STL Volume 27 Number 6 – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Tue, 20 Jun 2023 00:45:04 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 Selective TYK2 Inhibition in the Treatment of Moderate to Severe Chronic Plaque Psoriasis https://www.skintherapyletter.com/psoriasis/selective-tyk2-inhibition/ Wed, 30 Nov 2022 22:00:20 +0000 https://www.skintherapyletter.com/?p=13851 Article is available in: English French

Melinda J. Gooderham, MSc, MD, FRCPC1,2; H. Chih-ho Hong, MD, FRCPC2,3; Ivan V. Litvinov, MD, PhD, FRCPC4

1Skin Centre for Dermatology, Peterborough, ON, Canada
2Probity Medical Research, Waterloo, ON, Canada
3Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
4Division of Dermatology, Department of Medicine, McGill University, Montreal, QC, Canada

Conflict of interest:
M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Arena Pharmaceuticals, Asana BioSciences, ASLAN Pharmaceuticals, Bausch Health/Valeant, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, and UCB. H. C. Hong has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Cutanea, Dermira, Dermavant, DS Biopharma, Eli-Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Leo Pharma, Medimmune, Merck, Mirimar, Novartis, Pfizer, Regeneron, Roche, Sanofi-Genzyme, Sun Pharma, and UCB. I. Litvinov has received a grant or an honorarium from AbbVie, Actelion, Bausch Health, Bristol-Myers Squibb, Galderma, ICPDHM, Janssen, Johnson & Johnson, Merck, Novartis, Pfizer, and Sun Pharmaceuticals.

Funding for this manuscript was provided in the form of an educational grant from Bristol Myers Squibb Canada Co.

Abstract:
Moderate to severe chronic plaque psoriasis may be difficult to control using current therapies, which has led to development of a novel class of therapy, selective tyrosine kinase 2 (TYK2) inhibitors, to address this unmet need. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, which has shown efficacy in moderate to severe chronic plaque psoriasis from two phase III pivotal trials (POETYK PSO-1 and PSO-2), whereby response rates were significantly higher with deucravacitinib vs. placebo or apremilast for Psoriasis Area Severity Index (PASI) 75 and static Physician’s Global Assessment (sPGA) 0/1. Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast. Although deucravacitinib is a type of Janus kinase (JAK) inhibitor, it only blocks specific cytokine-driven responses, potentially reducing off-target effects more commonly associated with other JAK inhibitors on the market. Incidence rates of serious adverse events, such as serious infections, malignancies, thrombosis, cardiovascular events, creatinine kinase elevation, hematologic changes, and lipid profile abnormalities were absent or low.

Key Words:
plaque psoriasis, TYK2 inhibitor, deucravacitinib, apremilast, clinical trial, efficacy, safety, PASI, sPGA

Introduction

Psoriasis is a common, chronic, immune-mediated inflammatory disease, estimated to affect 1 million people in Canada.1,2 The most common type is chronic plaque psoriasis, which affects 90% of this patient population.1

Moderate chronic plaque psoriasis is typically defined as involving ≥3-10% body surface area (BSA), with severe disease involving more than 10% BSA.3 When inadequately treated, this can cause severe psychosocial impact and impair patients’ quality of life (QoL).3

Currently, various oral systemic agents, biologic agents, and phototherapy have Health Canada-approved indications for management of moderate to severe chronic plaque psoriasis. Despite numerous treatment options, unmet needs still exist. An emerging class of therapy in development are selective tyrosine kinase 2 (TYK2) inhibitors, which may meet those needs. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, recently US FDA approved and currently under review by Health Canada. Other oral selective TYK2 inhibitors for treatment of moderate to severe plaque psoriasis in various stages of development include GLPG3667 and NDI-034858.4,5

Pathogenesis of Plaque Psoriasis

The pathogenesis of chronic plaque psoriasis starts with environmental, immunologic, and/or genetic triggers that can lead to release of cytokines from innate immune cells, activating myeloid dendritic cells.6,7 Activated myeloid dendritic cells present antigens to T cells and release cytokines, including interleukin (IL)-23 and IL-12;6-8 both IL-23 and IL-12 signal through TYK2-mediated pathways. IL-12 contributes to T helper (Th)1-cell differentiation and IL-23 activates keratinocytes via pro-inflammatory Th17 cells;6 both processes lead to tumor necrosis factor (TNF)-α and interferon (IFN)-γ production. Cytokines secreted by Th17 and Th1 cells activate keratinocytes;9 this is one of the first steps in the development of psoriatic lesions. A positive feedback loop recruits other immune cells, further potentiating the inflammatory process.6

Rationale for Targeting TYK2 in Plaque Psoriasis Treatment

TYK2 is a Janus kinase (JAK) enzyme that is coded by the TYK2 gene and constitutively expressed in immune cells.10 Mutations and polymorphisms in TYK2 impact IL-23, IFN-α/β, and IL-12 immune-mediated signalling, and are associated with an altered risk for psoriasis; for example, loss of function mutations in TYK2 have been found to be protective against autoimmunity, including psoriasis.10 Selective TYK2 inhibition blocks IL-23, IL-12, and type I IFN-driven responses, but not those driven by other JAKs (Figure 1).11-13

Selective TYK2 Inhibition in the Treatment of Moderate to Severe Chronic Plaque Psoriasis - image
Figure 1. Cytokine responses in tyrosine kinase 2 (TYK2) and Janus kinase (JAK) pathways
EPO, erythropoietin; GH, growth hormone; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; JAK, Janus kinase; MHC, major histocompatibility complex; Th, T helper; TNF, tumor necrosis factor; TPO, thrombopoietin; Treg, regulatory T cell; TYK, tyrosine kinase.
Adapted from Baker and Isaacs. 2018.11

Deucravacitinib: Mechanism of Action

Deucravacitinib is a specific, oral, intracellular TYK2 inhibitor that targets immune responses driven by type 1 IFN and IL-23 that contribute to psoriasis pathogenesis, including IL-17 production and Th1/Th17 polarization.12-14 It binds with high specificity to the TYK2 regulatory domain, blocking kinase activity and conferring selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis (Figure 2).12-14

Selective TYK2 Inhibition in the Treatment of Moderate to Severe Chronic Plaque Psoriasis - image
Figure 2. Deucravacitinib mechanism of action
ATP, adenosine triphosphate; IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; Th, T helper; TYK, tyrosine kinase.

Deucravacitinib uniquely binds to the regulatory domain of TYK2 and only blocks specific cytokine-driven responses, leading to a broad therapeutic range while reducing off-target effects.11-13 In contrast, JAK 1–3 inhibitors bind to the active domain adenosine triphosphate (ATP) binding site common to all JAK molecules (including TYK2) to mediate both immune responses and broader systemic processes (e.g., myelopoiesis, granulopoiesis, lymphoid cell maturation and function, hematopoiesis, growth factor response, metabolic activity regulation, lipid metabolism, etc.), some of which are necessary for normal physiologic functioning, resulting in a narrower therapeutic range.13

Efficacy of Deucravacitinib: Key Evidence from Pivotal Phase III Clinical Trials

In a phase II trial of patients with psoriasis, deucravacitinib demonstrated superior efficacy vs. placebo based on ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) over 12 weeks.14 Efficacy results from two phase III pivotal trials of deucravacitinib were recently reported and confirmed results from the phase II trial.

In the 52-week, double-blinded, phase III POETYK PSO-1 trial, participants with moderate to severe chronic plaque psoriasis were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=332), placebo (n=166), or apremilast 30 mg twice daily (n=168).15 Similarly, participants in the 52-week, doubleblinded, phase III POETYK PSO-2 trial were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=511), placebo (n=255), or apremilast 30 mg twice daily (n=254).16

The coprimary endpoints of both trials were response rates for PASI 75 and static Physician’s Global Assessment score of 0 or 1 (sPGA 0/1) with deucravacitinib vs. placebo at week 16.15,16 Key secondary endpoints included the scalp-specific Physician’s Global Assessment (ss-PGA) and patient-reported symptoms and signs of psoriasis (evaluated using the Psoriasis Symptoms and Signs Diary [PSSD]) and QoL (evaluated using the Dermatology Life Quality Index [DLQI]).15

In both PSO-1 and PSO-2 trials, PASI 75 response rates at week 16 were significantly higher with deucravacitinib (58.4% and 53.0%) vs. placebo (12.7% and 9.4%) or apremilast (35.1% and 39.8%). Response rates for sPGA 0/1 were also significantly higher with deucravacitinib (53.6% and 50.3%) vs. placebo (7.2% and 8.6%) or apremilast (32.1% and 34.3%) (Table 1).15,16 Deucravacitinib responses improved beyond week 16 and were maintained through week 52.15 Furthermore, patients who switched from placebo to deucravacitinib at week 16 demonstrated PASI 75 and sPGA 0/1 responses at week 52 comparable to those observed in patients who received continuous deucravacitinib treatment from day 1.15

Regarding key secondary endpoints, significantly greater proportions of patients in the deucravacitinib vs. placebo and apremilast arms achieved ss-PGA 0/1 and DLQI 0/1 responses, as well as greater reduction from baseline in PSSD symptom scores at week 16 and week 24 (Table 1).15,16

Table 1. POETYK PSO-1 and PSO-2 efficacy results

Endpoint POETYK PSO-1 (n=666) POETYK PSO-2 (n=1,020) POETYK PSO-1 (n=666) POETYK PSO-2 (n=1,020)
Deucravacitinib 6 mg QD (n=332) Apremilast 30 mg BID (n=168) Placebo (n=166)

P value vs. apremilast

P value vs. placebo

 Deucravacitinib 6 mg QD (n=511) Apremilast 30 mg BID (n=254) Placebo (n=255)

P value vs. apremilast

P value vs. placebo
PASI 75, %
Week 16 58.4%* 35.1% 12.7%* <0.0001 <0º.0001 53.6%* 40.2% 9.4%* 0.0003 <0.0001
Week 24 69.3% 38.1% - <0.0001 - 59.3% 37.8% - <0.0001 -
sPGA 0/1, %
Week 16 53.6%* 32.1% 7.2%* <0.0001 <0.0001 50.3%* 34.3% 8.6%* <0.0001 <0.0001
Week 24 58.7% 31.0% - <0.0001 - 50.4% 29.5% - <0.0001 -
ss-PGA 0/1, %
Week 16 70.3% 39.1% 17.4% <0.0001 <0.0001 60.3% 37.3% 17.3% <0.0001 <0.0001
Week 24 72.2% 42.7% - <0.0001 - 59.7% 41.3% - 0.0002 -
DLQI 0/1, %
Week 16 41.0% 28.6% 10.6% 0.0088 <0.0001 38.0% -28.3 9.8% <0.0001 <0.0001
Week 24 48.1% 24.2% - <0.0001 - 41.8% -29.1 - <0.0001 -
Change from baseline PSSD symptom score, adjusted mean
Week 16 -26.7 -17.8 -3.6 <0.0001 <0.0001 -28.3 -21.1 -4.7 <0.0001 <0.0001
Week 24 -31.9 -20.7 - <0.0001 - -29.1 -21.4 - <0.0001 -

Table 1. POETYK PSO-1 and PSO-2 efficacy results
*Coprimary endpoints: response rates for PASI 75 and sPGA 0/1 with deucravacitinib vs. placebo at week 16.
BID, twice daily; DLQI, Dermatology Life Quality Index; PASI 75, ≥75% reduction from baseline in Psoriasis Area and Severity Index; PSSD, Patient-reported symptoms and signs of psoriasis, evaluated using the Psoriasis Symptoms and Signs Diary; QD, once daily; SE, standard error; sPGA 0/1, static Physician’s Global Assessment score of 0 or 1; ss-PGA, scalp-specific Physician’s Global Assessment. Adapted from Armstrong AW, et al. 2022 and Armstrong A, et al. 2021.15,16

Pooled PSO-1 and PSO-2 data showed that significantly greater proportions of patients receiving deucravacitinib achieved absolute PASI ≤1, ≤2, and ≤5 vs. patients receiving placebo (week 16) or apremilast (weeks 16 and 24), and proportions of patients achieving different PASI thresholds with deucravacitinib increased from week 16 to week 24.17

In an analysis of PSO-1 and PSO-2 that compared efficacy of deucravacitinib vs. placebo and apremilast in individual scoring components (erythema, induration, desquamation) and body regions of PASI (head/neck, upper extremities, trunk, lower extremities), deucravacitinib was associated with numerically greater percent reductions from baseline in each PASI body region and component scores at week 16 than placebo and apremilast.18 Higher proportions of patients in the deucravacitinib vs. placebo and apremilast groups achieved ≥75% reduction at week 16 in each PASI body region and PASI scoring; differences in efficacy when compared to apremilast were maintained at week 24.18 For patients in the deucravacitinib group, improvements occurred as early as week 1 and increased over time on treatment.18

In a long-term extension study of PSO trials, investigators analyzed the efficacy of deucravacitinib in patients who did not respond adequately to treatment with apremilast by week 24. Patients initially randomized to apremilast who failed to achieve a PASI 50 in PSO-1 (n=54) or PASI 75 in PSO-2 (n=111) were switched to deucravacitinib through week 52. After switching from apremilast to deucravacitinib, 46.3% of PASI 50 nonresponders and 42.3% of PASI 75 non-responders achieved PASI 75 by week 52.19 Improvements were also seen for sPGA 0/1, DLQI 0/1, and mean change from baseline PSSD symptom score.19

Two-year data from a long-term extension of both PSO trials showed that deucravacitinib had durable clinical efficacy, including mean response rates of 79.8% for PASI 75 and 60.7% for sPGA 0/1 at week 60, regardless of which treatment was initiated at week 16 (when patients in the placebo group could switch to deucravacitinib) or at week 24 (when apremilast nonresponders could switch to deucravacitinib) in the parent study.20

Deucravacitinib: Safety and Tolerability Profile

During weeks 0–16 and weeks 0–52 assessment periods in both PSO trials, overall adverse event (AE) rates were similar across all 3 treatment groups (deucravacitinib, placebo, and apremilast).15,16,21 The most frequent AEs in patients treated with deucravacitinib were nasopharyngitis (9.0%) and upper respiratory tract infection (5.5%). The most frequent AEs in apremilast-treated patients were diarrhea (11.8%), headache (10.7%), nausea (10.0%), and nasopharyngitis (8.8%); placebotreated patients most frequently experienced nasopharyngitis (8.6%) and diarrhea (6.0%).16,21 Incidence rates for AEs of interest, including skin events (e.g., acne and folliculitis), herpes zoster, serious infections, malignancies, thrombotic events, cardiovascular events, creatinine kinase elevation, changes in complete blood count, and changes in lipid profile were absent or low in the deucravacitinib group.15

The frequency of serious adverse events (SAEs) reported in weeks 0–16 were low across all groups (1.8% in deucravacitinib treated patients vs. 2.9% with placebo and 1.2% with apremilast).16,21 Discontinuation rates due to AEs were lowest in the deucravacitinib group (2.4%) vs. placebo (3.8%) and apremilast (5.2%).16,21

A pooled analysis of PSO-1 and PSO-2 trials confirmed that deucravacitinib was well tolerated for up to 52 weeks across patient subgroups based on baseline characteristics of age, sex, race, and body weight. The frequency and type of AEs and SAEs in each subgroup were consistent with the overall patient population, with similar trends for overall AEs and AE classes in the placebo and apremilast groups across subgroups.21

In the long-term extension trial, safety results were consistent with those reported in PSO-1 and PSO-2 trials. SAEs remained low, including those that led to discontinuation. There were no new safety signals or clinically meaningful changes in laboratory values.20 The most common AEs included nasopharyngitis (16.8% at 1 year; 17.8% at 2 years), upper respiratory tract infection (9.1% at 1 year; 9.9% at 2 years), headache (5.9% at 1 year; 6.5% at 2 years), diarrhea (5.1% at 1 year; 5.5% at 2 years), and arthralgia (4.0% at 1 year; 5.6% at 2 years).20 An increase in serious infections was observed, which the authors concluded was attributable to COVID-19 infections due to the ongoing pandemic (studies were conducted during the pandemic through the cut-off date of October 1, 2021, prior to widespread availability of vaccines).

These safety results have not as of yet uncovered treatmentemergent SAEs that are more commonly associated with JAK inhibitors, such as herpes zoster, malignancies, thrombosis, major adverse cardiovascular events (MACE), creatinine kinase elevation, hematologic changes, lipid profile abnormalities, and renal and hepatic abnormalities.20-24

Discussion

Selective TYK2 inhibition is a promising novel target for the treatment of moderate to severe chronic plaque psoriasis. Molecules that confer selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis, without involvement of other JAKs, can lead to a broad therapeutic range while reducing off-target effects such as serious infections, malignancies, thrombosis, and MACE.

Key data from the pivotal phase III POETYK PSO-1 and PSO-2 clinical trials showed that patients with moderate to severe chronic plaque psoriasis treated with the first-in-class, oral, selective TYK2 inhibitor deucravacitinib achieved statistically significant PASI 75 and sPGA 0/1 outcomes that were superior to placebo and apremilast at week 16.15,16 Additionally, significantly greater proportions of patients achieved absolute PASI ≤1, ≤2, and ≤5 with deucravacitinib vs. placebo or apremilast.17 Body region-specific data showed that deucravacitinib had numerically larger percentage improvements at weeks 16 and 24 from baseline vs. apremilast and placebo, across all components of scoring and with onset of action as early as week 1.18

Deucravacitinib was efficacious at week 52 in patients who had inadequate responses to apremilast at week 24 and subsequently switched to deucravacitinib, which was demonstrated in physician-assessed endpoints (PASI 75/90, percentage change from baseline in PASI, and sPGA 0/1) and in patient-reported outcomes (DLQI 0/1 and change from baseline in PSSD symptom score).19

Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast, with overall AE rates similar across all 3 treatment groups.15,21 The most common AEs in patients treated with deucravacitinib were nasopharyngitis and upper respiratory tract infection, while incidence rates of SAEs and AEs of interest were low.15,21

Test Your Knowledge

  1. What are the off-target serious adverse effects associated with JAK inhibitors?
  2. In the PSO-1 and PSO-2 clinical trials, what were the outcomes of apremilast non-responders who were switched to deucravacitinib at week 24?

 

Answers



Test Your Knowledge – Answers



  1. Serious adverse effects that are more commonly associated with JAK inhibitors include serious infections, malignancies, thrombosis, major adverse cardiovascular events (MACE), creatinine kinase elevation, hematologic changes, lipid profile abnormalities, and renal and hepatic abnormalities. Although deucravacitinib is a type of JAK inhibitor, it uniquely binds to the regulatory domain of TYK2 and only blocks specific cytokine-driven responses, leading to a broad therapeutic range, potentially reducing off-target effects.

  2. A large proportion of patients with an inadequate response to apremilast at week 24 in the PSO-1 and PSO-2 trials had clinical improvement and strong responses after switching to deucravacitinib through week 52. Improvements were seen for PASI 75, sPGA 0/1, DLQI 0/1, and mean change from baseline PSSD symptom score. For example, after switching from apremilast to deucravacitinib, 46.3% of PASI 50 non-responders (in PSO-1) and 42.3% of PASI 75 nonresponders (in PSO-2) achieved PASI 75 by week 52.



Conclusion

Selective TYK2 inhibition is a novel target in the treatment of moderate to severe plaque psoriasis. The first-in-class oral TYK2 inhibitor deucravacitinib, already approved by the FDA in the US, has been shown to be efficacious, safe, and tolerable for up to 2 years of use. It is expected that deucravacitinib, and potentially other oral TYK2 inhibitors in development, will offer dermatologists and their patients with a convenient, effective, and safe alternative to other currently available oral systemic agents biologic agents, and phototherapy for the management of moderate to severe chronic plaque psoriasis.

Acknowledgements

The authors wish to thank Teri Morrison and Athena Kalyvas from the International Centre for Professional Development in Health and Medicine (ICPDHM) for editorial support.

References



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  3. Papp K, Gulliver W, Lynde C, et al. Canadian guidelines for the management of plaque psoriasis: overview. J Cutan Med Surg. 2011 Jul-Aug;15(4):210-9.

  4. Nimbus Lakshmi, Inc. Study of NDI-034858 in subjects with moderate to severe plaque psoriasis. In: ClinicalTrials.gov [Internet], Identifier: NCT04999839. Last updated June 21, 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT04999839. Accessed August 2, 2022.

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  7. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009 Jul 30; 361(5):496-509.

  8. Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009 Jun;129(6):1339-50

  9. Mahil SK, Capon F, Barker JN. Update on psoriasis immunopathogenesis and targeted immunotherapy. Semin Immunopathol. 2016 Jan;38(1):11-27.

  10. Dendrou CA, Cortes A, Shipman L, et al. Resolving TYK2 locus genotypeto-phenotype differences in autoimmunity. Sci Transl Med. 2016 Nov 2; 8(363):363ra149.

  11. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann Rheum Dis. Feb 2018;77(2):175-87.

  12. Burke JR, Cheng L, Gillooly KM, et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci Transl Med. 2019 Jul 24;11(502).

  13. Wrobleski ST, Moslin R, Lin S, et al. Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: discovery of the allosteric inhibitor BMS-986165. J Med Chem. 2019 Oct 24;62(20):8973-95.

  14. Papp K, Gordon K, Thaci D, et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med. 2018 Oct 4;379(14):1313-21.

  15. Armstrong AW, Gooderham M, Warren RB, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, placebocontrolled phase 3 POETYK PSO-1 trial. J Am Acad Dermatol. 2022 Jul 9:S0190-9622(22)02256-3.

  16. Armstrong A, Gooderham M, Warren RB, et al. Efficacy and safety of deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, compared with placebo and apremilast in moderate to severe plaque psoriasis: results from the phase 3 POETYK PSO-1 POETYK PSO-2 studies. Presented at: American Academy of Dermatology (AAD) Annual Meeting; March 19-23, 2021. San Francisco, CA. Session S033.

  17. Lebwohl M, Gooderham M, Warren RB, et al. Deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, versus placebo and apremilast in moderate to severe plaque psoriasis: achievement of absolute PASI thresholds in the phase 3 POETYK PSO-1 and PSO-2 trials. Presented at: American Academy of Dermatology (AAD) Annual Meeting; March 25-29, 2022. Boston, MA. Session 34660.

  18. Sobell JM, Eyerich K, Blauvelt A, et al. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, versus placebo and apremilast in psoriasis: reductions in individual component scores and body regions of the Psoriasis Area and Severity Index in the phase 3 POETYK PSO-1 and PSO-2 trials. Presented at: American Academy of Dermatology (AAD) Annual Meeting; March 25-29, 2022. Boston, MA. Session 34668.

  19. Armstrong AW, Warren RB, Sofen H, et al. Deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, in patients with moderate to severe plaque psoriasis who had inadequate responses to apremilast at week 24 in the phase 3 POETYK PSO-1 and PSO-2 trials. Presented at: American Academy of Dermatology (AAD) Annual Meeting; March 25-29, 2022. Boston, MA. Session 34658.

  20. Warren R, Sofen H, Imafuku S, et al. Deucravacitinib long-term efficacy and safety in plaque psoriasis: 2-year results from the phase 3 POETYK PSO program. Presented at: European Academy of Dermatology and Venereology (EADV) Symposium; May 12-14, 2022 Ljubljana, Slovenia. Session P465.

  21. Alexis AF, Kircik LH, Imafuku S, et al. Deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, versus placebo and apremilast in moderate to severe plaque psoriasis: safety by prespecified baseline demographic characteristics in the phase 3 POETYK PSO-1 and PSO-2 trials. Presented at: European Academy of Dermatology and Venereology (EADV) Symposium; May 12-14, 2022 Ljubljana, Slovenia. Session P466.

  22. Burmester GR, Nash P, Sands BE, et al. Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure. RMD Open. 2021 May;7(2):e001595.

  23. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. U.S. Food & Drug Administration. Available from https://www.fda.gov/drugs/drug-safety-and-availability/fda-requireswarnings-about-increased-risk-serious-heart-related-events-cancer-bloodclots-and-death. Accessed August 2, 2022.

  24. Health professional risk communication: XELJANZ/XELJANZ XR (tofacitinib)– risk of major adverse cardiovascular events, malignancy, thrombosis and infection. Health Canada. Available at https://recalls-rappels.canada.ca/en/alert-recall/xeljanzxeljanz-xr-tofacitinib-risk-major-adverse-cardiovascularevents-malignancy. Accessed August 2, 2022.


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]]> Acne Scars: An Update on Management https://www.skintherapyletter.com/acne/acne-scars-management/ Wed, 30 Nov 2022 21:00:53 +0000 https://www.skintherapyletter.com/?p=13881 Abdulhadi Jfri, MD, MSc, FRCPC, FAAD1-5; Ali Alajmi, MD, FRCPC, FAAD6; Mohammad Alazemi, MD7; Malika A. Ladha, MD, FRCPC, FAAD1,8

1Harvard Medical School, Harvard University, Boston, MA, USA
2Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA
3King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
4King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
5Division of Dermatology, Department of Medicine, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia
6Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
7Farwaniya Hospital, Kuwait City, Kuwait
8Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest:
The authors have no conflicts to disclose.

Abstract:
Acne vulgaris is a troubling skin disease known to have both physiologic and psychological effects on patients. Acne scars, a frequent complication, can further impact patients’ quality of life. Scars result from an impairment in the healing process. Acne scars can be categorized as follows: atrophic scars (including ice pick, rolling, boxcar subtypes) and trophic (including hypertrophic and keloid scars), the latter being less common. Though various treatment approaches have been suggested, there is a lack of high‐quality evidence on effective, type-specific acne scar approaches. Herein, we aim to review the current evidence for treating various acne scars.

Key Words:
acne scars, atrophic, ice pick, rolling, boxcar, hypertrophic, keloid

Introduction

Acne vulgaris is the most common skin disease affecting adolescents and adults.1 Studies have demonstrated that about 99% of the population has had acne at some point in their lives, varying in degree of severity, duration, and age of onset.1

The psychological impact of acne is well known. Acne can have social and psychological consequences beyond the apparent visual deformity. This common condition has been linked to stress, anxiety, depression, and suicidal ideation.2 Singam et al. reported that severe acne is associated with comorbid mental health disorders in 25% of acne patients, including anxiety, adjustment, personality, and substance use disorders.3 Acne has also been associated with reduced academic achievement and social difficulties.1

Acne scars are a frequent complication that results from damage to the skin during the healing process of lesions, with studies indicating that 50% of those suffering from acne may develop scars.4 Increased risk of scarring is associated with severe disease, time between acne onset and first effective treatment, relapsing acne, and males.4 Herein, we discuss different types of acne scars and present an updated review on type-specific management approaches.

Discussion

Acne scars can be classified as atrophic, hypertrophic, or keloidal. The morphology of these scars is summarized in Figure 1. Atrophic acne scars are further subdivided into three subtypes: ice pick, rolling, and boxcar.

Acne Scars: An Update on Management - image
Figure 1. Acne scar types. Courtesy of Abdulhadi Jfri MD.

The management approach for treating acne scars should be type-specific given the differences in underlying pathophysiology. Treatment options for each type of scar are summarized in Table 1.

Table 1. Clinical presentation and treatment options of acne scars

 Presentation Treatment Options
Ice pick
  • Narrow (<2 mm) at the surface and tapers as they extend to deep dermis
  • Extend vertically into the deep dermis or subcutaneous tissue
  • Punch excision
  • Chemical reconstruction of skin scars (CROSS) using trichloroacetic acid (TCA)
  • Laser resurfacing
  • Radiofrequency
  • Platelet-rich plasma
Rolling
  • Dermal tethering of abnormal fibrous bands which produces a dell in the skin.
  • Scars are 4-5 mm wide that are sloped with shallow borders
  • Subcision
  • Injectable fillers
  • Non-ablative laser
  • Microdermabrasion
  • Microneedling
  • Platelet-rich plasma
Boxcar
  • Broad, round-to-oval or rectangular depressions, usually box-like depressions with sharply defined edges
  • Resurfacing laser
  • Punch excision
  • Punch elevation
  • Microdermabrasion
  • Chemical peeling
  • Injectable fillers
  • Non-ablative lasers
  • Platelet-rich plasma
Hypertrophic
  • Pink raised lesions that persist within the borders of the original site of injury
  • Intralesional corticosteroid injections
  • Vascular laser (e.g., pulsed dye)
  • Intralesional 5-fluorouracil (5-FU)
  • Laser resurfacing
  • Cryotherapy
  • Imiquimod cream
Keloids
  • Reddish-purple scars that frequently extend beyond the borders of the original site of injury
  • Intralesional corticosteroid injections
  • Intralesional 5-FU
  • Intralesional interferon
  • Intralesional bleomycin
  • Imiquimod cream
  • Laser resurfacing

Table 1. Clinical presentation and treatment options of acne scars

Ice Pick Scars

Ice pick scars extend vertically into the deep dermis or subcutaneous tissue. They are narrow (<2 mm) at the surface and taper as they extend into the deep dermis. Conventional skin resurfacing treatment options may not be adequate due to their depth. Punch excision can be used to treat ice pick scars. Though this method forms a new scar, it is generally less visible than the original ice pick scar.5 The punch excision can be followed by a resurfacing procedure after 4 to 6 weeks, which can further improve the scar’s appearance. Notably, laser skin resurfacing can be safely and effectively performed on the same day that the punch scar is created.6

Another treatment option for ice pick scars is chemical reconstruction of skin scars (CROSS) using high concentrations of trichloroacetic acid (TCA) to induce skin regeneration. TCA is strictly applied to localized areas; the controlled application results in a shorter recovery time compared to medium or deep chemical peels. The degree of clinical improvement is dependent on the total number of treatments.7

TCA CROSS can also be used in darker skin types. In a study evaluating the efficacy and safety of CROSS technique, researchers used 100% TCA to treat ice pick scars in patients with Fitzpatrick phototypes IV and V. Nearly 75% of participants experienced excellent improvement in the appearance of their scars after 4 sessions at 2-week intervals.8

Radiofrequency (RF) is another option for treating ice pick scars. RF devices use electromagnetic radiation to produce an electric current that delivers heat to the dermis, which in turn causes neocollagenesis and skin contraction. This technique is considered both safe and efficacious, offering minimal downtime and adverse events.9 Additionally, RF is a safe procedure in skin of color (SOC) as it does not directly target pigment.

Several studies have demonstrated the effectiveness of RF in the management of ice pick scars. Ramesh et al. reported that fractional bipolar RF (FRF) achieved good results in 73% patients after 4 sessions. Patients with ice pick scars exhibited a better response than those with rolling and boxcar scars.10

Conversely, Peterson et al. found that 15 patients diagnosed with rolling and boxcar scars responded better to 5 sessions of a combination of RF and FRF than patients with ice pick scars.11

Another mode of therapy for ice pick scars is resurfacing lasers. This treatment modality has yielded only mild-to-moderate efficacy for ice pick scars, compared to other subtypes. Sardana et al. reported that treatment with a 1,540 nm fractional nonablative laser improved scar appearance for only 25.9% of patients with ice pick scars, compared with 52.9% and 43.1% improvement in boxcar and rolling scars, respectively.12

Combining ablative fractional carbon dioxide (CO2) laser with platelet-rich plasma (PRP) injections represents an innovative approach. PRP involves preparing and administering the patient’s own concentrated platelets in plasma containing variable growth factors and cytokines that promote wound healing. A recent meta-analysis investigated the efficacy and safety of combining fractional CO2 laser with PRP for managing atrophic acne scars. It was concluded that the dual approach led to enhanced outcomes compared to using ablative fractional CO2 laser alone. Specifically, the combination resulted in clinical improvement, increased patient satisfaction, and accelerated recovery after laser damage. However, further research is needed to evaluate the efficacy of PRP for acne scars.13 PRP can also be combined with microneedling to treat any atrophic acne scars.

Rolling Scars

Rolling scars result from dermal tethering of abnormal fibrous bands that produce skin indentation. The scars are 4-5 mm wide and are sloped, with shallow borders.

Rolling scars can be best managed surgically with subcision, which involves the use of a tri-beveled hypodermic needle to free the tethering subdermal fibrous bands. Al-Dhalimi et. al showed
that subcision downgraded the severity of rolling acne scars from moderate-to-severe grade to mild grade in 53% of patients, with minimal side effects.14 The subcision was done once and repeated every 6 weeks, as required.

Subcision has been combined with the application of soft tissue fillers and non-ablative laser to improve the appearance of rolling scars. Hyaluronic acid fillers can expand the volume of tissue in these scars and encourage collagen production. Sapra et al. assessed the management of rolling scars with poly-L-lactic acid (PLLA) in 22 patients and demonstrated that after 3 to 4 treatments at 4-week intervals with PLLA, 54.4% of patients exhibited excellent results.15 A controlled and blinded study was performed on 147 patients with rolling acne scars to evaluate the effectiveness of 1 injection of polymethylmethacrylate (PMMA) filler. Neary 65% of patients demonstrated good improvement, compared to 33% of control subjects.16

Microdermabrasion and dermabrasion are physical ablating modalities used to manage rolling scars. Microdermabrasion is more superficial whereas dermabrasion reaches the deeper papillary dermis layer. The procedures promote a wound healing response and new collagen formation. Eventually, dermabrasion treatment results in smoother and uniform appearance of the scar.17 Microdermabrasion received at weekly intervals appears to be safe in SOC.18

Microneedling is another beneficial option for managing rolling scars. Microneedling involves creating small wounds in the dermis to activate a cascade of growth factors and eventually stimulate collagen production.19 Microneedling can be effective in managing rolling scars for darker-skinned patients due to the low risk of hyperpigmentation compared to fractional nonablative laser therapy.7

RF can also be used safely and effectively to manage rolling acne scars with minimum adverse effects and limited downtime.7

Non-ablative lasers can also be used to manage rolling scars. Their mechanism of action involves targeting tissues in the dermis for selective photothermolysis to encourage collagen and
dermal remodeling, thereby improving the appearance of scars.20

Boxcar Scars

Boxcar scars are broad, round-to-oval or rectangular box-like depressions with sharply defined edges. Punch excision and punch elevation are two excellent techniques for the treatment of boxcar scars, but there is still a paucity in literature evaluating their effectiveness for improving acne scarring.7 For punch elevation, the punch biopsy tool is used to fragment the deeper aspect of the scar without removing any epidermis or dermis.

Dermabrasion can be an effective option for managing boxcar scars, but it is a painful procedure that requires local or general anesthesia and the healing time may extend to several weeks, with significant postoperative discomfort.21 Microneedling RF is another useful technique that can be employed to manage atrophic boxcar scars.11 RF does not directly target melanin and can thus be safely used in SOC.

Subcision is moderately effective for managing boxcar scars, but it can be combined with other resurfacing procedures such as cosmetic fillers and non-ablative lasers to achieve better results.20 Chemical peeling with TCA can be used to manage hard-to-treat boxcar scars.22 Finally, laser skin resurfacing can deliver excellent results for managing acne scars. One study demonstrated that use of a high-energy pulsed CO2 laser provided 75% improvement in atrophic facial scars, including boxcar scars.23 Ablative lasers, such as CO2 and erbium-doped yttrium aluminum garnet (Er:YAG), should be used with caution when treating atrophic scars in SOC. The risk of postinflammatory hyperpigmentation (PIH) appears to be decreased with Er:YAG. Post ablative laser PIH may last for 5 weeks and can be treated with a topical depigmenting agent such as hydroquinone 4% or combination topicals (retinoid, hydroquinone and corticosteroid).24,25

Hypertrophic Scars and Keloids

Hypertrophic scars and keloids are more severe types of acne scars. They are less common compared to atrophic acne scars, but can be difficult to treat. Typically, hypertrophic scars appear as pink, raised lesions that persist within the borders of the original site of injury.26 Keloids present as reddish-purple scars that frequently extend beyond the borders of the original site of injury.27 From a pathophysiological perspective, hypertrophic and keloidal scars demonstrate excessive expression of collagen with reduced collagenase activity.28

Intralesional corticosteroid injections represent the mainstay of treatment for hypertrophic and keloid scars. However, multiple treatment approaches can be used simultaneously to maximize the potential for success and minimize adverse effects.29 For example, intralesional corticosteroid injections can be accompanied by 5-fluorouracil (5-FU) to reduce the risk for hypopigmentation, skin atrophy, telangiectasias, rebound scars, ineffectiveness, and injection site pain.28

Laser resurfacing can be considered for managing hypertrophic and keloid acne scars. Specifically, pulsed dye laser is an excellent option to consider.30 Thick keloid or hypertrophic scars can benefit from using a combination of pulsed dye laser and intralesional corticosteroid injections along with 5-FU.31 In fact, this combination seems to be the most promising, currently available therapy for keloids.32

Another effective non-surgical method for managing small hypertrophic acne scars is cryotherapy, which can also be combined with intralesional triamcinolone to maximize effectiveness.33

Surgical excision can be used in combination with other approaches including radiotherapy, interferon, bleomycin, cryotherapy, or corticoids to optimize the efficacy of the management protocol.34 Surgical excision may be needed when acne scars are disabling, but in some cases laser and light-based therapies may be preferential.35

Large keloid scars have been effectively managed with surgical excision followed by radiation using brachytherapy. This is better tolerated and enables delivery of high radiation doses to a focused area, with decreased side effects, in comparison to traditional external beam radiation.36 Intralesional injection of interferon and bleomycin are additional options for managing keloid and hypertrophic scars. These treatments work to increase collagen breakdown and inhibit collagen synthesis, respectively. Both therapies can enhance the scar’s appearance.37,38

The post-excision recurrence of keloids has shown to decrease with daily application of topical imiquimod 5% cream for 8 weeks.39,40

Conclusion

The management of acne scars often requires a combination of different treatment options. An understanding of each scar type and formulating a case-specific approach are required to achieve optimal outcomes.

References



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]]> Update on Drugs & Devices: November – December 2022 https://www.skintherapyletter.com/drug-updates/nov-dec-2022/ Wed, 30 Nov 2022 20:00:13 +0000 https://www.skintherapyletter.com/?p=13890 Deucravacitinib tablets

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