Chapter 40 · Module 4
JAK Inhibitors and Targeted Small Molecules
Isoform selectivity, approved agents, ORAL Surveillance safety, and non-JAK oral therapies
ACR50 = 50% improvement in American College of Rheumatology criteria  ·  AD = atopic dermatitis  ·  AS = ankylosing spondylitis  ·  AUC = area under the curve  ·  cAMP = cyclic adenosine monophosphate  ·  CYP3A4 = cytochrome P450 3A4  ·  GI = gastrointestinal  ·  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, IL-4, IL-7, IL-9, IL-15, IL-21 (with JAK3)
  • IL-6 family (gp130)
  • Type I + II interferons
JAK2
Hematopoietic Growth Factors
  • Erythropoietin, thrombopoietin
  • G-CSF, GM-CSF, growth hormone
  • Inhibition → anemia, neutropenia
JAK3
Common Gamma Chain Only
  • IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 exclusively
  • Always pairs with JAK1
  • Expressed on hematopoietic cells only
TYK2
IL-12/IL-23/Type I IFN
  • IL-12, IL-23 (Th1/Th17 axis)
  • Type I interferons (IFN-alpha/beta)
  • Target of deucravacitinib
Approved JAK Inhibitors
Feature Tofacitinib Baricitinib Upadacitinib Abrocitinib
Selectivity JAK1 + JAK3 JAK1 + JAK2 JAK1 (selective) JAK1 (selective)
Key indications RA, PsA, AS, UC RA, AD, alopecia areata RA, PsA, AS, AD, Crohn's, UC AD only
Notable feature First approved JAK inhibitor (2012) First approved systemic for alopecia areata Superior to adalimumab in RA (SELECT-COMPARE) Rapid itch relief via IL-31 blockade
ORAL Surveillance → Class-Wide Black Box Warning
ORAL Surveillance Trial (tofacitinib vs. TNF inhibitor)
Key Findings
  • Tofacitinib failed non-inferiority for MACE vs. TNF inhibitor
  • Higher malignancy: lung cancer, lymphoma
  • Higher VTE: DVT and pulmonary embolism
  • Higher serious infections, mortality
Class-Wide Black Box Warning (all JAK inhibitors)
FDA Restrictions
  • Use after TNF inhibitor failure (rheumatic indications)
  • Avoid in age ≥65, smokers, prior CV disease, prior malignancy, prior VTE
  • Pre-treatment: TST/IGRA, HBV serology, CBC, lipids
  • Shingrix before starting — herpes zoster 2-4x baseline risk
Non-JAK Oral Small Molecules — No Black Box Warnings
PDE4 inhibitor
Apremilast
  • Inhibits PDE4 → raises cAMP → suppresses TNF, IL-17, IL-23
  • Psoriasis, PsA, Behcet's oral ulcers
  • No serious infection / malignancy / CV signals
  • Main AE: GI (nausea, diarrhea — titrate over 5 days)
  • Rifampin (CYP3A4 inducer): contraindicated
S1P receptor modulator
Ozanimod
  • Downregulates S1P receptor 1 on lymphocytes
  • Traps lymphocytes in lymph nodes → peripheral lymphopenia
  • Relapsing MS, UC
  • First-dose bradycardia → cardiac monitoring 6 hr
  • MAO inhibitors: contraindicated (serotonin syndrome)
TYK2 allosteric inhibitor
Deucravacitinib
  • Binds TYK2 JH2 pseudokinase domain (allosteric)
  • >2,000-fold selectivity for TYK2 over JAK1/2/3
  • Blocks IL-12, IL-23, type I IFN signaling
  • Plaque psoriasis; no prior TNF failure required
  • No JAK inhibitor black box warnings
IBD Small Molecule Positioning

Tofacitinib / upadacitinib: rapid onset, oral, JAK black box applies  ·  Ozanimod: oral, slower onset, no JAK warnings  ·  Vedolizumab (biologic): gut-selective, safest for high-risk patients (elderly, malignancy history)  ·  Do not combine biologics or small molecules in IBD.