Promising options to treat mucocutaneous disease in SLE Save

Cutaneous lupus erythematosus (CLE) consists of a wide range of dermatologic manifestations seen in people with or without systemic lupus erythematosus (SLE). CLE can be categorised into LE-specific lesions, i.e. acute CLE (ACLE), subacute CLE (SCLE) and chronic CLE (CCLE), and nonspecific LE skin lesions (e.g. vasculitis). In addition to CLE, people with SLE also suffer from mucosal ulceration and alopecia. The standard first line therapy for mucocutaneous SLE is anti-malarials. However, about 50% of people have refractory disease. If left untreated, mucocutaneous disease significantly impair quality of life and self-esteem.

Mucocutaneous disease is particularly heterogeneous in terms of pathogenesis. Although immune complex deposition is a common feature in skin biopsy histology, non–B cell mechanisms such as keratinocyte activation and apoptosis, chemokine and inflammatory cytokine production (e.g. type 1 interferon (IFN-I) and T-cell infiltrate are important. Given this immunological heterogeneity, it is not surprising that responses to therapy vary. Indeed, response rates in skin domain to the licensed biologic in SLE are mixed in clinical trials with lower numbers of British Isles Lupus Activity Group Disease Activity Index (BILAG-2004) and SLE Disease Activity Index (SLEDAI-2K) improvements compared to the musculoskeletal domain. Therefore, there is an unmet need for effective therapies specifically addressing mucocutaneous disease in SLE.

So, what option do we have in the near future? Anifrolumab, IFN-receptor mAb is currently under review by the FDA for approval in SLE. Prof Merrill (OP0131) presented pooled data from two pivotal Phase III trials of anifrolumab (TULIP-1 and -2) on its effects on rash and arthritis. These features were assessed using mucocutaneous and musculoskeletal domains of the SLEDAI-2K and BILAG-2004 indices, as well as the modified CLE Disease Area and Severity Index (mCLASI) score for rash. 360 patients treated on anifrolumab and 366 on placebo were analysed. More anifrolumab-treated patients achieved rash improvement vs placebo based on SLEDAI-2K (complete resolution: difference 13.5%, nominal P<0.001), BILAG (at least 1 severity grade lowering: difference 15.5%, nominal P<0.001), and mCLASI (≥50% improvement, if baseline score >0: difference 15.6%, nominal P<0.001). Similar improvement in the anifrolumab group were also seen for arthritis. Response rates to anifrolumab for both rash and arthritis were significantly evident in those with high baseline IFN gene signature. In those with low IFN signature, there was a trend to improvement in rash and arthritis with anifrolumab therapy (as assessed using the BILAG-2004) although this analysis was limited by sample size.

Prof Werth (OP0132) presented post-hoc analyses of cutaneous response from a Phase II trial of iberdomide in moderately active SLE (i.e. SLEDAI-2K≥6). As you may recall, the primary endpoint, SRI-4 was met in the iberdomide group vs placebo when these data were presented at the 2020 ACR Conference. Iberdomide is a modulator of the E3 ubiquitin ligase complex containing cereblon (CRL4-CRBN E3 ubiquitin ligase), with immunomodulating and pro-apoptotic activities (i.e. near similar property to thalidomide or lenalidomide). 266 patients were randomised (2:2:1:2) to oral iberdomide (0.45, 0.3, 0.15 mg) or placebo once daily for 24 weeks. Prespecified, exploratory endpoints were change from baseline and the proportion of patients who achieved ≥50% reduction from baseline (CLASI-50), those with baseline CLASI-A≥8, and by CLE subtypes. At 24 weeks, CLASI-50 responses were not significantly different comparing iberdomide to placebo in all patients and those with baseline CLASI≥8. However, a high placebo response (45%) was noted. For patients with SCLE or CCLE, CLASI-50 response rates were higher with iberdomide 0.45 mg vs placebo (P<0.04). In terms of stratification, effect size in CLASI between iberdomide 0.45 mg and placebo were larger for SCLE and CCLE subgroups with high baseline IKZF3 or IFN-I gene signatures, with statistical significance achieved for SCLE but not CCLE.

So what do these results mean? The licensing of anifrolumab in the next few months will be welcomed as an important addition to the ever-expanding armamentarium of therapies for SLE especially in those with refractory skin and joints disease. For the most resistant CLE subtype, CCLE (i.e., comprises discoid lupus erythematosus), iberdomide appears to be an attractive option. Thus, results from the ongoing Phase III trial will be eagerly awaited in the next few years. The choice of therapy could be influenced by CLE subtypes and baseline IFN-I and IKZF3 signatures.