Anifrolumab to Treat Severe Hepatic Involvement in a De Novo IFIH1 Mutation

To the Editor,

We read with great interest the article by Kretzschmar et al. [1], reporting normalization of the Interferon Signature and clinical improvement by IFNR1 blocking antibodies (Anifrolumab) in patients with Type I Interferonopathies (T1Is), specifically, four STING–associated vasculopathy with onset in infancy (SAVI) and one chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE).

Two patients with SAVI were able to use Anifrolumab as monotherapy and overall reduced doses of Baricitinib and steroids were needed in all patients. These results confirmed the causal role of IFN-I signaling in T1Is and added Anifrolumab to the armamentarium for the treatment of these rare disorders.

Here, we report Anifrolumab response in another T1I associated with a pathogenic variant in IFIH1.

A 16-year-old girl was born after an uncomplicated pregnancy to non-consanguineous parents of English and Irish descent. Motor development was delayed with assisted walking achieved at age 2 years. MRI demonstrated periventricular white matter changes leading to a diagnosis of cerebral palsy. She underwent dorsal rhizotomy at age 4.5 years after which her gait improved. However, she developed spastic-dystonic diplegia. She caught up with initial mild delays in fine motor and language spheres and was diagnosed with non-verbal learning disability. There has been no neurological regression or episodic neurological symptoms. Hearing and vision have been normal.

She had mild scoliosis of the thoracolumbar spine and left hip dysplasia, which was surgically treated at age 9 years. There has been no arthritis or joint contractures. In addition to having multiple lentigines, the patient developed severe psoriasis, diagnosed at age 1 year. The psoriasis was initially managed with topical therapies and corticosteroids, but progressive disease required transition to ustekinumab at age 10 years. Ustekinumab, a monoclonal antibody targeting interleukins-12 and − 23, resulted in sustained clinical improvement and disease stabilization. She had delayed tooth eruption, with her first tooth erupting at 14 months, with profound premature bone and dental loss. At age 11 years, weight was 21.3 kg (<-3 SD) and height was 119 cm (-4.2 SD), and head circumference was 50.2 cm (-2.03 SD). IGF-1 level, growth hormone stimulation test, TSH and T4 levels were all normal. Intermittent leukopenia and neutropenia were observed, positive ANA and negative anti-dsDNA, anti-ENA, ANCA and RF. An echocardiogram ruled out pulmonary hypertension, and a chest CT showed no aortic calcification or interstitial lung disease.

Given her multisystem presentation with spastic diplegia, psoriasis, lentigines, abnormal dentition and growth delays, genetic testing was initiated at the age 12 years. Trio-based exome sequencing identified a heterozygous, de novo, likely pathogenic variant in the IFIH1 gene (NM_022168.3 c.995G > C, p.Gly332Ala), located within the N-terminal region of the helicase domain, where several other pathogenic variants have also been reported. As of January 2025, this variant has not been reported in the literature, in clinical or population databases, and is predicted to be damaging by in silico tools. Pathogenic variants in IFIH1 are associated with a spectrum of autoinflammatory phenotypes, including Aicardi-Goutières (AGS) and Singleton Merten syndromes (SMS). While AGS is classically an early-onset encephalopathy causing severe developmental delays, rare pathogenic variants in IFIH1 can cause a later onset subtype, sometimes presenting as pure spastic paraparesis with normal intellect [2]. IFIH1-associated SMS has considerable phenotypic variability including arterial calcification, delayed dental eruption, early loss of permanent teeth, psoriasis, glaucoma and severe SLE. There are several individuals now described with an overlap syndrome, such as in our patient [2].

At age 12 years, our patient developed episodes of painful acrocyanosis unresponsive to oral steroids, aspirin or nifedipine. Significant improvement in her painful skin lesions were attained with a trial of tofacitinib (0.4 mg/kg/day), however, mild transaminases were elevated, likely disease related. Before starting tofacitinib, her ALT was 77 IU/L, her AST was 88 IU/L, and abdominal ultrasound showed diffuse fatty infiltrates. Pediatric hepatology work-up revealed mild steatosis, portal inflammation and fibrosis on liver biopsy. Due to the control of the acrocyanosis, tofacitinib was stopped after 10 months and liver enzymes remained stable although did not normalize.

At age 13 years, she developed fatigue, intermittent episodes of vomiting, pruritus, severe nausea, and intermittent bouts of diarrhea with 5 kg weight loss. A trial of high-dose steroids was initiated, but her liver enzymes (ALT 230 IU/L, AST 280 IU/L, GGT 332 IU/L) worsened on this therapy. The autoimmune liver disease panel, as well as CMV and EBV serologies, were negative. Ultrasound showed hepatic steatosis without biliary pathology. At this stage, a second liver biopsy revealed steatohepatitis with cirrhosis. A presence of relatively abundant plasma cells was seen. A FibroScan was performed and revealed a value of 25.6 kPA (normal range 0-7 kPa) keeping with 4/4 fibrosis. She was noted to be developing complications of portal hypertension with splenomegaly and thrombocytopenia.

Given the diagnosis of T1Is, we initiated our patient on a humanized IgG1k monoclonal antibody (Anifrolumab) that binds to a subunit of the IFNI receptor (IFNAR1). She received intravenous infusions of Anifrolumab 300 mg every 4 weeks. She has shown a complete response with resolution of fatigue, nausea, diarrhea, and abdominal pain. Liver enzymes normalized and remained within normal limits throughout the follow-up period (Fig. 1). After 28 months of Anifrolumab treatment, her FibroScan was 8.0 kPa.

Fig. 1.

After 28 months of Anifrolumab treatment liver enzymes completely normalized. AST, Aspartate transferase; ALT, Alanine aminotransferase; GGT, Gamma-glutamyl transferase

Functionally, Anifrolumab led to the suppression of IFN-I-induced gene expression (IFN response gene Signature or IRS). Expression levels of 28-IFN-target genes were measured using NanoString Technologies. All IRS measurements were performed in the Translational Autoinflammatory Disease Section, NIAID, NIH, Bethesda, Maryland, US. Patient’s IRSs were consistently elevated during tofacitinib treatment (294 and 309 three weeks and 6 months after starting tofacitinib respectively with a cutoff of 25.2). Marked suppression of IFN-I induced gene expression (-3.5) was observed three months after the initiation of Anifrolumab and this was consistently maintained (-21.1) at 16 months.

This is the first reported use of Anifrolumab to treat T1Is caused by a novel de novo IFIH1 mutation. IFIH1 gain-of‐function is usually associated with a spectrum of phenotypes and testing for blood IRS is a promising biomarker for defining variants that may have direct pathogenic effects. Acute regression was described in almost one-third of individuals with AGS [3], while our patient mainly displayed a static spastic-dystonic diplegia and a mild learning disability. Her neurological examination remained stable. However, the ability of Anifrolumab to cross the blood-brain barrier should be explored. Until now, the clinical efficacy of Anifrolumab in genetic T1Is has been reported in the treatment of non-neurological manifestations such as fever, anemia, and interstitial lung disease in patients partially responsive/resistant to JAK inhibitors [1, 4]. In our patient, the treatment with Anifrolumab had a favorable impact, both on a clinical and laboratory level as detailed above. Although liver involvement is known to be associated with the neonatal presentation of AGS and with TREX1-related disease, the incidence of AGS-related hepatitis across the lifespan is unknown. Gavazzi et al. [5] found that 25% of individuals with AGS had liver enzyme elevations consistent with hepatitis during their lifetime. All genotypes were susceptible to liver enzyme elevation, including IFIH1.

In conclusion, Anifrolumab shows a promising effect on treating systemic and organ-specific inflammation of T1Is as demonstrated in our patient with clinical efficacy in IFIH1-related disease. To date, the role Anifrolumab has on neuroinflammation is still unknown. More studies are required to evaluate the efficacy and safety of this new biologic agent.

Author Contributions

Contribution to the conception or design of the work: MR, ED, RB. Drafting the work or revising it critically: MR, ED, AZ, RAB, TB, JP, SV, AG.

Funding

Not applicable.

Data Availability

No datasets were generated or analyzed during the current study.

Declarations

Competing Interests

The authors declare no competing interests.