Table 1.

Targeted treatments used in primary immunodeficiency (PID).

Drug group	Name of the drug	Type of molecular structure	Target	Mechanism of action	Indications in PID (including off-label)	Approvals and dosing
JAK Inhibitors (130, 137–140)	Ruxolitinib	Small molecule	JAK1 and JAK2	Competitively binds to the adenosine triphosphate-binding site of JAK and inhibits the enzyme activity of JAK leading to suppression of cytokine signal transduction and cytokine action	STAT3-GOF STAT1-GOF CANDLE synd. HLH Interferonopathies	FDA* and EMA*
	Tofacitinib	Small molecule	JAK1 and JAK3	Competitively binds to the adenosine triphosphate-binding site of JAK and inhibits the enzyme activity of JAK leading to suppression of cytokine signal transduction and cytokine action	STAT3-GOF STAT1-GOF CANDLE	FDA* and EMA*
	Baricitinib	Small molecule	JAK1 and JAK2	Competitively binds to the adenosine triphosphate-binding site of JAK and inhibits the enzyme activity of JAK leading to suppression of cytokine signal transduction and cytokine action	STAT1-GOF CANDLE synd.	FDA* and EMA*
TNF-α Inhibitors (130, 140, 141)	Infliximab	Chimeric (human/murine) monoclonal IgG1 antibody	TNF-α	Binds to both soluble subunit and the membrane-bound precursor of TNF-α causing a disruption of the interaction of TNF-α with its receptors	CANDLE synd. POMP deficiency PAPA synd. Blau synd. CVID STAT3 GOF	FDA*♦ and EMA*♦ ♦(IBD phenotypes – 5 mg/kg every 8 weeks after induction)
	Adalimumab	Recombinant human monoclonal IgG1 antibody	TNF-α	Binds to both soluble subunit and the membrane-bound precursor of TNF-α causing a disruption of the interaction of TNF-α with its receptors	CANDLE synd. POMP deficiency PAPA synd. Blau synd. CVID	FDA*♦ and EMA*♦ ♦(IBD phenotypes- <40kg: 20 mg/week ♦40 mg: 40 mg/week or 80 mg every other week after induction)
	Etanercept	Dimeric fusion protein	TNF-α	By competitive inhibition prevents TNF to bind to cell surface, inhibiting the pro-inflammatory activity of TNF-α	CANDLE synd. POMP synd. PAPA synd. Blau synd. CVID	FDA* and EMA*
IFN-γ inhibitor (130, 140, 142)	Emapalumab	Human monoclonal IgG1 antibody	IFN-γ	Binds to free and receptor-bound interferon-γ, inhibiting receptor dimerization and transduction of interferon-γ signaling, leading to an inhibition of its biologic activity	HLH	FDA♦ ♦ (HLH – 1 mg/kg twice a week)
Interleukin antagonist or interleukin binding drugs (110, 130, 140, 143–146)	Anakinra	Nonglycosylated, recombinant, human interleukin-1 receptor antagonist	IL-1R	Binds competitively to the Interleukin-1 type I receptor (IL-1RI), inhibiting the action of elevated levels IL-1, a proinflammatory cytokine	CASP	FDA*♦ and EMA*♦ ♦ (CASP- 1 -2 mg/kg/day)
	Canakinumab	Human IgGκ monoclonal antibody	IL- 1β	Binds to human IL-1β and neutralizes its inflammatory activity by blocking its interaction with IL-1 receptors	CAPS TRAPS MKD	FDA*♦ and EMA*♦ ♦(CASP - > 40 kg:150 mg  15-40 kg:2mg/kg  7.5-15 kg: 4 mg/kg Every 8 weeks) ♦ (TRAPS, MKD- - > 40 kg:150 mg 7.5-40 kg: 2 mg/kg Every 4 weeks)
	Rilonacept	Dimeric fusion protein	IL- 1β	Blocks IL-1β signaling by acting as a soluble decoy receptor, preventing interaction of IL-1β with cell surface receptors	CAPS	FDA♦ ♦ (CASP ♦ 18 years:320 mg at first dose; 160 mg following doses once a week 12-17 years: 4.4 mg/kg (maximum 320 mg) in the first dose, 2.2 mg/kg following doses (maximum 160 mg Once a week)
	Tocilizumab	Recombinant humanized monoclonal antibody	IL-6R	Inhibits the binding of interleukin-6 (IL-6) to its receptor (IL-6R), preventing IL-6 signal transduction to inflammatory mediators that stimulate B and T cells.	STAT3-GOF	FDA* and EMA*
	Tadekinig-alfa	Recombinant human IL-18 binding glycoprotein	IL-18	Binds to free IL-18, a proinflammatory cytokine of the IL-1 family that is produced by various cell types, including monocytes/macrophages, preventing its binding to the receptor and consequently the IL-18 biologic activity	NLCR4-GOF	Granted orphan designation by FDA and EMA
	Ustekinumab	Human immunoglobulin (Ig) G1 kappa monoclonal antibody	IL-12 and IL-23 (p40 subunit)	Binds to the p40 subunit common to IL-12 and IL-23 and prevents their interaction with the IL-12 receptor β1 subunit of the IL-12 and IL-23 receptor complexes, neutralizing human IL-12- and IL-23-mediated cell signaling, activation and cytokine production.	LAD CGD-colitis	FDA*♦ and EMA♦ ♦(IBD phenotypes ≤55 kg:260 mg 55-85Kg: 390 mg >85 mg: 520 mg)
Modulator of CD80/86 (130, 136, 140, 147)	Abatacept	Fusion protein (CTLA4 -Ig)	CD80/CD86	Binds to CD80/CD86 receptors, preventing the interaction with the CD28 receptor, blocking the signal for immune activation of T cells and antigen-presenting cell	CTLA-4 haploinsufficiency LRBA deficiency	FDA* and EMA*
	Balatacept	Fusion protein (CTLA4 -Ig) 2nd generation	CD80/CD86	Binds to CD80/CD86 receptors, preventing the interaction with the CD28 receptor, blocking the signal for immune activation of T cells and antigen-presenting cell	CTLA-4 haploinsufficiency LRBA deficiency	FDA* and EMA*
B cell directed therapies (140, 148, 149)	Belimumab	Human recombinant IgG1λ monoclonal antibody	B cell	Inhibits B-lymphocyte stimulator (BLyS), and indirectly inhibits B cell survival (autoreactive B-cell apoptosis)	Autoimmune cytopenias	FDA* and EMA*
	Bortezomib	Dipeptide boronic acid derivative	Plasma cells	Inhibits the 26S proteasome, a protein complex that degrades ubiquitinated proteins in the ubiquitin-proteasome pathway, leading to cell cycle arrest and apoptosis	Autoimmune cytopenias	FDA* and EMA*
	Epratuzumab	Anti-CD22 humanized monoclonal antibody derived from the murine IG2a monoclonal antibody	CD22	Contributes to an alteration of the B cell receptor signaling complex, reducing signaling and activation of B cells	Autoimmune cytopenias
	Ibrutinib	Small molecule	Burton’s tyrosine kinase	Inhibits Burton’s tyrosine kinase leading to perturbation of B-cell development due to the role of this target in the B-cell receptor signaling pathway	Autoimmune cytopenias	FDA* and EMA*
	Rituximab	Chimeric murine/human monoclonal antibody against the CD20	CD20	After binding to CD20, rituximab mediates B-cell lysis (or breakdown). The possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC	Autoimmune cytopenias Granulomatous lymphocytic interstitial lung disease Granulomatous disease	FDA* and EMA*
Mammalian target of rapamycin (mTOR) inhibitor (13, 150, 151)	Sirolimus	Small molecule (macrolide antibiotic)	mTOR	inhibition of the mTOR, which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, and survival.	NLCR4-GOF POMP deficiency CTLA-4 haploinsufficiency APDS	FDA* and EMA*

APDS, Activated PI3K Delta Syndrome; CANDLE, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature; CAPS, cryopyrin-associated periodic syndrome; CGD, chronic granulomatous disease; CTLA-4, cytotoxic T lymphocyte antigen-4; CVID, common variable immunodeficiency; EMA, European Medicines Agency; FDA, Food and Drug administration; GOF, Gain of function; HLH, Hemophagocytic lymphohistiocytosis; JAK, Janus kinase; LAD, leukocyte adhesion deficiency; MKD, mevalonate kinase deficiency; mTOR, mammalian target of rapamycin; PAPA, pyogenic arthritis, pyoderma gangrenosum, and acne; POMP, Proteasome maturation protein; TRAPS, tumor necrosis factor receptor associated periodic syndrome.

*Approved for other generic conditions not specified in this table.

♦ Conditions that can be considered as part of the PID described.