External Medicine
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JAK-inhibitors
MECHANISM OF ACTION
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The JAK kinases are a family of signal transduction proteins that act in the JAK-STAT pathway. Their activation is via binding of numerous cytokines (table of cytokines and corresponding JAK molecule, here) which leads to phosphorylation and dimerization of STAT proteins, which translocate to the nucleus and regulate gene transcription (figure). An infographic provided by Pfizer can be found here, and reproduced internally on this website here.
Drug Name (Brand) | Mechanism of Action (Inhibition) | FDA Indications |
|---|---|---|
Abrocitinib (Cibinqo) | JAK 1 | Atopic dermatitis |
Baracitinib (Olumiant) | JAK 1/2 | Skin: alopecia areata; Other: RA, COVID |
Deucravacitinib (Sotyktu) | TYK 2 | Psoriasis |
Ruxolitinib (Jakafi, Opzelura) | JAK 1/2 | Skin: atopic dermatitis, vitiligo (Opzelura); Other: myelofibrosis, polycythemia vera, GvHD |
Tofacitinib (Xeljanz) | JAK 1/3 | PsA, RA, UC |
Upadacitinib (Rinvoq) | JAK 1 | Skin: atopic dermatitis; Other: RA, PsA, Ank Spon, UC |
Adapted from PMID: 34246698, table 2.
SAFETY
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The concerns regarding safety with JAK inhibitors largely comes from data comparing tofacitinib to TNF-alpha inhibitors in RA patients (ORAL surveillance study) in which all participants were >50 yo, were also on methotrexate, AND had at least one pre-existing cardiovascular risk factor. The study showed increased rates of MACE and cancers (including NMSC) at both 5mg and 10mg tofacitinib doses compared to TNFi. Risk of PE, but not DVT, was increased at 10mg dose, as well as death from any cause. (35081280) This resulted in a black box warning which extended to other JAK inhibitors regardless of molecular selectivity (JAK1, 2, or 3), even though selectivity for certain receptors may impact safety. JAK inhibitors also appear to display dose-dependent selectivity of JAK1, 2, 3, and TYK2. (35679017) Patients taking JAK inhibitors are at increased risk of herpesvirus infections, notably herpes zoster, and also malignancy, MACE, and VTE. The latter two, MACE and VTE, are particularly increased in patients who have a history of venous thromboembolism, smoke, are >65 years old, and are on hormone replacement therapy/oral contraceptive use. However, increased risk of MACE and VTE have not been demonstrated for more selective JAKi like abrocitinib and upadicitinib. ()
Daniele S, Bunick C. JAK Inhibitor Safety Compared to Traditional Systemic Immunosuppressive Therapies. J Drugs Dermatol. 2022. PMID: 36468956.
SUMMARY: This is a nice original paper looking to compare safety of abrocitinib (Cibinqo) and upadacitinib (Rinvoq) in patients with atopic dermatitis to methotrexate, cyclosporine, and systemic corticosteroids. Data were not available specifically for the non-JAKi in the setting of atopic dermatitis, so it was compared to use of methotrexate in RA patients, cyclosporine in psoriasis patients, and prednisone in a few different cohorts: and inflammatory bowel disease in men >65 (malignancy and NMSC), population-based cohort in patients taking prednisone >7.5mg (MACE). Authors correctly not limitations in comparing studies with different patient populations with respect to comorbidities and age, primarily, and also the more limited total person-years of exposure for JAKi given their relative newness.
Drug/Event Rate per 100 patient-yrs | Malignancy (excluding NMSC) | NMSC | MACE | VTE |
|---|---|---|---|---|
Upadacitinib 15mg (30mg) | 0.2 (0.5) | 0.4 (0.4) | 0.1 (0.0) | 0.1 (0.1) |
Abrocitinib 100mg (200mg) | 0.2 (0.2) | 0.6 (0.4) | 0.6 (0.2) | 0.0 (0.4) |
Methotrexate | 0.5 | 0.3 | 0.5 | 0.5 |
Cyclosporine | 0.6 | 0.5 | 2.8 | no data |
Systemic Corticosteroids | 4.3 | 3.9 | 7.6 | 0.02 |
Atopic Dermatitis Baseline Rate | 0.33 | 0.09 | 0.63 | 0.31 |
Reference (Control) Population | 0.42 | 0.12 | 0.14 | 0.25 |
Association of Risk of Incident Venous Thromboembolism With Atopic Dermatitis and Treatment With Janus Kinase Inhibitors: A Systematic Review and Meta-analysis. JAMA Dermatol. 2022. PMID: 36001310.
SUMMARY: Large meta-analysis of over 8,700 patients showed no increased risk of VTE in 5,722 patients taking abrocitinib, baricitinib, upadacitinib, or SHR0302 (unknown JAK1 inhibitor) for atopic dermatitis. Risk of VTE was 0.15 per 100 patient-years in those taking JAKs, 0.12 per 100 patient-years in those taking placebo.
Ingrassia JP, Maqsood MH, Gelfand JM, et al. Cardiovascular and Venous Thromboembolic Risk With JAK Inhibitors in Immune-Mediated Inflammatory Skin Diseases: A Systematic Review and Meta-Analysis. JAMA Dermatol. 2024. PMID: 37910098.
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Review of all phase 3 RCTs for abrocitinib, baricitinib, upadicitinib, tofacitinib, and ritlecitinib for skin conditions, as well as ruxolitinib and delgocitinib creams.
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Looked at compositie MACE and all-cause mortality, and VTE as primary outcomes.
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There was no difference between JAK inhibitors and placebo for MACE and all cause mortality (OR 0.83, 0.44-1.57) or VTE (OR 0.52, 0.26-1.04).
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Patients in this review were notably younger than in the ORAL surveillance study, mean age 38.5yrs vs 61yrs, and did not have at least 1 cardiovascular risk factor or concomitant use of methotrexate or prednisone.
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However, the duration of followup in this study was only average 4.9 months compared to the ORAL surveillance study for which it was 4 years.
BARICITINIB (OLUMIANT)
Clinical Trials/Studies
King B, Ohyama M, Kwon O, Zlotogorski A, Ko J, Mesinkovska NA, Hordinsky M, Dutronc Y, Wu WS, McCollam J, Chiasserini C, Yu G, Stanley S, Holzwarth K, DeLozier AM, Sinclair R; BRAVE-AA Investigators. Two Phase 3 Trials of Baricitinib for Alopecia Areata. N Engl J Med. 2022 May. Epub 2022 Mar 26. PMID: 35334197.
BACKGROUND: The biggest concerns about the JAK inhibitors is their safety surrounding clotting and cardiovascular incidents primarily as a result of the experiences and trials of tofacitinib for rheumatoid arthritis. As a result, it is important to analyze details of the studies and draw comparisons so that the true risk of baricitinib can be assessed. For reference, a NEJM article comparing tofacitinib to TNF inhibitors for RA will be used (35081280). For this baricitinib RCT, average age was ~38yo, and no mention of excluding patients with certain cardiovascular risk factors in the paper or in the supplementary material, although in the supplementary material it does mention to see the "study protocol" for further inclusion and exclusion details. The NEJM article for tofacitinib for RA had an average patient age of ~61yo, and have at least one additional cardiovascular risk factor (RA itself is a risk factor).
SAFETY: Considering adverse events of special interest (MACE, VTE, cancer, or GI perforation, only 1 MACE occurred in the baricitinib 2mg arm in a 48yo patient with multiple CV risk factors. There was also 1 cancer in the placebo arm and 1 in the 4mg arm. UTIs appeared more common in baricitinib treated patients. Herpes zoster occurred in ~1% of patients, 0.5% in the placebo group, 1.1% in baricitinib 2mg group, and 1% in baricitinib 4mg group. Herpes simplex occurred more frequently in the placebo arm. There were no opportunistic infections or cases of TB.