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. 2024 Aug 27;83(9):1181-1188.
doi: 10.1136/ard-2023-225463.

Disease flares with baricitinib dose reductions and development of flare criteria in patients with CANDLE/PRAAS

Kader Cetin Gedik  1   2 , Ana M Ortega-Villa  3 , Grace Materne  4 , Andre Rastegar  4 , Gina A Montealegre Sanchez  5 , Adam Reinhardt  6 , Paul A Brogan  7   8 , Yackov Berkun  9 , Sara Murias  10 , Maria Robles  11 , Susanne Schalm  12 , Adriana A de Jesus  4 , Raphaela Goldbach-Mansky  1
Affiliations

Disease flares with baricitinib dose reductions and development of flare criteria in patients with CANDLE/PRAAS

Kader Cetin Gedik et al. Ann Rheum Dis. .

Abstract

Objectives: Patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) respond to the janus kinase inhibitor 1/2 inhibition with baricitinib at exposures higher than in rheumatoid arthritis. Baricitinib dose reductions to minimise exposure triggered disease flares which we used to develop 'flare criteria'.

Methods: Of 10 patients with CANDLE/PRAAS treated with baricitinib in an open-label expanded-access programme, baricitinib doses were reduced 14 times in 9 patients between April 2014 and December 2019. Retrospective data analysis of daily diary scores and laboratory markers collected before and after the dose reductions were used to develop 'clinical' and 'subclinical' flare criteria. Disease flare rates were compared among patients with <25% and >25% dose reductions and during study visits when patients received recommended 'optimized' baricitinib doses (high-dose visits) versus lower than recommended baricitinib doses (low-dose visits) using two-sided χ2 tests.

Results: In the 9/10 patients with CANDLE with dose reduction, 7/14 (50%) times the dose was reduced resulted in a disease flare. All four dose reductions of >25% triggered a disease flare (p <0.05). Assessment of clinical and laboratory changes during disease flares allowed the development of disease flare criteria that were assessed during visits when patients received high or low doses of baricitinib. Disease flare criteria were reached during 43.14% of low-dose visits compared with 12.75% of high-dose visits (p <0.0001). Addition of an interferon score as an additional flare criterion increased the sensitivity to detect disease flares.

Conclusion: We observed disease flares and rebound inflammation with baricitinib dose reductions and proposed flare criteria that can assist in monitoring disease activity and in designing clinical studies in CANDLE/PRAAS.

Keywords: Immune System Diseases; Inflammation; Outcome Assessment, Health Care.

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Conflict of interest statement

Competing interests: PAB received consulting and lecture fees and travel support from SOBI, lecture fees from Novartis and serves as a trustee of society, a patient led Kawasaki charity (unpaid). SM received lecture and presentation fees and travel support from Abbvie, Novartis, Roche, Pfizer. SS received lecture fee from Novartis and presentation fee from Pfizer. RG-M received study support under government CRADAs from Eli Lilly, IFM and SOBI and serves in a leadership position at the TARN initiative and as liaison to the Autoinflammatory Alliance (unpaid).

Figures

Figure 1
Figure 1
Timeline of baricitinib dose changes and development of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) disease flare. Timeline of baricitinib initiation (blue circle), achieving the first remission (green circle), reaching clinically effective dose (orange circle), dose reduction not triggering a flare (purple triangle), dose reduction that triggered a clinical flare (red triangle), dose reduction that triggered a subclinical flare (yellow triangle) and study discontinuation (black square). Mean time to establish clinically effective dose was 1.06 years (±0.65 year) in 10 patients with CANDLE/PRAAS. Mean duration of baricitinib treatment was 6.3 years (±2.3 years). Of 10 patients, 9 had 14 baricitinib dose reductions. P8 did not have a dose reduction. Of 14 dose reductions, five (P1, P3, P5, P6 and P10) resulted in a clinical disease flare in five out of nine patients and two (P4 and P7) resulted in laboratory changes alone consistent with a disease flare with no clinical symptoms. *Indicates incidences of flare, clinical or subclinical.
Figure 2
Figure 2
Acute clinical and laboratory biomarker changes with baricitinib dose reduction in seven patients judged to have a clinical or subclinical disease flare. This figure depicts comparison of the reference visit (=last visit before baricitinib dose reduction) with flare visit (=the first visit after baricitinib dose reduction) for DDS and the laboratory values for the patients who developed baricitinib dose reduction associated clinical and/or laboratory changes. Each parameter for each patient is graphed (see symbols used in upper right-hand corner of the graph for each patient). A two-sided non-parametric Wilcoxon signed rank test with uncorrected p values was used to underscore the descriptive representation. ALC, absolute lymphocyte count; CRP, C reactive protein; DDS, daily diary score; ESR, erythrocyte sedimentation rate; HGB, haemoglobin; PLT, platelets; WBC, white blood cell. *P7: DDS and ESR were not available for predose or postdose reduction visit or for both. P5: ESR was not available postdose reduction.
Figure 3
Figure 3
Time from baricitinib reduction to the fulfilment of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) disease flare criteria (clinical and subclinical without interferon score). This Kaplan-Meier curve depicts the rate of disease flares (%) associated with baricitinib dose reductions in patients with CANDLE/PRAAS on y-axis, and time from dose reduction to flare in days on x-axis. Red line (group A) represents patient visits with a less than or equal to 25% baricitinib dose reduction (n=10) and the grey line (group B) represents occurrences of greater than 25% of baricitinib dose reductions (n=4). All four baricitinib dose reductions greater than 25% in group B resulted in a disease flare and fulfilled the flare criteria within 60** days. The proportion of flares in group A (20%) versus group B (100%) was significantly different (p=0.012). The time to flare in both groups was evaluated by Cox proportional hazards models and displayed using Kaplan-Meier curves. *P1 developed clinical symptoms with one laboratory abnormality postdose reduction and although he had a clinical flare, he did not fulfil the flare criteria and is not included in the count. **P7 developed symptoms several days after baricitinib dose reduction however did not have a blood draw until 55 days later when the disease was still active. P7 fulfilled the flare criteria on day 55 postdose reduction when the laboratory markers were available.
Figure 4
Figure 4
Proportion of disease flares comparing low-dose baricitinib visits to high-dose baricitinib visits. A total of 153 visits in 6 patients who had both high-dose (n=102) and low-dose (n=51) visits were identified and assessed. The proportion of visits that patients fulfil flare criteria during the low-dose period (43.14%) is significantly higher (p<0.0001) than during the high-dose period (12.75%). The proportion of visits that patients fulfil flare criteria during the low-dose and high-dose period was compared by using a two-sided χ2 test of homogeneity.
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