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Review

Biologic Therapies and Janus Kinase Inhibitors for Medium and Variable Vessel Vasculitides: A Review of Clinical and Preclinical Evidence

by
Allison Bai
1,2,*,
Rachel Granovsky
3,
Courtney Chau
4 and
Gabriela Cobos
2
1
Department of Dermatology, University of Illinois College of Medicine Peoria, 1 Illini Dr, Peoria, IL 61605, USA
2
Department of Dermatology, Tufts Medical Center, Boston, MA 02116, USA
3
Department of Dermatology, Tufts University School of Medicine, 145 Harrison Ave, Boston, MA 02111, USA
4
Department of Dermatology, Icahn School of Medicine at Mt. Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA
*
Author to whom correspondence should be addressed.
Allergies 2025, 5(3), 29; https://doi.org/10.3390/allergies5030029
Submission received: 26 March 2025 / Revised: 21 July 2025 / Accepted: 1 August 2025 / Published: 22 August 2025
(This article belongs to the Section Physiopathology)
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Abstract

Medium and variable vessel vasculitides are a heterogeneous group of rare, immune-mediated vascular disorders that are associated with significant morbidity and mortality. The standard treatment approach involves glucocorticoids and immunosuppressive agents. However, many patients exhibit poor tolerance or respond inadequately to these medications. Recent advances in biologic therapies and Janus Kinase inhibitors (JAKis) offer promising alternatives. This review consolidates current knowledge on the pathogenesis, immunology, and therapeutic efficacy of biologics and JAKis in the management of medium and variable vessel vasculitis. While further research is needed to establish long-term safety and optimize treatment protocols, biologics and JAKis represent emerging therapeutic strategies with the potential to improve outcomes.

1. Introduction to Medium and Variable Vessel Vasculitis

Medium vessel vasculitis (MVV) and variable vessel vasculitis (VVV) refer to a group of autoimmune disorders characterized by inflammation and damage to the blood vessel walls. Medium-sized vessels are defined as those measuring 800 μm or less in diameter, featuring four to eight layers of medial smooth muscle, and possessing an indistinct tunica adventitia. These vessels are primarily located in the subcutis or at the dermal–subcutaneous junction and include the main visceral vessels and their initial branches [1]. MVV includes polyarteritis nodosa (PAN) and Kawasaki disease (KD). VVVs involve arteries and veins of all sizes and include Behçet’s disease (BD), deficiency of ADA2 (DADA2), and Cogan syndrome (CS) (Figure 1).
Advancements in our understanding of the pathogenesis of MVV and VVV have led to the utilization of biologic and Janus Kinase inhibitor (JAKi) therapies. Case reports, case series, and preliminary clinical trials have highlighted their therapeutic potential, with ongoing and future studies aimed at validating their effectiveness and determining how they may complement or potentially supplant existing treatment regimens with traditional immunosuppressants. Importantly, these medications may also reduce prolonged glucocorticoid use [2].
In recent years, literature has been published reviewing the use of biologics and JAKis in large- and small-vessel vasculitis, leading to evidence-based recommendations for the use of tocilizumab (TCZ) in giant cell arteritis (GCA) and rituximab (RTX) for ANCA-associated vasculitis [3,4,5,6]. Yet, no comparable reviews exist for medium and variable vessel vasculitis. This review seeks to build upon existing findings to fill this gap in the literature (Table 1 and Table 2) [7,8].

2. Polyarteritis Nodosa

2.1. Overview

PAN is a necrotizing vasculitis of medium-sized vessels, characterized by the absence of glomerulonephritis and antineutrophil cytoplasmic antibodies (ANCA). The majority of cases are idiopathic. While historically linked to the hepatitis B virus (HBV), the incidence of HBV-associated PAN has markedly decreased in recent years, largely due to widespread vaccination efforts [195,214]. Systemic PAN presents with multisystem involvement, with the skin and peripheral nerves being the most commonly affected. Gastrointestinal tract, kidneys, heart, or central nervous system involvement is associated with increased mortality [215]. Of note, cutaneous PAN is a rare localized variant of PAN that presents without systemic organ involvement and manifests predominantly with cutaneous manifestations, such as livedo racemosa, nodules, and ulcers [216]. Histopathologic confirmation, preferably from skin, muscle, or nerve biopsies, is helpful for diagnosis. When biopsy results are inconclusive or difficult to obtain, microaneurysms observed in a visceral angiography can provide additional diagnostic support [217].
The pathophysiology of PAN is not fully understood but is believed to involve an inflammatory response mediated by various cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-alpha (IFN-α), interleukin-2 (IL-2), and interleukin-1 beta (IL-1β) [218,219]. Biologics and JAKis that target these cytokines have shown promising results. The unclear role of B-cells in PAN, with no specific antibodies identified, may explain the mixed evidence for RTX efficacy in treating the disease.

2.2. Treatment

Historically, idiopathic PAN has been treated first-line with high-dose systemic glucocorticosteroids for induction, combined with immunosuppressants like cyclophosphamide (CYC), azathioprine (AZA), methotrexate (MTX), and mycophenolate mofetil (MMF) for maintenance therapy [220,221,222]. HBV-associated PAN is treated primarily with antivirals and with short-term glucocorticoids for acute inflammation; however, broad immunosuppression is typically avoided to prevent the exacerbation of viral replication [220].
Regarding biologics, a 2021 narrative review of 51 articles, involving 58 patients with PAN, found promising results from TNF-α inhibitors (infliximab (IFX), etanercept (ETN), and adalimumab (ADA)) and the IL-6 receptor antagonist TCZ, with mixed results for RTX. IFX successfully treated 83% (25/30) of patients, ETN treated 80% (8/10), ADA treated 50% (2/4), TCZ treated 92% (11/12), and RTX treated 61% (8/13), with four treatment failures and one relapse [21]. A 2022 European retrospective study of 42 PAN patients found TCZ achieved the highest remission rate at 50% (5/10), followed by TNF-α blockers at 40% (6/15), and RTX at 33% (6/18). No response was observed in patients treated with other biologics, including anakinra (n = 4), alemtuzumab (n = 3), IFN-α (n = 2), and abatacept (n = 1) [111]. TCZ has since successfully treated cutaneous PAN (cPAN) with refractory lower-limb ulcers in a 61-year-old Japanese patient, who had not responded to corticosteroids, cyclophosphamide, and endovascular therapy in a 2024 case report [135]. A phase-two, randomized, placebo-controlled clinical trial (NCT05168475) investigating the efficacy of IFX, RTX, and TCZ in treating refractory non-ANCA-associated vasculitis (NAAV), including PAN, is currently underway [38].
There is very limited data on the use of JAKis in PAN, with only seven cases published to date, with six describing the use of JAK1/3 inhibitor tofacitinib (TOF) and one describing the use of JAK1/JAK2 inhibitor baricitinib (BAR). JAKis modulate JAK-STAT signaling pathways, disrupting pro-inflammatory cytokine signaling, including IL-6, IFN-γ, and GM-CSF, which are implicated in PAN vascular inflammation and endothelial dysfunction [221,222]. JAK1 mediates signaling for IL-6, IL-10, IL-11, and type I interferons, while JAK3, when paired with JAK1, transmits signals from cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [222,223]. A 2016 case report described a 28-year-old man with systemic PAN who was successfully treated with TOF [196]. In 2022, a case was published detailing a 9-year-old girl with PAN who, after remaining steroid-dependent on ETN, achieved disease remission after switching to TOF [224]. In a 2023 case series, four patients with cPAN were successfully treated with TOF monotherapy [192]. In a 2024 case, a 29-year-old woman with cPAN quickly achieved remission with a low dose of BAR and prednisone [201].

3. Kawasaki Disease

3.1. Overview

KD is an acute pediatric vasculitis characterized by fever, conjunctivitis, rash, and lymphadenopathy, with the potential to cause coronary artery aneurysms. KD is theorized to be an abnormal immune response in genetically predisposed individuals to a common environmental trigger, possibly a virus or environmental toxin. Early in the disease, there is necrotizing arteritis of medium-sized vessels, most notably the coronary arteries. Infiltration of vessel walls by monocytes, macrophages, neutrophils, CD8+ T cells, and IgA+ plasma cells damages the intima, media, and adventitia layers of vessel walls. Pro-inflammatory cytokines, namely TNF-α and IL-1β, further promote endothelial cell injury. Serum concentrations of IL-1β and IL-18 are higher in children with KD. Mouse models provide further support for the overactivation of the NLRP3 inflammasome and resultant excessive production of IL-1β. This contributes to both the acute inflammatory response and the persistent chronic inflammation seen in KD. IL-1β is therefore an emerging target for therapeutic intervention by biologic therapies. As KD progresses, vascular damage evolves into subacute or chronic vasculitis and luminal myofibroblast proliferation. The immune infiltrates at this stage consist mainly of CD8+ T cells, IgA+ plasma cells, eosinophils, and macrophages, continuing to secrete inflammatory cytokines that drive the progression of disease. Myofibroblast proliferation leads to progressive luminal narrowing, stenosis, and potential thrombosis of the vasculature [225].

3.2. Treatment

Standard treatment involves early administration of intravenous immunoglobulin (IVIG) and aspirin. For patients with persistent symptoms, repeat IVIG or methylprednisolone may be effective. Among biologics, anakinra and infliximab (IFX) are the most commonly used. Emerging evidence also supports the potential use of ETN, RTX, TCZ, canakinumab (CAN), and abciximab (ABC), though their applications are less well-defined compared to anakinra and IFX.
Anakinra binds to the IL-1 receptor, blocking the action of the pro-inflammatory cytokine IL-1. A comprehensive systematic review performed in March 2020 identified 36 cases of anakinra use. Since then, four additional cases have been described of anakinra used as adjunctive treatment for KD [62,173,177]. A phase-I/IIa dose-escalation study (NCT02179853) of anakinra in 22 children with acute KD and coronary artery aneurysms found that up to 6 weeks of treatment (up to 11 mg/kg/day) was safe, well-tolerated, and effective in reducing coronary artery inflammation. Patients receiving IVIG and anakinra had similar reductions in inflammation markers (IL-6, IL-8, TNF-α) as those treated with IVIG and IFX alone. Both IV and SC anakinra were safe and effective, with simulations suggesting that more frequent IV dosing could sustain drug levels without increasing peak concentrations, highlighting the potential benefits of short-term IV therapy during hospitalization [156]. In a phase-II study (NCT02390596) of 16 IVIG-resistant KD patients, anakinra was well-tolerated and led to a rapid reduction in fever, with 75% (12/16) of patients in the intention-to-treat group and 87.5% (7/8) in the per-protocol group becoming afebrile within 48 h. Additionally, anakinra improved disease activity, normalizing CRP levels by day 30, and showed some efficacy in reducing coronary artery dilation, with 50% (8/16) of patients achieving improved coronary artery Z scores by day 45 [158].
Several clinical trials investigating anakinra for KD are ongoing. Currently, there is an active pilot study (NCT04747847) investigating the ability of anakinra administered with atorvastatin to prevent coronary artery damage in children with early KD-related coronary abnormalities [169]. There is a phase-III trial underway (ANACOMP, NCT04656184) comparing anakinra with IVIG retreatment in KD patients who failed initial IVIG therapy, which is currently recruiting [170]. Planned for the future, there is an interventional trial (NIKITA, NCT06697431) evaluating whether anakinra is non-inferior to IVIG in terms of controlling fever and preventing coronary dilation or aneurysms in the acute phase of KD [171]. These trials will help offer conclusive evidence for anakinra as an effective, safe alternative to traditional therapies for KD, particularly in patients with refractory symptoms or ongoing coronary risks.
The TNF-α inhibitor IFX has been widely explored for IVIG-resistant KD with promising results. There have been 1257 cases published thus far [14]. A multicenter, randomized, prospective trial (NCT00271570) of IFX versus second IVIG infusion in individuals up to 18 years of age with IVIG-resistant KD published in 2008 found that fever resolved within 24 h for 92% (11/12) of subjects treated with IFX, compared to 67% (8/12) of subjects retreated with a second IVIG infusion. There were no infusion reactions, serious adverse events, or significant differences in laboratory variables, fever, or echocardiographic assessments of coronary arteries between treatment groups [35]. In a 2016 study of IVIG-resistant KD patients, 66% (21/32) of patients responded to retreatment with IVIG compared to 91% (10/11) of patients who responded to IFX and did not need additional treatment. There was no significant difference in the occurrence of adverse events or coronary artery lesions [36]. A 2018 phase-three, randomized multicenter trial (NCT01596335) of 31 IVIG-resistant KD patients, with 16 assigned to IFX and 15 to repeat IVIG, found that IFX improved the 48 h defervescence rate and time to defervescence compared to IVIG and was well tolerated, with no significant difference in the occurrence of adverse effects or coronary artery lesions [13]. A randomized, multicenter comparative effectiveness trial (NCT03065244) of IFX versus second IVIG infusion for IVIG-resistant KD published in 2021 found that 77% (40/52) of patients in the IFX group achieved absence of fever recurrence during the first week after discharge, compared to 51% (25/49) in the second IVIG group. The IFX group patients also experienced fewer days of fever, less severe anemia, and fewer serious adverse events [12].
The TNF-α inhibitor ETN has also been explored as a potential treatment for KD. The highest-level evidence comes from a 2018 randomized, double-blind, placebo-controlled study (NCT00841789) of ETN as an adjunct to IVIG in 205 Kawasaki disease (KD) patients, with 100 receiving ETN and 101 receiving a placebo. Subgroup analysis revealed a significant reduction in IVIG resistance in patients older than one year (p = 0.03) and mitigation of coronary artery dilation, particularly in those with baseline abnormalities (p = 0.03), without added safety concerns. A follow-up analysis reported IVIG resistance in 13/100 ETN patients versus 22/101 placebo patients, with coronary artery dilation in 56/100 ETN patients compared to 53/101 placebo patients [86,87,99,100,101,112,124]. A long-term follow-up, however, found that the ETN (n = 22) group had similar long-term outcomes to the placebo group, suggesting that ETN may accelerate the resolution of coronary artery dilation but does not alter long-term disease progression [226].
RTX (n = 4) and TCZ (n = 4) have successfully treated KD in a few published cases [227]. CAN, a monoclonal antibody against IL-1β, shows promise. In 2017, an industry-sponsored, phase-two, multicenter trial (EudraCT 2019-002783-2) was initiated in Europe, enrolling IVIG-resistant and early-diagnosed, treatment-naïve patients with KD for treatment with CAN [173]. However, findings have yet to be reported. Although no findings are available for human subjects, a mouse model of KD treated with an anti-IL-1β antibody showed reduced vasculitis severity [228].
ABC, a chimeric monoclonal antibody that inhibits the platelet glycoprotein IIb/IIIa receptor, may help treat large coronary aneurysms in Kawasaki disease. It has shown greater regression of the aneurysm size when combined with standard therapy, suggesting it promotes vascular remodeling, though further research is needed [68,86,87,99,100,101,112,124,156,158,160,161,162,163,164,165,166,167,169,170,171,173,177,178,179,180,181,182].

4. Behçet’s Disease

4.1. Overview

BD, a variable vessel vasculitis affecting medium, small, and large vessels, is characterized by mucocutaneous ulcers and heterogeneous skin and organ involvement. Th1 cells are the key players in BD via TNF-α and IFN-γ- mediated inflammation [229]. Emerging evidence highlights Th17 cell involvement, with increased IL-17 and IFN-γ production by CD8+ and γδ+ T cells [230]. Studies have found elevated levels of TNF-a, IL-1, sIL-2R, IL-6, IL-8, IL-10, and IL-12 in the serum of patients with Behçet’s disease [231,232]. B cells, especially memory B cells, also play a role. Elevated levels of BAFF, a protein implicated in B-cell function, are present in serum, and BAFF mRNA expression in the skin is increased [233]. Neutrophils in Behçet’s disease exhibit increased activation markers (CD64, CD66b, CD11b, and CD11c), enhanced reactive oxygen species production, and elevated NETosis, alongside significant dysregulation of genes associated with innate immunity, signaling, and chemotaxis. These pathways have led to increased interest in biologics that target these cytokines for the treatment of Behçet’s disease. For instance, phosphodiesterase-4 (PDE4) inhibitors, which suppress neutrophil activation markers and modulate dysregulated immune pathways, have been utilized with success [234]. Similarly, TNF-α inhibitors, ustekinumab (binds p40 of IL-12 and IL-23), anakinra (blocks IL-1, interfering with production of TNF-α and other pro-inflammatory cytokines), and CAN (binds and neutralizes IL-1β, inhibiting the upregulation of IL-6), have shown efficacy.

4.2. Treatment

The highly heterogeneous presentation of BD necessitates a tailored therapeutic approach based on the specific clinical manifestation. Biologic therapies, particularly TNF inhibitors, have shown strong efficacy in managing refractory ocular, neurological, and vascular BD. RTX has demonstrated promise for severe ocular disease, while TCZ and low-dose IL-2 are emerging options for refractory manifestations. Secukinumab and CAN may provide targeted benefits for mucocutaneous and systemic inflammation. These trials underscore the potential of biologics in BD management, although further large-scale studies are needed to establish their long-term efficacy and safety across diverse disease phenotypes. Cluster analyses of BD clinical presentations have identified three disease phenotypes: (1) mucocutaneous and articular, (2) extra-parenchymal neurological and peripheral vascular, and (3) parenchymal neurological and ocular [235].

4.2.1. Mucocutaneous and Articular

Colchicine is first-line for BD, leading to significant improvements in oral and genital ulcers, erythema nodosum, and articular symptoms. Colchicine mitigates inflammation by inhibiting neutrophil chemotaxis and downstream cytokine production, including IL-1β, TNF-α, and IL-6 [236]. In patients intolerant to colchicine, second-line options include AZA, apremilast [237], thalidomide [238], TNF-α inhibitors, and IFN-α inhibitors [239,240,241]. When it comes to biologic agents for mucocutaneous and articular manifestations of BD, TNF-α inhibitors (ETN, ADA, and IFX), ustekinumab, anakinra, secukinumab, and abatacept show the greatest promise. Among JAKis, TOF possesses mixed evidence, while baracitinib (BAR) demonstrates potential.
TNF-α inhibitors have demonstrated significant efficacy in managing Behçet’s disease (BD), particularly for mucocutaneous and intestinal manifestations. In a double-blind, placebo-controlled study involving 40 BD patients, ETN was shown to effectively reduce the frequency of oral ulcers, nodular lesions, and papulopustular lesions [88]. Additionally, a prospective cohort study of 19 patients with intestinal BD found that ETN increased the healing rate of intestinal ulcers and decreased inflammatory markers [102]. For severe refractory mucocutaneous BD, ADA and IFX have proven highly effective. The BEGIN Study (NCT02505568) is a phase three open-label, single-arm multicenter study evaluating IFX use in participants with moderate-to-severe refractory mucocutaneous BD. A total of 33 patients treated with IFX therapy experienced significant decreases in the mean disease activity index for intestinal BD (DAIBD) scores (50.5 ± 36.4 at week 8 and 61.5 ± 38.5 following 24 weeks of maintenance therapy), with 92.3% (25/27) of patients maintaining a clinical response at week 32 [37]. A multicenter randomized controlled trial revealed that 94% of patients treated with ADA achieved remission (defined as the improvement of active manifestations and absence of new episodes of oro-genital ulcers or erythema nodosum), compared to 64% in the IFX group. Both therapies significantly improved quality of life, with a low incidence of adverse events. Notably, ADA demonstrated a faster median response time (42 days) compared to IFX (152 days) [69]. Further supporting their use, a 2023 systematic review and meta-analysis highlighted the efficacy of ADA and IFX in intestinal BD. IFX showed high partial response rates of 82% at 3 months, 71% at 6 months, 65% at 12 months, and 50% at 24 months. Similarly, ADA demonstrated partial response rates of 45% at 6 months, 60% at 12 months, and 40% at 24 months [70].
Ustekinumab, an IL-12/23 inhibitor, was evaluated in a prospective, open-label phase-two study (NCT02648581) involving Behçet’s patients with recurrent oral or genital ulcers refractory to colchicine. The study demonstrated promising short- and long-term efficacy, with 73.3% (11/15) of patients achieving a clinical response within 24 weeks (60% complete response) and 90.9% (10/11) maintaining treatment effects at 52 weeks [147,148]. Significant improvements were also observed in key clinical measures: mean oral ulcers decreased from 2.1 ± 1.3 to 0.3 ± 0.5 (p = 0.0017), oral ulcer pain scores were markedly reduced (p = 0.0005), and both quality of life and disease activity scores improved significantly [148].
A phase-two, open-label, pilot study (NCT01441076) evaluated dose-escalated anakinra (100–300 mg daily) in six patients with refractory oral and genital ulcers with mixed results [157]. Two out of six patients achieved remission in 3–6 months, and five out of six experienced a decrease in the number of ulcers. While the 200 mg dose showed an acceptable safety profile and moderate effectiveness, increasing the dose to 300 mg did not enhance outcomes [157,242]. Although no ocular flares occurred during treatment, two patients with prior eye disease experienced flares shortly after stopping anakinra [243].
The British Association of Dermatologists and British Society for Rheumatology suggests the consideration of secukinumab as a fourth-line option after the failure of conventional systemic therapies (glucocorticosteroids, colchicine, azathioprine, and mycophenolate mofetil) and anti-TNF therapy for patients older than 6 years with Behçet’s disease, specifically for the treatment of mucocutaneous lesions without gastrointestinal and/or ocular involvement. Secukinumab is also suggested for treating arthritis and arthralgias in this population [244].
A multicenter (Italy, Australia) retrospective study of 15 patients with refractory mucosal and articular BD evaluated secukinumab at doses of 150 mg or 300 mg. At 3 months, 66.7% (9/15) of patients had a partial or full response, as measured by the number of new oral ulcers in the 28 days prior to the appointment (compared to baseline). At 6 months, 12 months, 18 months, and 24 months, 86.7% (13/15), 76.9% (10/13), 90.0% (9/10), and 100.0% (8/8) of patients, respectively, exhibited a response. All six patients who began with secukinumab 300 mg/month achieved a complete response by 6 months, while 46.7% (7/15) of patients required increasing the dose to achieve a response [154].
In 2024, a patient undergoing lymphoma treatment developed abdominal pain, intestinal ulceration, and perforation, leading to a diagnosis of intestinal BD. The patient underwent ileostomy and omentoplasty, followed by postoperative treatment with CAN and glucocorticoids. As of two years post-surgery, there has been no recurrence of intestinal BD [175].
Abatacept (ABA), a CTLA-4 agonist, was evaluated in an open-label pilot study (NCT01693640) in mucocutaneous BD. A total of 30 female patients with resistant Behçet’s ulcers (20 patients with oral ulcers, 10 patients with genital ulcers) received weekly injections of 125 mg of ABA over 6 months, though official results have not yet been published [190].
Evidence for TOF for the management of BD-related gastrointestinal manifestations is mixed, with success reported in only three of eight cases described in the literature [193,194,197,198,199]. The precise mechanism underlying TOF’s therapeutic effects in these conditions is not fully understood. Its ability to directly stimulate the JAK-STAT3 pathway may allow it to bypass IL-6 signaling, specifically pathways mediated by TLR4, TLR7, TLR9, and IL-23 [196]. BAR demonstrated a favorable safety profile in refractory intestinal BD (n = 13), with 76.92% (10/13) of patients achieving complete remission of global gastrointestinal symptom scores, and 66.7% (6/9) had mucosal healing on endoscopy [203].
TCZ should be avoided in patients presenting with this phenotype, considering the reported TCZ-induced exacerbation of mucosal ulcers in Behçet’s patients [240].

4.2.2. Extra-Parenchymal Neurological and Vascular

BD can present extra-parenchymal neurological and vascular involvement, including superficial venous thrombosis (SVT), deep vein thrombosis (DVT), cerebral venous sinus thrombosis (CVST), arterial occlusion, and aneurysm formation [235]. The coexistence of central and peripheral vascular involvement is thought to stem from a shared thrombotic pathway driven by neutrophil-induced oxidative inflammation, endothelial dysfunction, tissue factor overexpression, and cytokine-mediated platelet activation (Th1 phenotype) [235,245]. Rapid remission with glucocorticoids remains the cornerstone of treatment, followed by maintenance therapy with traditional immunosuppressants such as AZA, cyclophosphamide (CYC), or cyclosporine (CsA). The role of anticoagulation in BD remains controversial, as thrombosis in BD arises from vessel wall inflammation rather than hypercoagulability [246]. A recent meta-analysis found that combination immunosuppressive therapy with anticoagulation decreased rates of VTE recurrence compared to immunosuppressive therapy alone [247]. However, other studies have found no benefit, and EULAR continues to recommend immunosuppressive agents alone [248].
Evidence supports the use of TNF-α inhibitors like ADA and IFX, TCZ, and BAR for neurological and vascular manifestations of BD. Anti-TNF-α agents, used as standalone therapy or in combination with DMARDs, showed benefit in improving outcomes in severe cases of both arterial and venous BD [249]. A 2024 study described a novel mechanism by which TNF inhibitors mitigated BD vasculitis, targeting the mevalonate pathway in neutrophils, and reducing the production of farnesyl pyrophosphate and subsequent TRPM2-calcium signaling [250]. ADA and IFX are the most widely studied, with a multicenter observational study of 18 patients with major vessel involvement in BD showing that patients treated with ADA/IFX experienced a high rate of vascular remission (89%) and a significantly lower risk of relapse compared to conventional immunosuppressants [242]. Furthermore, a retrospective analysis comparing ADA to DMARDs in 70 patients with BD-related venous thrombosis found that ADA-based regimens were more effective and rapid in improving venous thrombosis and allowed for a significant corticosteroid dose reduction [251,252]. A 2023 retrospective cohort study found that IFX was effective for inducing remission in Behçet’s syndrome patients with vascular involvement, with a 73% remission rate at six months, though relapse and adverse events occurred in some cases [245].
Results from a phase-three, multicenter, randomized controlled trial (NCT03371095) comparing IFX to CYC therapy among 53 patients with severe vascular (n = 37) and neurological (n = 15) BD were recently published, demonstrating superiority of IFX over CYC in achieving a complete response [15]. A total of 81% (22/27) of patients treated with intravenous IFX (5 mg/kg at weeks 0, 2, 6, 12, and 18) achieved a complete response, versus 56% (14/25) of those receiving CYC (0.7 g/m2 intravenously at weeks 0, 4, 8, 12, 16, and 20, with a maximal dose of 1.2 g/infusion), and patients demonstrated decreased CRP levels, fewer adverse effects, and lower rates of relapse [15].
BAR has also shown promise in refractory vascular BD. A pilot study reported that 76.5% (13/17) of patients achieved a complete response at three months, increasing to 88.2% at the last visit. Significant reductions were observed in inflammatory markers (ESR, CRP), disease activity scores (BDCAF, BVAS), and glucocorticoid dosage, with no serious adverse events reported, highlighting BAR as a potential therapeutic option for vascular BD [202].

4.2.3. Parenchymal CNS and Ocular Phenotype

To date, no RCT has determined the optimal therapeutic management of neurological BD [253]. Standard treatment includes high-dose glucocorticosteroids, followed by maintenance with disease-modifying antirheumatic drugs [254,255]. There is growing evidence for the role of biologic agents and JAKis. Specifically, these include TNF-α inhibitors, IL-6, B-cell targeted therapies like TCZ and RTX, secukinumab, CAN, golimumab (GOL), abatacept (ABA), and the JAK inhibitors BAR, UPA, and potentially filgotinib.
TNF-α inhibitors, particularly IFX and ADA, are well-supported by evidence for their effectiveness in neuro-Behçet’s and Behçet’s uveitis (BU). A 2023 systematic review and meta-analysis assessing IFX for neuro-Behçet’s across 21 studies found that 93.7% (60/64) of patients responded positively, defined as a significant improvement in neurological symptoms or stabilization/improvement in neuroimaging findings [73]. Additionally, cumulative analysis over the past 20 years demonstrated an increasing trend in the effectiveness of IFX therapy for neuro-Behçet’s, potentially due to advances in diagnostic accuracy [73]. A 2024 systematic review and meta-analysis of TNF-α-inhibitors for patients with BU found that 85.0% (982/1156) of patients across 12 studies achieved ocular inflammation remission, with 77.4% (895/1156) experiencing an improvement in visual acuity [256]. Subgroup analysis revealed a slight advantage for ADA as compared to IFX in terms of improved remission and drug retention rates, and lower incidence of severe reaction [256].
A prospective, phase two non-comparative interventional study demonstrated intravitreal IFX safety and efficacy amongst 20 patients with refractory BU. Patients who received three consecutive intravitreal injections of infliximab (1 mg/0.05 mL) six weeks apart demonstrated significant improvement in best-corrected visual acuity (BCVA), decreased mean central foveal thickness OCT, and a reduction in mean vitreous haze gradings [72]. Furthermore, no significant ocular adverse inflammatory reactions were observed. ADA has effectively prevented relapses and maintained visual acuity in ocular BD, making it a preferred option for long-term treatment.
Another TNF-α inhibitor, golimumab (GOL), successfully managed BD-related nervous system involvement in a 50-year-old female in 2020, leading to significant improvements in numbness and tremor [126]. Additionally, GOL has been effective for Behçet’s uveitis in published cases (n = 14) [105,106]. However, there have been two cases of myelitis developing in patients receiving GOL treatment for neuro-Behçet’s, thus indicating the importance of long-term monitoring and the necessity of further research [107,108]. A 2017 retrospective study of 17 patients with BD found that GOL was able to control BD manifestations in 94.1% (16/17) of cases [109]. BD Current Activity Form (BDCAF) was significantly improved in patients receiving a combination of GOL and DMARDs than those undergoing GOL monotherapy [109]. Additionally, GOL was effective regardless of the number of previously failed biologic agents, suggesting GOL may be helpful for patients with especially refractory disease [109].
Beyond TNF inhibitors, IL-6 and B-cell targeted therapies also show promise. A 2020 systematic review assessing the effectiveness of IL-6 inhibitor TCZ for the treatment of Behçet’s disease found TCZ was highly effective in managing refractory ocular, neurological, and vascular involvement, as well as reducing glucocorticoid dependence. However, it did cause the worsening of oral/genital ulcers and skin lesions in some cases [125]. A 2022 observational cohort study of 10 patients with refractory arterial Behçet’s lesions receiving 8 mg/kg TCZ infusions every 4 weeks for 24 weeks found TCZ to be a safe and effective treatment option [126]. A total of 90% (9/10) of patients experienced improvement in symptoms (6/10 complete remission, 3/10 partial response), average ESR and CRP values decreased from 50 mm/h and 32.9 mg/dL to 4 mm/h and 2.9 mg/dL, respectively, and the average daily glucocorticoid dose reduced from 54.5 to 8.3 mg/dL [126]. A 2023 multicenter study of 30 patients with BD found that TCZ was effective in 83% (25/30) of patients, with a complete response of 67%, 60%, and 42% in patients with uveitis (18/30), neurological (5/30), and mucocutaneous/articular manifestations (7/30), respectively [126]. TCZ therapy also led to decreased median steroid doses and fewer patients needing concomitant DMARD therapy. However, a 2024 study warned that TCZ could potentially exacerbate vascular manifestations of Behçet’s, with relapses including severe presentations, such as bilateral pulmonary artery aneurysms, pulmonary artery thrombus, and pseudotumor cerebri [126].
Rituximab (RTX), a CD20 monoclonal antibody, demonstrated significant efficacy in severe ocular BD in a completed single-blind, randomized trial (NCT00700297) [122]. Patients showed marked improvements in Total Adjusted Disease Activity Index (TADAI) scores after six months compared to those treated with CYC and AZA. RTX also reduced glucocorticoid dependence and stabilized ocular inflammation, highlighting its potential for refractory cases [122]. RTX has also been shown to be promising in treating refractory neuro-Behçet’s in several case studies. One 49-year-old man presenting with parenchymal subtype Behçet’s with brainstem lesions, and one 46-year-old woman with non-parenchymal meningeal Behçet’s, both experienced the resolution of lesions and clinical symptoms following RTX therapy with low-dose prednisone [257]. Three additional cases of patients with neuro-Behçet’s disease who failed traditional therapy achieved continuous remission in both clinical and neuroimaging parameters, with normal inflammatory markers after low-dose RTX therapy [258,259,260].
Low-dose IL-2 is being explored for Behçet’s disease [185,186,213,261,262,263]. A completed phase II trial (NCT04065672) evaluating low-dose IL-2 in BD patients with vascular and mucocutaneous manifestations demonstrated reduced lesion counts and improved inflammatory markers [185,186]. An open-label, phase-2a basket trial (NCT01988506) of 13 autoimmune diseases included eight patients with Behçet’s disease (total n = 81). On day eight, there was a 1.9-fold increase in the percentage of regulatory T cells and a 2.17-fold increase in the ratio of regulatory T cells to CD25+ effector T cells. For the participants with Behçet’s disease, there was a trend of improvement in the Behçet’s Disease Current Activity Form. At 3 and 6 months, there were significant improvements in Clinical Global Impression activity, severity, and efficacy that persisted, but was less pronounced, two months after treatment discontinuation. At the 6-month time point, over 50% of the participants with Behçet’s disease were classified as treatment responders [187].
Secukinumab, an IL-17 inhibitor, has shown mixed but promising results in treating parenchymal neuro-Behçet’s disease [264]. In a small case series, two patients with refractory neurological symptoms achieved significant improvements. One patient with seizures unresponsive to levetiracetam experienced complete remission and the resolution of brain lesions on MRI after secukinumab therapy (150 mg weekly for one month, then monthly) combined with colchicine and methotrexate [265]. The second patient, with fevers, headaches, diplopia, and brainstem lesions, saw symptom resolution and reduced lesions after four months of treatment (150 mg weekly for one month, then biweekly) [265].
The SHIELD study (NCT00995709), a phase III trial evaluating secukinumab for recurrent Behçet’s uveitis (n = 118), found no significant difference in ocular exacerbation rates compared to a placebo, though secukinumab-treated patients required less immunosuppressive medication and had fewer recurrences. Adverse effects, including the exacerbation of Behçet’s syndrome, uveitis, and folliculitis, led to the discontinuation of seven patients [150].
A multicenter, randomized phase II study (NCT00685399) comparing the safety and efficacy of various IV and SC doses of secukinumab in patients with non-infectious BU found statistical and clinical superiority of the 30 mg/kg IV dose compared with the 300 mg SC dose. Participants treated with high-dose IV secukinumab experienced a faster time to response onset and improved visual acuity and changes in the vitreous haze score than those receiving SC administration [152]. These mixed results highlight the need for further research to clarify the role of secukinumab in Behçet’s disease.
A retrospective study of IL-1 inhibition included 15 BD patients treated with canakinumab. A total of 46.7% (7/15) of patients (1 pediatric, 6 adults) achieved a partial response to canakinumab therapy, while another 46.7% (7/15) of patients achieved a complete response, and 6.6% (1/15) of patients demonstrated no response [154]. CAN was also shown to be effective in the case of a BD patient with refractory bilateral retinal vasculitis, who achieved symptom control after failing multiple therapies, including AZA, cyclophosphamide (CYC), IFX, and ADA [175].
ABA, a CTLA-4 inhibitor, did not achieve clinical remission in a 13-year-old patient with BD-related uveitis in a 2024 study, but it did achieve short-term efficacy in a 47-year-old woman with ocular and skin BD but failed to sustain remission, necessitating a switch to TC [152,266].
JAKis are emerging as potential therapeutic options. BAR is being explored in an open-label, multicenter phase three trial (NCT04088409) as a treatment for pediatric non-infectious uveitis in Behçet’s disease (BD) [204,267,268]. A retrospective case series (n = 2) demonstrated the efficacy of UPA in the treatment of BD-related macular edema, with improvements observed in visual acuity and intraocular inflammation [212]. A prospective study of uveitis, including one patient with BD and anterior uveitis, demonstrated complete disease control, with treatment consisting of UPA 15 mg and AZA 200 mg daily [210,269]. A phase two randomized clinical trial (NCT03207815) found that filgotinib significantly reduced the risk of treatment failure in patients with active non-infectious uveitis (37.5%, 12/32) compared to a placebo (67.6%, 23/34) by week 24. Unfortunately, the study was terminated early for undisclosed business reasons, unrelated to the efficacy or safety of filgotinib [207]. Additionally, a case study demonstrated UPA effectively treated BD symptoms in a 42-year-old woman, leading to significant improvements in oral and genital ulcers, ocular inflammation, and hearing loss [213].

5. Deficiency of ADA2

5.1. Overview

Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disease caused by a monogenic loss-of-function (LOF) mutation in the ADA2 gene (previously the CECR1 gene) located on chromosome 22q11.1 [263]. While initially described in 2014 as a vasculopathy of infants and young children clinically resembling PAN, its clinical phenotype has since expanded to involve adults and includes hematologic, immunologic, and autoinflammatory manifestations in addition to vasculitis [270].
ADA2 is a dimeric enzyme produced by myeloid cells responsible for catalyzing the deamination of adenosine and 2′-deoxyadenosine into insosine and deoxyinosine, respectively. By modulating extracellular adenosine levels, ADA2 is crucial in regulating both innate and adaptive immune activity, including promoting T-cell-dependent monocyte differentiation into macrophages, with predominance of the anti-inflammatory M2 phenotype [271]. ADA2 also has a role as a paracrine growth factor promoting endothelial proliferation, angiogenesis, and tissue repair [272].
In DADA2, inactivating biallelic mutations of the ADA2 gene leads to accumulation of extracellular adenosine, initiating a downstream inflammatory cascade characterized by chronic neutrophil activation and dysregulation with neutrophil extracellular trap (NET) formation, macrophage polarization towards the inflammatory M1 subtype with resultant hypersecretion of TNF-α and other inflammatory cytokines, and increased endothelial IFN-β secretion [271]. Newer research describes additional adaptive immunity effects in DADA2 patients, with altered CD40L expression leading to impaired B-cell differentiation and switching with subsequent hypoimmunoglobulinemia [266]. Recent studies have also shown an activation of the IFN–JAK–STAT1 pathway in T cells and monocytes of DADA2 patients, further contributing to M1 macrophage polarization [268].
DADA2 presents with a broad, highly variable spectrum of clinical phenotypes, including systemic vasculopathy, recurrent ischemic and hemorrhagic strokes, livedoid rash, and fevers. While the majority of patients are young children, with 50% of cases presenting before the age of five, and nearly 80% of patients experiencing their first symptom by 18, more adult-onset cases are being recognized [269]. While the pathophysiology remains unclear, systematic reviews indicate potential differences in clinical presentation based on age of onset, with hematological and immunological manifestations predominating in early childhood and cutaneous and vascular symptoms occurring more commonly in adult patients [269]. PAN-like small and medium vessel vasculitis and ischemic stroke remain the hallmark presentations of DADA2, occurring in 76% and 52% of patients, respectively [273]. However, immunological manifestations such as hypoimmunoglobulinemia and lymphopenia are also significant, with low IgM being the most common (30.7%), followed by low IgG (23%) and low IgA (18%) [273].
The complex pathogenesis and variable clinical presentation of DADA2 necessitate a phenotype-driven approach to treatment. For patients with severe inflammation and vasculopathy, tumor necrosis factor (TNF) inhibitors are the mainstay, effectively reducing stroke risk and systemic inflammation [273]. In contrast, those with immunodeficiency or hematologic involvement may require immunoglobulin replacement therapy or hematopoietic stem-cell transplantation (HSCT) in severe cases [274]. Emerging interest in targeting specific molecular pathways has led to exploration of JAK/STAT inhibitors, such as ruxolitinib and TOF, for their potential to modulate the aberrant inflammatory signaling seen in DADA2 [275]. These therapies represent promising avenues for patients with refractory or overlapping disease phenotypes.

5.2. Treatment

There is evidence from published case reports and series of the use of TNF-α-inhibitors in DADA2. A 2021 narrative review identified 76 cases of DADA2 treated with a biologic agent between 2005 and 2020. The strongest evidence was for ETN, with 78% (32/41) of patients achieving complete or partial remission, although ETN was found to be ineffective in halting peripheral vasculopathy progression. Complete or partial remission was also achieved in 61.5% (8/13) of cases treated with IFX and 87.5% (14/16) with ADA. Evidence in favor of biologic agents other than TNF-α-inhibitors is lacking. Only 50% (1/2) of patients treated with canakinumab (CAN) achieved remission, and none responded to GOL (0/1), TCZ (0/4), RTX (0/3), or anakinra (0/4) [21].
Since the 2021 narrative review, additional cases have been reported, further supporting the efficacy of TNF-α inhibitors in DADA2. Complete or partial remission was achieved in six out of seven patients treated with IFX, seven out of eight patients treated with ETN, and six out of six patients treated with ADA [18,19,20,80,81,82,89,90,91,92,93,174].
Although individual outcomes for ETN and ADA were not specified, a 2024 descriptive analysis of 27 DADA2 patients treated with TNF-α-inhibitors (ETN, n = 26; ADA, n = 1) found that 35.7% achieved a complete response, primarily in cases with nervous system or skin involvement, while another 35.7% had a partial response [276].
There are a few cases indicating the limited utility of TCZ and RTX for DADA2. TCZ was trialed but discontinued in the treatment of a 3-year-old boy due to intestinal perforation and in a 5-year-old boy due to severe epigastric pain, headaches, and livedo reticularis on all extremities [277,278]. RTX was one of many medications attempted but found to be ineffective for a woman with a delayed genetic diagnosis of DADA2 [279].
CAN has been used in two pediatric cases with variable success [174,280].

6. Cogan’s Syndrome

6.1. Overview

Cogan’s Syndrome (CS) is a rare VVV that primarily affects the eyes and ears, typically presenting with non-syphilitic interstitial keratitis and Menière-like vestibulo-auditory symptoms [281]. Approximately one-fifth of patients experience vasculitic manifestations, such as arteritis, aortitis, aortic aneurysms, and valvulitis [282]. The exact pathogenesis of CS remains unclear, but it is theorized to be an autoimmune disorder, potentially triggered by viral infections. The basis of this theory stems from the identification of auto-antibodies against corneal and inner ear antigens, endothelial cells, and Cogan peptide, which have been identified in patients with CS [282].

6.2. Treatment

TNF-α inhibitors, RTX, and TOF have been utilized with variable efficacy in CS. A recent 2024 systematic review searching for cases of CS found auditory improvements or complete resolutions in 0/2 individuals with CS treated with ADA, 9/9 individuals treated with IFX, 1/2 individuals treated with RTX, and 3/3 individuals treated with TCZ [283]. We found three additional cases of TCZ used for CS that were not included in that review. These include a 31-year-old with continual hearing impairment despite treatment with dexamethasone, MTX, and IFX, a 49-year-old male with an insufficient response to steroids alone, and a 59-year-old male with an insufficient response to steroids, MTX, AZA, MMF, and CYC; they were all successfully treated with TCZ [128,129,130,131,132,133,284]. In a 2023 case, RTX, TCZ, and ETN were all utilized as part of the treatment regimen for a 35-year-old female with CS, with some clinical improvement. The addition of TOF, however, enabled the remission of tinnitus and joint pain, the normalization of inflammatory markers, and facilitated glucocorticosteroid tapering [195]. There is one case of successful use of TOF for CS [195].
The use of biologics and JAKis in CS is still relatively experimental at this point in time, with IFX demonstrating the greatest efficacy in published cases thus far. Further research and clinical trials are needed to determine their long-term efficacy and safety.

7. Conclusions

Biologic therapies and JAKis hold significant promise for the treatment of medium and variable vessel vasculitis, offering a more targeted approach that can improve both disease induction and maintenance. As these therapies evolve, important questions regarding the integration of biologics and JAKis into the treatment landscape will need to be addressed. Biologics have the potential to improve patient survival rates and enhance our understanding of disease pathogenesis, paving the way for more precise and effective treatments in the future.

Author Contributions

Conceptualization, A.B. and G.C.; writing—original draft preparation, A.B., R.G., C.C. and G.C.; writing—review and editing, A.B., R.G., C.C. and G.C.; supervision, A.B. and G.C.; project administration, A.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
MVVMedium Vessel Vasculitis
VVVVariable Vessel Vasculitis
PANPolyarteritis Nodosa
KDKawasaki Disease
BDBehçet’s Disease
DADA2Deficiency of Adenosine Deaminase 2
CSCogan’s Syndrome
JAKiJanus Kinase Inhibitor
TCZTocilizumab
GCAGiant Cell Arteritis
RTXRituximab
ANCAAntineutrophil Cytoplasmic Antibodies
AZAAzathioprine
MTXMethotrexate
MMFMycophenolate Mofetil
CYCCyclophosphamide
IFXInfliximab
ETNEtanercept
ADAAdalimumab
IL-6Interleukin-6
TNF-αTumor Necrosis Factor-Alpha
IFN-αInterferon-Alpha
IL-2Interleukin-2
IL-1βInterleukin-1 Beta
NAAVNon-ANCA-Associated Vasculitis
TOFTofacitinib
BARBaricitinib
GM-CSFGranulocyte-Macrophage Colony-Stimulating Factor
JAK-STATJanus Kinase-Signal Transducer and Activator of Transcription
IVIGIntravenous Immunoglobulin
CANCanakinumab
ABCAbciximab
NLRP3NLR Family Pyrin Domain Containing 3
ANACOMPAnakinra vs. IVIG Comparative Trial
NIKITANon-Inferiority of anakinra vs. IVIG in Kawasaki Disease Treatment Assessment
PDE4Phosphodiesterase-4
DAIBDDisease Activity Index for Intestinal Behçet’s Disease
BEGINStudy of Infliximab in Behçet’s Disease
SHIELDSecukinumab in Behçet’s Uveitis Trial
GOLGolimumab
UPAUpadacitinib
ABAAbatacept
CTLA-4Cytotoxic T-Lymphocyte-Associated Protein 4
TLR4/7/9Toll-Like Receptor 4/7/9
BDCAFBehçet’s Disease Current Activity Form
BVASBehçet’s Vasculitis Activity Score
TADAITotal Adjusted Disease Activity Index
LOFLoss-of-Function
NETNeutrophil Extracellular Trap
HSCTHematopoietic Stem Cell Transplantation
CRPC-Reactive Protein
ESRErythrocyte Sedimentation Rate
SCSubcutaneous
IVIntravenous
OCTOptical Coherence Tomography
MRIMagnetic Resonance Imaging

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Allergies 05 00029 g001
Figure 1. Overview of Vasculitis.
Figure 1. Overview of Vasculitis.
Allergies 05 00029 g001
Table 1. Level of Evidence for Biologic and Janus Kinase Inhibitor Therapies in PAN, KD, BD, DADA2, and CS.
Table 1. Level of Evidence for Biologic and Janus Kinase Inhibitor Therapies in PAN, KD, BD, DADA2, and CS.
MedicationFDA-Approved ConditionsMechanism of ActionPANPAN
Level of Evidence		PAN StudyKDKD
Level of Evidence		KD StudyBDBD
Level of Evidence		BD StudyDADA2DADA2
Level of Evidence		DADA2 StudyCoganCogan
Level of Evidence		Cogan Study
InfliximabAS, CD, PsA, RA, UCChimeric mouse/human monoclonal antibody that binds
soluble and transmembrane TNF-α. Reduces inflammation
by inhibiting TNF-α-driven cytokine production (IL-1, IL-6,
IL-8) [9].		✓Level 4Retrospective descriptive case series [10,11]✓Level 1Phase 3 RCT KIDCARE (NCT03065244) comparing IFX versus second IVIG infusion: shorter
duration of fever, reduced need for additional therapy, less severe anaemia, and shorter
hospitalization compared with second IVIG infusion, no difference between treatment groups
for markers of inflammation or coronary artery outcome [12]

Phase 3 multicenter RCT (NCT01596335): improved 48-h fever resolution and shorter
time to defervescence with IFX compared to IVIG retreatment [13]

2024 systematic review: meta-analysis of 14 randomized and non-randomized trials with 1257
participants found IFX alone was more effective than IVIG for refractory KD, showing: higher
effectiveness rate (OR 4.48, 95% CI: 2.67-7.52), higher defervescence rate (OR 5.01, 95%
CI: 2.99-8.37), a 1.08-day shorter duration of fever (95% CI: 0.61-1.55, p < 0.001), a 1.36-day
shorter hospital stay (95% CI: 0.65-2.08), no difference in the incidence of coronary artery,
lesions (CALs) & IFX plus IVIG showed: a higher effectiveness rate (OR 2.26, 95% CI:
1.02-5.01), a larger reduction in the right coronary artery Z score (MD = -0.24, 95% CI:
-0.27 to -0.21), and no significant improvement in other outcomes [14]		✓Level 1Vascular/neurological—Phase 3 RCT (NCT03371095) comparing IFX to CYC: IFX superior to CYC (81% (22/27)
complete response versus 56% (14/25) in CYC group), decreased CRP levels, fewer adverse effects, and lower
rates of relapse [15]		✓Level 5Case reports
[16,17,18,19,20]
Level 5Case reports [16,21,22,23,24,25,26,27,28,29,30,31,32,33,34]Level 2Phase 1 multicenter, randomized, prospective trial (NCT00271570): fever resolved within 24
hours for 92% (11/12) subjects treated with IFX, compared 67% (8/12) subjects retreated
with a second IVIG infusion [35]

2016 non-randomized retrospective study: 66% (21/32) patients responded to re-treatment
with IVIG compared to 91% (10/11) of patients who responded to IFX and did not need additional
treatment [36]		Level 1Intestinal—Phase 3 Open-label, Single-Arm BEGIN study (NCT02505568): patients (n = 33) experienced
significant decreases in mean disease activity index, 92.3% (25/27) maintained clinical response at week 32 [37]
OngoingPhase 2 RCT (NCT05168475) investigating the efficacy of IFX, RTX,
and TCZ in treating refractory non-ANCA-associated vasculitis
(NAAV), including PAN [38]		Level 5Case reports [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68]Level 1Mucocutaneous—Phase 3, multicentre, prospective, randomised, active-controlled trial: 64% (14/22) achieved
remission [69]
Level 22023 systematic review and meta-analysis: pooled proportions found 82% response rate at 3 months, 71% at 6 months,
65% at 12 months, and 50% at 24 months [70,71]
Level 2Uveitis—Phase 2 Prospective Non-Comparative Study of intravitreal IFX injection: patients (n = 22) experienced
significant improvement in best corrected visual acuity, decreased mean central foveal thickness OCT, and reduction
in mean vitreous haze gradings [72]
Level 5Case reports [73,74,75,76]
AdalimumabAS, CD, HS, PsA, RA, UCHigh affinity fully human, recombinant IgG anti-TNF-α
monoclonal antibody which affects both soluble and
membrane-bound forms, functioning to inhibits the interaction
of TNF-α to the cell surface TNF receptors, p55 (TNFR1) and
p75 (TNFR2), blocking downstream cytokine production such
as IL-1 and IL-6 [77].		✓Level 5Case series, reports [21,78,79]✓Level 1Mucocutaneous—Phase 3, multicentre, prospective, randomised, active-controlled trial: 94% (17/18) achieved
remission [37]		✓Level 5Case reports
[80,81,82]
Level 22023 systematic review and meta-analysis: pooled proportions found partial response rates of 45% at 6 months, 60%
at 12 months, and 40% at 24 months [70,71]
Level 5Case reports [72,73,74,76]
OngoingUveitis—observational study (NCT05683626) [83]
OngoingUveitis—Phase 2 RCT (NCT05874505): evaluating the efficacy and safety of ADA compared to TCZ for uveitis in
Behçet’s disease, set to begin recruitment and estimated for completion in July 2027 [84]
EtanerceptAS, PsA, RASoluble TNF receptor fusion protein consisting of two p75
TNF receptors fused to a FC human IgG that acts as a
soluble TNF receptor, binding both TNF-alpha and beta
and inhibiting downstream inflammatory pathways,
such as NFkB and MPK [85]		✓Level 4Retrospective descriptive case series [11]✓Level 1Phase 3 RCT (NCT00841789): ETN as adjunct treatment reduced IVIG resistance in patients
and mitigated coronary artery dilation without added safety concerns, but long-term
follow-up suggested no impact on disease progression. [86,87]		✓Level 1Mucocutaneous, articular—Double-blind, placebo-controlled study involving 40 BD patients found that ETN
effectively reduced the frequency of oral ulcers, nodular lesions, and papulopustular lesions [88]		✓Level 5Case reports
[89,90,91,92,93]
Level 5Case series, reports [21,94,95,96,97,98]Level 5Case reports [99,100,101]Level 2Intestinal—prospective cohort study of 19 patients found that ETN increased the healing rate of intestinal
ulcers and decreased inflammatory markers [102]
Level 5Case reports [74]
GolimumabAS, PsA, RA, UCFully human anti-TNF-α monoclonal antibody designed
to have better TNF affinity and reduced complement
activation by binding to both soluble and transmembrane
forms of TNF-α [103]		✓Level 4Retrospective descriptive case series [104]
Level 5Case reports [105,106,107,108,109]
RituximabCLL, GPA, MPA, NHL, RAChimeric monoclonal antibody targeting CD20, leading to
B-cell depletion, that exerts its effects via
complement-mediated cytotoxicity, antibody-dependent
cell-mediated cytotoxicity, and by inducing apoptosis [110]		✓Level 3Retrospective European collaborative study: RTX was used in 18 cases of
relapsing PAN. 33% of patients achieved remission, 11% had a partial
response, and 56% experienced treatment failure. None of the patients
discontinued RTX due to severe adverse events. [111]		✓Level 5Case report [112]✓✓Level 5Case report
[113]
Level 5Case reports [21,114,115,116,117,118,119,120,121]Level 2Uveitis—Randomized single-blind control pilot study: patients showed marked improvements in Total Adjusted
Disease Activity Index (TADAI) scores after six months compared to those treated with CYC and AZA. RTX also
reduced glucocorticoid dependence and stabilized ocular inflammation, highlighting its potential for refractory
cases [122]
OngoingPhase 2 RCT (NCT05168475) investigating the efficacy
of IFX, RTX, and TCZ in treating refractory
non-ANCA-associated vasculitis (NAAV), including PAN [38]		Level 5Case reports [123]
TocilizumabGCA, JIA, RAHumanized monoclonal antibody that binds to IL-6 receptors,
thereby blocking IL-6 effects, interfering with the differentiation
of Th2 and Th17 cells, suppressing the generation of Treg cells
and production of acute-phase proteins, serving to dampen
immune response and B-cell differentiation [110]		✓Level 3Retrospective European collaborative study: TCZ was used in 10 cases of
relapsing PAN. 50% of patients achieved remission, 0% had a partial
response, and 30% experienced treatment failure. 20% of the patients
discontinued RTX due to severe adverse events. [111]		✓Level 4Retrospective descriptive case series [124]✓Level 3Systematic review of cases: Of 47 BD patients treated with TCZ, improvement in almost all patients with ocular
(24/25), neurological (6/6), and vascular (7/7) involvement, as well as secondary amyloidosis (2/2) [76,125]

2022 observational cohort study: improvement and maintenance of symptoms in 9/10 patients, complete remission
in 6/10, partial response in 3/10, immunosuppressant dose reduction in 4/10, radiologic improvement of arterial
lesions in 4/10 [126]

2023 multicenter study: TCZ was effective in 25/30 patients, of whom 18/30 completely responded and 7/30
partially responded; 67% patients with uveitis (18/30) achieved complete response, 60% with
neurological (5/30) manifestations achieved complete response and 42% with mucocutaneous and/or articular
(7/30) manifestations completely responde [127]		✓Level 5Case reports
[128,129,130,131,132,133,134]
Level 5Case reports [125]
Level 5Case reports [21,135,136,137,138,139,140,141,142,143,144]OngoingVascular—Phase 2 multi-center RCT (NCT05845723): evaluates the efficacy and safety of TCZ or TOF with
glucocorticoid compared to the traditional combination of glucocorticoids with cyclophosphamide [145]
OngoingPhase 2 RCT (NCT05168475) investigating the efficacy
of IFX, RTX, and TCZ in treating refractory
non-ANCA-associated vasculitis (NAAV), including PAN [38]		OngoingUveitis—Phase 2 RCT (NCT05874505): evaluating the efficacy and safety of ADA compared to TCZ for uveitis in
Behçet’s disease, set to begin recruitment and estimated for completion in July 2027 [84]
UstekinumabCD, PsA, PsOHuman monoclonal antibody targeting the p40 subunit shared
by IL-12 and IL-23, thereby modulating Th1 andTh17 responses
respectively [146]		✓Level 3Mucocutaneous—Phase 2 study (NCT02648581): 73.3% (11/15) of patients achieving a clinical response within 24
weeks (60% complete response) and 90.9% (10/11) maintaining treatment effects at 52 weeks [147,148]
Level 5Case reports [149,150]
SecukinumabAS, PsA, PsOHuman monoclonal antibody against IL-17A which interferes
with the secretion of chemokines (CCL20, CXCL1m CXCL8)
that activate the innate immune system, promote epidermal
hyperproliferation, T-cell infiltration, and pathogenic gene
expression [151]		✓Level 1Uveitis—Phase 3 RCT SHIELD study (NCT00995709) [152]
Level 2Uveitis—Phase 2 RCT (NCT00685399) [153]
Level 4Mucosal, articular—multicenter retrospective study of 15 patients found at 3 months, 66.7% (9/15) patients had a
partial or full response. At 6 months, 12 months, and 18 months, and 24 months, 86.7% (13/15), 76.9% (10/13),
90.0% (9/10), and 100.0% (8/8) of patients exhibited response [154]
AnakinraCAPS, DIRA, RA, sJIARecombinant IL-1 receptor antagonist that competitively
inhibits the binding of both IL-1α and IL-1β to their respective
receptors, thereby interfering with activvation of the
nuclear factor kappa B and mitogen-activated protein kinase
pathways, which promote the transcription of pro-inflammatory
cytokines such as TNF-α and IL-6 [155]		✓Level 1Phase I/IIa Study (NCT02179853): dose-escalation study of anakinra in 22 children with acute
KD and coronary artery aneurysms found that up to 6 weeks of treatment was safe,
well-tolerated, and effective in reducing coronary artery inflammation, with both IV and SC
administration showing promise [156]		✓Level 2Phase 2, open-label pilot study (NCT01441076): dose-escalated anakinra (100–300 mg daily) in patients with
refractory oral and genital ulcers (n = 6) showed mixed results, with remission in 2 of 6 patients, ulcer reduction
in 5 of 6, a safe and moderately effective 200 mg dose, no added benefit at 300 mg, and post-treatment ocular
flares in two patients with prior eye disease [157]
Level 2Phase II Study (NCT02390596): In 16 IVIG-resistant KD patients, anakinra was well-tolerated,
led to rapid fever resolution (75% ITT, 87.5% per-protocol within 48 h), improved CRP
levels by day 30, and showed potential in reducing coronary artery dilation, with 50% of
patients achieving improved Z scores by day 45 [158]		Level 3Retrospective cohort study: 8/9 refractory BD patients showed a prompt improvement after starting anakinra [159]
Level 5Case reports [62,100,160,161,162,163,164,165,166,167]Level 4Retrospective descriptive case series [168]
Ongoing Pilot study (NCT04747847): anakinra and atorvastatin to treat KD [169]

Phase III trial (ANACOMP, NCT04656184): compare anakinra with IVIG retreatment [170]

NIKITA trial (NCT06697431): aims to establish conclusive evidence for anakinra as an
alternative therapy for refractory KD [171]
CanakinumabCAPS, FMF, HIDS/MKD,
sJIA, TRAPS		Human monoclonal antibody that binds to and neutralizes IL-1β,
forming an antigen-antibody complex that can no longer bind
the IL-1β receptor preventing pro-inflammatory signal
transduction [172]		✓Results not published yetPhase 2, multi-center trial in Europe (EudraCT 2019-002783-2): enrolled IVIG-resistant and
early-diagnosed treatment-naïve patients with completeKD for treatment with canakinumab
[173]		✓Level 4Retrospective study—46.7 % (7/15) patients (1 pediatric, 6 adults) achieved a partial response, 46.7% (7/15)
achieved complete response, and 6.6% (1/15) patient demonstrated no response [154]		✓Level 5Case reports [174]
Level 5Case report [168,175]
AbciximabChimeric Fab fragment derived from a murine monoclonal
antibody that inhibits platelet aggregation by binding to Gp
IIb–IIIa receptors [176]		✓Level 5Case reports [68,177,178,179,180,181,182]
Low-dose IL-2NoneLow-dose IL-2 selectively amplifies regulatory T cells due to
their high CD25 expression, while downregulating RORγt,
IL-17A, and IL-17F production, and inhibiting follicular helper
T cell differentiation via the AKT/mTORC1 pathway, thereby
modulating immune responses without promoting CD4+,
CD8+, or NK cell proliferation [183,184]		✓Level 2Vascular, mucocutaneous—Phase II trial (NCT04065672): reduced lesion counts and improved inflammatory markers
[185,186]
Level 3Open-label, phase 2a basket trial (NCT01988506): included 8 patients with Behçet’s disease.
At the 6-month time point, over 50% were classified as treatment responders [187]
Abatacept JIA, RAFusion protein that combines the extracellular domain of
CTLA-4 and the Fc fragment of human IgG1 (CTLA-4–Ig),
enabling it to bind to CD80 and CD86, thereby blocking
the interaction between CD28 on T cells and CD80/CD86
receptors on APCs, interfering with T cell proliferation and
B cell response [188]		✓Level 5Case reports [189]
Results not yet publishedMucocutaneous—open-label pilot study (NCT01693640) of 30 female patients with resistant Behcet’s ulcers [190]
TofacitinibJIA, PsA, RA, UCJAK1/3 inhibitor that disrupts IL-2, IL-4, IL-15, and IL-21
signaling and has been found to reduce TNF-α and
IL-6 while maintaining IL-10 [191]		✓Level 4Retrospective case series [192]✓Level 3Retrospective cohort: 9/13 achieved clinical remission after a mean treatment duration of 10.1 ± 7.0 months, and the
other 4/13 had low disease activity [193]

2020 pilot study: 13 patients included with clinical improvement in all cases of vascular involvement (5/5), and
unchanged or worsened in 5/7 cases of GI involvement [194]		✓Level 5Case reports
[195]
Level 5Case report [196]Level 5Case reports [197,198,199]
BaricitinibAA, AD, COVID-19, RAJAK1/2 inhibitor that interferes with IL-6 and IFN signaling [200]✓Level 5Case report [201]✓Level 4Vascular—Single-center, one-arm, self-controlled, open-label pilot study: 13/17 (76.5%) of patients achieving
complete response at 3 months, increasing to 88.2% (15/17) at the last visit [202]

Intestinal—Pilot study: 76.92% (10/13) patients achieved complete remission of global gastrointestinal symptom
scores, and 66.7% (6/9) had mucosal healing on endoscopy [203]
OngoingUveitis—open-label, multicenter Phase 3 trial (NCT04088409) [204]
Level 5Case report [205]
FilgotinibRA, UCJAK1 inhibitor that possesses reduced activity for JAK2 [206]✓Terminated earlyUveitis—Phase 2 RCT (NCT03207815): significantly reduced the risk of treatment failure in patients with active
noninfectious uveitis (37.5%, 12/32) compared to placebo (67.6%, 23/34) by week 24. Unfortunately, the study
was terminated early for business reasons [207]
UpadacitinibAD, AS, axSpA, CD, GCA,
PsA, RA, UC		JAK1 inhibitor that reduces IL-6 and IFN-γ [208]✓Level 5Case report [209]✓Level 2Prospective, open-label, multi-center pilot trial: 1/8 patient complete remission, 4/8 partial remission [210]

Prospective study of uveitis, including one patient with BD and anterior uveitis: complete disease control
with treatment consisting of UPA 15 mg daily and AZA 200 mg daily [211]
Level 5Case reports [17,212,213]
Table 2. Overview of Biologic and Janus Kinase Inhibitor Therapies in Medium- and Variable-Vessel Vasculitides.
Table 2. Overview of Biologic and Janus Kinase Inhibitor Therapies in Medium- and Variable-Vessel Vasculitides.
ClassMedicationMechanismFDA-Approved IndicationsMVV ApplicationsVVV Applications
Biologics
InfliximabTNF-α inhibitorAS, CD, PsA, RA, UCPAN, KDBD, DADA2
AdalimumabTNF-α inhibitorAS, CD, HS, PsA, RA, UCPANBD, DADA2
EtanerceptTNF-α inhibitorAS, PsA, RAPAN, KDBD, DADA2
GolimumabTNF-α inhibitorAS, PsA, RA, UCNoneBD
RituximabAnti-CD20CLL, GPA, MPA, NHL, RAPAN, KDBD, Cogan
TocilizumabIL-6 inhibitorGCA, JIA, RAPAN, KDBD, Cogan
UstekinumabIL-12/23 inhibitorCD, PsA, PsONoneBD
SecukinumabIL-17A inhibitorAS, PsA, PsONoneBD
AnakinraIL-1 inhibitorCAPS, DIRA, RA, sJIAKDBD
CanakinumabIL-1β inhibitorCAPS, FMF, HIDS/MKD,
sJIA, TRAPS		KDBD, DADA2
AbciximabAnti-Gp-IIb–IIIaKDNone
Low-dose IL-2Treg expansionNoneNoneBD
Abatacept CTLA-4–Ig that blocks
CD28-CD80/CD86
costimulatory pathway		JIA, RANoneBD
JAK inhibitorsTofacitinibJAK1/3 inhibitorJIA, PsA, RA, UCPANBD, Cogan
BaricitinibJAK1/2 inhibitorAA, AD, COVID-19, RAPANBD
FilgotinibJAK1 inhibitorRA, UCNoneBD
UpadacitinibJAK1 inhibitorAD, AS, axSpA, CD, GCA,
PsA, RA, UC		PANBD
Abbreviations: AD, atopic dermatitis; AS, ankylosing spondylitis; axSpA, axial spondyloarthritis; BD, Behçet’s disease; BU, Behçet’s uveitis; CAPS, cryopyrin-associated periodic syndromes; CD, Crohn’s disease; CLL, chronic lymphocytic leukemia; DADA2, Deficiency of ADA2; DIRA, deficiency of IL-1 receptor antagonist; FMF, familial Mediterranean fever; GCA, giant cell arteritis; GPA, granulomatosis with polyangiitis; HIDS/MKD, hyper IgD syndrome/mevalonate kinase deficiency; HS, hidradenitis suppurativa; JIA, juvenile idiopathic arthritis; KD, Kawasaki Disease; MPA, microscopic polyangiitis; PAN, Polyarteritis Nodosa; NHL, non-Hodgkin’s lymphoma; PsA, psoriatic arthritis; PsO, plaque psoriasis; RA, rheumatoid arthritis; sJIA, systemic juvenile idiopathic arthritis; TRAPS, TNF receptor-associated periodic syndrome; UC, ulcerative colitis.
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Bai, A.; Granovsky, R.; Chau, C.; Cobos, G. Biologic Therapies and Janus Kinase Inhibitors for Medium and Variable Vessel Vasculitides: A Review of Clinical and Preclinical Evidence. Allergies 2025, 5, 29. https://doi.org/10.3390/allergies5030029

AMA Style

Bai A, Granovsky R, Chau C, Cobos G. Biologic Therapies and Janus Kinase Inhibitors for Medium and Variable Vessel Vasculitides: A Review of Clinical and Preclinical Evidence. Allergies. 2025; 5(3):29. https://doi.org/10.3390/allergies5030029

Chicago/Turabian Style

Bai, Allison, Rachel Granovsky, Courtney Chau, and Gabriela Cobos. 2025. "Biologic Therapies and Janus Kinase Inhibitors for Medium and Variable Vessel Vasculitides: A Review of Clinical and Preclinical Evidence" Allergies 5, no. 3: 29. https://doi.org/10.3390/allergies5030029

APA Style

Bai, A., Granovsky, R., Chau, C., & Cobos, G. (2025). Biologic Therapies and Janus Kinase Inhibitors for Medium and Variable Vessel Vasculitides: A Review of Clinical and Preclinical Evidence. Allergies, 5(3), 29. https://doi.org/10.3390/allergies5030029

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