STL Volume 29 Number 2 – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Tue, 14 May 2024 22:43:50 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 An Update on Current Clinical Management and Emerging Treatments in Hidradenitis Suppurativa https://www.skintherapyletter.com/hidradenitis-suppurativa/emerging-treatments-update/ Mon, 08 Apr 2024 17:27:46 +0000 https://www.skintherapyletter.com/?p=15172 Austinn Miller, MD1,2*; Parastou Shahzeidi, MS3*; Michael Bernhardt, MD1,2,3

*Co-first authors

1University of Central Florida/HCA Consortium, Tallahassee, FL, USA
2Dermatology Associates of Tallahassee, Tallahassee, FL, USA
3Florida State University College of Medicine, Tallahassee, FL, USA

Conflict of interest: The authors have no conflicts of interest to declare. Funding sources: None.

Abstract:
Hidradenitis suppurativa (HS) is a severe, debilitating, chronic inflammatory skin disease characterized by recurrent painful nodules, abscesses and draining sinus tracts in intertriginous areas. While this condition appears to stem from follicular unit dysfunction, its cause is multifactorial and the exact pathogenesis has yet to be fully elucidated. These factors make treatment selection challenging and contribute to variable therapeutic response among affected patients. Typical regimens consist of a combination of medical and surgical modalities, tailored to individual responses. However, HS is often refractory to traditional treatments, prompting the need for newer and more effective therapies. Herein, we review current and emerging HS therapies.

Keywords: hidradenitis suppurativa, treatment, secukinumab, bimekizumab, izokibep, upadacitinib, povorcitinib, eltrekibart

Introduction

Hidradenitis suppurativa (HS) is a severe, debilitating, chronic inflammatory skin disease characterized by recurrent painful nodules, abscesses and draining sinus tracts.1 The condition primarily affects intertriginous areas, often leading to permanent scarring and disfigurement. There is a strong psychosocial impact of the condition, with HS patients reporting high rates of depression, anxiety, social stigmatization, and shame leading to significant reductions in quality of life. While an estimated 1% prevalence rate is often described in literature, HS is thought to be widely underdiagnosed. The onset of HS typically occurs between ages 20-40 years with a 3:1 predilection for women over men and higher rates among those of African descent.1 HS has been linked to genetic predisposition, skin microbiota, chronic inflammatory conditions, and hormonal factors, as well as environmental factors like obesity and smoking.2

Although the pathophysiology of HS has not been fully elucidated and is multifactorial, current evidence supports an inflammatory etiology with follicular unit dysfunction.3 The current driving theory suggests disease initiation is associated with a chronic subclinical inflammatory state and/or excess keratinocyte proliferation, which results in follicular occlusion and rupture with subsequent abnormal and diffuse inflammatory response. Recurrent events lead to the eventual loss of follicular structures and replacement with dense inflammatory infiltrates and scarring. Elevated levels of many pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-10, IL-17, and IL-23 have been observed in blood and skin biopsy samples of HS patients, further implicating immune dysregulation. There is welldocumented evidence regarding positive feedback loops where IL-17 interactions with other cytokines (namely IL-1, IL-6 and TNF-α) lead to further auto-production of these cytokines as well as downstream activation of acute phase reactants, neutrophilic and complement mediated inflammatory responses.3 It should be noted that while the primary driver of HS is not infectious, bacterial colonization of lesions can complicate acute flares and worsen symptoms.

Current Management in HS

The management of HS involves a multimodal approach including lifestyle modifications, such as weight loss and smoking cessation, various medical/surgical therapies and psychological support. The efficacy of medical therapies depends largely on disease severity and, thus, clinical grading using the Hurley staging system can guide medical decision making. This system is universally accepted and classifies stage 1 (mild) as abscess formation without scarring, stage 2 (moderate) as recurrent abscesses with limited scarring and/or sinus tracts and stage 3 (severe) as diffuse involvement with extensive scarring and/or interconnected sinus tracts.1 The mainstay of medical management in mild-to-moderate disease is oral antibiotics and topical therapies, with consideration of hormonal treatments and systemic retinoids as adjunctive therapy.4 Intralesional or systemic steroids are often used for acute flares. For more severe, extensive disease, however, these regimens are rarely sufficient and immunomodulatory agents should be introduced. Currently, there are two biologics approved in the US for HS treatment: adalimumab, a monoclonal antibody (MAb) that targets TNF-α, and secukinumab, an IL-17A inhibitor.

Topicals

For mild disease, topical clindamycin is considered a first-line treatment option that can reduce bacterial colonization and inflammation within HS lesions.4 Based on low-level evidence involving 30 patients, topical clindamycin use decreased pustules by approximately 95% after 3 months of treatment, but had no significant effect on deeper abscesses or nodules.5 Resorcinol is a topical keratolytic and anti-inflammatory that has shown some benefit for pain and lesion reduction in small studies, though data is limited. Of note, resorcinol is only available in the US through compounding pharmacies, further limiting its practicality. Overthe- counter cleansers containing chlorhexidine, benzoyl peroxide or zinc pyrithione, while not evidence-based, are commonly used in clinical practice as adjunct maintenance therapy across all disease stages.5

Systemic Antibiotics

Based on North American clinical guidelines published in 2022, oral tetracyclines or clindamycin plus rifampin are two antibiotic regimens that are generally recommended as first- or secondline options in HS management.4 While quality evidence is lacking across the board, previous case series have demonstrated meaningful clinical improvement with these antibiotics. A recent prospective cohort study involving 283 patients (majority with moderate or severe HS) is the first and only to compare the two antibiotic regimens head-to-head over 12 weeks.6 Investigators found that while a large proportion of both groups achieved 50% or greater reduction from baseline in the total abscess and inflammatory nodule count and remission, there was no significant difference between the oral tetracyclines group (40.1%) and clindamycin plus rifampin group (48.2%, P=0.26). Another recent study in 28 Hurley stage 1 HS patients reported the efficacy of combination rifampin-moxifloxacin-metronidazole therapy.7 They observed that 75% of patients achieved clinical remission of all lesions at 12 weeks of treatment. After the initial 12-week study period, those who achieved remission were switched to a low dose maintenance regimen of cotrimoxazole and at 1-year follow up experienced significantly less flares (average of 1/year vs. 21/ year before treatment). Substantial gastrointestinal side effects and remission rates, as well as concern for bacterial resistance, may limit long-term antibiotic use.

Adjunctive Oral Agents

While hormones are thought to play a role in HS, there have not been many studies on the efficacy of hormonal therapies in this setting. Current guidelines state that estrogen-containing contraceptives and anti-androgens therapies like spironolactone, metformin and finasteride can be considered in women, namely those with comorbid polycystic ovary syndrome and/or reported HS flares around menses.4 Similarly, oral retinoids can be considered if adequate control is not achieved with other therapies, as an adjunct, or in patients with concomitant nodulocystic acne. Results from small studies have been mixed and show modest improvement in milder disease.4 Finally, those with HS have high risk of certain vitamin and mineral deficiencies, such as vitamin D and zinc. Two case series have shown modest clinical improvements with zinc supplementation.8 While zinc supplementation can be considered in patients, there is insufficient evidence to recommend vitamin D supplementation based on North American guidelines.8

Surgery

Surgical intervention is often necessary with advanced disease refractory to medical management to address tunnels and chronic scarring. The options are beyond the scope of this review, but include laser therapies, deroofing and surgical excision. These procedures come with their own set of risks and even after radical excision, it is reported that nearly a third of patients still experienced disease recurrence.9

Biologics

Biologic therapies are recommended for patients with mildmoderate disease that previously failed first-line therapies or as first-line therapy in individuals with moderate-severe disease.4

Adalimumab (Selective TNF-α Inhibitor)

Until very recently, adalimumab was the only approved treatment of HS. In two phase 3 trials, Pioneer I and II (n=633), 316 patients were randomized to receive 40 mg adalimumab once weekly.10 Pooled data of the trials demonstrated a modest but significant clinical improvement at week 12 with 50.6% of patients in the treatment group achieving Hidradenitis Suppurativa Clinical Response score of 50 (HiSCR50, reduction of at least 50% in the total abscess and inflammatory nodule count, with no increase in abscess or draining tunnel count) compared to 26.8% receiving placebo. Additional surveillance as part of an open-label trial extension demonstrated sustained results on weekly adalimumab with HiSCR50 of 52.3% at week 168.11 During this period, about 15% of patients experienced adverse events leading to discontinuation of the drug. While efficacious, this leaves about half of patients without adequate response. Other TNF-α inhibitors used in HS face the same challenges, including infliximab and etanercept.

Secukinumab (Selective IL-17A Monoclonal Antibody)

In October 2023, the FDA approved the expanded label of secukinumab to cover moderate-to-severe HS in adults. This decision was based on results from two major phase 3 randomized controlled trials (RCT)12 showing promise of subcutaneous secukinumab in patients with moderate-to-severe HS. SUNSHINE (n=541) and SUNRISE (n=543) included a placebo-controlled study period of 16 weeks, followed by long-term treatment without placebo to 52 weeks. In both trials, significantly more patients receiving secukinumab biweekly achieved HiSCR50 at 16 weeks when compared to placebo (42-45% vs. 31-34%). Response rates were sustained and even increased throughout the study period, with 56% of patients in SUNSHINE and 65% in SUNRISE achieving meaningful clinical response as well as significant pain reduction at 52 weeks. Roughly 84% of participants experienced an adverse event, though the great majority were minor with the most common being headache (10%) followed by nasopharyngitis and worsening of HS.

Emerging Biologic Therapies in HS

While the aforementioned therapies have been efficacious, there are many treatment gaps that highlight the need for better options. For one, HS is biologically complex and driven by multiple mechanisms that differ from individual to individual, as evidenced by significant variations in disease severity and lack of response to treatment in many. This warrants a shift away from a ‘one size fits all’ or random trial-and-error treatment algorithm, but rather a personalized approach that caters to the specific markers expressed in each patient. Even for those who achieve excellent results on medication, there is high probability of eventual recurrence, likely related to the fact that current treatment options do not address the underlying causes of HS.

Given the need for further therapeutic options in HS, a plethora of targets are currently being explored, including other inflammatory cytokines (IL-1, IL-17, IL-23), neutrophils, the complement pathway, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The remainder of this paper will focus on the efficacy and safety of these drugs from recent phase 2 and 3 clinical trial results. Unless otherwise stated, the primary trial endpoint was HiSCR50. Additional endpoints could also include HiSCR of 75%, 90% and/or 100%. Participants included those with moderate-to-severe HS, defined as Hurley stages 2 or 3. The main points of these clinical trials and next steps are summarized in Table 1.

An Update on Current Clinical Management and Emerging Treatments in Hidradenitis Suppurativa - image
Table 1: Results of clinical trials evaluating emerging treatments for HS (only phase 2/3 completed studies with reported results).
AEs, adverse events; OD, once daily; OLE, open-label extension; Q2W, once every 2 weeks; Q4W, once every 4 weeks; IV, intravenous injection; SC, subcutaneous injection; UPA, upadacitinib

IL-17 Inhibitors

Bimekizumab (Dual IL-17A and IL-17F MAb)

Bimekizumab is a MAb that selectively targets IL-17F, in addition to IL-17A. Since both subunits independently cooperate with other inflammatory mediators like IL-1 and TNF-α to drive the chronic inflammatory cascade and tissue destruction seen in HS, bimekizumab’s efficacy profile has been hypothesized to be more favorable than IL-17A inhibitors alone.

In recently released data from BE HEARD I (n=505) and BE HEARD II (n=509) phase 3 trials,13 those receiving bimekizumab biweekly achieved statistically significant improvements over placebo in HS severity (HiSCR50 48-52% vs. 29-32%, placebo) and self-reported quality of life at week 16, which was sustained out to 48 weeks without any unexpected safety concerns. According to a March 2023 late-breaking presentation at the annual American Academy of Dermatology (AAD) conference, in an observed case analysis of the two trials combined, over 55% of patients on continuous bimekizumab achieved the higher benchmark of HiSCR75 at week 48.14

Izokibep (Non-MAb IL-17A Inhibitor)

Izokibep is a novel fusion protein that may address several shortcomings of some other MAbs. The molecule is about oneeighth the size of a traditional MAb, which is thought to allow for high drug exposure levels and deeper tissue penetration. Additionally, izokibep is produced in an inexpensive Escherichia coli (E. coli) system versus the costly mammalian expression systems that MAbs are routinely manufactured in, which could translate into a more affordable treatment option.15

Data from a small open-label part A of phase 2b/3 trial (n=30) presented at the AAD conference in March 2023 observed 65% of participants achieved HiSCR50 at 12 weeks.16 Further, about 1 in 3 patients had complete clearance of abscesses and inflammatory nodules (HiSCR100) by week 12. The drug was generally welltolerated, with localized injection site reaction as the most common adverse event. The double-blind, placebo-controlled part B of this phase 2b/3 trial is currently ongoing with plans for an additional phase 3 trial. These results will be much more telling.

Janus Kinase Inhibitors

Expression of genes in the JAK-STAT pathway transduce proinflammatory cytokine signals like IL-6, IL-23, and interferons which have been shown to be upregulated in sites affected by HS,17 making for a potential therapeutic target. Currently, JAK inhibitors are mainly used in rheumatological conditions, but are increasingly being used and studied across a broad spectrum of dermatological disorders including atopic dermatitis, psoriasis, alopecia areata and vitiligo.18 Still, there is very limited published clinical data in the use of these drugs for HS specifically. A literature review published in April 2023 included 25 articles using JAK inhibitors in HS patients, mainly small case series and reports, and concluded encouraging findings of their efficacy and safety in this setting thus far.17 Several clinical trials are currently ongoing and upcoming to further investigate.

Upadacitinib

Results from a phase 2 RCT19 presented at AAD in March 2023 showed that 38.3% of 41 patients treated with daily oral upadacitinib achieved HiSCR50 at week 12, compared to 23.8% of the placebo group. Response rates were sustained through week 40 with no new safety concerns. They also reported similar efficacy rates in those who had previously failed anti-TNF biologics (HiSCR50 41.7%) and TNF-naïve patients (HiSCR50 37.1%). It should be noted that results were only statistically significant when compared to historic placebo levels from previous trials, but not when compared to the placebo arm within the same study.

Povorcitinib

In 2022, a phase 2 RCT20 that spanned 16 weeks and enrolled 209 patients with HS of any Hurley stage met its primary endpoint of statistically significant decreases from baseline abscess and inflammatory nodule count at all three tested dose levels (povorcitinib 15 mg, 45 mg, 75 mg) compared to placebo with no new safety concerns. Early 2023, new 52-week results21 were presented at the European Academy of Dermatology and Venereology Congress as part of the open-label extension period in which all 174 qualifying patients received povorcitinib 75 mg daily. Nearly 30% of patients had 100% clearance of abscesses and inflammatory nodules (HiSCR100) by week 52. Additional 52-week efficacy results include HiSCR50 and HiSCR75 values of roughly 60% and 50%, respectively. Stop-HS1 and Stop-HS2 are two phase 3 RCTs currently recruiting 600 patients each with results expected in 2025 and would be the largest HS drug trial to date.

Chemokine Receptor (CXCR) Inhibitors

Eltrekibart (LY3041658) is a MAb that selectively binds to the ligands that signal CXCR1 and CXCR2. These chemokine receptors are known to play a role in neutrophil migration to areas of inflammation, which is a key aspect in the pathogenesis of HS.22 Phase 2 RCT trial (n=72) data was presented at the AAD in March 2023 where 66% of patients receiving eltrekibart biweekly achieved HiSCR50 at 16 weeks compared to 41% in the placebo arm.23 These improvements were sustained in the treatment group to week 36. While these results are quite favorable, further quantification of safety and efficacy will need to be determined in a subsequent phase 3 trial which has not yet been announced.

Upcoming Notable Clinical Trial Results

An additional IL-17 inhibitor worth mentioning is sonelokimab, which incorporates specific desirable features of both bimekizumab and izokibep. Similar to izokibep, sonelokimab uses newer nanobody biotechnology for better drug delivery and enhanced tissue penetration while also having dual targets of IL-17A and IL-17F, like bimekizumab.24 A phase 2 RCT, the MIRA trial, comprising 210 patients is currently underway testing two doses of sonelokimab compared to placebo and adalimumab.24 Notably, this is the first time that a HS trial has the higher benchmark of HiSCR75 as the primary endpoint; 57% of patients achieved HiSCR75 at 24 weeks.

The same company developing secukinumab for HS, has testing underway for several other targets in HS. A phase 2 RCT is recruiting 200 individuals to determine the safety and efficacy of five different drugs for moderate-to-severe HS: Bruton’s tyrosine kinase (BTK) inhibitor, leukotriene A4 hydrolase (LTA4H) inhibitor, CD40 MAb, T-cell immunoglobulin and mucin domain 3 (TIM-3)/ IL-1β/IL-18 MAb, and anti-B-cell activating factor (BAFF) receptor MAb.25 LTA4H, BTK and TIM-3 all play a role in inflammation, though have not been tested previously as targets for HS therapy.

Additional clinical drug trials with results expected in the near future are summarized in Table 2.

An Update on Current Clinical Management and Emerging Treatments in Hidradenitis Suppurativa - image
Table 2: Additional drugs in clinical trials for HS without results yet reported.
BAFF-R, B-cell activating factor receptor; BTK, Bruton tyrosine kinase; CD40, cell-surface member of TNF receptor superfamily; IRAK4, interleukin-1 receptorassociated kinase 4; LTA4H, leukotriene A4 hydrolase; OX40L, TNF superfamily member 4; PDE4, phosphodiesterase-4; TIM-3, T-cell immunoglobulin and mucin domain-containing protein-3

Conclusion

The management of HS is a challenge, in part due to its chronic and variable nature with a poorly understood pathophysiology. Further, delays in diagnosis can lead to disease progression and extensive scarring which creates another layer of complexity in treatment. In addition to its painful dermatologic implications, HS is associated with many comorbidities including inflammatory bowel disease, psoriasis, and metabolic syndromes, as well as significant mental health burden with increased depression, anxiety and suicide rates observed.26 While the existing standard management with antibiotics and topicals with steroids for flares can be sufficient for mild disease, more intensive measures involving surgery and/or biologic drugs are frequently required in more severe cases.

An improved understanding of the disease mechanisms and wider range of biologic therapies aimed at these underlying inflammatory pathways and specific pathophysiology of HS is poised to create a major shift in this management conundrum. Currently, only two biologics are approved for HS. Adalimumab has demonstrated its effectiveness and sustained response in over half of individuals with moderate-severe HS across several studies. However, even in responders, complete remission is uncommon, and an even larger treatment gap exists when adalimumab fails or is contraindicated. Notwithstanding, the recent approval of secukinumab has the potential to change clinical practice by offering meaningful and durable improvement of symptoms.

Furthermore, a number of alternative biologics are being studied in HS with different targets including inhibitors of IL-17, IL-1, chemokine receptors and the JAK pathway, to name a few. The drugs discussed within this paper are furthest along in the pipeline and recent favorable phase 2/3 trial data indicate support for positive regulatory decisions in the coming future. While these therapeutics will undoubtedly bring value to patients, there remains a need for personalized medicine through enhanced insight into the etiology and progression of HS, along with identifying optimal targets. The further development of new therapies for the treatment of HS is crucial in continuing to improve outcomes and quality of life for patients with this debilitating disease.

References



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  2. Alotaibi HM. Incidence, risk factors, and prognosis of hidradenitis suppurativa across the globe: insights from the literature. Clin Cosmet Investig Dermatol. 2023 Mar 2;16:545-52.

  3. Scala E, Cacciapuoti S, Garzorz-Stark N, et al. Hidradenitis suppurativa: where we are and where we are going. Cells. 2021 Aug 15;10(8):2094.

  4. Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part II: topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019 Jul;81(1):91-101.

  5. Clemmensen OJ. Topical treatment of hidradenitis suppurativa with clindamycin. Int J Dermatol. 1983 Jun;22(5):325-8.

  6. van Straalen KR, Tzellos T, Guillem P, et al. The efficacy and tolerability of tetracyclines and clindamycin plus rifampicin for the treatment of hidradenitis suppurativa: results of a prospective European cohort study. J Am Acad Dermatol. 2021 Aug;85(2):369-78.

  7. Delage M, Jais JP, Lam T, et al. Rifampin-moxifloxacin-metronidazole combination therapy for severe Hurley stage 1 hidradenitis suppurativa: prospective short-term trial and 1-year follow-up in 28 consecutive patients. J Am Acad Dermatol. 2023 Jan;88(1):94-100.

  8. Orenstein LAV, Nguyen TV, Damiani G, et al. Medical and surgical management of hidradenitis suppurativa: a review of international treatment guidelines and implementation in general dermatology practice. Dermatology. 2020;236(5):393-412.

  9. Bouazzi D, Chafranska L, Saunte DML, et al. Systematic review of complications and recurrences after surgical interventions in hidradenitis suppurativa. Dermatol Surg. 2020 Jul;46(7):914-21.

  10. Kimball AB, Okun MM, Williams DA, et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med. 2016 Aug 4;375(5):422-34.

  11. Zouboulis CC, Okun MM, Prens EP, et al. Long-term adalimumab efficacy in patients with moderate-to-severe hidradenitis suppurativa/acne inversa: 3-year results of a phase 3 open-label extension study. J Am Acad Dermatol. 2019 Jan;80(1):60-9.

  12. Kimball AB, Jemec GBE, Alavi A, et al. Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, doubleblind phase 3 trials. Lancet. 2023 Mar 4;401(10378):747-61.

  13. Zouboulis CC, Frew JW, Giamarellos-Bourboulis EJ, et al. Target molecules for future hidradenitis suppurativa treatment. Exp Dermatol. 2021 Jun;30 Suppl 1:8-17.

  14. Kimball AB, Zouboulis CC, Sayed C, et al. Bimekizumab in patients with moderate-to-severe hidradenitis suppurativa: 48-week efficacy and safety from BE HEARD I & II, two phase 3, randomized, double-blind, placebo controlled, multicenter studies. Late-breaking presentation at: American Academy of Dermatology 2023 Annual Meeting, New Orleans, LA, March 17-21, 2023.

  15. Klint S, Feldwisch J, Gudmundsdotter L, et al. Izokibep: Preclinical development and first-in-human study of a novel IL-17A neutralizing Affibody molecule in patients with plaque psoriasis. MAbs. 2023 Jan-Dec;15(1):2209920.

  16. Papp K, et al. Izokibep, a novel IL-17A inhibitor, demonstrates HiSCR100 responses in moderate-to-severe hidradenitis suppurativa: open-label part a results of a phase 2b/3 study. Late-breaking presentation at: American Academy of Dermatology 2023 Annual Meeting, New Orleans, LA, March 17-21, 2023.

  17. Martora F, Scalvenzi M, Ruggiero A, et al. Hidradenitis suppurativa and JAK inhibitors: a review of the published literature. Medicina (Kaunas). 2023 Apr 20;59(4):801.

  18. Klein B, Treudler R, Simon JC. JAK-inhibitors in dermatology – small molecules, big impact? Overview of the mechanism of action, previous study results and potential adverse effects. J Dtsch Dermatol Ges. 2022 Jan;20(1):19-24.

  19. Kimball A, Ackerman L, Schlosser B, et al. Efficacy and safety of upadacitinib in moderate-to-severe hidradenitis suppurativa: a phase 2, randomized, placebo-controlled study. Poster 43799. Presented at: American Academy of Dermatology 2023 Annual Meeting, New Orleans, LA, March 17-21, 2023.

  20. Kirby JS, Okun MM, Alavi A, et al. Efficacy and safety of the Janus kinase 1 inhibitor povorcitinib (INCB054707) in patients with hidradenitis suppurativa: results from a randomized, placebo-controlled, phase 2 dose-ranging study. Poster 0004. Presented at: 31st European Academy of Dermatology and Venereology (EADV) Congress, Milan, Italy, September 7-10, 2022.

  21. Incyte announces 52-week results from phase 2 study evaluating povorcitinib (INCB54707) in patients with hidradenitis suppurativa. Incyte Corporation. Press release. Published February 10, 2023. Accessed May 10, 2023. Available from https://investor.incyte.com/news-releases/news-release-details/incyteannounces-52-week-results-phase-2-study-evaluating

  22. Markota Čagalj A, Marinović B, Bukvić Mokos Z. New and emerging targeted therapies for hidradenitis suppurativa. Int J Mol Sci. 2022 Mar 29;23(7):3753.

  23. Forman S, Patel DR, Kimball AB, et al. Safety and efficacy of LY3041658, a novel septa-specific monoclonal antibody to CXCR1 and CXCR2 ligands, in a phase 2 study in hidradenitis suppurativa. Presented at: American Academy of Dermatology 2023 Annual Meeting, New Orleans, LA, March 17-21, 2023.

  24. MoonLake Immunotherapeutics completes patient enrollment and randomization ahead of schedule in a phase 2 trial of the Nanobody® sonelokimab in moderate-to-severe hidradenitis suppurativa. Moonlake Immunotherapeutics. Press release. Published February 2, 2023. Accessed May 10, 2023. Available from https://ir.moonlaketx.com/news-releases/news-release-details/moonlake-immunotherapeutics-completes-patientenrollment-and

  25. Novartis Pharmaceuticals. A randomized, subject and investigator blinded, placebo-controlled and multi-center platform study, to assess efficacy and safety of different investigational drugs in patients with moderate to severe hidradenitis suppurativa. Clinical Trial Registration NCT03827798, In:ClinicalTrials.gov. Accessed May 20, 2023. Available from https://clinicaltrials.gov/ct2/show/NCT03827798

  26. Nguyen TV, Damiani G, Orenstein LAV, et al. Hidradenitis suppurativa: an update on epidemiology, phenotypes, diagnosis, pathogenesis, comorbidities and quality of life. J Eur Acad Dermatol Venereol. 2021 Jan;35(1):50-61.


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]]> Overview of Dermatological Manifestations Associated with the COVID-19 Infection https://www.skintherapyletter.com/dermatology/manifestations-covid-19/ Mon, 08 Apr 2024 10:08:44 +0000 https://www.skintherapyletter.com/?p=15181 Heli Patel, BS1; Linh Tran, BS2; Steven R. Feldman, MD, PhD1,3
1Center for Dermatology Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
2University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
3Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, USA

Conflict of interest: The authors have no conflicts of interest to declare. Funding sources: None.

Abstract:
COVID-19 is an infectious disease caused by SARS-CoV-2 that is characterized by respiratory symptoms, fever, and chills.1 While these systemic symptoms are widely known and well understood, there have also been reports of dermatological manifestations in patients with COVID-19. These manifestations include chilblain-like lesions, maculopapular lesions, urticarial lesions, necrosis, and other varicella-like exanthems.2 The pathogenesis of these lesions are not well understood, but the procoagulant and pro-inflammatory state induced by COVID-19 infections may be contributing to varied cutaneous manifestations.3 Drug interactions and concurrent hypersensitivity reactions have also been postulated.4 This review aims to compile and analyze various retrospective studies and case reports to summarize the clinical presentation of dermatological lesions associated with COVID-19 infections and suggest further areas of research.

Keywords: COVID-19, cutaneous manifestations, hypersensitivity, dermatology

Introduction

Coronavirus disease 2019 (COVID-19) has had a huge impact on global health, with well over 700 million cases reported worldwide (World Health Organization, February 2024). It is believed to originate from bats and the transmission modality is through contact and respiratory droplets.5 Once the virus enters the body, the capsid protein binds to angiotensin-converting enzyme 2 (ACE2) receptors on host cells and enters the cell through a process called endocytosis.5 After cellular entry, the virus releases its content and utilizes host machinery to replicate and produce new viral particles to be released.6 This process triggers a cytokine storm, involving interleukin (IL)-8, IL-10, IL-12, tumor necrosis factor-α, and interferon-β,6 as well as induces a pro-inflammatory and procoagulant state that has been linked to the development of skin lesions and eruptions.3 In a microscopic and immunohistologic study, Margo et al. demonstrated that purpuric skin lesions in COVID-19 patients exhibited deposition of complement proteins (C5b-9 and C4d) and inflammatory thrombogenic vasculopathic changes.3 In some cases, the presence of spike proteins was detected in the microcirculation of the skin.3 Additionally, skin manifestations may be secondary in nature, possibly due to side effects of medications or other concurrent infections.4 Another cause of skin symptoms is the pro-inflammatory state induced by COVID-19 promoting drug hypersensitivity that results in cutaneous eruptions.7 Through analyzing the literature, we provide a categorization for the different dermatological manifestations associated with COVID-19 infections: chilblain-like lesions, maculopapular lesions, vesicular eruptions, urticarial lesions, and necrosis/livedo. Histological features and clinical patterns of the lesions are also described.

Classifications

Chilblain-like Lesions

Chilblain lesions are characterized by inflammatory and swollen patches and blisters on the extremities, such as the hands and feet.8 Classically, they occur after cold exposure causing the arteries and veins to constrict.8,9 Formation of vesicles or pustules can be accompanied by edema.10 These lesions are more commonly found in young children and are correlated with lower disease severity.4,8,10 Chilblain-like eruptions seem to be the most common manifestations reported in patients with COVID-19 exposure or infection, often appearing after the presentation of other COVID-19 symptoms.9 In a nationwide prospective study in Spain analyzing 375 patient cases, 19% of the cases were associated with chilblainlike lesions in the acral areas.10 A retrospective study in France also indicated that acral chilblain-like lesions were the most common and histological examination of some of these lesions showed microthrombi.11 Histological features of chilblain lesions include perivascular lymphocytic infiltrate, microhemorrhages, necrotic keratinocytes, and lymphocytic vasculitis.8,12 In some pediatric patients, viral particles were detected in the epithelium of eccrine glands.12

Maculopapular Lesions

Maculopapular lesions are characterized by both discolored patchy rashes (macules) as well as raised lesions (papules) that span larger areas of the skin.13,14 These can occur in any part of the body, but are predominantly found on the back, abdomen, chest, and extremities.10 Rashes can vary extensively in terms of distribution, appearance, scaling, and degree of itching.14,15 Alba et al., in an analysis of 176 maculopapular cases, presented 6 further subcategorization of maculopapular lesions associated with COVID-19 infections: 1) morbilliform, 2) purpuric, 3) erythema multiforme-like eruptions, 4) pityriasis rosea-like, 5) perifollicular, and 6) erythema-elevatum diutinum.15 Morbilliform is the most common of the maculopapular lesions and is characterized by erythematous macules interspersed between areas of normal skin.15 In a histopathological examination of these lesions, researchers demonstrated the presence of perivascular dermatitis, dense lymphocyte infiltration, and, in some cases, thrombosis in vessels.16,17 Interestingly, these features are consistent with the lymphocytic vasculitis seen in immune complex and cytokine activation, which occurs in COVID-19 infections.4,16 It is also important to note that drugs can induce maculopapular rashes, so it may not be the best indicator for diagnostic purposes.4,18 Casas et al. noted that patients with maculopapular and urticarial lesions were more commonly taking drugs at the same time.10 Some of these drugs include hydroxychloroquine, azithromycin, remdesivir, and corticosteroids.4,17

Vesicular Lesions (Varicella-like Exanthem)

Vesicular lesions, also known as varicella-like exanthem, are characterized by small red vesicles that appear on the trunk and extremities.10,13 They tend to appear after respiratory COVID-19 symptoms and last a mean total of 10 days.19 A nationwide study in Spain demonstrated that vesicular lesions are more commonly seen with middle aged patients and are associated with mild severity of disease.10 Among 277 COVID-19 patients in a study, 15% developed a vesicular rash.11 Vesicular eruptions are often induced by viral infections, specifically varicella zoster virus and herpes simplex virus, but it is not known whether SARS-CoV-2 follows the same pattern due to limited studies.20 Interestingly, a prospective study demonstrated two main patterns of distribution and appearance of vesicular lesions: 1) smaller monomorphic localized lesions that were 3-4 mm and 2) diffuse larger polymorphic lesions that can be up to 7-8 mm.19 Histologically, these lesions show swollen keratinocytes, some of which exhibited necrosis and acantholysis, surrounded by fibrosis and inflammation.19 Disrupted organization of the epidermis was also a key characteristic.2 In the prospective study by Nieto et al., the majority of patients were not on medications, which suggests that these vesicular eruptions are less likely to be induced by drugs,19 This contrasts with urticarial or maculopapular eruptions, in which the pathogenesis may have a drug-related component.

Urticarial Lesions

Urticarial lesions (hives) are characterized by wheals.21 In retrospective studies from France and Spain, urticarial eruptions were seen in 9% and 19% of patients with COVID-19 infections, respectively.10,11 Most of the eruptions occurred on the face, trunks, and limbs.10,22 These lesions are often short-lasting, compared to other skin manifestations such as chilblains, maculopapular rashes, or necrotic lesions.10 Although, frequently appearing concurrently with other symptoms of COVID-19, hives can precede these other signs.10,22 Like maculopapular rashes, urticarial lesions are often drug induced, which can make it difficult to determine whether the reaction is due to the viral infection or due to the drug effect.21 Treatment with antihistamines is effective for urticarial lesions.21,22

Necrosis/Livedo

Necrotic and livedo lesions are much less common, but their presentation can signal a more severe disease course in COVID-19 patients.10 In a study of 375 patients, 7% exhibited necrotic lesions with a 10% mortality rate.10 The lesions are generally dark and can either be diffuse or localized.10 Livedo patterns are characterized by reticular reddish-blue, lace like lesions due to poor and constricted blood flow.13 Many studies categorize livedo and necrotic lesions in the same category along with other vasculitis manifestations due to similarities in the occlusive vascular pathology.10 Histopathology shows pauci-inflammatory thrombogenic vasculopathy, necrotic keratinocytes, and infiltration of lymphocytes.13,23 Other severe necrotic manifestations include skin bullae and dry gangrene, which was reported in 7 patients in 2020.24 These lesions are important to recognize due to their strong association with more aggressive and severe COVID-19 disease.10

Conclusion

There has been an increasing number of case reports illustrating the prevalence of dermatological manifestations in COVID-19 patients that are concurrent with respiratory and other systemic symptoms of COVID-19. These manifestations can be categorized into 5 broad types: chilblain-like lesions, maculopapular papular lesions, vesicular eruptions, urticarial lesions, and necrosis. Chilblain, maculopapular, and urticarial lesions are associated with milder disease, whereas necrotic lesions are seen in more severe disease courses. These lesions also have a strong association with age, in which chilblain lesions appear more commonly in younger patients and increased prevalence of necrosis/livedo in older patients.4,8,10 Viral infections (such as herpes simplex and varicella-zoster) can lead to skin symptoms, but it is still unclear whether the lesions seen in COVID-19 patients are directly the result of viral infection, concurrent illnesses, drug interactions, or other secondary causes.20 The pro-inflammatory and procoagulant state in COVID-19 infections may be implicated in the development of the skin eruptions, but this remains a topic for further investigation.

References



  1. Huynh T, Sanchez-Flores X, Yau J, et al. Cutaneous manifestations of SARS-CoV-2 infection. Am J Clin Dermatol. 2022 May;23(3):277-86.

  2. Marzano AV, Genovese G, Fabbrocini G, et al. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients. J Am Acad Dermatol. 2020 Jul;83(1):280-5.

  3. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020 Jun;220:1-13.

  4. Daneshgaran G, Dubin DP, Gould DJ. Cutaneous manifestations of covid-19: an evidence-based review. Am J Clin Dermatol. 2020 Oct;21(5):627-39.

  5. Sharma A, Ahmad Farouk I, Lal SK. COVID-19: A review on the novel coronavirus disease evolution, transmission, detection, control and prevention. Viruses. 2021 Jan 29;13(2):202.

  6. Parasher A. COVID-19: current understanding of its pathophysiology, clinical presentation and treatment. Postgrad Med J. 2021 May;97(1147):312-20.

  7. Sakaida T, Tanimoto I, Matsubara A, et al. Unique skin manifestations of COVID-19: is drug eruption specific to COVID-19? J Dermatol Sci. 2020 Jul;99(1):62-4.

  8. El Hachem M, Diociaiuti A, Concato C, et al. A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblainlike lesions: lights and shadows on the relationship with COVID-19 infection. J Eur Acad Dermatol Venereol. 2020 Nov;34(11):2620-9.

  9. Gottlieb M, Long B. Dermatologic manifestations and complications of COVID-19. Am J Emerg Med. 2020 Sep;38(9):1715-21.

  10. Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020 Jul;183(1):71-7.

  11. de Masson A, Bouaziz JD, Sulimovic L, et al; SNDV (French National Union of Dermatologists-Venereologists). Chilblains is a common cutaneous finding during the COVID-19 pandemic: a retrospective nationwide study from France. J Am Acad Dermatol. 2020 Aug;83(2):667-70.

  12. Colmenero I, Santonja C, Alonso-Riaño M, et al. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol. 2020 Oct;183(4):729-37.

  13. Genovese G, Moltrasio C, Berti E, et al. Skin manifestations associated with COVID-19: current knowledge and future perspectives. Dermatology. 2021;237(1):1-12.

  14. Shams S, Rathore SS, Anvekar P, et al. Maculopapular skin eruptions associated with Covid-19: a systematic review. Dermatol Ther. 2021 Mar;34(2):e14788.

  15. Català A, Galván-Casas C, Carretero-Hernández G, et al. Maculopapular eruptions associated to COVID-19: a subanalysis of the COVID-Piel study. Dermatol Ther. 2020 Nov;33(6):e14170.

  16. Gianotti R, Veraldi S, Recalcati S, et al. Cutaneous clinico-pathological findings in three covid-19-positive patients observed in the metropolitan area of Milan, Italy. Acta Derm Venereol. 2020 Apr 23;100(8):adv00124.

  17. Ahouach B, Harent S, Ullmer A, et al. Cutaneous lesions in a patient with COVID-19: are they related? Br J Dermatol. 2020 Aug;183(2):e31.

  18. Avellana Moreno R, Estela Villa LM, Avellana Moreno V, et al. Cutaneous manifestation of COVID-19 in images: a case report. J Eur Acad Dermatol Venereol. 2020 Jul;34(7):e307-9.

  19. Fernandez-Nieto D, Ortega-Quijano D, Jimenez-Cauhe J, et al. Clinical and histological characterization of vesicular COVID-19 rashes: a prospective study in a tertiary care hospital. Clin Exp Dermatol. 2020 Oct;45(7):872-5.

  20. Novak N, Peng W, Naegeli MC, et al. SARS-CoV-2, COVID-19, skin and immunology – what do we know so far? Allergy. 2021 Mar;76(3):698-713.

  21. Sabroe RA. Acute urticaria. Immunol Allergy Clin North Am. 2014 Feb; 34(1):11-21.

  22. Henry D, Ackerman M, Sancelme E, et al. Urticarial eruption in COVID-19 infection. J Eur Acad Dermatol Venereol. 2020 Jun;34(6):e244-5.

  23. Khalil S, Hinds BR, Manalo IF, et al. Livedo reticularis as a presenting sign of severe acute respiratory syndrome coronavirus 2 infection. JAAD Case Rep. 2020 Sep;6(9):871-4.

  24. Zhang Y, Cao W, Xiao M, et al. [Clinical and coagulation characteristics in 7 patients with critical COVID-2019 pneumonia and acro-ischemia]. Zhonghua Xue Ye Xue Za Zhi. 2020 Apr 14;41(4):302-7.


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]]> Update on Drugs & Devices: March – April 2024 https://www.skintherapyletter.com/drug-updates/march-april-2024/ Mon, 08 Apr 2024 08:17:18 +0000 https://www.skintherapyletter.com/?p=15192 Adalimumab-ryvk for SC injection

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B-Raf inhibitor gel

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Approval Dates/Comments: In January 2024, FDA device clearance was granted to DermaSensor, the first AI-powered tool to diagnose skin cancer, including melanoma, basal cell carcinoma, and squamous cell carcinoma, at the point of testing and noninvasively in patients aged ≥40 years. This wireless, handheld, prescription device uses spectroscopy technology to examine lesions at cellular and subcellular levels, then analyze their characteristics using an FDA-cleared algorithm. The device demonstrated 96% sensitivity, with negative results having a 97% chance of being benign.

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