Promising therapeutic developments for cutaneous lupus erythematosus: Interfering with interferon – Part II – Focus on Anifrolumab
By Warren R. Heymann, MD, FAAD
Sept. 13, 2023
Vol. 5, No. 36
This is an exciting time for cutaneous lupus erythematosus (CLE). Recently published findings from three clinical trials show substantial progress in developing more targeted, efficacious, and better-tolerated medications for patients with CLE, particularly by inhibiting the production or action of type I interferons in affected skin.
I am quoting Dr. Victoria Werth from her expert viewpoint in Part I of this commentary. I encourage you to reread part I, which reviews the current pathogenesis and therapeutic landscape for cutaneous lupus. In her viewpoint, Dr. Werth notes that “there are currently only two FDA-approved medications for CLE, hydroxychloroquine and glucocorticoids, both of which have been in use since before 1962, when the FDA grandfathered them in without clinical trials.” (1)
Part I focused on the anti-BDCA2 antibody litifilimab for CLE. (2) This commentary is devoted to the expanding literature on anifrolumab for CLE.
Development of CLE likely commences in a pro-inflammatory epidermis, conditioned by excess type I interferon (IFN) production at baseline and following ultraviolet light exposure. (3) Anifrolumab is a human IgG1K monoclonal antibody that binds to type 1 interferon receptor, thereby blocking type 1 interferon signaling. The FDA approved anifrolumab for systemic lupus erythematosus (SLE), although not lupus nephritis, in July 2021. (4) In a randomized study named TULIP-2 (Treatment of Uncontrolled Lupus via the Interferon Pathway-2), Morand et al evaluated 362 lupus patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) [180 patients] or placebo [182 patients] every 4 weeks for 48 weeks. The authors found that monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE (TULIP-1) that had a different primary endpoint. As an adverse reaction, the frequency of herpes zoster was higher with anifrolumab than with a placebo. Notably, skin disease was a secondary endpoint in this study. Among patients with at least moderately active skin disease (CLASI ≥10 [Cutaneous Lupus Erythematosus Disease Area and Severity Index]) at baseline, a reduction of 50% or more in the CLASI at week 12 occurred in 49.0% of the patients (24 of 49) receiving anifrolumab and in 25.0% (10 of 40) receiving placebo (P=0.04) (5)
As noted in Part I, Blum et al identified 3 patients (Black women, aged 22 to 51 years) with CLE recalcitrant to standard therapies (variably — antimalarials, immunosuppressive agents, prednisone, rituximab, belimumab). Each patient received at least 12 weeks of treatment (anifrolumab 300 mg infusions every 4 weeks). Anifrolumab was added to their existing regimens of hydroxychloroquine, prednisone, and other immunosuppressants (mycophenolate mofetil or azathioprine). All 3 patients had significant improvement in their cutaneous disease with areas of repigmentation after only 2 infusions of anifrolumab, enabling all to discontinue prednisone. There were no adverse reactions during 4 months of follow-up. (6)
During the past year, several papers touting the efficacy of anifrolumab for CLE have been published. Shope et al reported an excellent response to monthly infusions of anifrolumab in a 43-year-old woman with Rowell syndrome (see images below). (7) In a study of 11 women with refractory CLE treated with monthly anifrolumab infusions, the median CLASI activity decreased from 15 (4-35) at baseline to 4 (0-19) at week 4 (P = .001) and 2 (0-13) at week 16 (P < .001). The median time to reach CLASI 50 was 1 month. A complete response (CLASI = 0) was observed in 6 (54%) patients. No patients discontinued anifrolumab permanently because of an adverse event. Infectious complications included 2 non-severe COVID-19 cases with spontaneous recovery (for which the anifrolumab infusion was delayed for 2 weeks), 1 case of herpes zoster, 1 case of worsening preexisting palmar warts, and 1 case of mucosal candidiasis. (8) Kowalski et al treated 6 patients with recalcitrant CLE (4 discoid, 2 hypertrophic, 5/6 women, 4/6 with concurrent SLE) with anifrolumab. All tolerated the infusions well; 1 patient had a herpetic eruption (either herpes simplex or varicella-zoster), and another experienced worsening of known lupus nephritis. All 6 patients demonstrated significant cutaneous improvement, most after the first infusion and near-complete clearance of disease activity within a few months. (9) Khan et al reported 2 refractory cases of SLE in women with severe CLE, demonstrating dramatic improvement when anifrolumab was added to their regimens. (10)
The rapidity of response to anifrolumab in all types of CLE is striking. Carter et al treated 7 patients [DLE (n = 5), chilblain lupus erythematosus (n = 1), subacute CLE (n = 1)]. The median CLASI showed a rapid and sustained improvement within 3 months, accompanied by a significant improvement in Dermatology Life Quality Index scores (and other indices). Clinical responses paralleled discrete suppression of interferon-stimulated genes (ISGs) from the SLE blood transcriptome module M1.2 with a more varied downregulation in other interferon modules. Myeloid and inflammation-annotated genes remained upregulated throughout treatment. Intermediate monocytes (CD14++CD16+) reduced to normal levels during therapy, while other flow subsets showed no substantive changes. (11) In an editorial accompanying Carter et al, Günther states, “The variability of the ISG response…further indicates that certain subtypes of ISGs might be more suitable than others as biomarkers for disease activity. It might also be possible that the set of responding ISGs might differ depending on the respective organ manifestation. The fact that a wider blood lupus transcriptomic signature was not altered also suggests that certain ISGs are not required for cutaneous inflammation. In addition, monocyte numbers were unaltered during anifrolumab treatment, further indicating that type 1 IFN is especially important for the cutaneous phenotype but does not solely impact on the systemic alterations in SLE.” (12)
Dr. Werth is correct — this is an exciting time for CLE — I just referred a patient with recalcitrant SLE with CLE for anifrolumab infusions. Anifrolumab may not be a panacea, but recent literature suggests that it may be a beneficial adjunctive therapy across the CLE spectrum, serving as a prelude to novel agents targeting IFN.
Point to Remember: Anifrolumab, a monoclonal antibody that blocks type 1 interferon signaling, has been increasingly reported as an effective treatment in patients with recalcitrant chronic cutaneous lupus erythematosus.
Our expert’s viewpoint
Victoria P. Werth, MD, FAAD
Professor of Dermatology and Medicine, University of Pennsylvania School of Medicine
Chief of the Division of Dermatology, Philadelphia Veterans Administration Hospital
The clinical improvement seen in CLE activity after treatment with anifrolumab further confirms that type I interferons are very important in the pathogenesis of the CLE. The rapid improvement seen in many with refractory skin disease is impressive. Ongoing studies in CLE are critical, since the current approval for SLE but not CLE makes it difficult to obtain the treatment for CLE patients who would benefit. There is much to be learned about long-term safety, ability to stop the medication if indicated, and the effects on co-morbidities. We have waited a long time to get safe and rapidly effective therapies for a disease that has such a huge impact on QoL. A number of therapies targeting type I interferons are in the pipeline for evaluation in CLE and promise to revolutionize the approach to treatment for refractory CLE.
Werth VP, in Heymann WR. Promising therapeutic developments for cutaneous lupus erythematosus: Interfering with interferon. Dermatology World Insights and Inquiries August 17, 2022, Vol 4, No 33. https://www.aad.org/dw/dw-insights-and-inquiries/archive/2022/cutaneous-lupus-erythematosus-interferon
Werth VP, Furie RA, Romero-Diaz J, Navarra S, Kalunian K, van Vollenhoven RF, Nyberg F, Kaffenberger B, Sheikh SZ, Radunovic G, Huang X, Carroll H, Gaudreault F, Meyers A, Barbey C, Musselli C, Franchimont N, for the LILAC Study investigators. Trial of anti-BDCA2 antibody litifilimab for cutaneous lupus erythematosus. N Engl J Med. 287:321-331, 2022 (July 28). doi: 10.1056/NEJMoa2118024
Maz MP, Martens JWS, Hannoudi A, Reddy AL, Hile GA, Kahlenberg JM. Recent advances in cutaneous lupus. J Autoimmun. 2022 Jul 17:102865. doi: 10.1016/j.jaut.2022.102865. Epub ahead of print. PMID: 35858957.
Sprow G, Dan J, Merola JF, Werth VP. Emerging Therapies in Cutaneous Lupus Erythematosus. Front Med (Lausanne). 2022 Jul 11;9:968323. doi: 10.3389/fmed.2022.968323. PMID: 35899214; PMCID: PMC9313535.
Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C, Bae SC, Brohawn PZ, Pineda L, Berglind A, Tummala R; TULIP-2 Trial Investigators. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020 Jan 16;382(3):211-221. doi: 10.1056/NEJMoa1912196. Epub 2019 Dec 18. PMID: 31851795.
Blum FR, Sampath AJ, Foulke GT. Anifrolumab for treatment of refractory cutaneous lupus erythematosus. Clin Exp Dermatol. 2022 Nov;47(11):1998-2001. doi: 10.1111/ced.15335. Epub 2022 Aug 26. PMID: 35844070.
Shope C, Andrews L, Cunningham M, Connett J. A case of Rowell syndrome with excellent improvement following anifrolumab. JAAD Case Rep. 2022 Nov 13;31:27-30. doi: 10.1016/j.jdcr.2022.11.008. PMID: 36478979; PMCID: PMC9720243.
Chasset F, Jaume L, Mathian A, Abisror N, Dutheil A, Barbaud A, Kottler D, Girard C, Jousse-Joulin S, Tauber M, Livideanu CB, Avettand-Fenoel V, Lhote R, Pha M, Amoura Z; EMSED (Etude des maladies systémiques en dermatologie) study group. Rapid efficacy of anifrolumab in refractory cutaneous lupus erythematosus. J Am Acad Dermatol. 2023 Jul;89(1):171-173. doi: 10.1016/j.jaad.2023.02.044. Epub 2023 Mar 5. PMID: 36878316.
Kowalski EH, Stolarczyk A, Richardson CT. Successful treatment of severe chronic cutaneous lupus with anifrolumab: A series of 6 cases. JAAD Case Rep. 2023 May 4;37:21-29. doi: 10.1016/j.jdcr.2023.04.024. PMID: 37324181; PMCID: PMC10265470.
Khan MA, Khan FH, Khan HB, Saadeh C, Davey N. Role of Anifrolumab in Refractory Cutaneous Manifestations of Lupus Erythematosus: A Case Series and Literature Review. Cureus. 2023 May 27;15(5):e39553. doi: 10.7759/cureus.39553. PMID: 37378095; PMCID: PMC10292022.
Carter LM, Wigston Z, Laws P, Vital EM. Rapid efficacy of anifrolumab across multiple subtypes of recalcitrant cutaneous lupus erythematosus parallels changes in discrete subsets of blood transcriptomic and cellular biomarkers. Br J Dermatol. 2023 Jul 17;189(2):210-218. doi: 10.1093/bjd/ljad089. PMID: 36944572.
Günther C. Rapid response of cutaneous lupus erythematosus to treatment with the type 1 interferon receptor antagonist anifrolumab. Br J Dermatol. 2023 Jul 17;189(2):151-153. doi: 10.1093/bjd/ljad111. PMID: 37002783.
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