Assessment of Clinical Response to Anifrolumab in Patients With Refractory Discoid Lupus Erythematosus

Abstract

This case series examines the efficacy of anifrolumab as a therapeutic option for patients with lupus erythematosus.

Cutaneous lupus erythematosus (CLE) reflects a heterogenous group of inflammatory skin diseases. Although the different subtypes of CLE are united by shared pathophysiology, chronic cutaneous lupus erythematosus (CCLE)—of which discoid lupus erythematosus (DLE) constitutes the majority of cases—is distinguished by its potential to cause irreversible scarring and disfigurement.¹ Traditional therapies including antimalarials, steroid-sparing immunosuppressive agents, retinoids, thalidomide, and lenalidomide demonstrate inconsistent success for refractory DLE.² Thus, a substantial need for more effective therapies for DLE persists.

Anifrolumab, a human monoclonal antibody targeting type 1 interferon receptor subunit 1, was US Food and Drug Administration (FDA)-approved in 2021 for adults with moderate-to-severe systemic lupus erythematosus (SLE). Importantly, in its hallmark phase 3 trial TULIP-2,³ anifrolumab not only met its primary end point via reduction in SLE activity, but it also demonstrated benefit in lupus-associated skin disease, with 49% of patients in the anifrolumab group having a 50% or more reduction in CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) activity score vs 25% in the placebo group. A subsequent case series⁴ of 3 patients with refractory CLE treated with anifrolumab reported improvements in physician observation of erythema and pigmentary changes, although a validated outcome measure of cutaneous lupus activity was not used. Although specific CLE subtypes were not characterized in these previous reports, given that type 1 interferon expression is known to correlate with DLE disease activity,⁵ we hypothesized that anifrolumab might be a viable therapeutic option for patients with DLE.

Methods

This study was approved by the Partners Healthcare institutional review board (IRB). Patient informed consent was waived owing to the use of deidentified data. After obtaining IRB approval, we performed an International Classification of Diseases (ICD-9 and ICD-10) code and natural-language query for medical records from Brigham and Women’s Hospital and Massachusetts General Hospital to identify all cases of DLE based on biopsy and/or expert opinion from January 2000 through October 2022. Demographic information, clinical features, treatment data, and adverse events were analyzed in November 2022.

Results

Ten patients with DLE treated with anifrolumab were identified. Of those patients who had received at least 8 weeks of therapy (n = 8; 8 women; median [range] age, 42.5 [19-75] years), all had DLE recalcitrant to standard therapies (Table). Outcome measures were improvement in patient-reported symptoms and CLASI score (including both CLASI activity [CLASI-A], score 0-70 and CLASI damage [CLASI-D], score 0-56). All patients demonstrated significant improvement in symptomatology and disease activity within 2 months of initiating anifrolumab; representative clinical images of a single patient are highlighted in the Figure. Mean (SD) decrease and mean (SD) percentage decrease in CLASI-A scores were 17.1 (6.8) and 65.1% (10.4%), respectively. Mean (SD) decrease and mean (SD) percentage decrease in CLASI-D scores were 0.5 (0.8) and 2.9% (4.9%), respectively.

Table. Characteristics of Patients With Discoid Lupus Erythematosus and Disease Response Following Treatment With Anifrolumab.

Sex/age, y	Race and ethnicity	Comorbid SLEa	Prior therapiesb	Therapies concomitant with anifrolumab	CLASI-A			CLASI-D			Pruritusd	Paind	Adverse events
					Baseline score	Posttherapy scorec	Change (% change)	Baseline score	Posttherapy scorec	Change (% change)
Female/40s	Black	Yes	HCQ, MTX, MMF, prednisone	Prednisone	32	14	18 (56.3)	33	33	0	Significantly improved	Significantly improved	None
Female/50s	Black	Yes	HCQ, MTX, cyclophosphamide, MMF, rituximab, belimumab	None	17	5	12 (70.6)	15	14	1 (6.7)	Significantly improved	Significantly improved	None
Female/30s	Black	Yes	HCQ, MTX, prednisone, thalidomide	HCQ, MMF, thalidomide	11	4	7 (63.6)	11	11	0	Significantly improved	Significantly improved	None
Female/30s	Hispanic	Yes	HCQ, MTX, MMF, prednisone, tofacitinib, rituximab, thalidomide, lenalidomide	Acitretin, IVIG	29	6	23 (79.3)	18	18	0	Significantly improved	Significantly improved	None
Female/60s	Hispanic	Yes	HCQ, MTX, MMF, AZA, acitretin, quinacrine, apremilast, dapsone, tofacitinib, thalidomide, belimumab	HCQ	39	21	18 (46.2)	34	33	1 (2.9)	Significantly improved	Significantly improved	None
Female/20s	Hispanic	Yes	HCQ, prednisone	HCQ	33	9	24 (72.7)	9	9	0	Significantly improved	Significantly improved	None
Female/70s	White (non-Hispanic)	Yes	HCQ, quinacrine, MMF, lenalidomide, apremilast, belimumab	None	16	6	10 (62.5)	15	13	2 (13.3)	Significantly improved	Significantly improved	None
Female/10s	White (non-Hispanic)	Yes	HCQ, MTX, MMF, AZA, leflunomide, thalidomide, cyclophosphamide, rituximab, belimumab, IVIG	HCQ, MMF, IVIG	36	11	25 (69.4)	28	28	0	Significantly improved	Significantly improved	None

Abbreviations: AZA, azathioprine; CLASI-A, Cutaneous lupus disease area and severity index activity score; CLASI-D, Cutaneous lupus disease area and severity index damage score; HCQ, hydroxychloroquine; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; MTX, methotrexate; SLE, systemic lupus erythematosus.

^a No patient had active lupus nephritis as a component of their systemic disease.

^b Prior medications were considered a failure if taken for 12 weeks without adequate disease control or not tolerated by the patient for any reason.

^c Posttherapy CLASI-A and CLASI-D scores were obtained at 2 months after anifrolumab initiation.

^d The change in patient-reported symptoms was assessed 2 months after anifrolumab initiation utilizing a 5-point Likert improvement scale ranging from 1 to 5 (1, “significantly worse”; 2, “worse”; 3, “same”; 4, “improved”; 5, “significantly improved”).

Figure. Representative Clinical Images Before and After 2 Months of Treatment With Anifrolumab.

A woman in her 40s with a history of long-standing DLE on chronic prednisone (10 mg daily) with extensive erythematous, scaly plaques with peripheral hyperpigmentation involving the face, scalp (A), extremities (B), and chest (C). Her disease had previously proven refractory to hydroxychloroquine, mycophenolate mofetil, methotrexate, azathioprine, and rituximab. After 2 months of treatment with anifrolumab, the patient still exhibited extensive postinflammatory hyperpigmentation and scarring, but experienced dramatic improvement in disease activity with reduced erythema and scaling (D-F). After 6 months of treatment with anifrolumab, prednisone was successfully weaned from 10 mg to 2 mg daily.

Discussion

Prior studies have demonstrated that clinically meaningful improvement in DLE is associated with a mean 4-point or 20% decrease in CLASI-A score,⁶ underscoring the impressive benefit of anifrolumab observed in our patient cohort. Moreover, the rapidity with which patients had clinical improvement was striking, with substantial reductions in CLASI-A scores noted within 8 weeks of anifrolumab initiation. This is in contrast to antimalarials, methotrexate, and mycophenolate mofetil (traditional first- and second-line therapies for DLE), for which clinical effects are often not realized for 3 to 6 months.¹ Given the risk for permanent scarring, dyspigmentation, and alopecia with poorly controlled DLE, the importance of rapidly mitigating disease activity cannot be overemphasized. This was further highlighted by our finding that CLASI-D scores, which capture the aforementioned cutaneous changes that arise secondary to DLE disease activity, remained largely unchanged in our cohort.

Finally, the overall favorable adverse effect profile of anifrolumab bears highlighting. Upper respiratory tract infections, nasopharyngitis, infusion-related reactions, bronchitis, and herpes zoster were the most common adverse effects noted in the original phase 3 trials of anifrolumab in patients with SLE—notably, cytopenias and thrombotic events (TEs) were not observed.³ Thus, anifrolumab may be an attractive option for those patients with refractory DLE with risk factors for TEs (including antiphospholipid antibodies) or comorbid cytopenias that would typically preclude the use of lenalidomide or thalidomide, after which efficacious treatment options are generally lacking.

Taken together, these early results highlight the potential for anifrolumab to be a viable therapeutic option for patients with DLE, particularly those with severe or recalcitrant disease. Although these findings are compelling, our study is limited by its small sample size and retrospective nature; as such, larger prospective studies of anifrolumab in DLE are warranted.

Supplement.

Data Sharing Statement