Indian Journal of Drugs in Dermatology

: 2021  |  Volume : 7  |  Issue : 2  |  Page : 51--59

IL-23 blockers in dermatology

Shrichand G Parasramani1, Manasi Shirolikar2,  
1 Department of Dermo-Cosmetology, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India
2 Kaya Skin Clinic, Mumbai, Maharashtra, India

Correspondence Address:
Shrichand G Parasramani
Anisha Clinic, Mangal Sudha, SV Road, Khar, Mumbai 400052, Maharashtra


Interleukin-23 (IL-23) is the key regulatory cytokine in psoriasis, which stimulates differentiation, proliferation, and survival of T-helper 17 (Th17) cells. Specific targeting of IL-23–IL-17 inflammatory pathway has become an effective therapeutic approach to treat psoriasis. Clinical studies have shown that antibodies directed against the p19 subunit of IL-23 show equal or superior response as compared to when both IL-12 and IL-23 are inhibited. Side effects of IL-12 inhibition are avoided. Tildrakizumab, guselkumab, and risankizumab are antibodies that target the p19 subunit of IL-23. These newer IL-23 blockers give high PASI response and are easy to administer once in 8–12 weeks. A comparison of these three drugs from different trials is carried out in this review with the help of bar charts. There are no head-to-head comparative trials of these monoclonal antibodies.

How to cite this article:
Parasramani SG, Shirolikar M. IL-23 blockers in dermatology.Indian J Drugs Dermatol 2021;7:51-59

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Parasramani SG, Shirolikar M. IL-23 blockers in dermatology. Indian J Drugs Dermatol [serial online] 2021 [cited 2022 Jan 25 ];7:51-59
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Psoriasis is a chronic immune-mediated, recurrent, distressing, inflammatory disease, which is present lifelong unless it undergoes natural remission.[1] Approximately 2% of adults in Europe and North America suffer from Psoriasis.[2] It can limit social interactions, impair school or work productivity, and lead to suicidal tendencies. Skin lesions consist of well-demarcated, scaly, erythematous plaques, which may at times be associated with pruritus. Some patients may have involvement of scalp, palms, soles, and nails. Comorbid conditions, such as obesity, metabolic syndrome, hypertension, cardiovascular diseases, and hyperlipidemia, may be associated with psoriasis.[3] Psoriasis is a result of hyperproliferation of the keratinocytes in the epidermal layer of skin. Approximately 20%–30% of the patients have arthritis, which leads to severe destruction of joints and deformities.[3]

There are many therapeutic agents available for treating psoriasis such as methotrexate, acetretin, cyclosporine, and fumaric esters. Alefacept was the first biologic used in psoriasis followed by Efalizumab in 2003; these are no longer in use today due to better understanding of psoriasis pathogenesis and availability of more efficacious and safe biologics.

The introduction of biological with anti-tumor necrosis factor-α (TNF-α) agents, led to a much-improved outcome in comparison to previous systemic treatments.[4],[5],[6],[7]

Targeting of interleukin-12 (IL-12) and IL-23 p40 subunit with Ustekinumab resulted in still greater clinical outcomes.[8],[9] This drug had its effect on both Th1 and Th17 immune pathway.

T-helper 17 (Th17) cells play a major part in pathogenesis of psoriasis, thereby leading to activation and proliferation of surrounding keratinocytes and endothelial cells via production of IL-17A and other pro-inflammatory cytokines.[10]

IL-23 is involved in differentiation of Th17 cells in the presence of TGF-β and IL-6. Activated Th17 cells produce IL-17A, IL-17F, IL-6, IL-22, and TNF-α.[11]

IL-23 is now said to be the key regulatory cytokine in psoriasis, which stimulates differentiation, proliferation, and survival of Th17 cells and not IL-12. Specific targeting of IL-23–IL-17 inflammatory pathway has become an effective therapeutic approach.[12]

Clinical studies targeting IL-23 via antibodies directed against the p19 subunit show as equal or even superior response as compared to inhibition of both IL-12 and IL-23.[13],[14],[15],[16],[17] Tildrakizumab, guselkumab, and risankizumab are antibodies that target the p19 subunit of IL-23.


Histology of psoriatic plaque shows epidermal hyperplasia overlying inflammatory infiltrate composed of dermal dendritic cells, macrophages, T cells, and neutrophils. Both innate and adaptive immune systems take part in pathogenesis of psoriasis which is initiated by trigger factors such as trauma, infection, drugs, and climate changes in the genetically predisposed individual and a maintenance phase leading to chronic clinical progression.[18] Antimicrobial peptides (AMPs) secreted by keratinocytes following injury are overexpressed in psoriasis. AMPs associated with psoriasis are LL-37, defensins, and S100 proteins. LL-37 or cathelicidin plays a pathogenic role in psoriasis by forming complexes with self-genetic material from damaged cells.[19] LL-37 bound to DNA stimulates toll-like receptor (TLR) 9 in plasmacytoid dendritic cells (pDCs). Activation of pDC is the starting point in the development of psoriatic plaque by producing type 1 interferon (IFN-α and IFN-β). Type-1 IFN promotes myeloid dendritic cell (mDC) maturation that activates Th1 and Th17 pathways.[20] Activated mDC migrates to draining lymph nodes and secretes TNF-α, IL-12, and IL-23. Activation of adaptive immune response drives the maintenance phase of psoriatic inflammation. IL-23–Th17–IL-17 axis forms a key pathway in the immunology of psoriasis thereby IL-23 blockers play a major role in control of psoriasis. Activated Th17 cells produce IL-17A, IL-17F, IL-6, IL-22, and TNF-α[11] [Figure 1].{Figure 1}

 IL-23 Blocker in Dermatology

IL-23 is a heterodimeric cytokine consisting of a unique subunit of p19 connected to a subunit of p40 which is also shared with IL-12[21] [Figure 2]. Tissue-resident or recruited dendritic cells and macrophages are the main sources of IL-23.[22] IL-23 is a key player in chronic autoimmune disease in general and in the pathogenesis of psoriasis in particular.[11] IL-23 signals via a complex of heterodimeric receptors consisting of two subunits IL-23R and IL-12Rβ1.[22] IL-23 has regulatory effects to maintain Th17 cells, whereas IL-17 and TNF-α mediate the functions of innate and adaptive (TNF, IL 17) immune cells. For the treatment of moderate to severe psoriasis, three inhibitors specifically targeting IL-23p19 are available, Guselkumab, Tildrakizumab, and Risankizumab [Table 1]. Further antibody, LY3074828, is under phase 2 clinical trial.[23]{Figure 2} {Table 1}


Tildrakizumab is a humanized monoclonal antibody that specifically binds to the IL-23 p19 subunit and blocks IL-23 from binding to its receptor. Tildrakizumab is administered subcutaneously and has a slow systemic clearance with a long half-life of about 3 weeks. It is given in the dose of 100 mg subcutaneously on day 0 and week 4 followed by one injection every 12 weeks.

Treatment efficacy has been reported in reSURFACE 1 and 2 randomized, double-blind, and controlled clinical trials for 64 and 52 weeks, respectively. In reSURFACE1, Tildrakizumab was administered to 722 patients with moderate-to-severe chronic plaque psoriasis at a dose of 100 mg (n = 309), 200 mg (n = 308), or placebo (n = 155) at baseline, week 4 and every 12 weeks thereafter. The main endpoints were the percentage of patients who achieved a PASI75 score and a physician global assessment (PGA) score of 0 (clear) or 1 (minimum) with a reduction in the score of 2 from the baseline at 12 weeks. After two doses of medication, the proportion of PASI 75 respondents in reSURFACE 1 from baseline at week 12 was 64% in the 100 mg dose group, 62% in patients receiving 200 mg tildrakizumab dose and 6% in patients on placebo, 35% of patients had PASI 90 response and 14% of patients had PASI 100 response at week 12, in both groups of patients receiving 200 and 100 mg dose of Tildrakizumab, respectively. Patients on placebo had PASI 90 and PASI 100 in 3% and 1% patients, respectively. PGA 0/1 was seen in 59% patients (Tildrakizumab 200 mg dose), 58% in patients (Tildrakizumab 100 mg dose), and 7% in placebo group at week 12. DLQI score 0/1 was seen in 44% of patients in the Tildrakizumab 200 mg dose group and 42% in the Tildrakizumab 100 mg dose group [Figure 3]. Similar results were seen in reSURFACE 2 study.[24]{Figure 3}

At week 28, the response rate of PASI 75, PASI 90, PASI 100, PGA 0/1, and DLQI 0/1 was 82%, 59%, 32%, 69%, and 57% for patients receiving 200 mg tildrakizumab dose and 80%, 52%, 24%, 66%, and 52%% for patients receiving 100 mg tildrakizumab dose, respectively [Figure 4]. reSURFACE 2 trials showed similar results.[24]{Figure 4}

At week 52 in reSURFACE 2 trial patients on 100 mg dose of tildrakizumab showed PASI 75, PASI 90, and PASI 100 in 91.2%, 73.3%, and 34.4% patients, respectively.[25] In long-term study of 148 weeks PASI 75 was seen in 91.2% of patients, PASI 90 in 67.6% patients, and PASI 100 was observed in 36.3% of patients receiving 100 mg dose of Tildrakizumab.[25]

Tildrakizumab was found to be superior to Etanercept in the reSURFACE 2 trial.[24]

Results from a network meta-analysis (NMA) showed that tildrakizumab was inferior to guselkumab for all examined PASI levels.[25],[26],[27]


Guselkumab is a human monoclonal antibody that blocks the signaling pathway mediated by IL-23 and is the first IL-23 blocker approved in adults with moderate to severe plaque psoriasis. It binds with high affinity and specificity to IL-23 through its p19 subunit and blocks the activation of the signaling pathway and prevents release of pro-inflammatory cytokines.[28]

In patients with plaque psoriasis, the mean half-life of Guselkumab was 15–18 days. The recommended dose of Guselkumab is 100 mg on day 0 and week 4, followed by 100 mg every 8 weeks given subcutaneously. Treatment efficacy of Guselkumab has been reported in VOYAGE trials, VOYAGE 1 and VOYAGE 2 trials assessed the efficacy and safety of Guselkumab compared to placebo and Adalimumab in patients with moderate-to-severe psoriasis.[28],[29]

In VOYAGE 1 patients receiving Guselkumab showed the following response at week 16: PASI 100, PASI 90, PASI 75, IGA 0/1 and DLQI 0/1 were 37.4%, 73.3%, 91.2%, 85.1%, and 56.3%, respectively. At week 16 patients receiving Adalimumab showed 17.1%, 49.7%, 73.1%, 65.9%, and 38.6% response, whereas patients on placebo showed 0.6%, 2.0%, 5.7%, 6.9%, and 4.2% response correspondingly. At week 24; PASI 100, PASI 90, PASI 75, IGA 0/1, and DLQI 0/1 response in the Guselkumab group was 44.4%, 80.2%, 91.2%, 84.2%, and 60.9%, whereas in the Adalimumab group it was 24.95, 53%, 72.2%, 61.7%, and 39.5%, respectively.[30]

Whereas at week 48; PASI 100, PASI 90, PASI 75, IGA 0/1 and DLQI 0/1 response in the Guselkumab group was 47.4%, 76.3%, 87.8%, 80.5%, and 62.5%, whereas in the Adalimumab group it was 23.4%, 47.9%, 62.6%, 55.4%, and 38.9%, respectively[28] [Figure 5][Figure 6][Figure 7][Figure 8][Figure 9].{Figure 5} {Figure 6} {Figure 7} {Figure 8} {Figure 9}

VOYAGE 2 showed similar results at week 16 and week 24 in both Guselkumab and Adalimumab groups.[30]


Risankizumab is a humanized IgG1 monoclonal antibody that selectively targets IL-23 through its p19 subunit. Risankizumab is administered subcutaneously and has a half-life from 20–28 days.[31]

It is given in the dose of 150 mg (75 mg 2 injections) on day 0, week 4 and every 12 weeks.

In phase 2 trials at week 12 patients receiving risankizumab 90 mg showed PASI 50, PASI 75, PASI 90, PASI 100, DLQI 0/1 in 100%, 98%, 73%, 41%, and 71%, respectively. Patients receiving Ustekinumab at week 12 showed PASI 50, PASI 75, PASI 90, PASI 100, DLQI 0/1 in 82%, 72%, 40%, 18%, and 53% correspondingly. At week 24 patients in phase 2 trials patients receiving Risankizumab 90 mg dose showed PASI 75 in 90% and PASI 90 in 63%. Those receiving Ustekinumab had PASI 75 in 70% and PASI 90 in 55%.[32]

In UltIMMa 1 trial at week 16 patients receiving Risankizumab 150 mg dose PASI 90, PASI 100 and DLQI 0/1 was observed in 75.3%, 35.9% and 65.8% patients, respectively. Although patients on ustekinumab PASI 90, PASI 100, and DLQI 0/1 response rates were 42%, 12%, and 43%, patients on placebo showed 4.9%, 0%, and 7.8% response correspondingly at week 16[33] [Figure 10].{Figure 10}

In the same trial at week 52 patients on Risankizumab 150 mg showed PASI 90, PASI 100, and PASI 75 in 81.9%, 56.3%, and 86.8%. Those patients who received Ustekinumab showed PASI 90, PASI 100, and PASI 75 in 44%, 21%, and 70% at week 52[33] [Figure 11]. Similar response rates were observed in UltIMMa 2 trial.[33]{Figure 11}

In the IMMvent trial at week 16, Risankizumab gave superior response as compared to Adalimumab, patients achieved the following results: PASI 75 (91% vs. 72%), PASI 90 (72% vs. 47%), PASI 100 (40% vs. 23.0%), and sPGA 0/1 (84% vs. 60%[30] [Figure 12]. At week 44 in the IMMvent trial Risankizumab showed PASI 75 in 91%, PASI 90 in 66.0% and PASI 100 in 40% patients and sPGA 0/1 in 74%, whereas adalimumab achieved PASI 75 in 46%, PASI 90 in 21% and PASI 100 in 7% and sPGA 0/1 in 34% patients, respectively[31] [Figure 13].{Figure 12} {Figure 13}

Findings from IMMerge trial showed superiority of risankizumab over secukinumab. PASI 90 at week 52 was seen in 87% of patients who were administered risankizumab compared to 57% in patients who received secukinumab. At week 16, risankizumab was noninferior to secukinumab with a PASI 90 response of 74% vs. 66%, respectively.[34]

 Safety Profile of IL-23 Blocking Agents

Adverse events (AE) reported in ReSurface 1 trial wherein Tildrakizumab 100 mg was administered, indicated that less than one AE was seen in 47% of patients, whereas serious AE were reported in 25 patients. No deaths were reported in reSurface 1 trial. The most common AEs were nasopharyngitis (8%), upper respiratory infection (3%), and psoriasis (1%). Severe infections were seen in less than 15 patients. No cases of malignancy or non-melanoma skin cancer (NMSC), major adverse cardiac events (MACE) and drug-related hypersensitivity reactions were reported. In reSurface 2 trial injection site erythema was reported in 2 cases whilst one death was also reported.[24]

Guselkumab administered in VOYAGE 1 trial reported at least one AE in 74.5% of patients during the period from 0–48 weeks. Common AE reported included nasopharyngitis (25.2%), upper respiratory infection (14.3%), injection site erythema (2.4%), headache (5.5%), arthralgia (5.5%), pruritus (2.4%), and back pain (3.6%). 2.7% of cases discontinued the study due to AE. At least one serious adverse event (SAE) was seen in 4.9% of patients. Infections were observed in 52.3% of patients, out of which 16.4% required treatment. Serious infections were seen in 0.6% of patients, malignancy was reported in 0.6%, NMSC in 0.6%, whereas MACE was seen in 0.3% of patients.[28]

In the phase 2 trial where Risankizumab was administered rate of any AE reported during the period 0–48 weeks was around 80%. Severe AE was seen in 10%, leading to discontinuation of study in 2% of patients. Serious AEs were reported in 15% of patients. Common AE included nasopharyngitis (34%), headache (5%), gastroenteritis (10%), and back pain (10%). SAE included neoplasm (benign/malignant) (5%), basal cell carcinoma (2%), salivary gland neoplasm (2%), CNS accident (2%), cardiac disorders (5%) which included myocardial infarction (2%), and coronary artery occlusion (2%). Other SAE reported were approximately 5%.[32]

 Comparison of the Three New IL-23 Blockers

Data for the three IL-23 blockers were interpolated from different trials and compared. These are not head-to-head trials. This data revealed that Risankizumab showed superior response amongst the three IL-23 monoclonal antibodies. Risankizumab showed greater PASI response followed by Guselkumab and Tildrakizumab.

At week 12 in the phase 2 trials,[32] risankizumab showed PASI 75 in 98% patients, compared to guselkumab which at week 16 in VOYAGE 1[29] showed PASI 75 in 91% patients, whereas tildrakizumab at week 12 in reSURFACE 2[24] showed PASI 75 in 61% patients, thus establishing risankizumab as a molecule which showed an early response [Figure 14].{Figure 14}

PASI 90 response with risankizumab in phase 2 trials[32] (at week 12), Guselkumab in VOYAGE 1[29] (at week 16) and tildrakizumab in reSURFACE 2[24] (at week 12) was 73%, 73.3%, and 39%, respectively. Correspondingly PASI 100 response for above three biologics was 41%, 37.4%, and 12%, respectively. PGA 0/1 response was also superior with risankizumab at week 12 (90%) compared to Guselkumab at week 16 (85.1%) and tildrakizumab at week 12 (55%) [Figure 14].

At week 24 in phase 2 trials[32] risankizumab showed PASI 75 in 90% patients and PASI 90 in 63% patients and PASI 100 in 40% patients (PASI 100 data from IMMvent trial[31] at week 44), guselkumab correspondingly had PASI 75 response in 91% patients and PASI 90 in 80.2% patients and PASI 100 in 44.4% patients in the VOYAGE 1 trial.[29] Tildrakizumab at week 28 in the reSURFACE 2[24] trial showed PASI 75, PASI 90, and PASI 100 in 73%, 55%, and 22% patients, respectively [Figure 15].{Figure 15}

At week 52 risankizumab in phase 2 trials[32] showed PASI 75 in 95% patients, PASI 90 in 81% patients and PASI 100 in 56.3% patients (PASI 100 data from UltIMMa 1 trial[33]). Guselkumab from VOYAGE 1[29] at week 48 showed PASI 75 in 80.5%, PASI 90 in 76.3% and PASI 100 in 47.4% patients. Tildrakizumab in reSurface 2 trial[27] showed PASI 75 in 91.2%, PASI 90 in 73.2% and PASI 100 in 34.4% patients [Figure 16].{Figure 16}

At week 52 in the UltIMMa 1 trial[31] risankizumab showed PASI 75, PASI 90 and PASI 100 to be 86.8%, 81.9% and 56.3%, guselkumab in VOYAGE 1 trial[29] showed 80.5%, 76.3% and 47.4% and in the reSURFACE 2 trial[27] Tildrakizumab showed 91.2%, 73.2% and 34.4% response rates [Figure 17].{Figure 17}

Risankizumab showed superior PASI 75, PASI 90, and PASI 100 response rates amongst the three IL-23 blockers at week 12, week 24, and also at week 52 [Table 2].{Table 2}

 IL-23 Blockers in Psoriatic Arthritis

In discover 2 trial,20% improvement in the American College of Rheumatology criteria (ACR 20) was achieved after 24 weeks in 71% of patients who received guselkumab every 4 weeks and in 75% of patients who received every 8 weeks, this response was maintained by week 52. The proportions of patients in whom ACR50/ACR70 and skin responses, minimal or very low disease activity, and dactylitis or enthesitis resolution were achieved at week 24 were also maintained through week 52. Guselkumab has been approved by US FDA for treatment of psoriatic arthritis (PsA).[35] Risankizumab resulted in significantly greater improvements in signs and symptoms of PsA. It has yet to get approval from US FDA.[36] Tildrakizumab significantly improved joint and skin manifestations of PsA other than dactylitis and enthesitis. It is yet to get US FDA approval for use in PsA.[37]


Introduction of biologics has heralded a new era in the treatment of psoriasis. IL 17 and IL-23 blockers have raised the bar in obtaining almost PASI 100 response. PASI 75 has now become the new benchmark. Especially, the most recently approved IL 17 and IL-23 blocking monoclonal antibodies have proved to be highly efficient with a good safety profile in short-term clinical trials. However, only long-term results from clinical studies and post-marketing surveillance can decide to what extent the new therapies are a success. Guidance on which of the biologics to choose for the highest rate of success for the individual patient, and how to proceed or discontinue treatment in patients that have achieved effect on biologics also seems warranted. Future studies based on link between genetics, co-morbidities, and psoriasis may bring information that may individualize the treatment approach.


The authors thank Dr. Delanthimar Joshika Bhandary, consultant dermatologist at Tvaksh Advanced Skin and Hair Clinic and clinical associate at Dermo-Cosmetology Department, Lilavati Hospital, Mumbai for providing [Figures 1] and [2].

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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