Effectiveness and tolerance of Janus kinase inhibitors for the treatment of recalcitrant atopic dermatitis in a real-life French multicenter adult cohort

Abstract

To the Editor: Janus kinase inhibitors (JAKis) are newly available drugs for the treatment of moderate-to-severe atopic dermatitis (AD). Their efficacy and safety have been demonstrated in clinical trials,1Guttman-Yassky E. Teixeira H.D. Simpson E.L. et al.Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.Lancet. 2021; 397: 2151-2168Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 2Blauvelt A. Teixeira H.D. Simpson E.L. et al.Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized clinical trial.JAMA Dermatol. 2021; 157: 1047-1055Crossref PubMed Scopus (130) Google Scholar, 3Simpson E.L. Lacour J.P. Spelman L. et al.Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.Br J Dermatol. 2020; 183: 199-200Crossref PubMed Scopus (208) Google Scholar, 4Reich K. Kabashima K. Peris K. et al.Efficacy and safety of baricitinib combined with topical corticosteroids for treatment of moderate to severe atopic dermatitis: a randomized clinical trial.JAMA Dermatol. 2020; 156: 1333-1343Crossref PubMed Scopus (119) Google Scholar but there is little published data from real-life practice. Upadacitinib (UPADA), a JAK1-selective inhibitor, has been available for use in France in adolescents and adults with moderate-to-severe AD in accordance with the French Early Access Program for patients who failed treatment due to inefficiency or intolerance or alternate treatments were contraindicated (eg, cyclosporine, dupilumab). A second JAKi, baricitinib (BARI) which targets JAK1/JAK2, has been available since March 2021 in adult patients with AD after failed cyclosporine treatment. We assessed the effectiveness and tolerance of JAKis in real life by conducting a multicenter retrospective cohort that included the first patients with AD who received UPADA and BARI from March 2021 to January 2022. The primary outcome was the percentage of patients obtaining an Investigator's Global Assessment score at 0, 1, or −2 at 3 (±1) months (M3) compared with baseline. The secondary outcomes were Scoring Atopic Dermatitis, Eczema Area and Severity Index, Pruritus Numerical Rating Scale , and Dermatological Life Quality Index scores at M3 and at 6 (±1) months. All adverse events during the study period were recorded. One hundred patients were enrolled from 18 centers: 54 treated with UPADA at 15 mg/day, 12 with UPADA at 30 mg/day, and 34 with BARI at 4 mg/day. Patient characteristics are detailed in Supplementary Table I, available via Mendeley at https://doi.org/10.17632/5zw326gw6v.1. Most patients had severe AD (median Investigator's Global Assessment at baseline, 3; IQR 3; 4) and had previously received a mean number of 3 types of systemic drugs before JAKi introduction (methotrexate in 56.6%, cyclosporine in 72%, and dupilumab in 78%), interrupted for inefficacy and/or poor tolerance. An Investigator's Global Assessment score at 0, 1, or −2 compared with baseline was reached at M3 for 33/54 (61.1%), 11/12 (91.7%), and 14/34 (41.2%) patients receiving UPADA 15 mg, UPADA 30 mg, or BARI 4 mg, respectively. The median decrease in Pruritus Numerical Rating Scale at M3 was −3 (IQR −5.5; −1.5), −5 (−7; −1), and −2 (−3; 0) in patients receiving UPADA 15 mg (data available for 24 patients), UPADA 30 mg (6 patients) and BARI 4 mg (19 patients), respectively. Other outcomes measured at month 3 and month 6 are shown in Table I. The median follow-up duration was M3 (IQR 3; 6). Overall, 60 patients presented at least 1 adverse event, the most frequent being increased blood levels of cholesterol (23.2%) or triglycerides (18.2%), facial papular eruption (12.9%), increased alanine aminotransferase and/or aspartate aminotransferase (11.1%) and herpes infection (6.4%) (Table II). No thromboembolic events were observed. JAKis were stopped in 18 patients (9 patients taking UPADA 15 mg, 1 taking UPADA 30 mg, and 8 taking BARI 4 mg), primarily for drug inefficacy (9/21) and/or for adverse event (6/21) (Supplementary Table II, available via Mendeley at https://doi.org/10.17632/5jy3c6jrrr.1). In summary, this real-life study highlighted the effectiveness of JAKis in a population of patients with AD recalcitrant to conventional systemics and biologics and demonstrated a good short-term safety profile.Table IEfficacy outcomes reported at 3 months and 6 months in patients treated with Janus kinase inhibitorOutcomes at M3Outcomes at M6All patientsUpadacitinib 15 mgUpadacitinib 30 mgBaricitinib 4 mgAll patientsUpadacitinib 15 mg∗Including 13 patients who received upadacitinib 15 mg from M0 to at least M3 and then 30 mg; 4 patients (30.7%) obtained an Investigator's Global Assessment score of 0-2 at M6.Upadacitinib 30 mgBaricitinib 4 mgNNumber of patients achieving score (%)NNumber of patients achieving score (%)NNumber of patients achieving score (%)NNumber of patients achieving score (%)NNumber of patients achieving score (%)NNumber of patients achieving score (%)NNumber of patients achieving score (%)NNumber of patients achieving score (%)IGA 0, 1 or 210058 (58%)5433 (61.1%)1211 (91.7%)3414 (41.2%)3012 (40%)249 (37.5)43 (75.0)20SCORAD505328 (52.8%)3017 (56.7%)97 (77.8%)144 (28.6%)175 (29.4%)123 (25%)32 (66.7%)20SCORAD75539 (17.0%)304 (13.3%)94 (44.4%)141 (7.1%)172 (11.8%)121 (8.3%)31 (33.3%)20SCORAD90535 (9.4%)303 (10%)92 (22.2%)140171 (5.9%)12031 (33.3%)20EASI502413 (54.2%)146 (42.9%)76 (85.7%)31 (33.3%)105 (50%)83 (37.5%)22 (100%)0-EASI75249 (37.5%)145 (35.7%)74 (57.1%)30105 (50%)83 (37.5%)22 (100%)0-EASI90245 (20.8%)141 (7.1%)74 (57.1%)30101 (10%)8021 (50%)0-NAbsolute value compared with baselineNAbsolute value compared with baselineNAbsolute value compared with baselineNAbsolute value compared with baselineNAbsolute value compared with baselineNAbsolute value compared with baselineNAbsolute value compared with baselineNAbsolute value compared with baselineMedian PNRS (Q1;Q3)49−3 (−5; −1)24−3 (−5.5; −1.5)6−5 (−7; −1)19−2 (−3; 0)14−3.5 (−5; 0)12−3.5 (−5.5; −1.5)13 (3; 3)1−5 (−5; −5)Median DLQI (Q1;Q3)15−5 (−9; −3)13−5 (−8; −3)2−11 (−15; −7)0-10−6.5 (−15; −1)8−2 (−12; 0)2−17 (−19; −15)0-Because the follow-up time was not standardized among the different centers, the IGA, SCORAD, EASI, PNRS and DLQI scores at 3 months (M3) were defined by the highest (or worst) scores recorded after either 2, 3, or 4 months of treatment. The same scores at 6 months (M6) were defined by the highest (or worst) scores recorded after either 5, 6, or 7 months of treatment.DLQI, Dermatological Life Quality Index; EASI, Eczema Area and Severity Index; EASI 50/70/90, patients achieving 50/75/90% amelioration of EASI compared to baseline; IGA, Investigator's Global Assessment; N, Number of patients with available data; PNRS, Pruritus Numerical Rating Scale; Q1, first quartile; Q3, third quartile; SCORAD, Scoring Atopic Dermatitis; SCORAD50/75/90, patients achieving 50/75/90% amelioration of SCORAD compared to baseline.∗ Including 13 patients who received upadacitinib 15 mg from M0 to at least M3 and then 30 mg; 4 patients (30.7%) obtained an Investigator's Global Assessment score of 0-2 at M6. Open table in a new tab Table IIAdverse events reported during the follow-up period in patients treated with Janus kinase inhibitorsAdverse event (AE)All patientsUpadacitinib 15 mgUpadacitinib 30 mgBaricitinib 4 mgN Patients with data availablePatients, n (%)N Patients with AEPatients, n (%)N Patients with AEPatients, n (%)N Patients with AEPatients, n (%)At least 1 adverse event10060 (60.0)5435∗Iincluding 13 patients who received upadacitinib 15 mg from M0 to at least M3 and then 30 mg. (64.8)126 (50.0)3419 (55.9)At least 1 biological adverse event9944 (44.4)5325 (47.2)122 (16.7)3417 (50.0)At least 1 clinical adverse event10030 (30.0)5419 (35.2)124 (33.3)347 (20.6)Increased†Increased according to local laboratory threshold values. LDL cholesterol or total cholesterol9923 (23.2)5313 (24.5)121 (8.3)349 (26.5)Increased†Increased according to local laboratory threshold values. triglycerides9918 (18.2)5312 (22.6)121 (8.3)345 (14.7)Facial papular eruptions9312‡Including 6 acne and 6 papulopustular eruptions. (12.9)539 (17)93 (33.3)310Increased ALAT and/or ASAT¶All cases asymptomatic.9911 (11.1)536 (11.3)122 (16.7)343 (8.8)Increased†Increased according to local laboratory threshold values. CPK¶All cases asymptomatic.998 (8.1)536 (11.3)122 (16.7)340HSV infections946 (6.4)544 (7.4)92 (22.2)310Headaches935 (5.4)544 (7.4)90301 (3.3)Upper airway infections953 (3.2)540100313 (9.7)Lymphopenia993 (3.0)533 (5.7)120340Nausea952 (2.1)541 (1.9)100311 (3.2)Increased†Increased according to local laboratory threshold values. creatinine clearance¶All cases asymptomatic.992 (2.0)530120342 (5.9)Neutropenia¶All cases asymptomatic.992 (2.0)532 (3.8)120340Diarrhea951 (1.1)540101 (10)311 (3.2)Abdominal pain951 (1.1)541 (1.9)100310Cough931 (1.1)541 (1.9)80310Herpes zoster951 (1.1)541 (1.9)100310Fever951 (1.1)540101 (10)310Weight increase951 (1.1)541 (1.9)100310Anemia¶All cases asymptomatic.991 (1.0)531 (1.9)120340Thrombocytosis¶All cases asymptomatic.991 (1.0)530120341 (2.9)Other clinical abnormalities§Including myalgia, asthenia, urticaria, chronic leg ulceration, wart, dermatophytosis, chest pain, dyspnea, molluscum contagiosum, folliculitis, gonalgia, urinary tract infection, facial edema, scalp pruritus, impetigo, dyspepsia, and dizziness.9515 (15.7)547 (12.3)102 (20)316 (19.4)Other biological abnormalities‖Including C reactive protein elevation, monocytosis, hyperbasophilia, and eosinophilia.¶All cases asymptomatic.9912 (12.1)536 (11.3)121 (8.3)345 (14.7)AE, Adverse event; ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; CPK, creatine phosphokinase; HSV, herpes simplex virus; LDL, low-density lipoprotein; N, number of patients with available data.∗ Iincluding 13 patients who received upadacitinib 15 mg from M0 to at least M3 and then 30 mg.† Increased according to local laboratory threshold values.‡ Including 6 acne and 6 papulopustular eruptions.§ Including myalgia, asthenia, urticaria, chronic leg ulceration, wart, dermatophytosis, chest pain, dyspnea, molluscum contagiosum, folliculitis, gonalgia, urinary tract infection, facial edema, scalp pruritus, impetigo, dyspepsia, and dizziness.‖ Including C reactive protein elevation, monocytosis, hyperbasophilia, and eosinophilia.¶ All cases asymptomatic. Open table in a new tab Because the follow-up time was not standardized among the different centers, the IGA, SCORAD, EASI, PNRS and DLQI scores at 3 months (M3) were defined by the highest (or worst) scores recorded after either 2, 3, or 4 months of treatment. The same scores at 6 months (M6) were defined by the highest (or worst) scores recorded after either 5, 6, or 7 months of treatment. DLQI, Dermatological Life Quality Index; EASI, Eczema Area and Severity Index; EASI 50/70/90, patients achieving 50/75/90% amelioration of EASI compared to baseline; IGA, Investigator's Global Assessment; N, Number of patients with available data; PNRS, Pruritus Numerical Rating Scale; Q1, first quartile; Q3, third quartile; SCORAD, Scoring Atopic Dermatitis; SCORAD50/75/90, patients achieving 50/75/90% amelioration of SCORAD compared to baseline. AE, Adverse event; ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; CPK, creatine phosphokinase; HSV, herpes simplex virus; LDL, low-density lipoprotein; N, number of patients with available data. Dezoteux has been an investigator and a consultant and speaker for AbbVie, Almirall, Eli Lilly, Janssen, Leo Pharma, Novartis and Sanofi-Regeneron. Jachiet has been an investigator and/or a consultant and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Pfizer, Galderma and Sanofi-Regeneron. Soria has been an investigator and/or a consultant and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Novartis, Pfizer and Sanofi-Regeneron. Tétart has been an investigator and/or a speaker and/or consultant for Sanofi-Regeneron. Modeste-Duval has been an investigator and/or a speaker and/or consultant fort Sanofi-Regeneron. Bursztejn has been a consultant and/or speaker for AbbVie, Almirall, Amgen, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Pfizer and Sanofi-Regeneron. Misery has been an investigator and/or a consultant and/or speaker for AbbVie, Almirall, Amgen, Astra-Zeneca, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer and Sanofi-Regeneron. Aubin has been an investigator and/or a consultant and/or speaker for AbbVie, Almirall, Amgen, Astra-Zeneca, BMS, Eli Lilly, Galderma, Leo Pharma, MSD, Novartis, Pfizer, Pierre Fabre and Sanofi-Regeneron. Lasek has been an investigator and/or a speaker and/or consultant for Sanofi-Regeneron. Leleu has been an investigator for Leo Pharma, a consultant and/or speaker for AbbVie, Amgen, Eli Lilly, Novartis, and Sanofi-Regeneron. Du-Thanh has been an investigator for Leo Pharma, a consultant and/or speaker for AbbVie, Amgen, Eli Lilly, Novartis, and Sanofi-Regeneron. Pasteur has been an investigator and/or a consultant and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Novartis, Pfizer, and Sanofi-Regeneron. Pralong has been an investigator for Eli Lilly, a speaker for AbbVie, Sanofi-Regeneron. Nosbaum has been an investigator and/or a consultant and/or speaker for AbbVie, Almirall, Amgen, Eli Lilly, Galderma, Leo Pharma, Medac, Novartis, Pfizer and Sanofi-Regeneron. Droitcourt has been an investigator and/or a consultant and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Novartis, Pfizer and Sanofi-Regeneron. Viguier has been an investigator, a consultant and/or speaker for AbbVie, Almirall, Biogen, Galderma, Eli Lilly, Boehringer Ingelheim, Medac, Janssen Cilag and Bristol Myers Squibb. Seneschal has received personal fees from AbbVie, Almirall, Leo Pharma, Eli Lilly, Novartis, Pfizer, Pierre Fabre, Sanofi-Genzyme. Barbarot has been an investigator or a speaker for AstraZeneca, Almirall, Sanofi-Genzyme, AbbVie, Novartis, Janssen, Leo Pharma, Pfizer, Eli Lilly, UCB Pharma, Chiesi. Staumont-Sallé has been an investigator and/or a consultant and/or speaker for AbbVie, Almirall, Amgen, AstraZeneca, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer, Janssen and Sanofi-Regeneron. Tauber is a consultant for Abbvie, Eli Lilly, Janssen, Medac and a speaker for Abbvie, Eli Lilly, Janssen and Sanofi. Vanlerberghe and Martin have no conflicts of interest to declare.