JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

Abstract

Background: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.

Methods: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.

Results: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.

Conclusion: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.

Trial registration: ClinicalTrials.gov NCT01724580 and NCT02974595.

Funding: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Keywords: Immunology; Innate immunity; Monogenic diseases; Therapeutics; Translation.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. Expanded access program overview and effect of baricitinib treatment on clinical outcomes.

(A) Expanded access program overview. Phase 1: Time before the first baricitinib dose. Phase 2: Period of dose escalation, including the time between the first baricitinib dose and achievement of an optimal dose regimen. Phase 3: Time on optimal baricitinib doses, excluding the last 90 days prior to the final visit. Phase 4: Ninety days prior to the final visit, with analysis of primary data (daily diaries, steroid doses, and biomarkers of IFN signaling). The program is ongoing. #The number of days in each phase is reported as the mean ± SD. For phases 2 and 3, patients O1 and O3 were not included in the calculation. Both patients discontinued treatment because of a lack of efficacy and/or osteonecrosis after only 77 and 56 days on optimal doses, respectively. (B) Effect of baricitinib treatment on clinical outcomes. To confirm trends in longitudinally collected data, the diary scores and corticosteroid doses were fitted to a repeated-measures model with “phase” as a categorical independent variable. Least-squares means with 95% CIs for each phase were assessed. *P < 0.05 and **P < 0.001 (both unadjusted) by 2-sided paired Student’s t test.

Figure 2. Self-reported and physician’s global assessments by disease subgroup.

Parent’s or patient’s overall assessment of pain and health (Pt. global) and the physician’s assessment (MD global) were measured using a visual analog scale (VAS), in which a value of 100 mm indicates the worst possible measure for the condition assessed by the test. Quality of life (PedsQL) was measured using a standardized age-matched test that ranged from 0% to 100%, with higher percentages indicating improvement. Data are presented by disease, with CANDLE in red, SAVI in blue, and other interferonopathies in green. Only the 2 patients who stayed in the study are shown. Darker shades indicate pretreatment, and lighter shades indicate the last included visit on baricitinib treatment. **P < 0.05 and ***P < 0.001 (both unadjusted) by 2-sided paired Student’s t test.

Figure 3. Improvement in clinical disease manifestations in CANDLE and SAVI patients treated with baricitinib.

(A–D) Images of 2 patients with CANDLE who achieved the remission criteria (C2 and C10, respectively) are shown. Pretreatment images of the face show typical distribution of facial panniculitis with periorbital swelling and erythema as well as lipodystrophy affecting temporal regions and areas above and below the zygomatic bone. Lip swelling is also evident. Post-treatment images show complete resolution of areas of panniculitis on the face and neck. (E and F) Images of 2 of the 4 patients with SAVI are shown. Images of the lower leg of a SAVI patient (S3) show extensive eschar formation overlying infected, nonhealing ulcers on the left lower leg. After treatment, the ulcers healed, with complete reepithelialization. (G and H) Images of the right palmar surface of the hand of a patient with SAVI (S4) show chronic cutaneous vasculitis that resulted in partial amputation of the second and third fingers and complete loss of the fourth and fifth fingers. On baricitinib treatment, a significant improvement in cutaneous vasculitis resulted in preservation of the fingers without further tissue loss.

Figure 4. Improvement in longitudinal growth and hematologic parameters.

(A) Clinically significant improvement was seen in height Z-scores and the percentiles of patients with growth potential (n = 13) when comparing data from before baricitinib treatment with data from the last visit. Mean height Z-scores improved from –4.03 ± 2.64 to –3.19 ± 2.33, with catch-up growth observed in 9 patients whose improvement translated into a mean height percentile increase from the 1.4th percentile to the 7.2nd percentile. (B) Photos of a patient with CANDLE (C8) with stunted growth since 2 years of age and a severe delay in bone age (chronological age of 14.3 years vs. bone age of 2 years). Within 30 months of treatment, her linear height increased from 90 cm to 106.8 cm, and her bone age improved from 2 years to 7.8 years. (C) Signs of bone marrow immunosuppression improved in all patients but 2 (C1 and O3), with increases in platelet counts, ALCs, and hemoglobin (Hgb) levels. Patient C1 continues to have persistent lymphopenia (ALC of 0.5), and patient O3 (discontinued from the program because of a poor response to treatment and osteonecrosis) had lower hemoglobin and platelet counts at the time of his last visit. This patient had multiple comorbidities including upper gastrointestinal bleeding, esophageal varices, IgA nephropathy, and idiopathic thrombocytopenia. **P < 0.05 (unadjusted) by paired Student’s t tests were used for both calculations; a 1-sided t test was used for height (in A) and paired Student’s t tests were used for all calculations, including the two asterisks (in C).

Figure 5. Assessment of conventional inflammatory parameters (CRP) and IFN biomarkers (serum IP-10 levels and 25-gene IFN score) with baricitinib treatment.

(A) CRP levels dropped most significantly in CANDLE patients, with CRP levels returning to normal in 5 of 10 of these patients. The patients with other interferonopathies (O2 and O4) who stayed in the program had improved CRP levels. The 2 patients who discontinued the program because of a lack of efficacy had no improvement and are circled. **P < 0.05 (unadjusted by paired 2-sided Student’s t-test). Data represent the mean ± SD. (B) The 25-gene IFN score was graphed for the baseline score and the IFN score obtained at the last included visit only. Colors indicate data by disease, with CANDLE in red, SAVI in blue, and other interferonopathies in green. Statistical data obtained by paired 2-sided Student’s t-test. The IFN score normalized in 5 of 10 patients with CANDLE who achieved the remission criteria. (C and D) Longitudinally assessed serum IP-10 levels and 25-gene IFN score measurements were fitted to a repeated-measures model with “treatment phase” as a categorical independent variable. Least-squares means (LSM) of serum IP-10 and IFN response gene score with 95% CIs for each phase are graphed. *P < 0.05 (unadjusted) by paired 2-sided Student’s t-test.