Table 1.

New targeted therapies in Takayasu Arteritis.

Drug	Pathogenetic basis	Evidence in TAK	Recommendations and clinical use
TNF-α inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab pegol)	Inhibitors of TNF-α (bDMARDs): • TNF-α has a major role in the development of TAK granulomatous inflammation • In active TAK higher serum levels of TNF-α and higher mRNA expression and intracellular production by T cells	• Cohort studies and open-label prospective study, showing positive results in TAK patients (clinical improvement, GC sparing effect, higher sustained remission rate compared to cDMARDs) (19–24) • No RCTs • Meta-analysis with 19 observational studies, showing more than 80% of treated patients attaining at least partial clinical response (25) • Good safety profile in cohort studies	• 2018 EULAR recommendations: TNF-α inhibitors as second line treatment in TAK patients resistant to csDMARD • 2021 ACR guidelines: TNF-α inhibitors as first line treatment, like methotrexate and azathioprine
Tocilizumab	Anti-IL-6r (bDMARD) • IL-6 is a pro-inflammatory cytokine • Higher IL-6 levels in TAK patients compared to HC and in TAK patients with active disease compared to patients with low disease activity	• Cohort studies, showing positive results in TAK patients (clinical improvement, GC sparing effect, higher sustained remission rate compared to cDMARDs) (22, 26–30) • Meta-analysis with 22 observational studies, showing more than 87% of treated patients attaining at least partial clinical response (25) • One RCT (TAKT study): relapse-free survival tended to be improved in treated patients, but no statistical significance. Longer-term open-label extension showed GC sparing effect, lower radiological disease progression, better PROs (31, 32) • Good safety profile in cohort studies and RCT	• 2018 EULAR recommendations: tocilizumab as second line treatment in TAK patients resistant to csDMARD • 2021 ACR guidelines: tocilizumab as second line treatment in patients with inadequate response to other immunosuppressive therapies
JAK-Inhibitors (tofacitinib, upadacitinib)	Inhibitors of JAK-STAT signaling pathway (tsDMARDs) • block signaling of cytokine implicated in TAK pathogenesis (type 1 and 2 interferons, IL-6, IL-12, IL-17 and IL-23) • suppress tissue-resident memory T cells and reduce inflammatory-related vascular damage	Tofacitinib: • Case reports and one prospective observational study, showing positive results in TAK patients (clinical improvement, lower radiological disease progression, superior to methotrexate) (33–37) • Good safety profile • One ongoing RCT (NCT04299971) Upadacitinib: • One ongoing RCT (NCT04161898) No data on other JAK-Inhibitors	• Only case reports • Not included in 2018 EULAR recommendations or 2021 ACR guidelines
Rituximab	Anti-CD20 (bDMARD) • In TAK patients B-cells infiltrates in the inflamed arteries adventitia and high levels of activated B-cell subsets in the peripheral blood • Rituximab blocks B cell differentiation and B-T cell stimulation	• Isolated case reports on rituximab in TAK with contradictory results (38–42) • No RCTs, no meta-analysis, no ongoing trial	• Very limited evidence with contradictory results • Only case reports • Not included in 2018 EULAR recommendations or 2021 ACR guidelines
Abatacept	Soluble fusion protein CTLA4-Ig (bDMARD) • In TAK patients B-cells infiltrates in the inflamed arteries adventitia and high levels of activated B-cell subsets in the peripheral blood • Abatacept blocks B-T cell co-stimulation	• One RCT with 34 TAK patients: abatacept not associated with a longer median duration of remission compared to placebo (43)	• 2021 ACR guidelines: Abatacept is not recommended in TAK
Ustekinumab	Anti-p40. IL-12 and IL-23 inhibitor (bDMARD) • Th17 and Th1 pathways contribute to TAK pathogenesis • Ustekinumab target p40, a common subunit of IL-12 and IL-23 (main cytokines involved in Th17 and Th1 pathways)	• A small prospective observational study (improvement in clinical symptoms but no changes in intramural enhancement on MRA) (44) • One ongoing RCT (NCT04882072)	• Very limited evidence • Not included in 2018 EULAR recommendations or 2021 ACR guidelines

TNF, Tumor necrosis factor; GC, glucocorticoids; cDMARDs, conventional disease modifying agents; bDMARDs, biological disease modifying agents; tsDMARDs, targeted synthetic disease modifying agents; IL, interleukin; IL-6r, interleukin-6 receptor; HC, healthy controls; MRA, magnetic resonance angiography; RCT, randomized controlled trial.