation of the use of new molecules in SLE. The expansion of the therapeutic armamentarium represents an important development for patients, with the constant aim of limiting the morbidity and mortality of SLE. This is particularly true for lupus nephritis, for which clinical trials and therapeutic innovations over the last 20 years have led to a marked improvement in prognosis.

  However, this progress needs to be tempered in certain populations where the risk of developing more severe kidney disease with poorer prognosis has long been known but still persists, and it is time to focus on these high-risk profiles. The most vulnerable population are individuals of African descent, who have the highest risk profile and the poorest long-term prognosis [2]. While socioeconomic factors and access to treatment are key determinants, other elements need to be explored to explain this risk profile. In a cohort of African-Europeans with similar access to care, long-term renal survival was significantly lower than in Caucasian patients [3]. One of the factors associated with this poor renal prognosis was the higher frequency of relapses in th...

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  The EULAR 2023 recommendations for the management of systemic lupus erythematosus (SLE) outline a number of principles and approaches, most of which are based on high-level evidence [1]. Indeed, numerous studies, meta-analyses and double-blind randomized controlled trials have been conducted in recent years, leading to the approval or consolidation of the use of new molecules in SLE. The expansion of the therapeutic armamentarium represents an important development for patients, with the constant aim of limiting the morbidity and mortality of SLE. This is particularly true for lupus nephritis, for which clinical trials and therapeutic innovations over the last 20 years have led to a marked improvement in prognosis.

  However, this progress needs to be tempered in certain populations where the risk of developing more severe kidney disease with poorer prognosis has long been known but still persists, and it is time to focus on these high-risk profiles. The most vulnerable population are individuals of African descent, who have the highest risk profile and the poorest long-term prognosis [2]. While socioeconomic factors and access to treatment are key determinants, other elements need to be explored to explain this risk profile. In a cohort of African-Europeans with similar access to care, long-term renal survival was significantly lower than in Caucasian patients [3]. One of the factors associated with this poor renal prognosis was the higher frequency of relapses in this population, raising the question of their sustained response to immunosuppressive therapy [3].

  In fact, there is no data in the literature to support superiority between drugs in individuals of African descent. The EUROLUPUS study included a very small number of patients of African descent, and the ALMS study, although including the largest number of patients of this ethnicity (46/370; 12.4%), does not allow to draw any conclusions about the superiority of mycophenolate over cyclophosphamide [4]. Although numerically superior, the difference in response rates was not statistically significant in the post hoc analysis (OR 1.8 95%CI [0.5 to 5.7], p=0.39) [5]. Here, one could argue that lack of power explains the lack of statistical significance, but is actually consistent with the need of special focus and increased inclusion in randomized clinical trials (RCTs) of these high-risk profile patients.

  Furthermore, lessons can be learned from RCTs with the recent example of belimumab, which failed to reach statistical significance on its primary endpoint in a trial specifically designed to assess its efficacy in African-Americans patients with SLE [6]. Some preliminary data have suggested ethnic differences in B Lymphocyte Stimulator levels, which may require adaptation of the treatment regimen in people of African descent [7]. Similarly, other preclinical data suggest ethnic differences in SLE pathways that may explain differences in treatment response and potentially highlight future therapeutic targets [7–9]. The prevalence and impact of high-risk apolipoprotein 1 (ApoL1) gene variants in this population, while important, should not be seen as a dead end [10], as renal inflammation can respond to immunosuppressive therapies, even among patients with these specific genetic background.

  Taken together, it is unlikely that increased enrollment of individuals of African descent in RCTs will be sufficient on its own until the potential molecular mechanisms behind the differences and excess risk in these populations are thoroughly investigated and elucidated. Given the worst outcomes of SLE and lupus nephritis among African descents, it's a safe bet that efforts to elucidate the pathophysiology of high-risk profiles will not be in vain and that the resulting therapeutic innovations will benefit to all patients, regardless of their ancestry.

  References

  1 Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2023;ard-2023-224762.
  2 Farinha F, Pepper RJ, Oliveira DG, et al. Outcomes of membranous and proliferative lupus nephritis – analysis of a single-centre cohort with more than 30 years of follow-up. Rheumatology. 2020;59:3314–23.
  3 Enfrein A, Pirson V, Le Guern V, et al. Worse long-term renal outcome of lupus nephritis patients of African descent living in Europe. RMD Open. 2022;8:e002386.
  4 Appel GB, Contreras G, Dooley MA, et al. Mycophenolate versus Cyclophosphamide for Induction Treatment of Lupus Nephritis. J Am Soc Nephrol. 2009;20:1103–12.
  5 Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology. 2010;49:128–40.
  6 Ginzler E, Guedes Barbosa LS, D’Cruz D, et al. Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022;74:112–23.
  7 Ritterhouse LL, Crowe SR, Niewold TB, et al. B lymphocyte stimulator levels in systemic lupus erythematosus: Higher circulating levels in African American patients and increased production after influenza vaccination in patients with low baseline levels. Arthritis Rheum. 2011;63:3931–41.
  8 Allen PC, Roberts K, Rubio JE, et al. Genome-wide DNA methylation analysis implicates enrichment of interferon pathway in African American patients with Systemic Lupus Erythematosus and European Americans with lupus nephritis. J Autoimmun. 2023;139:103089.
  9 Slight-Webb S, Thomas K, Smith M, et al. Ancestry-based differences in the immune phenotype are associated with lupus activity. JCI Insight. 2023;8:e169584.
  10 Freedman BI, Langefeld CD, Andringa KK, et al. End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1: APOL1 in Lupus Nephritis ESRD. Arthritis Rheumatol. 2014;66:390–6.

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  Conflict of Interest:
  Benoit Suzon : GSK, Sanofi, Otsuka, Astra-Zeneca
  
  Alexandre Karras : Vifor, GSK, Novartis, Otsuka, Astra-Zeneca, Bohringer-Ingelheim, Pfizer
  
  Christophe Deligny : Sanofi, GSK, Astra-Zeneca
  
  

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• Published on: 2 January 2024

  Correspondence on "EULAR recommendations for the management of systemic lupus erythematosus: 2023 update" by "Antonis Fanouriakis, et al”"

  • Zhuochao Zhou, Physician Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
  • Other Contributors:
    • Jingyi Wu, Medicial Student
    • Chengde Yang, Physician
    • Junna Ye, Physician

  We are thrilled and grateful to see an update of the systemic lupus erythematosus (SLE) treatment recommendations after 4 years’ time since 2019. Because of the efforts of a Task Force of world-leading SLE experts, we are now able to follow these useful recommendations in daily clinical practice. In this version, several new ideas to treat SLE come into view. We are now entering the era of biologics, with more on the way, which might significantly change the way we treat SLE. Apart from rituximab, belimumab, and anifrolumab, there is another B cell related biologic, telitacicept, a BLyS/APRIL dual inhibitor, with a successful phase II trial1; larger confirmatory trials are currently underway. As recommended in the version, early diagnosis and treatment are emphasized. The biologics are used earlier than before, not requiring conventional immunosuppresants first; this change is a bit step forward, indicating that early intervention is important.

  The treatment of SLE is like walking on a blade. Balancing the benefits and harms is an art, for which the use of glucocorticoids (GC) is a typical example. I totally agree that the use of GC is only for ‘bridging therapy’ in SLE. But we can expect that, different from the treatment of rheumatoid arthritis (RA), the taper of GC in SLE is not as easy as in RA and the duration will be longer. In this recommendation, it is clearly stated that GC should be taped gradually. However, in terms of the cessation of GC, it is not clear...

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  We are thrilled and grateful to see an update of the systemic lupus erythematosus (SLE) treatment recommendations after 4 years’ time since 2019. Because of the efforts of a Task Force of world-leading SLE experts, we are now able to follow these useful recommendations in daily clinical practice. In this version, several new ideas to treat SLE come into view. We are now entering the era of biologics, with more on the way, which might significantly change the way we treat SLE. Apart from rituximab, belimumab, and anifrolumab, there is another B cell related biologic, telitacicept, a BLyS/APRIL dual inhibitor, with a successful phase II trial1; larger confirmatory trials are currently underway. As recommended in the version, early diagnosis and treatment are emphasized. The biologics are used earlier than before, not requiring conventional immunosuppresants first; this change is a bit step forward, indicating that early intervention is important.

  The treatment of SLE is like walking on a blade. Balancing the benefits and harms is an art, for which the use of glucocorticoids (GC) is a typical example. I totally agree that the use of GC is only for ‘bridging therapy’ in SLE. But we can expect that, different from the treatment of rheumatoid arthritis (RA), the taper of GC in SLE is not as easy as in RA and the duration will be longer. In this recommendation, it is clearly stated that GC should be taped gradually. However, in terms of the cessation of GC, it is not clear when, during clinical remission, GC can be stopped completely. Moreover, the GC dose is recommended to be lower than 5mg, but evidence is still scarce. In the 2019 recommendation, GC dose is recommended as lower than 7.5mg. In the future, is it possible that the dose of GC will fall to even less? As new drugs continue to appear, complete remission without GC might not be a dream.

  In the treatment of thrombocytopenia, tacrolimus (TAC) and sirolimus were also reported 2,3. Moreover, recombinant human thrombopoietin can also be used as adjunct treatment4. Regarding the treatment of lupus nephritis (LN), the initial dose of GC in China, 1mg/kg/day of GC, is widely used and 250-1000mg/day as a pulse dose is not commonly used. Is 1mg/kg/day also an acceptable dose in new-onset LN? In figure 1, it is a question whether a calcineurin inhibitor such as TAC can be used as a second line treatment of mild disease, similar to mycophenolate mofetil, azathioprine, methotrexate. In clinical practice, it is also a commonly used regime, not only used in LN.

  In this version, fatigue, non-inflammatory pain, mood disturbance and cognitive dysfunction, which are widely reported by the patients, were considered. More studies are needed to help patients obtain relief from these symptoms.

  References:
  1.Sohita Dhillon.Telitacicept: First Approval.Drugs.2021 Sep;81(14):1671-1675.
  2.Y Li, X Feng.Efficacy and safety of tacrolimus in systemic lupus erythematosus patients with refractory thrombocytopenia: a retrospective study.Lupus. 2018 Jan;27(1):60-65.
  3.Chanyuan Wu, Qian Wang, Dong Xu,et al. Sirolimus for patients with connective tissue disease-related refractory thrombocytopenia: a single-arm, open-label clinical trial.Rheumatology (Oxford). 2021 Jun 18;60(6):2629-2634.
  4.Yafei Yu, Yu Hou, Yajing Zhao,et al.Platelet autoantibody specificity and response to rhTPO treatment in patients with primary immune thrombocytopenia.Br J Haematol. 2021 Jul;194(1):191-194.

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  Conflict of Interest:
  None declared.

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• Published on: 2 January 2024

  Comment on the 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus by Fanouriakis, et al

  • Naoto Yokogawa, Rheumatologist Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Fuchu, Tokyo, Japan

  Dear Editor,

  The 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus (SLE) recommend hydroxychloroquine (HCQ) for all patients with SLE at a target dose of 5 mg/kg real body weight (RBW)/day but also suggest individualizing the regimen in accordance with the risk of flares or retinal toxicity. The updated recommendations also emphasize the importance of non-pharmacological interventions, including the cessation of smoking, which may interfere with the efficacy of antimalarial agents, as seen in patients with cutaneous lupus erythematosus (CLE). 1 However, the evidence on the efficacy of the target dose of 5 mg/kg(RBW)/day and the effect of smoking on SLE is scarce.

  In Japan, HCQ was approved in 2015 after a double-blind randomized clinical trial demonstrated a favorable effect on CLE. The approved dosage was based on 6.5 mg/kg of ideal body weight (IBW), namely, 200 mg/day for IBW ˂46 kg; 200 mg and 400 mg on alternating days for IBW ≥ 46 kg and ˂ 62 kg; and 400 mg/day for IBW ≥62 kg. The steady-state maximum whole blood HCQ level (ng/ml) at these dosages were simulated with 630.3±220.4, 942.7±191.2 and 850.3±174.5, respectively.23 Thereafter, a multicentric, prospective study evaluating the effect of HCQ on SLE and CLE in the real world setting was conducted for post-marketing surveillance in accordance with the Good Post-Marketing Study ordinance of the Ministry of Health, Labour and Welfare of Japan. 4

  The ob...

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  Dear Editor,

  The 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus (SLE) recommend hydroxychloroquine (HCQ) for all patients with SLE at a target dose of 5 mg/kg real body weight (RBW)/day but also suggest individualizing the regimen in accordance with the risk of flares or retinal toxicity. The updated recommendations also emphasize the importance of non-pharmacological interventions, including the cessation of smoking, which may interfere with the efficacy of antimalarial agents, as seen in patients with cutaneous lupus erythematosus (CLE). 1 However, the evidence on the efficacy of the target dose of 5 mg/kg(RBW)/day and the effect of smoking on SLE is scarce.

  In Japan, HCQ was approved in 2015 after a double-blind randomized clinical trial demonstrated a favorable effect on CLE. The approved dosage was based on 6.5 mg/kg of ideal body weight (IBW), namely, 200 mg/day for IBW ˂46 kg; 200 mg and 400 mg on alternating days for IBW ≥ 46 kg and ˂ 62 kg; and 400 mg/day for IBW ≥62 kg. The steady-state maximum whole blood HCQ level (ng/ml) at these dosages were simulated with 630.3±220.4, 942.7±191.2 and 850.3±174.5, respectively.23 Thereafter, a multicentric, prospective study evaluating the effect of HCQ on SLE and CLE in the real world setting was conducted for post-marketing surveillance in accordance with the Good Post-Marketing Study ordinance of the Ministry of Health, Labour and Welfare of Japan. 4

  The observation period for effectiveness was one year. The physician and patient used a seven-point scale consisting of the eight categories, “remarkably improved,” “improved,” “slightly improved,” “not changed,” “slightly aggravated,” “aggravated,” “remarkably aggravated,” and “unable to be evaluated” to assess skin manifestations while the physician assessed the other clinical symptoms. The responses, “remarkably improved” and “improved” indicated good treatment efficacy. Patients with SLE with non-dermatological, clinical symptoms then used the visual analog scale (VAS: 0-10) to evaluate fatigue and musculoskeletal pain.

  In total, 1142 patients comprising the safety analysis population received a mean HCQ dosage of 4.9±1.2 mg/kg (RBW)/day. Throughout the period, the physician found drug adherence to be “as prescribed（75％ or higher）” in 94.3％ of the patients.

  In a cohort consisting of 75 CLE patients and 385 SLE patients with skin manifestations at baseline, physicians judged the treatment to be effective in 49.3% (remarkably improved: 13.9%, improved: 35.4%, slightly improved: 21.3%, unchanged: 27.4%, slightly aggravated: 0.9%, aggravated: 1.1%, remarkably aggravated: 0%). Multivariate analysis produced an odds ratio (OR) (95% confidence interval) of 0.315 (0.139-0.716) and 0.547 (0.295-1.017) for current smoking habit and lower-than-approved dosage, respectively, and 48.7% of the patients judged the treatment to be effective (remarkably improved: 13.0%, improved: 35.7%, slightly improved: 18.9%, unchanged: 29.8%, slightly aggravated: 1.5%, aggravated: 0.9%, remarkably aggravated: 0.2%). Multivariate analysis produced an OR of 0.369 (0.167-0.819) and 0.533 (0.287-0.991) for current smoking habit and lower-than-approved dosage, respectively.

  In the cohort of 872 SLE patients with clinical symptoms other than skin manifestations at baseline, physicians judged the treatment to be effective in 37.8% (remarkably improved: 4.8%, improved: 33.0%, slightly improved: 20.2%, unchanged: 38.5%, slightly aggravated: 1.5%, aggravated: 1.6%, remarkably aggravated: 0.3%). On multivariate analysis, the OR for current smoking habit and lower-than-approved dosage was 0.413 (0.215-0.793) and 0.587 (0.379-0.909), respectively. The patients’ VAS for fatigue and musculoskeletal pain decreased from 3.13±2.75 to 1.85±2.25 (p<0.0001) and from 2.76±2.70 to 1.56±2.09 (p<0.0001), respectively.

  These results support the 2023 update of the EULAR recommendations regarding the use of HCQ at the target dosage of 5 mg/kg (RBW)/day and the importance of the non-pharmacological intervention of smoking cessation in the management of SLE.

  References:
  1. Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Annals of the rheumatic diseases 2023:ard-2023-224762. doi: 10.1136/ard-2023-224762
  2. Yokogawa N, Eto H, Tanikawa A, et al. Effects of Hydroxychloroquine in Patients With Cutaneous Lupus Erythematosus: A Multicenter, Double-Blind, Randomized, Parallel-Group Trial. Arthritis & rheumatology (Hoboken, NJ) 2017;69(4):791-99. doi: 10.1002/art.40018 [published Online First: 2016/12/20]
  3. Morita S, Takahashi T, Yoshida Y, et al. Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients With Cutaneous or Systemic Lupus Erythematosus. Therapeutic drug monitoring 2016;38(2):259-67. doi: 10.1097/ftd.0000000000000261
  4. Tomura A, et al. Safety and effectiveness of hydroxychloroquine in Japanese people with cutaneous lupus erythematosus and systemic lupus erythematosus:results of a drug use–results survey. Therapeutic Research 2022;43(10):817-42.

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  Conflict of Interest:
  I received lecture fees from AbbVie, BMS, Chugai, GSK, Mitsubishi-Tanabe, Ono, and Asahikasei.

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• Published on: 2 January 2024

  Correspondence on “EULAR recommendations for the management of systemic lupus erythematosus: 2023 update” by “Fanouriakis A, et al”

  • Hiroshi Oiwa, Rheumatologist Hiroshima City Hiroshima Citizens Hospital

  Correspondence on “EULAR recommendations for the management of systemic lupus erythematosus: 2023 update” by “Fanouriakis A, et al”

  I read the recently updated EULAR recommendations for the management of systemic lupus erythematosus (SLE) with great interest.[1] In recommendation 8, voclosporine was categorized alongside belimumab and tacrolimus. However, I am concerned about recommending voclosporine as an initial induction therapy for active lupus nephritis (LN).
  The effectiveness of voclosporine, when added to a rapid-reduction glucocorticoid regimen and mycophenolate (MMF, typically administered at 2 g/day), has been demonstrated to be superior to placebo.[2] However, it is important to note that this study significantly deviated from the trials involving belimumab or tacrolimus[3, 4] as it included a large number of patients who were refractory to MMF. This indicates that 55% of the participants while taking MMF, met one of the inclusion criteria: a current urine protein creatinine ratio (UPCR) of ≥1·5. These individuals were then randomised to either the placebo or voclosporine group. Patients with these specific characteristics, if placed in the placebo group, would have been reintroduced to MMF, despite its previous ineffectiveness in addressing their lupus nephritis. Therefore, the treatment effect in the placebo group was assumed to be considerably lower. As expected, the efficacy of incorporating voclosporine was observed solely in the patient group...

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  Correspondence on “EULAR recommendations for the management of systemic lupus erythematosus: 2023 update” by “Fanouriakis A, et al”

  I read the recently updated EULAR recommendations for the management of systemic lupus erythematosus (SLE) with great interest.[1] In recommendation 8, voclosporine was categorized alongside belimumab and tacrolimus. However, I am concerned about recommending voclosporine as an initial induction therapy for active lupus nephritis (LN).
  The effectiveness of voclosporine, when added to a rapid-reduction glucocorticoid regimen and mycophenolate (MMF, typically administered at 2 g/day), has been demonstrated to be superior to placebo.[2] However, it is important to note that this study significantly deviated from the trials involving belimumab or tacrolimus[3, 4] as it included a large number of patients who were refractory to MMF. This indicates that 55% of the participants while taking MMF, met one of the inclusion criteria: a current urine protein creatinine ratio (UPCR) of ≥1·5. These individuals were then randomised to either the placebo or voclosporine group. Patients with these specific characteristics, if placed in the placebo group, would have been reintroduced to MMF, despite its previous ineffectiveness in addressing their lupus nephritis. Therefore, the treatment effect in the placebo group was assumed to be considerably lower. As expected, the efficacy of incorporating voclosporine was observed solely in the patient group that had undergone MMF treatment at the time of screening. In contrast, there was no significant improvement in the group of patients who had not received MMF previously (i.e. those who were treatment-naïve cases or cases treated with agents other than MMF). Furthermore, the add-on effect of voclosporine was significant in the subgroup that received an MMF dose of ≤2g/day during the trial, but not in the subgroup receiving a dose of >2g/day. [2] These results suggest that the add-on effect of voclosporine, when compared with the current standard of care (SOC) comprising MMF (target dose: 2 to 3 g/day) and glucocorticoids, remains to be fully elucidated.[5]
  Conversely, the efficacy of belimumab when added to the current SOC was investigated, regardless of whether it included MMF or intravenous cyclophosphamide.[3] Regarding the inclusion criteria, individuals with prior MMF or cyclophosphamide use could be considered eligible, but the investigators retained the authority to select the immunosuppressive agents for induction therapy. The primary efficacy renal response (PERR) at both 1 and 2 years was significantly higher in the belimumab group than in the placebo group. In subgroup analyses, the efficacy of belimumab was particularly evident in relapsing cases (odds ratio of PERR at 2 years, 2.31 [95% confidence interval, 1.07 – 5.01]).[6] However, for newly diagnosed cases, the efficacy exhibited only a non-significant trend (odds ratio of 1.36 [0.85 – 2.20]). Nevertheless, belimumab lowered the hazard ratio (HR) for kidney-related events or death not only in the relapsing cases but also in the newly diagnosed cases [0.47 (95% CI 0.23 – 0.95) and 0.55 (0.33–0.93), respectively]. These results suggest that compared to the current SOC, the incorporation of belimumab in the SOC presents specific advantages in both the relapsing and newly diagnosed cases.
  Taken together, we believe that combination therapy with belimumab (in conjunction with either cyclophosphamide or MMF) could be a viable option for initial induction therapy in cases of active proliferative lupus nephritis. However, combination therapy with voclosporine and MMF should be reserved exclusively for patients who remain refractory or resistant to the SOC.

  Reference
  1 Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis 2023. doi: 10.1136/ard-2023-224762.
  2 Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2021;397:2070–80.
  3 Furie R, Rovin BH, Houssiau F, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med 2020;383:1117–28.
  4 Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med 2015;162:18–26.
  5 Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis 2020 Jun;79:713–23.
  6 Anders HJ, Furie R, Malvar A, et al. Effect of belimumab on kidney-related outcomes in patients with lupus nephritis: post hoc subgroup analyses of the phase 3 BLISS-LN trial. Nephrol Dial Transplant 2023. doi: 10.1093/ndt/gfad167.

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  Conflict of Interest:
  I have received lecture fees from GlaxoSmithKline, Astrazeneca, Astellas Pharma Inc. and Chugai pharmaceutical company.

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