Anifrolumab is one of three anti-type-1 interferon agents currently under investigation as a potential treatment for systemic lupus erythematosus (SLE). Initial in vivo studies observed higher levels of serum interferon (IFN) in patients with autoimmune disease as opposed to those of healthy controls.[1] Further genetic analyses identified a consistent upregulation of IFN gene signatures in peripheral mononuclear cells of SLE patients.[2] This signature was inducible by IFN, repressed with glucocorticoids, and possibly correlated with disease severity.[3][4][5][6][7] Therefore, specific IFN gene signatures have been used in clinical trials as diagnostic and pharmacodynamic biomarkers in SLE.[8][9]

Anifrolumab has gained traction as a promising drug for SLE, as demonstrated in the MUSE study (phase IIb), TULIP-1 (phase III), and TULIP-2 (phase III).[10][11][12][13][14] Though TULIP-1 did not meet its primary endpoint, results from MUSE and TULIP-2 suggest that clinical and immunological improvements can be achieved with administration of anifrolumab up to 48 weeks in SLE patients with mostly high type 1 IFN gene signatures. Both experimental and control groups had concurrent background immunosuppressant therapy. Clinical benefits were shown through multi-organ and symptomatic assessments. On a molecular level, there was the neutralization of IFN gene signatures and improvements in levels of anti-dsDNA antibodies and complement levels, though statistical significance was not formally assessed.

The U.S Food and Drug Administration has not yet approved anifrolumab. As of this writing (July 2021), the drug is still in process with the regulators.

Mechanism of Action

Anifrolumab is a humanized IgG1k monoclonal antibody that binds to subunit 1 of the type 1 IFN receptor (IFNAR1). It inhibits the formation of an IFN/IFNAR complex and subsequent gene transcription.[15] As opposed to other anti-type 1 IFN agents that aim only to neutralize IFN alpha, anifrolumab antagonizes the receptor responsible for cellular signaling induced by IFN alpha, IFN beta, IFN epsilon, IFN kappa, and IFN omega.[15][16][17]

IFN alpha is the predominant type 1 IFN implicated in SLE pathogenesis. As a pleiotropic cytokine secreted by plasmacytoid dendritic cells, IFN alpha is responsible for monocyte maturation, neutrophilic NETosis, and polyclonal B-cell expansion and differentiation.[18] A cascade of events ensues, including inflammatory cytokine production, immune complex deposition, and complement activation. IFN alpha has additional anti-viral properties, inhibiting viral DNA and RNA replication. A comprehensive overview of the pathogenesis in SLE is reviewed elsewhere.[19][20]

Anifrolumab has been shown to correct defects of the innate and adaptive immune system. SLE patients, especially those with high type 1 IFN gene signature status, had altered protein expression, the reversal of cytopenias, and normalization of immune cell populations when treated with anifrolumab.[21]


Two routes of administration, subcutaneous (SC) and intravenous (IV), have been studied in human subjects.[22] In a phase I study, anifrolumab 300 mg SC achieved 87% of the IV administration exposure as measured by area under the serum concentration-time curve (AUC). It exhibited approximate linear kinetics as maximum serum concentration (Cmax) increased proportionally with an escalation of anifrolumab dose (300 mg to 600 mg). The time to reach maximum concentrations (Tmax) was 4.1 days, which was consistent with the literature on the pharmacokinetics of SC IgG1 monoclonal antibodies.[23] 

Anifrolumab 300 mg IV appeared to be more efficacious as it achieved a higher Cmax and shorter Tmax. Researchers did not measure bioavailability in this study; however, there was a quantifiable serum anifrolumab concentration in the treatment groups at least 28 days after the initial dose. Serum concentrations dropped below a detectable threshold by 84 days post-dose. In the MUSE study, anifrolumab 300 or 1000 mg IV was administered every four weeks for 48 weeks to the treatment groups. Interestingly, it exhibited non-linear pharmacokinetics via trends in trough concentrations.[12][24] Subsequently, a regimen of anifrolumab 150 mg to 300 mg IV every four weeks for 48 weeks was chosen for phase III clinical trials. This decision was made due to the higher incidences of certain infections and no gain in efficacy with higher doses of anifrolumab (i.e., 1000 mg).

Adverse Effects

The most commonly reported adverse effects include upper respiratory tract infection, nasopharyngitis, infusion-related reaction, bronchitis, and urinary tract infection. Other effects include sinusitis, arthralgia, back pain, and cough. Notably, the incidence of herpes zoster was higher with anifrolumab compared to that of placebo.[14][22] There were no significant differences in rates of serious nonopportunistic infections, influenza, malignancy, major cardiovascular events, and tuberculosis between the experimental and control groups. Phase IV clinical trials would be particularly helpful in assessing the long-term adverse effects of anifrolumab.


There is no clinical trial data of anifrolumab use in pediatrics, pregnancy, and patients with renal/hepatic impairments. Additionally, researchers excluded patients with active severe lupus nephritis or neuropsychiatric SLE in clinical trials. Thus, at the current moment, anifrolumab should not be administered in this subset of populations.

Due to anifrolumab’s side effect profile, clinicians should exercise caution in patients with an active infection or a history of herpes zoster.


Drug effects are measured primarily with clinical response. Examples of assessments utilized in clinical trials to measure efficacy include the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), SLE responder index (SRI), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), counts of swollen and tender joints, reductions in glucocorticoid dose, and annual flare rates.

Trending IFN titers, IFN gene signatures, anti-dsDNA antibodies, and complement as parameters to monitor disease activity following anifrolumab administration remain unclear.


Anifrolumab is safe, tolerable, and effective for the treatment of systemic lupus erythematosus. In MUSE and TULIP-1, at higher anifrolumab doses, there were numeric increases of serious adverse events and adverse events leading to study discontinuation. However, statistical significance was not evaluated. To date, there is no distinct anifrolumab serum level that predicts effectiveness and toxicity. Routine measuring of serum levels in clinical practice remains unclear. There is no antidote available. Phase IV clinical trials would help assess the possible toxic effects of anifrolumab. 

Enhancing Healthcare Team Outcomes

SLE is a heterogeneous condition composed of many responsible biochemical pathways and a wide array of phenotypes. An interprofessional healthcare team approach to treating SLE that includes clinicians (including mid-level practitioners), specialists, nursing staff, and pharmacists is necessary.[25] Agents against multiple targets and/or personalized medicine through genomic analyses can improve therapeutic outcomes. Though our understanding of SLE pathophysiology continues to evolve, many SLE trials have failed to meet their primary endpoints. These failures could be from flaws in the drug, trial design, or outcome measures. The interprofessional paradigm will drive optimal patient outcomes while minimizing adverse events. [Level 5]

Overall, anifrolumab is a novel IFNAR1 antagonist that can assist in achieving clinical remission or low disease activity in patients with SLE. If approved by the U.S Food and Drug Administration, anifrolumab should only be used as adjunctive therapy to standard immunosuppressants in adults aged 18 to 70 with SLE. Future clinical trials exploring the use of anifrolumab in lupus nephritis and neuropsychiatric SLE are needed to expand clinical indication. Before using anifrolumab, healthcare providers should conduct a thorough history and physical to assess baseline clinical status. Patients should be vigilant in monitoring for signs of infections, particularly herpes zoster.

Article Details

Article Author

Albert Bui

Article Editor:

Devang Sanghavi


7/4/2021 7:26:23 AM

PubMed Link:




Hooks JJ,Moutsopoulos HM,Geis SA,Stahl NI,Decker JL,Notkins AL, Immune interferon in the circulation of patients with autoimmune disease. The New England journal of medicine. 1979 Jul 5     [PubMed PMID: 449915]


Bennett L,Palucka AK,Arce E,Cantrell V,Borvak J,Banchereau J,Pascual V, Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. The Journal of experimental medicine. 2003 Mar 17     [PubMed PMID: 12642603]


Petri M,Singh S,Tesfasyone H,Dedrick R,Fry K,Lal P,Williams G,Bauer J,Gregersen P,Behrens T,Baechler E, Longitudinal expression of type I interferon responsive genes in systemic lupus erythematosus. Lupus. 2009 Oct;     [PubMed PMID: 19762399]


Baechler EC,Batliwalla FM,Karypis G,Gaffney PM,Ortmann WA,Espe KJ,Shark KB,Grande WJ,Hughes KM,Kapur V,Gregersen PK,Behrens TW, Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proceedings of the National Academy of Sciences of the United States of America. 2003 Mar 4;     [PubMed PMID: 12604793]


Becker AM,Dao KH,Han BK,Kornu R,Lakhanpal S,Mobley AB,Li QZ,Lian Y,Wu T,Reimold AM,Olsen NJ,Karp DR,Chowdhury FZ,Farrar JD,Satterthwaite AB,Mohan C,Lipsky PE,Wakeland EK,Davis LS, SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PloS one. 2013;     [PubMed PMID: 23826184]


Crow MK,Kirou KA,Wohlgemuth J, Microarray analysis of interferon-regulated genes in SLE. Autoimmunity. 2003 Dec;     [PubMed PMID: 14984025]


Landolt-Marticorena C,Bonventi G,Lubovich A,Ferguson C,Unnithan T,Su J,Gladman DD,Urowitz M,Fortin PR,Wither J, Lack of association between the interferon-alpha signature and longitudinal changes in disease activity in systemic lupus erythematosus. Annals of the rheumatic diseases. 2009 Sep;     [PubMed PMID: 18772188]


Yao Y,Higgs BW,Morehouse C,de Los Reyes M,Trigona W,Brohawn P,White W,Zhang J,White B,Coyle AJ,Kiener PA,Jallal B, Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus. Human genomics and proteomics : HGP. 2009 Nov 17;     [PubMed PMID: 20948567]


Feng X,Huang J,Liu Y,Xiao L,Wang D,Hua B,Tsao BP,Sun L, Identification of interferon-inducible genes as diagnostic biomarker for systemic lupus erythematosus. Clinical rheumatology. 2015 Jan;     [PubMed PMID: 25344775]


Felten R,Scher F,Sagez F,Chasset F,Arnaud L, Spotlight on anifrolumab and its potential for the treatment of moderate-to-severe systemic lupus erythematosus: evidence to date. Drug design, development and therapy. 2019;     [PubMed PMID: 31190735]


Klavdianou K,Lazarini A,Fanouriakis A, Targeted Biologic Therapy for Systemic Lupus Erythematosus: Emerging Pathways and Drug Pipeline. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2020 Jan 30;     [PubMed PMID: 32002918]


Furie R,Khamashta M,Merrill JT,Werth VP,Kalunian K,Brohawn P,Illei GG,Drappa J,Wang L,Yoo S, Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis     [PubMed PMID: 28130918]


Merrill JT,Furie R,Werth VP,Khamashta M,Drappa J,Wang L,Illei G,Tummala R, Anifrolumab effects on rash and arthritis: impact of the type I interferon gene signature in the phase IIb MUSE study in patients with systemic lupus erythematosus. Lupus science     [PubMed PMID: 30588322]


Morand EF,Furie R,Tanaka Y,Bruce IN,Askanase AD,Richez C,Bae SC,Brohawn PZ,Pineda L,Berglind A,Tummala R, Trial of Anifrolumab in Active Systemic Lupus Erythematosus. The New England journal of medicine. 2020 Jan 16;     [PubMed PMID: 31851795]


Peng L,Oganesyan V,Wu H,Dall'Acqua WF,Damschroder MM, Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-α receptor 1 antibody. mAbs. 2015;     [PubMed PMID: 25606664]


Khamashta M,Merrill JT,Werth VP,Furie R,Kalunian K,Illei GG,Drappa J,Wang L,Greth W, Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Annals of the rheumatic diseases. 2016 Nov;     [PubMed PMID: 27009916]


Kalunian KC,Merrill JT,Maciuca R,McBride JM,Townsend MJ,Wei X,Davis JC Jr,Kennedy WP, A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE). Annals of the rheumatic diseases. 2016 Jan;     [PubMed PMID: 26038091]


Rönnblom L,Leonard D, Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus science     [PubMed PMID: 31497305]


Zharkova O,Celhar T,Cravens PD,Satterthwaite AB,Fairhurst AM,Davis LS, Pathways leading to an immunological disease: systemic lupus erythematosus. Rheumatology (Oxford, England). 2017 Apr 1;     [PubMed PMID: 28375453]


Moulton VR,Suarez-Fueyo A,Meidan E,Li H,Mizui M,Tsokos GC, Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective. Trends in molecular medicine. 2017 Jul;     [PubMed PMID: 28623084]


Casey KA,Guo X,Smith MA,Wang S,Sinibaldi D,Sanjuan MA,Wang L,Illei GG,White WI, Type I interferon receptor blockade with anifrolumab corrects innate and adaptive immune perturbations of SLE. Lupus science     [PubMed PMID: 30538817]


Tummala R,Rouse T,Berglind A,Santiago L, Safety, tolerability and pharmacokinetics of subcutaneous and intravenous anifrolumab in healthy volunteers. Lupus science     [PubMed PMID: 29644080]


Richter WF,Jacobsen B, Subcutaneous absorption of biotherapeutics: knowns and unknowns. Drug metabolism and disposition: the biological fate of chemicals. 2014 Nov;     [PubMed PMID: 25100673]


Yu T,Enioutina EY,Brunner HI,Vinks AA,Sherwin CM, Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus. Clinical pharmacokinetics. 2017 Feb;     [PubMed PMID: 27384528]


Dörner T,Furie R, Novel paradigms in systemic lupus erythematosus. Lancet (London, England). 2019 Jun 8;     [PubMed PMID: 31180031]