Katie Robinson

Studies have evaluated whether controlling the inflammation in psoriasis by inhibiting interleukins (IL) targeting the IL-23/T helper-17 (Th17) axis could reduce the accompanied atherosclerotic process, but the results are inconsistent and the data are sparse. This is according to a systematic review published in 

The IL-23/Th17 pathway plays a role in the pathogenesis of psoriasis and is believed to be implicated in the development of cardiometabolic comorbidities. This systematic reviewsummarized the impact of treatment with biologics targeting the IL-23/Th17 axis on subclinical atherosclerosis in patients with plaque psoriasis and/or 

Eight studies met the criteria and were included in the review. No studies that assessed the effect of IL-23 inhibitors were identified. Six studies were observational and 2 were randomized controlled trials that evaluated the effect of anti-IL-17 therapy on varied markers of subclinical atherosclerosis. The markers were assessed through static or dynamic imaging or blood-based, soluble biomarkers that indicate or are indirectly related to early alterations of the blood vessels. While 6 studies showed positive effects of biologic therapy, 2 showed no benefit on subclinical atherosclerosis.

It is undetermined whether “discrepancies on the anti-atherogenic effect are associated with differences in patient-related characteristics, principally with regards to their cardiovascular disease (CVD)-risk profile at the onset of biologic therapy, drug-related characteristics such as pharmacologic properties of each IL-17 inhibitor, or difference in sensitivity between the utilized diagnostic techniques,” wrote Aikaterini Tsiogka, MD, of the University of Athens in Greece, and colleagues.

The investigators cited further research that assessed the effect of biological agents on psoriasis-associated CVD and cardiometabolic comorbidities. A 2021 systematic review and meta-analysis examined the impact of IL-12 and IL-23 antagonist ustekinumab, IL-17A antagonist secukinumab or the tumor necrosis factor (TNF)-a inhibitor adalimumab on imaging and biomarkers of CVD, including lipoproteins, inflammation, obesity and insulin resistance. Ustekinumab reduced aortic vascular inflammation and adalimumab reduced C-reactive protein (CRP) and IL-6, but no other benefits were reported in the patients taking the biologics compared with those on placebo. A 2011 meta-analysis reported a potential risk of severe cardiovascular events during ustekinumab initiation, a finding that was supported by a 2020 case-control study.

The latest EuroGuiderm guideline on the treatment of psoriasis vulgaris, including patients with concomitant PsA, recommends that appropriate investigations and treatment should be initiated in patients with established CVD. The guideline also suggested the use of methotrexate, TNF-a inhibitors, ustekinumab and IL-17 inhibitors and avoidance of cyclosporine or acitretin in patients with psoriasis and ischemic heart disease.

“Future research could include the identification of clinical markers in patients with psoriasis and/or PsA that could predict an optimal anti-atherogenic effect of systemic treatment of psoriasis with biologics,” investigators said. “Future, well-controlled studies could elucidate if different biologic agents may exhibit a more pronounced anti-atherogenic effect and target CVD inflammation more effectively, an association which is yet particularly to be studied in patients receiving IL-23 inhibitors, considering the sparsity of such data in the medical literature.”

Tsiogka A, Gregoriou S, Stratigos A, et al. 

The Impact of Treatment with IL-17/IL-23 Inhibitors on Subclinical Atherosclerosis in Patients with Plaque Psoriasis and/or Psoriatic Arthritis: A Systematic Review

. 2023;11(2):318. Published 2023 Jan 23. doi:10.3390/biomedicines11020318

Nast A, Smith C, Spuls PI, et al. EuroGuiDerm Guideline on the systemic treatment of Psoriasis vulgaris - Part 2: specific clinical and comorbid situations. J Eur Acad Dermatol Venereol. 2021;35(2):281-317. doi:10.1111/jdv.16926

Articles

The systematic review summarized the impact of biologics targeting the IL-23/Th17 axis.

Impact of IL-17/IL-23 Inhibitors on Subclinical Atherosclerosis in Patients With Plaque Psoriasis, PsA

In a real-world setting, around half of the patients with psoriatic arthritis (PsA) receiving apremilast (Otezla, Amgen) achieved Disease Activity Index for Psoriatic Arthritis (DAPSA) low disease activity or remission at 6 and 12 months. The study, which was published in 

 also found that baseline DAPSA was the only factor associated with this achievement.

“DAPSA low disease activity or remission rates of apremilast in a real-world setting of PsA patients were comparable to the ones reported in registration trials,” Andrea Becciolini, of the University Hospital of Parma in Italy, and colleagues, wrote. We confirmed that “the major factor associated with achievement of DAPSA low disease activity or remission was baseline disease activity.”

Apremilast is an oral inhibitor of phosphodiesterase 4 (PDE4) indicated for the treatment of adults with active PsA. In several phase 3 trials, apremilast showed a significant clinical response in patients with PsA who were naïve or experienced with other disease-modifying antirheumatic drugs (DMARDs). However, the real-word data reporting on the effectiveness of apremilast are lacking.

This retrospective observational study included all consecutive patients with PsA treated with apremilast in 15 rheumatological referral centers in Italy. The researchers aimed to report on the long-term DAPSA response of apremilast and to analyze the predictors of clinical response. A total of 293 patients (median age 60, females 57%) were enrolled. The median PsA disease duration was 49 months and 46.8% had relevant comorbidities. Of the patients, 23.5% did not receive any DMARDs before apremilast.

The DAPSA low disease activity or remission rates were 42.7% at 6 months and 54.9% at 12 months. Baseline DAPSA was inversely associated with the odds of achieving low disease activity or remission at 6 months (odds ratio [OR] 0.841, 95% confidence interval [CI] 0.804–0.879; 

 < 0.01) and at 12 months (OR 0.911, 95% CI 0.883–0.939; 

“We found that at both time points, higher baseline DAPSA was significantly associated with reduced probability of achieving low disease activity or remission,” investigators concluded. “Further studies, especially in patients treated for a longer duration with apremilast, should be encouraged in order to confirm our results.”

Limitations of the study included the observational retrospective design and the relatively short follow-up period. Also, rheumatologists in Italy must comply with regional provisions, which the investigators noted may have driven the choice of apremilast use.

Becciolini A, Parisi S, Del Medico P, et al. Predictors of DAPSA Response in Psoriatic Arthritis Patients Treated with Apremilast in a Retrospective Observational Multi-Centric Study. Biomedicines. 2023;11(2):433. Published 2023 Feb 2. doi:10.3390/biomedicines11020433

Higher baseline Disease Activity Index for Psoriatic Arthritis (DAPSA) was associated with reduced probability of achieving low disease activity or remission. 

Apremilast Achieves Low Disease Activity, Remission in Real-World PsA Setting

The efficiency of tofacitinib (Xejianz, Pfizer) was greater than placebo in Chinese patients with active psoriatic arthritis (PsA) and inadequate response to at least 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD), according to a study published in

“The results of this study are the first to demonstrate that tofacitinib may be an effective treatment option for Chinese patients with active PsA,” Xiaofeng Zeng, MD, of Peking Union Medical College Hospital in Beijing, China, stated. “Tofacitinib was well tolerated, with safety outcomes consistent with the established safety profile in the PsA global clinical program and other indications.”

Tofacitinib, an oral Janus kinase inhibitor, is approved by the US Food and Drug Administration (FDA) for the treatment of active PsA when 1 or more tumor necrosis factor (TNF) blocker medicine has been used and did not work well or cannot be tolerated. Tofacitinib is also approved for the treatment of PsA in Taiwan, but there are no approved advanced therapies for PsA in mainland China. Mainland China was not included in the global clinical development program of tofacitinib in PsA and only a small number of patients from Taiwan were enrolled in the program. Therefore, data supporting the efficacy and safety of tofacitinib in Chinese patients with PsA are limited.

This 6-month, double-blind, phase 3 study randomized 136 patients (mean age 45.3 years, 79% male) to tofacitinib 5 mg twice daily and 68 patients (mean age 43.9 years, 42% male) to placebo; switched to tofacitinib 5 mg twice daily after month 3. The primary endpoint was the American College of Rheumatology (ACR50) response at month 3. Secondary endpoints, through month 6, included: ACR20/50/70 response; change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI); ≥75% improvement in Psoriasis Area and Severity Index (PASI75) response, and enthesitis and dactylitis resolution. Safety was assessed throughout.

The primary endpoint was met, with 38.2% of the tofacitinib group and 5.9% of the placebo group achieving the ACR50 response rate at month 3 (p <.0001). For secondary endpoints, ACR20/ACR70/PASI75 responses were higher with tofacitinib versus placebo. Enthesitis and dactylitis resolution rates and HAQ-DI reduction were greater with tofacitinib versus placebo.

The incidence of adverse events (AEs)/serious AEs through to month 3 were 68.4%/0% for tofacitinib and 75.0%/4.4% for placebo. One death was reported in the placebo group due to an accident. By month 6, one serious infection, non-serious herpes zoster, and lung cancer case each were reported in the tofacitinib group, and 4 serious infections and 1 non-serious herpes zoster case were reported the placebo group. There were no reports of non-melanoma skin cancer, major adverse cardiovascular or thromboembolism events.

The limitations of this study include the 6-month duration, which prevents conclusions on the long-term effectiveness and assessment of long-latency safety events of tofacitinib in Chinese patients with PsA.

Leng X, Lin W, Liu S, et al. Efficacy and safety of tofacitinib in Chinese patients with active psoriatic arthritis: a phase 3, randomised, double-blind, placebo-controlled study. RMD Open. 2023;9(1):e002559. doi:10.1136/rmdopen-2022-002559

Study results are the first to demonstrate that tofacitinib may be an effective treatment option for Chinese patients with active psoriatic arthritis.

Tofacitinib Effective, Safe in Chinese Patients With Active Psoriatic Arthritis

In patients with psoriatic arthritis (PsA) who were refractory to various lines of biologic and targeted synthetic drugs, ixekizumab (Taltz; Eli Lilly), an anti-interleukin (IL)-17A therapy, showed a good retention rate at 1 and 2 years, according to a study published in the 

Moreover,depression wasthe only comorbid factor associated with lower survival of ixekizumab, while cardiometabolic risk factors including obesity and smoking did not affect the drug survival rate.

In this Q&A, corresponding author Rubén Queiro, MD, PhD, associate professor at the University of 

Hospital Universitario Central de Asturias

 in Oviedo, Spain discussed the research and its findings.

This retrospective longitudinal observational single-center study included 72 patients (mean age 50 years; 72% women) with PsA who had received at least 1 dose of ixekizumab. More than 90% received 2 or more biologic and/or targeted synthetic disease-modifying anti-rheumatic drugs prior to ixekizumab. Ixekizumab showed 1- and 2-year retention rates of 65% and 57%, respectively. Meanwhile, 0.18 adverse events per person-year were identified. While the number of previous biologics did not influence drug survival, prior use of methotrexate (hazard ratio [HR] 2.31 [95% confidence interval (CI) 1.05 – 5.10], 

 < .05) and depression (HR 2.40 [95% CI 1.07 – 5.41], 

 < .05) increased the risk of ixekizumab discontinuation. Ixekizumab showed a good retention rate in patients with PsA regardless of age, gender, metabolic comorbidities, or smoking status.

We have carried out this study because, despite the fact that ixekizumab has been on the therapeutic market for PsA for several years now, most of the information we have about this drug comes from pivotal randomized clinical trials (RCTs) and their open-label extension phases. The information from registries or observational studies from the point of view of daily clinical practice is very scarce.

We all know that the type of patient that enters RCTs is very different from the type of day-to-day patients in rheumatology clinics. For this reason, studies that come from real-life experience provide valuable information whose dissemination should be facilitated and shared with the international rheumatology community.

What were the surprises from the findings?

 We have found very favorable data on the persistence and safety of ixekizumab in real clinical practice conditions. It must be considered that in our study we included patients with active disease, who had failed 2 or more biological and targeted-specific therapies.

In this difficult-to-approach patient population, ixekizumab retention rates at the first and second year have been optimal, and the safety profile acceptable, with no alarm signals other than what is already known with the drug. In particular, we have seen that the factors that usually penalize the persistence of other biologics (particularly female gender, previous use of other biologics, and cardiometabolic comorbidities such as obesity and others) did not affect the persistence rates of ixekizumab. On the contrary, the previous use of methotrexate and depression were associated with a worse survival of the drug.

 Our findings show that even in populations of PsA patients with a very difficult prior therapeutic approach, ixekizumab demonstrates a good profile of effectiveness and safety, which translates into the good survival curves that we have detected in our research. This means that ixekizumab is a very good rescue option for those patients with active disease refractory to multiple lines of prior treatment.

We also show that depression stands as a universal factor of worse persistence with any biologic therapy.

What is the current practice and how could the findings possibly change things?

 Currently, at least in many European countries, it is common to start biologic therapy in PsA patients with an anti-tumor necrosis factor (TNF) biosimilar. However, we know that many patients undergoing these treatments will present persistence and safety problems. In addition, the persistence of anti-TNF drugs is greatly hampered by the comorbidities of the disease, such as obesity, for example.

Our findings show that ixekizumab works well regardless of these limiting factors for anti-TNFs. On the other hand, many anti-TNF drugs are co-prescribed with methotrexate, both to increase their persistence and their efficacy. Once again, our findings show that this co-prescribing is not necessary with ixekizumab, which may translate into less iatrogenicity and lower treatment costs per patient.

What are the takeaway points for clinicians?

 We want to highlight the high effectiveness and safety of ixekizumab in real clinical practice scenarios. Also, the non-need to co-medicate ixekizumab with methotrexate, and the high persistence of the drug in conditions where many other agents tend to have persistence problems (ie, obesity, previous failure of other biologics, female gender).

: Depression, one of the common comorbidities in psoriatic disease, penalizes the survival of any biological drug, including ixekizumab, and therefore this aspect of the disease must be detected and treated jointly with other health professionals to establish the appropriate measures. Cardiometabolic comorbidity should be considered in treatment decisions for these patients, since we are verifying how IL-17A inhibitors tend to persist better in this subgroup of patients with PsA.

Braña I, Pardo E, Burger S, González Del Pozo P, Alperi M, Queiro R. Treatment Retention and Safety of Ixekizumab in Psoriatic Arthritis: A Real Life Single-Center Experience. J Clin Med. 2023;12(2):467. Published 2023 Jan 6. doi:10.3390/jcm12020467

In this Q&A, Rubén Queiro, MD, PhD, discussed the findings of a study that evaluated the retention rate and safety of ixekizumab in patients with psoriatic arthritis in real clinical practice conditions.