Interleukin 23 receptor: Expression and regulation in immune cells.

The importance of IL-23 and its specific receptor, IL-23R, in the pathogenesis of several chronic inflammatory diseases has been established, but the underlying pathological mechanisms are not fully understood. This review focuses on IL-23R expression and regulation in immune cells.

Bispecific soluble cytokine receptor-nanobody fusions inhibit Interleukin (IL-)6 trans-signaling and IL-12/23 or tumor necrosis factor (TNF) signaling.

At least 0.5% of people in the Western world develop inflammatory bowel disease (IBD). While antibodies that block tumor necrosis factor (TNF) α and Interleukin (IL-)23 have been approved for the treatment of IBD, IL-6 antibodies failed in the phase II clinical trial due to non-tolerable side effects. However, two clinical phase II studies suggest that inhibiting IL-6/soluble IL-6R (sIL-6R)-induced trans-signaling via the cytokine receptor gp130 benefit IBD patients with fewer adverse events. Here we develop inhibitors targeting a combination of IL-6/sIL-6R and TNF or IL-12/IL-23 signaling, named cs130-TNFVHHFc and cs130-IL-12/23VHHFc. Surface plasmon resonance experiments showed that recombinant cs130-TNFVHHFc and cs130-IL-12/23VHHFc bind with high affinity to IL-6/sIL-6R complexes and human TNFα (hTNFα) or IL-12/IL-23, respectively. Immunoprecipitation experiments have verified the higher ordered complex formation of the inhibitors with IL-6/sIL-6R and IL-12. We demonstrated that cs130-TNFVHHFc and cs130-IL-12/23VHHFc block IL-6/sIL-6R trans-signaling-induced proliferation and STAT3 phosphorylation of Ba/F3-gp130 cells, as well as hTNFα- or IL-23-induced signaling, respectively. In conclusion, cs130-TNFVHHFc and cs130-IL-12/23VHHFc represent a class of dimeric and bispecific chimeric cytokine inhibitors that consist of a soluble cytokine receptor fused to anti-cytokine nanobodies.

Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study.

BACKGROUND & AIMS: The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy. METHODS: In this double-blind, placebo-controlled, dose-ranging, induction study, patients were randomized (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0/4/8. The primary endpoint was clinical response (compared with baseline, modified Mayo score decrease ≥30% and ≥2 points, rectal bleeding subscore ≥1-point decrease or subscore of 0/1) at week 12. Guselkumab and placebo week-12 clinical nonresponders received subcutaneous or intravenous guselkumab 200 mg, respectively, at weeks 12/16/20 (uncontrolled study period). RESULTS: The primary analysis population included patients with baseline modified Mayo scores ≥5 and ≤9 (intravenous guselkumab 200 mg, n = 101; 400 mg, n = 107; placebo, n = 105). Week-12 clinical response percentage was greater with guselkumab 200 mg (61.4%) and 400 mg (60.7%) vs placebo (27.6%; both P < .001). Greater proportions of guselkumab-treated vs placebo-treated patients achieved all major secondary endpoints (clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization) at week 12. Among guselkumab week-12 clinical nonresponders, 54.3% and 50.0% of patients in the 200- and 400-mg groups, respectively, achieved clinical response at week 24. Safety was similar among guselkumab and placebo groups. CONCLUSIONS: Guselkumab intravenous induction was effective vs placebo in patients with moderately to severely active UC. Guselkumab was safe, and efficacy and safety were similar between guselkumab dose groups. CLINICALTRIALS: gov number: NCT04033445.

The opposite effect of tapinarof between IMQ and IL-23 induced psoriasis mouse models.

Tapinarof is an aryl hydrocarbon receptor (AHR) ligand which is used to treat plaque psoriasis in adults. However, the underlying mechanism is not yet fully understood. In this study, we applied two of the most studied psoriasis mouse models: topical application of imiquimod (IMQ) and subcutaneous injection of IL-23. Although both models successfully induced psoriasis-like lesions in mice, tapinarof had a completely opposite effect on the two models. Tapinarof decreased the expression of multiple essential cytokines involved in the pathological IL-23/IL-17/IL-22 axis and ameliorated IMQ-induced psoriatic dermatitis, inhibiting keratinocyte proliferation and abnormal differentiation. However, in the IL-23-injection-model, tapinarof instead aggravated the disease. Here, tapinarof increased epidermal thickness and differentiated epidermal dysplasia in mice. Our data suggest that tapinarof may have different effects on varied types of psoriasis.

Mirikizumab: A New Therapeutic Option for the Treatment of Ulcerative Colitis.

OBJECTIVE: To review the pharmacologic and clinical profile of mirikizumab in the treatment of moderate to severe ulcerative colitis (UC). DATA SOURCES: A PubMed search was performed from inception to December 2023 using keywords mirikizumab, interleukin-23 inhibitor, and UC. Information was also obtained from package inserts as well as published abstracts. STUDY SELECTION AND DATA EXTRACTION: Phase 3 studies plus relevant literature on mirikizumab pharmacologic and clinical profile were reviewed. DATA SYNTHESIS: Mirikizumab approval was based on LUCENT-1 and LUCENT-2. In the phase 3 studies involving patients with moderate to severe UC, mirikizumab, when compared to placebo, resulted in clinical remission in a significantly higher proportion of patients in both the induction and maintenance phase. In addition, mirikizumab met the secondary endpoints of alternate definition of clinical remission, endoscopic remission, glucocorticoid-free clinical remission, histologic-endoscopic mucosal remission, and improvement in bowel urgency status, bowel-urgency remission, and maintenance of clinical remission. Common adverse events noted include infection (15.1%), injection-site reaction (8.7%), nasopharyngitis (7.2%), and headache (3.3%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING AGENTS: Mirikizumab is the first selective interleukin 23 (IL-23) inhibitor approved for UC. Additional studies are required to determine how to position mirikizumab in both biologic-naïve and biologic-experienced patients with moderate to severe UC. CONCLUSION: Mirikizumab provides a novel mechanism of action for the treatment of moderate to severe UC and is another welcomed treatment advance in the treatment arsenal, providing a more selective mechanism of action while maintaining a comparable safety profile.

Efficacy and safety of risankizumab for Crohn's disease in patients from Asian countries: a post hoc subanalysis of the global phase 3 ADVANCE, MOTIVATE, and FORTIFY studies.

BACKGROUND AND AIM: The anti-interleukin-23 antibody risankizumab is being investigated as a treatment for moderate-to-severe Crohn's disease. This post hoc subanalysis evaluates the efficacy and safety of risankizumab therapy in Asian patients. METHODS: ADVANCE (NCT03105128) and MOTIVATE (NCT03104413) were randomized, double-blind, placebo-controlled, phase 3 induction studies. Patients with intolerance/inadequate response to biologic (MOTIVATE) and/or conventional therapy (ADVANCE) were randomized to receive intravenous risankizumab (600 or 1200 mg) or placebo at weeks 0, 4, and 8. Clinical responders to risankizumab could enter the phase 3, randomized, double-blind, placebo-controlled maintenance withdrawal study (FORTIFY; NCT03105102). Patients were rerandomized to receive subcutaneous risankizumab (180 or 360 mg) or placebo (withdrawal) every 8 weeks for 52 weeks. RESULTS: Among 198 Asian patients in the induction studies, clinical remission and endoscopic response at week 12 were achieved by 61.4% and 40.0%, 59.5% and 35.8%, and 27.3% and 9.1% of patients in the risankizumab 600 mg, risankizumab 1200 mg, and placebo groups, respectively. Among 67 patients who entered the maintenance study, clinical remission and endoscopic response at week 52 were achieved by 57.1% and 52.4%, 75.0% and 40.0%, and 53.8% and 34.6% of patients in the risankizumab 180 mg, risankizumab 360 mg, and placebo (withdrawal) groups, respectively. Fistula closure was observed with risankizumab treatment in 28.6% (induction) and 57.1% (maintenance) of patients. Efficacy trends and safety profile were similar to those in non-Asian patients. CONCLUSION: Consistent with non-Asian and global population results, risankizumab was effective and well tolerated in Asian patients with Crohn's disease.

Activation of the interleukin-23/Th17 axis in major depression: a systematic review and meta-analysis.

The interleukin-23/Th17 axis is a promising modifiable target for depression. However, its association with depression has not been systematically evaluated. We systematically searched four databases (EMBASE, Web of Science, Pubmed and PsycINFO) for studies comparing patients with major depression and healthy controls for plasma/serum levels of Th17 cells and their canonical cytokines (interleukin-17A [IL-17A], IL-22, granulocyte macrophage colony stimulating factor [GM-CSF]). We also compared counts of Th1, Th2 and Th9 cells between depressed/non-depressed patients and their respective canonical cytokines. We performed random-effects meta-analysis of the standardised mean difference (SMD) in immune measures between groups. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 3154 studies screened, 36 studies were included in meta-analysis. Patients with depression had elevated IL-17A compared to controls (SMD = 0.80 [95% CI 0.03 to 1.58], p = 0.042), an association moderated by antidepressant use (Z = 2.12, p = 0.034). Patients with depression had elevated GM-CSF (SMD = 0.54 [95% CI 0.16 to 0.91], p = 0.0047), and a trend towards higher Th17 counts (SMD = 0.44 [- 0.01 to 0.88], p = 0.052). Whilst the Th2-associated cytokine IL-5 was elevated in depression (SMD = 0.36 [95% CI 0.05 to 0.66], p = 0.02), Th2 cell counts (p = 0.97), Th1 cell counts (p = 0.17) and interferon-γ (p = 0.22) were not. Data for Th9 cells, IL-9 and IL-22 were insufficient for meta-analysis. Respectively, 22, 25 and 5 studies were good, fair and poor in quality. Patients with major depression show peripheral over-activation of the IL-23/Th17 axis. Future interventional studies should test whether this is a modifiable target for depression.

Gene polymorphisms of an interleukin-23 receptor associated with susceptibility to rheumatoid arthritis in the Western Chinese Han population.

Rheumatoid arthritis (RA) is a chronic inflammatory disease which is closely related to genetic background. Single-nucleotide polymorphisms (SNPs) have been found to play an important role in the development of RA. This study intends to investigate the links between gene polymorphisms in the interleukin-23 receptor (IL23R) and interleukin 17A (IL17A) and susceptibility to RA in the Western Chinese Han population. Four SNPs (rs6693831 T > C, rs1884444 G > T, and rs7517847 T > G in IL23R gene, and rs2275913 G > A in IL17A gene) were genotyped in 246 RA patients and 362 healthy controls by high resolution melting analysis. The comparative analyses among genotype distributions, clinical indicators, and IL-17A and IL-23R levels in RA patients were also performed. The study revealed that the SNP rs6693831 and rs1884444 of IL23R had a significant association with RA susceptibility. The frequencies of rs6693831 genotype CC and allele C were significantly higher in the RA group and associated with higher RA risk compared with genotype TT and allele T (OR = 7.797, 95% confidence interval [CI] = 4.072-14.932 and OR = 5.984, 95%CI = 3.190-11.224, respectively). The TT genotype of rs1884444 appeared to decrease the RA risk compared with the GG genotype (OR = .251, 95%CI = .118-.536). The genotype CC and allele C of rs6693831 and the genotype GG and allele G of rs1884444 may be risk factors for RA. IL23R gene polymorphisms may be involved in the risk of RA susceptibility in the Western Chinese Han population.

Serum Levels of Interleukins in Endometriosis Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: The aims of this systematic review and meta-analysis were to produce a comprehensive survey of the serum levels of interleukins (ILs) in untreated people with endometriosis compared with people without endometriosis. DATA SOURCES: A systematic literature search of English language studies within Cinahl, Medline Complete, PubMed, and Scopus from inception to May 2023 was performed. METHODS OF STUDY SELECTION: We included studies that compared IL serum levels in people with endometriosis to those without endometriosis. Meta-analysis was performed on IL-1RA, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17A, IL-18, IL-23, and IL-37. TABULATION, INTEGRATION, AND RESULTS: The systematic search retrieved 651 studies, of which 77 underwent a full-text review. A total of 30 studies met inclusion criteria for the meta-analysis. IL-1Ra, IL-6, and IL-37 serum levels were 2.56 (95% CI 2.20-2.92, p <.001), 1.38 (95% CI 0.58-2.17, p <.001), and 1.77 (95% CI 1.33-2.20, p <.001) standard deviations higher in the patients with endometriosis compared with patients without endometriosis while IL-23 serum levels 0.40 (95% CI -0.73 to -0.07, p = .02) standard deviations lower, respectively. CONCLUSION: There is mounting evidence that ILs, especially IL-6, may be good candidates for unique noninvasive diagnostic tools and/or treatment pathways for endometriosis.

IL-23/IL-17 axis levels in gingival crevicular fluid of subjects with periodontal disease: a systematic review.

BACKGROUND: The IL-23/IL-17 axis plays an important role in the immunopathogenesis of periodontal disease. A systematic review was conducted to synthesize all research reporting on the levels of the IL-23/IL-17 axis in gingival crevicular fluid (GCF) from subjects with gingivits, and periodontitis, compared to healthy controls. METHODS: The protocol followed the PRISMA, and Cochrane guidelines, and was registered with the Open Science Framework (OSF): https://doi.org/10.17605/OSF.IO/7495V . A search was conducted in the electronic databases PubMed/MEDLINE, Scopus, Google Schoolar, and Cochrane from November 15th, 2005, to May 10th, 2023. The quality of the studies was assessed using the JBI tool for cross-sectional studies. RESULTS: The search strategy provided a total of 2,098 articles, of which 12 investigations met the inclusion criteria. The total number of patients studied was 537, of which 337 represented the case group (subjects with gingivitis, and chronic periodontitis), and 200 represented the control group (periodontally healthy subjects). The ages of the patients ranged from 20 to 50 years, with a mean (SD) of 36,6 ± 4,2, of which 47% were men, and 53% were women. 75% of the investigations collected GCF samples with absorbent paper strips, and analyzed cytokine IL-17 levels individually. In addition, qualitative analysis revealed that there are differences between IL-23/IL-17 axis levels in subjects with chronic periodontitis, gingivitis and healthy controls. CONCLUSIONS: Thus, IL-23/IL-17 axis levels could be used in the future as a diagnostic tool to distinguish between periodontal diseases.

Interleukin-23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy.

The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL-23R or the interleukin-23 (IL-23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin-17 (IL-17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL-23R-expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL-23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL-23R-expressing myeloid cells and various innate and adaptive T cells that produce IL-17 family cytokines have also been described in the human enthesis. Blockade of IL-23 pathway with either anti-p40 or anti-p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL-23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

Is Th17-Targeted Therapy Effective in Systemic Lupus Erythematosus?

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical manifestations. The proposed pathophysiological hypotheses of SLE are numerous, involving both innate and adaptive abnormal immune responses. SLE is characterized by the overproduction of different autoantibodies that form immune complexes, which cause damage in different organs. Current therapeutic modalities are anti-inflammatory and immunosuppressive. In the last decade, we have witnessed the development of many biologicals targeting different cytokines and other molecules. One of them is interleukin-17 (IL-17), a central cytokine of a proinflammatory process that is mediated by a group of helper T cells called Th17. Direct inhibitors of IL-17 are used in psoriatic arthritis, spondyloarthritis, and other diseases. Evidence about the therapeutic potential of Th17-targeted therapies in SLE is scarce, and probably the most promising is related to lupus nephritis. As SLE is a complex heterogeneous disease with different cytokines involved in its pathogenesis, it is highly unlikely that inhibition of only one molecule, such as IL-17, will be effective in the treatment of all clinical manifestations. Future studies should identify SLE patients that are eligible for Th17-targeted therapy.

IL-27 attenuates IL-23 mediated inflammatory arthritis.

Interleukin 27 has both pro-inflammatory and anti-inflammatory properties in autoimmunity. The anti-inflammatory effects of IL-27 are linked with inhibition of Th17 differentiation but the IL-27 effect on myeloid cells is less studied. Herein we demonstrate that IL-27 inhibits IL-23-induced inflammation associated not only with Th17 cells but also with myeloid cell infiltration in the joints and splenic myeloid populations of CD11b+ GR1+ and CD3-CD11b+CD11c-GR1- cells. The IL-27 anti-inflammatory response was associated with reduced levels of myeloid cells in the spleen and bone marrow. Overall, our data demonstrate that IL-27 has an immunosuppressive role that affects IL-23-dependent myelopoiesis in the bone marrow and its progression to inflammatory arthritis and plays a crucial role in controlling IL-23 driven joint inflammation by negatively regulating the expansion of myeloid cell subsets.

Guselkumab for the Treatment of Crohn's Disease: Induction Results From the Phase 2 GALAXI-1 Study.

BACKGROUND & AIMS: Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in patients with moderately to severely active Crohn's disease with inadequate response or intolerance to conventional or biologic therapy. METHODS: GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn's Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm. RESULTS: Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn's Disease Activity Index from baseline (least squares means: 200 mg: -160.4, 600 mg: -138.9, and 1200 mg: -144.9 vs placebo: -36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn's Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups. CONCLUSIONS: At week 12, all 3 dose regimens of guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile. CLINICALTRIALS: gov, Number: NCT03466411.

Baseline clinical, hormonal and molecular markers associated with clinical response to IL-23 antagonism in hidradenitis suppurativa: A prospective cohort study.

Hidradenitis suppurativa is a complex inflammatory disease in which predicting therapeutic response remains challenging. IL-23 interacts with sex hormones but the relationships between the two in HS remains uninvestigated. To assess whether baseline clinical, hormonal or molecular markers are associated with clinical response to IL-23 antagonism with risankizumab in hidradenitis suppurativa. Twenty six individuals with Hurley stage 2/3 disease were administered risankizumab 150 mg Week 0, 4, 12. Baseline sex hormones and skin biopsies were taken. Clinical response at Week 16 assessed by the HiSCR, and differences between responders and non-responders assessed. Eighteen of 26 participants achieved HiSCR50 at week 16 (69.2%). Clinical response to IL-23 antagonism was associated with male gender, elevated total serum testosterone and decreased levels of FSH. Stratification by clinical responders/nonresponders identified differentially expressed genes including PLPP4 and MAPK10. Immunohistochemistry identified elevated numbers of CD11c, IL-17A and IL-17F positive cells compared to nonresponders. CD11c + cells significantly correlated with serum levels of total testosterone and inversely correlated with serum FSH. Clinical response to IL-23 antagonism in HS is associated with serum sex hormones, Th17 polarized inflammation in lesional tissue and CD11c + cells. These potential therapeutic biomarkers require further validation in larger cohorts but may suggest potential targeted HS therapy.

Potential cerebrovascular accident signal for risankizumab: A disproportionality analysis of the FDA Adverse Event Reporting System (FAERS).

AIMS: The interleukin-23 (IL-23) inhibitor risankizumab was recently approved for the treatment of moderate-to-severe plaque psoriasis in the United States. Low rates of cerebrovascular accident (CVA) were observed in risankizumab-treated patients during clinical trials. The aim of this study was to determine whether risankizumab may be associated with CVA in a real-world setting. METHODS: A retrospective disproportionality analysis was conducted utilizing postmarketing adverse event reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) through the fourth quarter of 2021. A custom query consisting of 22 CVA-related Medical Dictionary for Regulatory Activities (MedDRA) preferred terms previously reported in clinical trials of plaque psoriasis medications was used to identify cases. Disproportionality was measured by calculating reporting odds ratios (ROR) and 95% confidence intervals (CI), whereby the lower limit of a 95% CI >1.0 and ≥ three cases was considered a signal. RESULTS: Risankizumab was associated with significantly disproportionate CVA reporting compared to all other drugs in FAERS (ROR 2.48; 95% CI 2.14-2.88) as well as 11 alternative plaque psoriasis therapeutics across five pharmacologic classes. The largest disproportionality signals for risankizumab were identified relative to apremilast (ROR 9.07; 95% CI 7.56-10.89), ixekizumab (ROR 6.75; 95% CI 5.14-8.86), guselkumab (ROR 6.74; 95% CI 4.68-9.71), certolizumab (ROR 5.70; 95% CI 4.74-6.85) and etanercept (ROR 4.91; 95% CI 4.21-5.73). CONCLUSION: This study detected a previously unreported signal of disproportionate CVA reporting with the real-world use of risankizumab. Further long-term observational data will be necessary to better characterize this unconfirmed potential safety signal.

Long-term safety and efficacy of risankizumab for the treatment of moderate-to-severe plaque psoriasis: Interim analysis of the LIMMitless open-label extension trial up to 5 years of follow-up.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease often requiring long-term therapy. OBJECTIVE: To evaluate the long-term safety and efficacy of risankizumab in patients with psoriasis. METHODS: LIMMitless is an ongoing phase 3, open-label extension study evaluating the long-term safety and efficacy of continuous risankizumab 150 mg every 12 weeks for adults with moderate-to-severe plaque psoriasis following multiple phase 2/3 base studies. This interim analysis assessed safety (ie, monitored treatment-emergent adverse events [TEAEs]) through 304 weeks. Efficacy assessments included determining the proportion of patients who achieved ≥90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90/100), static Physician's Global Assessment of clear/almost clear (sPGA 0/1), and Dermatology Life Quality Index of no effect on patient's life (DLQI 0/1) through 256 weeks. RESULTS: Among 897 patients randomized to risankizumab in the base studies, 706 were still ongoing at data cutoff. Rates of TEAEs, TEAEs leading to discontinuation, and TEAEs of safety interest were low. At week 256, 85.1%/52.3% of patients achieved PASI 90/100, respectively, 85.8% achieved sPGA 0/1, and 76.4% achieved DLQI 0/1. LIMITATIONS: Open-label study with no placebo or active-comparator group. CONCLUSIONS: Long-term continuous risankizumab treatment for up to 5 years was well tolerated and demonstrated high and durable efficacy.

Efficacy and Safety of IL-12/23 and IL-23 Inhibitors for Crohn's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Targeting interleukin-23 (IL-23) is an important therapeutic strategy for Crohn's disease (CD). AIMS: This systematic review and meta-analysis assessed the efficacy and safety of selective IL-23p19 and IL-12/23p40 inhibitors in patients with moderate-to-severe CD. METHODS: MEDLINE, Embase, and the Cochrane library (CENTRAL) were searched from inception to May 24, 2023, for randomized, placebo- or active comparator-controlled induction and/or maintenance trials of selective IL-23p19 and IL-12/23p40 inhibitors in pediatric and adult patients with CD. The primary outcome was the proportion of patients in clinical remission. Secondary outcomes were clinical response, endoscopic remission, endoscopic response, and safety. Data were pooled using a random-effects model. Risk of bias and certainty of evidence were assessed using the Cochrane risk of bias tool and the GRADE criteria, respectively. RESULTS: Eighteen trials (n = 5561) were included. Most studies were rated as low risk of bias. Targeting IL-23 was significantly superior to placebo for inducing clinical (risk ratio [RR] = 1.87, 95% confidence interval [CI] 1.58-2.21) and endoscopic (RR = 3.20, 95%CI 2.17-4.70) remission and maintaining clinical remission (RR = 1.39, 95%CI 1.10-1.77) (GRADE high certainty evidence for all outcomes). Subgroup analysis showed that targeting IL-23 was superior to placebo for inducing clinical remission in biologic-naïve (RR = 2.20, 95%CI 1.46-3.32, I2 = 0%, p = 0.39) and biologic-experienced patients (RR = 1.82, 95%CI 1.27-2.60, I2 = 56.5%, p = 0.01). Targeting IL-23 was associated with a decreased risk of serious adverse events in induction (RR = 0.55, 95%CI 0.44-0.73) and maintenance (RR = 0.72, 95%CI 0.53-0.98) trials compared to placebo (high certainty evidence). CONCLUSION: Targeting IL-23 is effective and safe for inducing and maintaining clinical and endoscopic remission in patients with moderate-to-severe CD.

A review of JAK and IL-23 inhibitors to treat vitiligo.

Vitiligo is an autoimmune skin disorder resulting in the depigmentation of skin characterised by patches of varying sizes and shapes. A common disorder of pigmentation that affects 0.5%-2% of the global population. Despite its well-understood autoimmune pathogenesis, the targets for effective cytokine intervention remain unclear. Current first-line treatments include oral or topical corticosteroids, calcineurin inhibitors and phototherapy. These treatments are limited, have varying efficacies, and are associated with significant adverse events or can be time-consuming. Therefore, biologics should be explored as a potential treatment for vitiligo. There are currently limited data for the use of JAK and IL-23 inhibitors for vitiligo. A total of 25 studies were identified in the review. There is promising evidence regarding the use of JAK and IL-23 inhibitors for the treatment of vitiligo.

The Effectiveness of Risankizumab Following Guselkumab Failure in Moderate-to-Severe Psoriasis Patients: A Retrospective Study.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease with a strong genetic predisposition and autoimmune component that is often treated with immunomodulators such as biologic therapy. Guselkumab is a biologic treatment option that selectively targets the p19 subunit of interleukin (IL)-23; risankizumab is a more recently developed monoclonal antibody of the same class that targets IL-23p19. There is limited research around effective treatment response with intra class switching within IL-23-targeted therapies for the treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: The purpose is to assess patient response to risankizumab after guselkumab failure for the treatment of plaque psoriasis. METHODS: A retrospective chart review was conducted for 13 patients meeting inclusion criteria. Physical examination findings were converted to a 5-point static physicians' global assessment (sPGA) score. Baseline, 4-month, and 12-month sPGA scores were assigned from visits immediately prior to and during their course of risankizumab treatment. sPGA scores were analyzed to compare changes between baseline and 4 months and 12 months of therapy. RESULTS: Patients treated with risankizumab had lower sPGA scores after both 4 and 12 months compared to their baseline sPGA score. 46% of patients met the primary outcome of an sPGA score of 0 or 1 at 4 months of risankizumab, increasing to 90% of patients at 12 months. CONCLUSIONS: Our findings reflect an improvement in sPGA scores when patients are treated with risankizumab following guselkumab failure. This highlights the benefit of in-class switch to risankizumab when patients with moderate-to-severe plaque psoriasis have failed multiple treatments including guselkumab.