Immunopharmacology · Module 4 of 5

JAK Inhibitors and Targeted Small Molecules

Isoform selectivity, approved agents, ORAL Surveillance safety, and non-JAK oral therapies

JAK isoform coupling determines which cytokines are suppressed: JAK3 pairs exclusively with the γ-c chain (IL-2, -4, -7, -9, -15, -21); JAK1 pairs broadly (gp130, type I/II IFN, plus γ-c chain with JAK3); JAK2 transduces hematopoietic growth factor signals (EPO, TPO, G-CSF, GM-CSF) — its inhibition at therapeutic doses causes anemia and neutropenia; TYK2 couples with IL-12, IL-23, and type I IFN receptors.
Four approved JAK inhibitors: tofacitinib (JAK1+3, first approved 2012, RA/PsA/AS/UC); baricitinib (JAK1+2, RA/atopic dermatitis/alopecia areata — first approved systemic for alopecia areata); upadacitinib (selective JAK1, broadest indication set including Crohn's, superior to adalimumab in SELECT-COMPARE RA trial); abrocitinib (selective JAK1, atopic dermatitis only, rapid itch relief via IL-31 blockade).
ORAL Surveillance (tofacitinib vs. TNF inhibitor in high-CV-risk RA, age ≥50): tofacitinib failed non-inferiority for MACE; also higher rates of malignancy (lung cancer, lymphoma), VTE (DVT, PE), serious infections, and mortality → FDA class-wide black box warning for all JAK inhibitors; restricted to use after TNF inhibitor failure in rheumatic indications; avoid in age ≥65, smokers, prior CV disease, prior malignancy, prior VTE; Shingrix before starting.
Apremilast (PDE4 inhibitor): raises cAMP in immune cells → suppresses TNF, IL-17, IL-23; approved for psoriasis, PsA, Behçet's oral ulcers; no serious infection/malignancy/CV signals; GI adverse effects (nausea/diarrhea) managed with 5-day dose titration; strong CYP3A4 inducers (rifampin) reduce exposure — contraindicated. Ozanimod (S1P receptor modulator): traps lymphocytes in lymph nodes; approved for relapsing MS and UC; first-dose bradycardia requires 6-hour cardiac monitoring; MAO inhibitors contraindicated (serotonin syndrome).
Deucravacitinib is mechanistically distinct from all JAK inhibitors: it binds the TYK2 JH2 pseudokinase (regulatory) domain allosterically rather than the JH1 ATP-binding site, conferring >2,000-fold selectivity for TYK2 over JAK1/2/3; blocks IL-12, IL-23, and type I IFN signaling; approved for plaque psoriasis; carries none of the ORAL Surveillance-derived black box warnings and does not require prior TNF inhibitor failure.

AS = ankylosing spondylitis · cAMP = cyclic adenosine monophosphate · CYP3A4 = cytochrome P450 3A4 · EPO = erythropoietin · G-CSF = granulocyte colony-stimulating factor · IBD = inflammatory bowel disease · IGRA = interferon-gamma release assay · JAK = Janus kinase · MACE = major adverse cardiovascular events · PDE4 = phosphodiesterase 4 · PsA = psoriatic arthritis · RA = rheumatoid arthritis · S1P = sphingosine-1-phosphate · STAT = signal transducer and activator of transcription · TST = tuberculin skin test · TYK2 = tyrosine kinase 2 · UC = ulcerative colitis · VTE = venous thromboembolism

JAK Isoform → Cytokine Receptor Pairing

JAK1

Broad Cytokine Signaling

IL-2, -4, -7, -9, -15, -21 (with JAK3, via γ-c chain)
IL-6 family (via gp130)
Type I interferons (IFN-α/β) and type II IFN (IFN-γ)

JAK2

Hematopoietic Growth Factors

Erythropoietin, thrombopoietin, growth hormone
G-CSF, GM-CSF; IFN-γ
Inhibition at therapeutic doses → anemia + neutropenia

JAK3

Common γ-Chain Only

IL-2, -4, -7, -9, -15, -21 exclusively (the common γ-chain cytokine family)
Always pairs with JAK1
Expressed on hematopoietic cells only — narrower off-target profile

TYK2

IL-12 / IL-23 / Type I IFN

IL-12 (Th1 differentiation), IL-23 (Th17 expansion)
Type I interferons (IFN-α/β)
Target of deucravacitinib (allosteric JH2 inhibition)

Approved JAK Inhibitors

Feature	Tofacitinib	Baricitinib	Upadacitinib	Abrocitinib
Selectivity	JAK1 + JAK3	JAK1 + JAK2	JAK1 (selective; ~60× over JAK2)	JAK1 (selective)
Key indications	RA, PsA, AS, UC, polyarticular JIA	RA, atopic dermatitis, alopecia areata	RA, PsA, AS, atopic dermatitis, Crohn's, UC	Atopic dermatitis only
Notable feature	First JAK inhibitor approved (2012); ORAL Surveillance index trial	First systemic therapy approved for alopecia areata (blocks IFN-γ and IL-15 driving follicle autoimmunity)	Broadest indication set; superior to adalimumab in SELECT-COMPARE RA trial (ACR50 at 26 wk)	Rapid itch relief within days via IL-31 blockade; approved for moderate-to-severe AD

ORAL Surveillance → Class-Wide Black Box Warning

ORAL Surveillance Trial (tofacitinib vs. TNF inhibitor)

Key Findings

Population: RA age ≥50 with ≥1 CV risk factor
Tofacitinib failed non-inferiority for MACE vs. TNF inhibitor
Higher malignancy: lung cancer, lymphoma
Higher VTE: DVT and pulmonary embolism
Higher serious infections and all-cause mortality
Results published N Engl J Med 2022; led to FDA class-wide action

Class-Wide Black Box Warning — All JAK Inhibitors

FDA Restrictions

Use after TNF inhibitor failure (rheumatic indications)
Avoid when possible: age ≥65, current/past smokers, established CV disease, prior malignancy, prior VTE
Pre-treatment: TST/IGRA, HBV serology, CBC, fasting lipid panel
Shingrix before starting — herpes zoster 2–4× baseline risk
Covers: serious infections, malignancy, MACE, thrombosis, mortality

Non-JAK Oral Small Molecules — No Black Box Warnings

PDE4 Inhibitor

Apremilast

PDE4 hydrolyzes cAMP → inhibition raises intracellular cAMP → activates PKA → suppresses TNF, IL-17, IL-23, IFN-γ; increases IL-10
Anti-inflammatory but not broadly immunosuppressive
Psoriasis, PsA, Behçet's oral ulcers; PASI 75 ~30–40% (vs. 60–80% for biologics)
No serious infection, malignancy, or CV risk signals
GI adverse effects (nausea, diarrhea ~30%) — manage with 5-day dose titration
Rifampin (strong CYP3A4 inducer): contraindicated

S1P Receptor Modulator

Ozanimod

Downregulates S1P receptor 1 on lymphocytes → traps mature lymphocytes in lymph nodes and Peyer's patches → peripheral lymphopenia (reversible on stopping)
Approved: relapsing multiple sclerosis, moderate-to-severe UC
First-dose bradycardia and AV block → 6-hour cardiac monitoring after first dose
Macular edema: ophthalmic exam before initiation
MAO inhibitors: contraindicated (serotonin syndrome via active ozanimod metabolites)
Herpes zoster risk increased; Shingrix recommended before initiation

TYK2 Allosteric Inhibitor

Deucravacitinib

Binds TYK2 JH2 pseudokinase (regulatory) domain — not the JH1 ATP-binding site used by all other JAK inhibitors
>2,000-fold selectivity for TYK2 over JAK1/2/3 — allosteric mechanism spares JAK-dependent hematopoiesis and metabolism
Blocks IL-12, IL-23, and type I IFN signaling → suppresses Th1/Th17 axis
Approved: moderate-to-severe plaque psoriasis; PASI 75 ~58–62% (POETYK PSO-1/PSO-2 — superior to apremilast)
No prior TNF inhibitor failure required; no JAK inhibitor black box warnings

Oral Small Molecule vs. Biologic Positioning — IBD and High-Risk Patients

Prefer JAK inhibitor (tofacitinib / upadacitinib) when: rapid onset needed (hospitalized UC); patient declines injections; oral therapy preferred. Prefer biologic over JAK inhibitor when: age ≥65; high cardiovascular risk; prior malignancy; prior VTE; heavy smoker; pregnancy planning (certolizumab is preferred biologic). Prefer vedolizumab over JAK inhibitor in IBD when: older patients, prior malignancy, recurrent serious infections, or high cardiovascular risk — its gut-selective alpha-4/beta-7 integrin blockade avoids systemic immunosuppression, with no TB screening requirement equivalent to TNF inhibitors and no signals for malignancy or cardiovascular events; trade-off is slower onset (benefit often not apparent until week 12–14). Deucravacitinib niche: oral psoriasis therapy without JAK inhibitor liability; no prior TNF inhibitor failure required; positioned between apremilast and biologic agents. Biologics and oral small molecules are not combined in clinical practice.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter on Immunopharmacology	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill; 2023
O’Shea JJ, Schwartz DM, Villarino AV, et al	The JAK-STAT pathway: impact on human disease and therapeutic intervention	Annu Rev Med. 2015;66:311–328
Smolen JS, Genovese MC, Takeuchi T, et al	Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment	J Rheumatol. 2019;46(1):7–18
Fleischmann R, Pangan AL, Song IH, et al	Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate	Arthritis Rheumatol. 2019;71(11):1788–1800
Ytterberg SR, Bhatt DL, Mikuls TR, et al	Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis	N Engl J Med. 2022;386(4):316–326
Winthrop KL	The emerging safety profile of JAK inhibitors in rheumatic disease	Nat Rev Rheumatol. 2017;13(4):234–243
Papp K, Reich K, Leonardi CL, et al	Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque psoriasis	J Am Acad Dermatol. 2015;73(1):37–49
Sandborn WJ, Feagan BG, Wolf DC, et al	Ozanimod induction and maintenance treatment for ulcerative colitis	N Engl J Med. 2016;374(18):1754–1762
Armstrong AW, Gooderham M, Warren RB, et al	Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis	J Am Acad Dermatol. 2023;88(1):29–39
Feagan BG, Rutgeerts P, Sands BE, et al	Vedolizumab as induction and maintenance therapy for ulcerative colitis	N Engl J Med. 2013;369(8):699–710
Sandborn WJ, Su C, Sands BE, et al	Tofacitinib as induction and maintenance therapy for ulcerative colitis	N Engl J Med. 2017;376(18):1723–1736
Loftus EV Jr, Panes J, Lacerda AP, et al	Upadacitinib induction and maintenance therapy for Crohn’s disease	N Engl J Med. 2023;388(21):1966–1980
Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S	American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases	Gastroenterology. 2017;153(3):835–857