The article by Tani et al, “Anifrolumab in Refractory Systemic Lupus Erythematosus: A Real-World, Multicenter Study,”1 evaluates the efficacy of anifrolumab (ANI) in patients with systemic lupus erythematosus (SLE) who failed to respond to other treatments, including biologics.

There are many unmet needs in the treatment of SLE. Despite recent advances, remission and low disease activity (LDA) rates remain suboptimal; therefore, some patients with SLE are at high risk of developing endstage renal disease, organ damage, drug-related toxicities—particularly related to the prolonged use of glucocorticoids (GCs)—and premature mortality.2-4 The introduction of biologics (belimumab and ANI) in the European Alliance of Associations for Rheumatology (EULAR) recommendations for the management of nonrenal SLE5 challenges the rheumatologic community to adopt a paradigm shift in how they approach treatment. Also, the management of lupus nephritis (LN) has witnessed important advances with the approval of belimumab and voclosporin, a new calcineurin inhibitor. Consequently, there is a gradual transition from the traditional induction-maintenance regimen to the early use of combination therapies for LN, including immunosuppressants and biologics for patients with moderate or even mild disease.5 However, tools that would allow us to make better therapeutic decisions based on precision medicine without risk of overtreatment, which exposes patients to greater risks and higher costs without sufficient clinical benefit, are still lacking. Other unanswered questions remain: What is the optimal profile of patients who require combination therapy from the outset? Which patients will develop flares? Can we foresee treatment refractoriness? Precise indicators for using combinations of immunosuppressants are still unavailable. Other important points to consider are the differences in access and costs of these treatments, which introduce inequities, particularly in some low- and middle-income countries. We wonder if we will be able to treat our patients adequately worldwide.

Currently, due to the limited efficacy of currently available therapies, especially given SLE’s severe manifestations and refractoriness to standard of care therapy, the treatment of SLE is challenging. This is well exemplified by the high failure rates to achieve remission or LDA, as observed in several studies worldwide. For example, in a 7-year follow-up study of patients with SLE in Padua, Italy, only 9.2%, 16%, 15.4%, 8.9%, and 38.6% achieved remission for 1, 2, 3, 4 and ≥ 5 consecutive years, respectively; further, 12% of these patients never achieved remission.6 In the original Latin American Group for the Study of Lupus (GLADEL) cohort, more than 60% of the patients were not optimally controlled at cohort entry, and among them, only 21.7% and 34.8% achieved remission and LDA state, respectively, 5 years later.7 Similarly, in the multinational, multiethnic inception Systemic Lupus International Collaborative Clinics (SLICC) cohort, only 20.9%, 19.8%, and 10% of the patients achieved remission off-treatment, remission on-treatment, and LDA, respectively, over 7 years of follow-up.8 Taking all these data into account, approximately 45% to 50% of patients with SLE treated conventionally exhibit persistent disease activity over time, highlighting the need for more effective therapeutic options for these patients. Faced with these unmet needs and with the purpose of trying to answer the above questions, we welcome the publication of the real-world study by Tani et al,1 which should help physicians taking care of patients with SLE gain a better understanding of the role of biologics in the treatment of these patients.

Over the past few years, the type 1 interferon (IFN) pathway has become increasingly recognized for its role in the pathogenesis of SLE9; thus, it has emerged as a significant therapeutic target.10,11 ANI is a human monoclonal antibody against the type I IFN receptor subunit1,12 that is approved for moderate to severe active autoantibody-positive SLE in adult patients, in combination with standard of care, in the United States (Food and Drug Administration; as of July 2021)13 and Europe (European Medicines Agency; as of February 2022).14 In the study by Tani et al,1 26 refractory patients with SLE from 9 Italian centers were treated with ANI under compassionate care. Clinical data, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), Systemic Lupus Erythematosus–Disease Activity Score (SLE-DAS), joint and skin involvement by the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)-activity and CLASI-damage, prednisone dose, and physician global assessment (PGA) were examined at baseline, 1 month, and quarterly thereafter, for a median follow-up time of 36 weeks. The authors also assessed the attainment of remission (using the definition of remission in SLE [DORIS]) and LDA state (using the Lupus Low Disease Activity State [LLDAS]), along with the occurrence of adverse events. To date, this is the largest real-world study, to our knowledge, supporting the efficacy of ANI not only for skin and joint involvement but also for achieving remission in patients with SLE.

One of the important issues to consider in a real-world analysis of patients with SLE is their racial and ethnic distribution. In the study by Tani et al,1 92% of the patients were White, which raises important questions about the generalizability of the results to other groups, such as Latin American ethnic groups. Given that Mestizo patients have a high frequency of IFN-expressing genes, we would expect them to respond even better to ANI than White patients with SLE, as in the study by Tani et al.1 Mestizo patients in Latin America are a heterogeneous group of people with a complex mix of Amerindian, European, African, and Asian ancestries, resulting from their diverse geographic origins and individual lineages. Alarcón-Riquelme et al have described that patients of Amerindian ancestry present a strong association with the TNPO3-IRF5 locus. IRF5 is a transcription factor involved in type I IFN production and proinflammatory signaling.15 In addition, in the study by Vital et al, a post hoc analysis of the phase III Treatment of Uncontrolled Lupus From the Interferon Pathway (TULIP)-1 and TULIP-2 studies, British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) responses, oral GC reduction, annualized flare rate, and CLASI response were higher in patients with high type I IFN gene signature (IFNGS) than in patients with low type I IFNGS.16 In light of these ethnic differences, in the future, will we be able to guide ANI treatment for patients with SLE with cutaneous, joint, and hematologic involvement using IFNGS, particularly in some ethnic groups such as Mestizo individuals?

Regarding ANI’s efficacy, Tani et al found a significant decrease in SLEDAI-2K, SLE-DAS, and PGA as early as 4 weeks after treatment initiation, which was sustained during follow-up. They also found a significant reduction in CLASI activity, in tender and swollen joint counts, and in the mean daily dose of GCs. These results are in agreement with those obtained in the TULIP-2 study.17 As previously mentioned, we know that the possibility of achieving remission or LLDAS is limited in patients with SLE with the therapeutic options we presently have. Therefore, we must emphasize that 33% of the patients reached a remission state and 46% were in LLDAS at 3 months, whereas at 6 months, 50% were in remission and 80% were in LLDAS. These results are promising and suggest a specific indication for ANI in patients who require a rapid response to their cutaneous and articular manifestations. In the EULAR 2023 recommendations, no hierarchy in the choice between ANI and belimumab was suggested, as both drugs have not been compared in a head-to-head clinical trial and their approval was the result of randomized controlled trials in similar extrarenal SLE populations. However, most panelists agreed that previous use of a conventional immunosuppressive drug should not be mandatory for initiating treatment with either ANI or belimumab.5 Given the prompt response to ANI, we can ask ourselves: At what point in the course of the disease should we use it? Early, from mild involvement, or later, in patients refractory to other conventional immunosuppressive drugs?

On the other hand, although most of the patients in the study by Tani et al1 had cutaneous and articular involvement, there were also 9 patients with LN (35%), of which 7 were biopsy-proven and 2 were based on persistent proteinuria without other reasonable causes, as well as 3 patients with neuropsychiatric involvement (12%). It is noteworthy that in the phase III studies (TULIP-1 and TULIP-2), patients with active severe LN or neuropsychiatric SLE were excluded.12,17 An elevated type I IFNGS has been proven to be present in > 80% of patients with LN and is associated with active renal disease and risk of treatment failure.18,19 In the phase II TULIP-LN study, Jayne et al evaluated the efficacy of ANI in active class III/IV LN.20 In this trial, the primary endpoint was not met at week 52, as the mean urine protein-creatinine ratios at 24 hours improved from baseline by 69% and 70% in the ANI and placebo groups, respectively. However, more patients also achieved sustained oral GC dose reduction and complete renal response with the ANI intensified regimen (900 mg × 3, 300 mg thereafter) vs placebo. These results support further assessment of the efficacy and safety of ANI in patients with active LN. The phase III trial, Study of Anifrolumab in Adult Patients With Active Proliferative Lupus Nephritis (IRIS), is ongoing, with an expected completion date of July 2028, and may help us understand if ANI may also be an effective treatment for LN.21 In the meantime, real-world data, as presented by Tani et al,1 may help in understanding the effects of ANI in LN.

Overall, the authors observed 4 disease flares according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI Flare Index (3 mild-moderate and 1 severe) and 20% of patients were considered nonresponders. In contrast, in the TULIP-2 trial, 52.2% of patients in the ANI group did not achieve a BICLA response and the annualized rate of SLE flare was not significantly different relative to placebo.17 It is important at this point to define the characteristics of the patients who should or should not be included in this treatment.

In relation to the safety profile, Tani et al recorded 27 adverse events overall during the entire study period; 85% were infections, which were generally mild, and included 3 cases of oligosymptomatic coronavirus disease 2019 (COVID-19), 1 case of COVID-19 requiring hospitalization, and 1 case of reactivation of multimetameric herpes zoster. Recurrent severe infections were the reason for treatment discontinuation in 1 patient. Although all patients had been previously vaccinated against SARS-CoV-2, only 39% had received the herpes zoster vaccine. Fittingly, an extension trial22 explored the long-term safety and tolerability of ANI in patients who completed the TULIP-1 and TULIP-2 trial and enrolled in the 3-year placebo-controlled long-term extension study. The results suggested a favorable long-term risk-benefit profile for patients with moderate to severe SLE. Larger and longer follow-up studies are needed to estimate the efficacy and safety of ANI.

If damage and refractoriness are to be prevented, educational strategies that allow primary care physicians to make early referrals of patients with SLE, thereby avoiding diagnostic delays, are necessary. Promoting early and sustained treatment and improving adherence also requires good patient education. Further, increasing access to the therapeutic arsenal with drugs of proven efficacy and good safety remains a pressing need. It is likely that new and better therapeutic options will continue to emerge and that the management of patients with SLE will undergo a shift toward even more efficacious initial treatment. All this has the main purpose of contributing not only to a reduction in organ damage and longer survival but also to the improvements in quality of life that our patients deserve. In conclusion, we know that clinical trials do not fully show the complexity of real-world patients; therefore, we need more studies like that of Tani et al1 to understand the true effect of biologics on patients with SLE in the real world, and to move forward with the adoption of new treatment paradigms.

LA is a consultant for AstraZeneca. GJPE is a consultant for and has received honoraria for lectures from AstraZeneca. The remaining authors declare no conflicts of interest relevant to this article.

See Anifrolumab in SLE, page 1096