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סקירה

Systemic lupus erythematosus: Highlights from EULAR 2021 virtual conference

The purpose of this letter is to summarize the news regarding systemic lupus erythematosus (SLE). The virtual conference included symposiums, oral presentations and posters

by Dr. Amir Sharabi, M.D., Ph.D. Senior Rheumatologist, Rabin Medical Center, Petach-Tikva, Senior Lecturer, Department of Microbiology & Immunology, Sackler Faculty of Medicine, Tel-Aviv University

Sponsored by AstraZeneca.

The EULAR 2021 was conducted virtually because of the COVID-19 pandemic. The purpose of this letter is to summarize the news regarding systemic lupus erythematosus (SLE). The virtual conference included symposiums, oral presentations and posters.

1. Symposiums

Two main, interesting subjects were raised among the symposium and oral presentations. First, the definition of remission in SLE, and second-optimizing the treatment of SLE.

Prof. Ronald van Vollenhoven (Amsterdam UMC) [1]. showed data to reflect that basically rheumatologists treat SLE  "o.k." but that this could be improved by using better medications and  better use of  existing therapies. As in other rheumatic diseases he pointed out that we should aim at "treat to target" strategy (T2T), with the target being the achievement of remission. A consensus for remission definition has been the subject of the DORIS project. Accordingly, the 2021 definition of remission is based on 2 parameters: clinical SLEDAI = 0 (e.g., SLEDAI that excludes anti-dsDNA antibodies and complement) together with physician global assessment (PGA) score below 0.5 (on a scale of 0-3), and with allowing current treatment with anti-malarials, up to 5 mg/day prednisone and stable immunosuppressive or biologics medications.

On another session, Prof. Maria Dall'Era (University of California, San-Franscisco)new potential therapies for SLE were reviewed at   [2].  reviewed . Belimumab is FDA approved medication for treating active SLE as well as active lupus nephritis. Belimumab is currently studied as combination treatment with rituximab in the BLISS-BELIEVE phase 3 study that recruited 200 patients. Anifrolumab and baricitinib are both in advanced stages of study before their approval for treating SLE. TULIP 1 and 2 clinical trials showed superiority of anifrolumab treatment over placebo on achieving BICLA response at week 52, as well as sustained steroid-sparing capacity during week 40 until week 52. A phase 2 clinical trial with baricitinib showed superiority over placebo on alleviating SLE-related rash and arthritis, and on achieving SRI-4 response. Phase 3 clinical trial of baricitinib still on going.

2. Oral and poster presentations

Different types of medications in clinical development for SLE were presented. Some of the data was based on post-hoc analysis and some data was based on reports from clinical trials that have been completed. This is a summary of most of SLE-related therapies that were presented in EULAR 2021.

Type I Interferons (IFNs)

Anifrolumab is a human monoclonal antibody against the type I IFN receptor subunit 1. It was shown that treatment with i.v. anifrolumab 300 mg every 4 weeks in compare with placebo ameliorated the skin and joint manifestations in SLE  in phase 2 (MUSE) and phase 3 (TULIP 1 & 2) clinical trials of 52-week duration. Prof. Joan Merrill presented pooled data from the phase 3 trials, which established further the involvement of type I IFN pathway in SLE [3]. The treatment groups, anifrolumab and placebo, included about 360 patients, of which high- and low-IFNG signatures were determined among 300 patients and 60 patients, respectively. In compare with placebo, treatment with anifrolumab improved the rash and arthritis  in all patients based on different outcome scores, including SLEDAI-2K, BILAG-2004, and mCLASI, starting from week 12. These results were mostly seen in the high-IFNG signature patients, but may also be beneficial in the low-IFNG signature subset.

Evaluation of the effects of anifrolumab on disease activity was studied in a post-hoc analysis of data derived from the phase 3 trials TULIP 1 & 2 and the phase 2b trial MUSE studying patients with moderate to severe SLE [4]. Evaluation of disease activity was based on strict criteria that would reflect low disease activity, flare prevention, and adherence to the lowest possible dose of steroids. They used a novel endpoint that requires both BICLA and SLE Responder Index (SRI)-4 responses. Specifically, they defined 5 novel stringent BICLA-based endpoints: (1) BICLA at week 52 and with sustained steroids taper, or with (2) no flares, or with (3) sustained steroids taper and no flares, (4) complete resolution BICLA, and (5) dual BICLA and SRI-4 response. The study demostrated that anifrolumab over placebo achieved better scores for all 5 domains including the complete resolution BICLA response, as observed from week 32 and sustained through week 52.

The potential therapeutic effects of anifrolumab on renal disease in patients with SLE was studied in a post-hoc analysis of data derived from TULIP 1 & 2 trials [5]. Although these studies excluded patients with SLE who have had severe active renal disease (LN), a subgroup of patients (n=99) had renal involvement at baseline,  57 of them had UPCR above 0.5 mg/mg, 24 patients in the anifrolumab treatment group, and 33 patients in the placebo group. Patients with renal involvement were more likely to be younger, male, Asian, and with high-INFG signature. They exhibited a high disease activity state, low complement, and received GC at a dose of 10 mg/day or above and MMF at baseline. The post-hoc analysis showed that treatment with anifrolumab was associated with numeric improvements versus placebo in the following parameters: cumulative UPCR (217 versus 271 AUC units, respectively), UPCR below 0.5 mg/mg (41% versus 36%, respectively), renal remission (24% versus 19%), and renal flares (5% versus 7.4 %) at week 52. In addition, cumulative GC use was numerically lower, and improvement in C3 and C4 levels were numerically greater with anifrolumab versus placebo regardless of renal involvement.

The efficacy and safety  of anifrolumab were studied in a randomized, double-blind  placebo controlled, phase 2 (TULIP-LN) trial in patients with active proliferative lupus nephritis [6]. The study included patients with biopsy-proven diagnosis of class III or IV (with or without class V) LN within 3 months of screening, 24h UPCR above 1 mg/mg, eGFR above 35 mL/min/1.73 m2, and fulfilled ACR SLE 1997 criteria, including serological positivity at screening. The trial was conducted  in 16 countries, 338 patients were screened, of whom 147 were randomized to receive anifrolumab either as basic regimen of 300 mg IV Q4W (BR, n=45) , or as intensified regimen of 900 mg for 3 doses followed by 300 mg IV Q4W (IR, n=51) , added to standard therapy (target MMF 2g/day by W8 and with oral GC taper target below 7.5 mg/d by W24) versus placebo (n=49). About 70% of patients completed the first year of investigational product. . The primary endpoint was defined as relative difference in change from baseline to week 52 in 24h UPCR for combined anifrolumab (IR plus BR) versus placebo, measured with a geometric mean ratio (GMR, <1 favors anifrolumab). The primary endpoint was not met. However, there were numerical improvements over placebo in mean 24h UPCR in both anifrolumab groups at week 12 and week 24, and for the anifrolumab IR group at week 36. The partial therapeutic effects of anifrolumab are explained, in part, by the suboptimal PK exposure of anifrolumab BR in compare with IR (8.2 versus 63.4 microg/mL), and lack of sustained PD neutralization >80%. Thus, when anifrolumab IR was compared with placebo at week 52, there were numerical improvements over placebo in complete renal response (CRR), oral GC reductions, SLEDAI-2K (-2.6 vs -1.3), PGA (-0.98 vs -0.66), and PtGA (-16.7 vs -8.7). There were also numerical improvements in C3 if low at baseline, and reductions in anti-dsDNA (median change -73.2 vs -11 U/mL). Most adverse events were non-serious and did not lead to discontinuation. Herpes zoster was more common in anifrolumab versus placebo groups. The TULIP-LN results support further study of anifrolumab IR in patients with active, proliferative LN.

Plasmacytoid dendritic cell (pDC)

BIIB059 is a humanized monoclonal antibody that targets blood dendritic cell antigen 2 (BDCA2), a plasmacytoid DC (pDC)-specific receptor. pDCs produce and secrete type I interferons and other inflammatory mediators that are implicated in SLE pathology. Thus, the binding of BIIB059 to this receptor results in a rapid internalization of BDCA2 from the surface of pDC, and the inhibition of type I interferons, cytokine, and chemokine production. The therapeutic effects of BIIB059 on patients with SLE were studied in LILAC phase 2 trial [7]. Most of the patients were female at the age of 40 years, half being of Asian and White ethnicity, with 8 years of disease duration, and 80% having a high-IFNGS signature. In part A of this trial the patients received either SC BIIB059 450 mg or placebo, every 4 weeks for 20 weeks, with an additional dose at week 2. The primary endpoint was the proportion of participants who achieved an SRI-4 response at week 24 for the BIIB059 450 mg group versus placebo group. SRI-4 response is defined as reduction from baseline of at least 4 points in SLEDAI-2K, no new BILAG-2004 A, one or less new B domain score, no worsening from baseline PGA, and no violation of protocol-specified medication rules. Sixty-four patients were treated with BIIB059, and 56 patients received placebo. About 90% completed the study. SRI-4 response was achieved in higher rates in BIIB059 group, with significant differences achieved at weeks 20 and 24, with odds ratio 3.05 (p=0.008) and 3.49 (p=0.003), respectively. Adverse events were similar between the BIIB059 and placebo. BIIB059 450 mg was well tolerated with no apparent increased risk of infections.

Antigen-presenting cell co-stimulation

BI 655064 is a second-generation anti-CD40, humanized antagonistic antibody that inhibits the CD40-CD40L interaction. Its Fc region includes two mutations that prevent Fc-mediated antibody-dependent, complement-mediated cytotoxicity, and platelet activation. It was thought that inhibition of T cell co-stimulation would alleviate lupus nephritis. In a phase 2 proof-of-concept trial, patients with lupus nephritis were recruited from 74 sites across 20 countries [8]. Most patients were female at their early 30s'. A number of 121 patients were randomized in a 2:1:1:2 ratio to placebo, BI 655064 120 mg, 180 mg, or 240 mg. All patients received standard of care, e.g. MMF 2-3 g/day, and pulse steroids followed by oral prednisone tapered below 10 mg within 12 weeks. The primary endpoint of complete renal response at week 52 was not met. However, numerical improvements in a CRR based on 24h urine collection at week 26 was achieved in 50% among BI 655064 180 mg and 37.5% among placebo. Further, BI 655064 180 mg treatment group was the only group with a higher proportion of patients achieving a CRR or PRR than the placebo group after both 26 and 52 weeks of treatment. Also, based on spot urine, a higher proportion of CRR was achieved with BI 655064 180 mg and 240 mg groups than in the placebo group. There were significant decreases in select activated memory B-cell subsets in BI 655064 180 mg and 240 mg versus placebo at week 12 and 26 post treatment. About 20% discontinued the trial mostly because of adverse events. There were no safety issues with the BI655064 180 mg group but there were more serious and severe infections and more decreases in neutrophil counts with 240 mg group. Second year treatment of responders is ongoing.

B cell lymphocytes

Belimumab is a human monoclonal antibody that inhibits B-cell activating factor (BAFF, BlyS), and is approved for treating SLE. Here, the real-life efficacy and safety of belimumab in patients with lupus nephritis is reported [9]. The patients were from a multicentre Italian cohort of SLE (BeRLiSS study) having proteinuria >0.5g/24 h and/or active sediment were enrolled to be treated with iv belimumab 10 mg/kg plus standard of care. Primary efficacy renal response was defined as proteinuria <0.7 g/24h, eGFR>60, and no rescue therapy. They screened 91 patients. Their mean age was 40 years and with mean disease duration of 12 years, and a median follow-up after belimumab initiation of 22 months. During the follow-up period 37% achieved CRR in a mean time of ~10 months, and ~85% maintained remission. Thus, belimumab is an effective add-on therapy in the treatment of GN in real-life practicing setting.

Small molecules

Baricitinib is an oral selective JAK1 and JAK2 inhibitor that is approved for the treatment of rheumatoid arthritis. Recently, baricitinib has met its primary endpoint and was shown to improve disease severity (rash and arthritis based on SLEDAI-2K) in adults with SLE receiving standard treatment in a phase 2 trial. In the current phase 2 randomized clinical trial the median change in serological biomarkers, in addition to SRI-4 response was evaluated in patients with normalization of anti-dsDNA by week 24 [10]. The patients recruited were mostly female with mean age of 43-45 years and a disease duration of about 10 years, with SLEDAI-2K score of ~8, BILAG-2004 1A or 2B (in 56-69% of patients), and positivity for anti-dsDNA (in ~50% of patients). Among patients with anti-dsDNA >30 IU/mL treatment with baricitinib 2 mg and 4 mg significantly decreased the median antibody levels compared to placebo, beginning at weeks 2 and 4, which were sustained through week 24. Similarly, decreases from baseline high levels of anti-Sm, IgG, and anti-cardiolipin IgM were achieved with baricitinib 4 mg. Thus, it is suggested that baricitinib may also have an effect on B cell activity in SLE.

References:

1. Symposium: Treating SLE to target: remission or low disease activity?

2. Symposium: Astra Zeneca – Transforming SLE: optimizing care for patients with lupus

3. Merrill JT et al. OP 0131: Anifrolumab Effects on Rash and Arthritis in Patients With SLE and Impact of Interferon Signal in Pooled Data From Phase 3 Trials.

4. Isenberg DA et al. POS 0683: Novel stringent outcome measures applied to the phase 2 and 3 anifrolumab trials.

5. Morand EF et al. POS 0691: Effects of anifrolumab on renal disease in patients with SLE.

6. Jayne D et al. POS 0690: Randomized, controlled, phase 2 trial of type I IFN inhibitor anifrolumab in patients with active proliferative lupus nephritis.

7. van Vollenhoven RF et al. POS 0698: BIIB059 demonstrated a consistent therapeutic effect on SRI-4 response across subgroups of participants with systemic lupus erythematosus in the LILAC PHASE 2 study.

8. Jayne DR et al. POS 0687: A randomized dose ranging, placebo-controlled, phase II study assessing the efficacy and safety of BI 655064, an antagonistic anti-CD40 antibody, in patients with lupus nephritis.

9. Saccon F et al. POS 0693: Efficacy and Safety of Belimumab in patients with Lupus Nephritis in Real-Life setting: results from a large, nationwide, multicentric, prospective cohort.

10. Dorner T et al. POS 0686: Baricitinib decreases anti-dsDNA and IgG antibodies in adults with systemic lupus erythematosus from a phase 2 double-blind, randomized, placebo-controlled trial.

IL2048

נושאים קשורים:  סקירה,  EULAR,  זאבת