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Ustekinumab in Dermatology: Approved Indications and Off-label Uses

  • Ahmed Samaouel Chehad1,2,* ,
  • Nada Boutrid3,4 and
  • Hakim Rahmoune3,5
Journal of Exploratory Research in Pharmacology   2023;8(4):323-341

doi: 10.14218/JERP.2022.00044

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Citation: Chehad AS, Boutrid N, Rahmoune H. Ustekinumab in Dermatology: Approved Indications and Off-label Uses. J Explor Res Pharmacol. 2023;8(4):323-341. doi: 10.14218/JERP.2022.00044.

Abstract

Ustekinumab is a human antibody that interacts with the p40 chain shared by both interleukin (IL)-12 and IL-23. Treatment with ustekinumab can effectively inactivate the biological functions of IL-12 and IL-23 to control aberrant Th1 and Th17 immunological responses. Ustekinumab is the first unique IL-12/IL-23 blocker approved by the Food and Drug Administration for the treatment of patients with moderate or severe psoriasis. Subsequently, its application has extended as a therapeutic option for psoriatic arthritis and inflammatory bowel diseases. Given its therapeutic mechanism, usterkinumab may be used as a potential alternative for treatment of a variety of inflammatory skin conditions. More importantly, usterkinumab is relatively safe, as the associated adverse reactions are generally non-serious and rare; although continuous monitoring of its adverse events is warranted. Here, we discuss the therapeutic effects of ustekinumab and its clinical applications specifically in dermatology.

Keywords

Ustekinumab, IL12, IL23, IL 12/IL 23 inhibitor, Biologic therapy

Introduction

Ustekinumab (CNTO-1275, Stelara) is a unique fully humanized monoclonal antibody (mAb) that interacts with the p40 chain shared by interleukin (IL)12/23 and functionally attenuates Type 1 T helper (Th1) and Type 17 (Th17) responses.1 Ustekinumab was approved for treatment of adult patients with moderate to severe psoriasis by both the European Medicine Agency (EMA) and the U.S. Food and Drug Administration (FDA) in January 2009 and September 2009, respectively. Subsequently, the FDA has expanded the approval for treatment of adolescents and children (≥6 years old) (Fig. 1). Although it was first approved for treatment of patients with psoriasis,2–5 ustekinumab has proven effective for treatment of other immune-mediated disorders (IMD), including active psoriatic arthritis (PsA) and active forms of major inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease. Aside from these labeled indications, ustekinumab has been used “off-label” for other inflammatory diseases.6 However, while multiple publications, mainly case reports and a small number of case series, have shown excellent results of ustekinumab when prescribed off-label for treatment of various skin conditions, there is a lack of systemic reviews in the literature. Hence, in this review we discuss ustekinumab’s pharmacological effects, efficacy, and safety in the treatment of psoriasis. More importantly, this review offers a special emphasis on the potential applications of ustekinumab in dermatology, based on its specific mechanism of action to inactivate both IL-12 and IL-23, and extend its therapeutic applications to a variety of skin disorders.

Timeline of the development and approval of ustekinumab for psoriasis.
Fig. 1  Timeline of the development and approval of ustekinumab for psoriasis.

FDA, Food and Drug Administration; IL, Interleukin; Th, T-helper.

Pharmacological mechanisms of ustekinumab

Successful mAb therapy began with the generation of chimeric, humanized, and, most recently fully human mAbs. Most mAbs that have been approved and are in the pipeline are indicated for the treatment of cancer, but there have also been other breakthroughs in the field of IMD.1 Presently, one of the largest classes of mAb therapy includes mAbs that bind and neutralize tumor necrosis factor α (TNFα), a potent inflammatory mediator associated with various IMD, such as rheumatologic, dermatologic, and gastroenterological diseases.7 IL-12 and IL-23 are significant contributors to the pathogenesis of IMD.8 IL-12 is a pro-inflammatory cytokine that consists of two different chain units designated by their average molecular weight as p40 and p35. The binding of IL-12 to its specific receptor (IL12Rβ1/IL12Rβ2), which is usually upregulated on pro-inflammatory T cells, stimulates tyrosine kinase 2 (TYK2) and Janus kinase 2 (JAK2) to activate signal transduction activation of transcription (STAT) 4. Once phosphorylated, STAT4 translocates to the nucleus where it modulates transcription of numerous genes, primarily interferon (IFN)-γ.9 Thus, IL-12 promotes the differentiation of activated CD4+ T cells into Th1 cells, a subset of CD4+ T cells involved in the pathogenesis of several IMD.10 IL-23 is also a heterodimeric cytokine formed by two chains of p19 and p40 (similar to IL-12). Engagement of IL-23 receptors (IL12Rβ1/IL23R) by IL-23 can activate STAT3 to induce IL-17, IL-22, and other cytokine production, leading to Th17 responses that contribute to the pathogenesis of various IMD and tissue damage.1

Within the skin, IL-17 can promote keratinocyte proliferation and the production of different chemoattractant molecules, such as CXCL1, CXCL8, and CCL20.11–13 According to animal and human studies, there is a strong link between Th1/Th17 signaling dysregulation and certain IMD, like psoriasis, PsA, rheumatoid arthritis, and inflammatory bowel disease. Furthermore, genome-wide association studies (GWAS) have identified a strong association between genetic alterations that affect the Th1/Th17 axis and chronic inflammation.14 Thus, in genetically susceptible individuals, over-activated IL-12 and IL-23 trigger aberrant Th1/Th17 responses, subsequently leading to IMD. Ustekinumab is a unique fully human IgG1 kappa mAb against that interacts with the p40 chain of IL-12 and IL-23 and blocks the binding of these two cytokines to their common receptor, IL12Rβ1. Importantly, ustekinumab preferably binds to soluble but not membrane-associated IL-12/IL-23 and does not usually induce complement activation or cell lysis through its immunoglobulin Fc domain.1

Figure 2 is an illustration of the mechanisms underlying the action of the drug in inflammatory skin diseases.

The mechanisms of actions of ustekinumab in inflammatory skin diseases.
Fig. 2  The mechanisms of actions of ustekinumab in inflammatory skin diseases.

IFN: Interferon; IL: Interleukin; Th: T-helper; TNF: Tumor necrosis factor.

Ustekinumab current approved indications in dermatology

Plaque psoriasis is the only validated indication for ustekinumab in dermatology. Psoriasis is a frequent, chronic skin IMD marked by sharply well-circumscribed erythematous-squamous lesions and is significantly associated with systemic comorbidities.15 The World Health Organization defines psoriasis as a serious, chronic, disfiguring, disabling, and non-communicable disease. Psoriasis affects approximately 2% to 3% of people worldwide, and 30% of cases are moderate to severe forms.16 Psoriasis and its related comorbidities may substantially lower a patient’s quality of life (QoL) and lead to a high degree of cumulative life course impairment.17 Clinically, psoriasis can manifest with a multitude of phenotypes; 90% of cases display chronic plaque psoriasis (also named psoriasis vulgaris).18 Therefore, all currently available treatments are approved for psoriasis vulgaris. Psoriasis can also exhibit other less common variants, including guttate, erythrodermic, and pustular psoriasis. Currently, the management of these variants relies on empiric therapies.16

During the past twenty years, the understanding of psoriasis pathogenesis has progressed considerably. The TNFα-IL23-Th17 axis has been recognized as a major inflammatory pathway for the pathogenesis of plaque-type psoriasis,19 which is supported by immunological and genetic studies. While GWAS have shown a link between psoriasis pathogenesis and genetic alterations in the IL-23/IL-17 axis,20 immunological researchers have stressed the important roles of IL-23 in the development and progression of psoriasis by enhancing Th17 responses. IL-17 is a key orchestrator of chronic inflammation in psoriasis. IL-17 induces the secretion of many other cytokines and chemokines, which promote the chemotaxis of immune cells to the site of inflammation and sustain the positive inflammatory loop and epidermal hyperplasia.21

However, until late last century, topical therapies and/or ultraviolet light therapies were the mainstay of psoriasis treatment. Subsequently, the first major therapeutic advancements have been conventional systemic drugs (methotrexate, cyclosporine, fumarates, and acitretin). Besides these older agents, the novel small molecule apremilast has recently expanded into the psoriasis armamentarium.22 Although these treatments may benefit some patients, they have lower therapeutic efficacy and higher adverse events (AEs) owing to a non-specific modulation of the immune system. For example, the PASI 75 (a decrease in PASI score by 75%, the current benchmark of psoriasis treatment) of methotrexate is typically 35.5–41%.22 The need for alternative and/or small molecule therapeutics and a better understanding of the immunopathogenesis of psoriasis have prompted the discovery of biological drugs directed against the aberrant immune response. Three main groups of biological agents, including blockers for TNFα, IL-23, and IL-17, have been approved for the treatment of psoriasis.

Ustekinumab is the first approved biological drug for treatment of chronic plaque psoriasis, based on its anti-IL-23 effect.23 Ustekinumab, manufactured by Johnson & Johnson Pharmaceutical, is created by immunizing human mAb-producing mice with recombinant human IL-12. Currently, this biological drug is approved by the FDA for treatment of patients aged ≥6 years who have moderate to severe psoriasis and who are eligible for systemic treatment or phototherapy.23 The efficacy-safety profiles of ustekinumab have been demonstrated through four large phase III studies: three placebo-controlled trials namely PHOENIX 1/2 and PEARL, and one active comparator-controlled trial (ACCEPT).2–5 The results from these trials indicate that ustekinumab has a more favorable efficacy-safety profile compared to anti-TNFα drugs. A total of 2,000 psoriatic patients with moderate to severe disease participated in the PHOENIX 1/2 trials. After the initial induction doses of the drug administered subcutaneously every 4 weeks, followed by a maintenance dosage every 12 weeks, 66.4% to 75.7% of participants achieved PASI 75, which was significantly greater than in the placebo groups (3–4%). Moreover, while the improvement was maintained during the 3-month interval between doses, the incidence of AEs (52% and 49%, respectively) and serious AEs (1.4% and 1.5%, respectively) were not significant between these two groups. In the ACCEPT trial, similar results were obtained in the ustekinumab group (67.5% to 73.8%) with a higher efficacy compared to etanercept (56.8%) and a comparable safety profile. Consistent data regarding the efficacy of ustekinumab and its safety profile were observed through 5 years of follow-up.24 However, dose escalation (90 mg every 8 weeks) resulted in better improvement in psoriatic patients who failed to respond to the initial regimen. In addition, since most patients with psoriasis experienced a flare-up after stopping ustekinumab therapy, there is no available data to support the long-term use of this biological drug.25

Figure 3 is an illustration of the therapeutic effect of ustekinumab on psoriasis and two other major skin diseases, atopic dermatitis and hidradenitis suppurativa.

Therapeutic effect of ustekinumab on psoriasis (top figure), atopic dermatitis (lower right figure), and hidradenitis suppurativa (lower left figure).
Fig. 3  Therapeutic effect of ustekinumab on psoriasis (top figure), atopic dermatitis (lower right figure), and hidradenitis suppurativa (lower left figure).

IFN, interferon; IL, Interleukin; Th, T-helper; TNF, Tumor necrosis factor; TARC, thymus and activation regulated chemokine; TSLP, thymic stromal lymphopoietin.

Ustekinumab off-label uses in dermatology

Ustekinumab has been used to treat many skin diseases given its distinct and targeted mechanism of action. However, robust evidence from well-designed studies addressing uncommon and life-threatening diseases is rare, and the scientific data available in this field are often restricted to small clinical reports. Thus, such limited evidence cannot support the use of ustekinumab as an initial therapy. On the other hand, there are a few low-level quality studies comparing IL-12/IL-23 blockers versus standard treatments. For this reason, ustekinumab should be reserved to treat cases that have failed or did not tolerate the first-line therapy and where other therapeutic alternatives are lacking. Table 1 summarizes the studies concerning the off-label use of ustekinumab.26–122

Table 1

Cases of diseases treated off-label with ustekinumab

Cutaneous disordersStudyStudy designNo of patientsPatient (s) Age (y)/sexPrior systemic treatmentUstekinumab dose (mg)Reported efficacy/outcomesSerious AEs
GPBrummer GC26cs629–42/3M–3FCsA, Apr, Phototherapy90 once/45Q4W/45Q4W, 90Q4W/90Q8WSuccess 6/6None
Amarnani52CR156/1FPhototherapy AciSDClearanceNone
EPSantos-Juanes28CS232 and 41/2FCsA, MTX, SCS, PUVA, Efa, anti-TNFαSDSuccess 2/2; PASI 90None
Viguier53CS3Anti-TNFαSD33% PASI 50-1 sudden death; -Widespread skin Staphylococcus
Wang29CS828–55/7M–1FCsA , MTX, PUVA, Efa, alefacept, Aci, anti-TNFα-7 patients: 45Q4W two doses, -1 patient: 45Q4W two doses + W16 + W 3250% PASI 75; 50% PASI 90None
Pescitelli27CS22NA/14M–8FCsA, MTX, SCS, UVB Ret, anti-TNFαSD68.2%; PASI 90None
GPPStoran30CR190/1FCsA, MTX, Ret, AdaSDSuccess 1/1None
Arakawa32CS420–50/4FCsA, MTX, Ana, Aci , anti-TNFαSDSuccess 4/4None
Dauden31CR147/1MNoneSDSuccess 1/1None
Matsumoto54CR170/1FCsA, etretinate, IFXStarted at 45 then 90Fail 1/1None
PPPMorales-Munera55CS530–50/2M–3FCsA, MTX, PUVA, Aci, Efa, leflunomide, anti-TNFαSDSuccess 5/5None
Au56open-label study2018- 85/9M–11FSystemic therapy, anti-TNFαSDImprovement 12/20, Clearance 7/20None
Bulai Livideanu57CS229 and 42/1F and 1MCsA, MTX, Ret, phototherapy, anti-TNFα45 or 90, not regularlySuccess 2/2None
Bissonnette58RCT15NA/14F–1M45Q4W two doses or placeboNo difference compared to placebo1 leg cellulitis
Husson35CS (PPP + ACH)30NANANASuccess 21/302 PPP worsening, 1 Paradoxical psoriasis, 1 Pneumonia
ACH4Success 4/4
Adisen59CR150/1MDap, CsA, MTX, Ret, phototherapy,anti-TNFαStart 90 then SD 45Success 1/1None
Palacios-Alvarez33CR167/1MMTX, phototherapy, Aci, anti-TNFαSD 45Success 1/1None
Saunier60CR153/1MAci , MTX, phototherapy, CsA, anti-TNFα, AnaSD 45Success 1/1None
Cymerman34CR120/1FCsASD 45Success 1/1None
Adas61CR161/1MEta45Q4W two doses then 90Q8WSuccess 1/1None
PRPRuiz Villaverde62CR145/1MNoneSD 45Success 1/1None
Byekova63CR175/1MIFX, AciSD 45Success 1/1None
Chowdhary64CR152/1FAci, UVB, minocycline, SCS, MTXSD 90Success 1/1None
Di Stefani65CR131/1MCsA, Aci, MTXSD 45Success 1/1None
Eytan66CR157/1MMTX, Ret, PUVA, Efa, anti-TNFα90Q8WSuccess 1/1None
Humme67CR150/1MAci, PUVA, CsA, IFX45–90NACD30(+) anaplastic large cell lymphoma
Lernia68CR129/1FCsA, MTX, anti-TNFα, PUVA,SD 45Fail 1/1None
Lwin69CS220 and 49/1M and 1FRet, phototherapy-1 patient: SD 45; -1 patient: Started at SD 45 then 90Success 2/2None
Paganelli70CR178/1FRet, phototherapy, MTX, CsA, IFXSD 45Success 1/1None
Wohlrab71CR128/1MAci, Bath-PUVA,SD 45Success 1/1None
Aragón-Miguel72CR130/1MAci, PUVASD 45Success 1/1None
Feldmeyer73CR140/MNoneSD 45Success 1/1None
Kalogeropoulos74CR160/1MAciSD 45NAMeningococcal and HSV-2 Meningitis
Napolitano75CS528–62/3M–2FCsA, SCS, Aci, MTXSD 45Success 4/5, 1partial improvementNone
Craiglow76CS6NANB-UVB, PUVA, Ret, MTX, CsA, anti-TNFα,-5 patients: 0,7 mg/kg-1,1 mg/kg Q12W; -1 patient 1,2 mg/kg Q8WSuccess 5/6, 1partial improvementNA
Matsuda77CR172/1MSCS, Secu, IFX, etretinate, CsA, MTX, AprSD 45Success 1/1None
Ponholzer78CS5NA/3M–2FNB-UVB, PUVA, Aci-3 patients: SD 45; -1 patient: SD 90; -1 patient: Started at SD 45 then 90Success 5/5NA
HSGulliver79CS330–32/1M–2FATBs, Ret, anti-TNFα, SCS, EfaSD 45- HS-PGA: 2/3; - DLQI: 2/3; - Pain: 2/3None
Sharon80CR155/1MISO, ATBs, SCS, MTX, ada, MMFSD 45Improvement 1/1None
Baerveldt81CR139/1FDiclofenac/misoprostol, colchicine, CsASD 45Improvement 1/1None
Santos-Pérez82CR150/1FISO, anti-TNFα, SCSSD 45Improvement 1/1
Blok36open-label study1720–53/4M–13FATBs, ISO, anti-TNFα, SCSSD- HiSCR: 8/17; - DLQI: 07/17urticaria
Romani83CS1219–60/9M–3FATBs, CsA, MTX, AZA, anti-TNFα, AnaIV loading dose adjusted by weight then SC 90 Q8W- HiSCR: 8/12; - DLQI: 11/12; - Pain: 11/12None
Scholl84CS325–31/2M–1FATBs, Ada, dapsone, SecuIV loading dose adjusted by weight then SC 90 Q8 or 12W- SAHS: 3/3; - DLQI: 3/3None
Takeda85CR129/1MIFX, SCS360 IV loading dose then SC 90 Q8WImprovement 1/1Non
Montero-Vichez86CS1014–52/6M–4FATBs, Ret, CsA, anti-TNFα, SCS, interferon, phototherapy,SD-HSPGA: 7/10; - Pain: 8/10None
Sánchez-Martínez87CS631–59/3M–3FATBs, Ret, MTX, finasteride, AZA, AdaIV loading dose adjusted by weight then SC 90 Q8WHiSCR: 3/6None
Hollywood88CS1622–77/4M–12FATBs, Ana, metformine, liragultide, Dap, sironolactone, anti-TNFα.NAImprovement 8/16Recurrent infection
Smith89CR149/1FAnti-TNFα.SD 90Primary ImprovementMultifocal myositis
Provini90CR117/1FATBs, sironolactone, SCS, Ada90Q8W then 90Q4WImprovement 1/1None
Valenzuela-Ubiña91CS1026–58/4M–6FATBs, Ret, MTX, finasteride, AZA, SCS, metformin, Dap, Ana, CsA, Anti-TNFα.- 9 patients: 90Q8W; -1 patient: SD 45-HSPGA: 9/10None
Neutrophilic diseases
PGGoldminz92CR147/1MSCS, Dap, MTX, CsA, AZA, Anti-TNFα.90Q4W then 90Q8WComplete healingNone
Cosgarea93CR171/1MSCS, CsANAComplete healingNone
Benzaquen94CR156/1FAdaSD 45Complete healingNone
Guenova37CR137/1FSCSTwo doses 45Q4WComplete healingNone
Nunes95CR145/1MSCS, IFX, AZA, CsA520 IV loading dose then SC 90 Q8WComplete healingNone
Piqueras-García39CR133/1FSCS, 6-Mercaptopurine, CsA, Anti-TNFα, vedolizumab, tacrolimus90 week 0, 4, 10 then Q8WComplete healingNone
Petty40CR150/1FSCS, CsA, IFX90 week 0, 4 then Q8WComplete healingNone
Low96CS336 –57/3FSCS, MMF, Dap, IVIG-1 patient: 90 week 0, 4 then Q6W then 45 Q3W; -2 patient: 90 week 0, 4 then Q8W then 45 Q4WComplete healing 3/3None
Greb97CR150/1MSCS, CsA, Anti-TNFα, Dap90 Q8W then 90 Q6W then 135 Q6WSignificant improvementNone
Fahmy98CR134/1FTacrolimus, AZA90 week 0, 2 then Q8WComplete healingNone
López González99CR129/1FATB, SCS, Ada260 IV loading dose then SC 90 Q8WComplete healingNone
Vallerand100CR147/1MSCS, IVIG, MMP520 IV loading dose then SC 90 Q8WSignificant improvementNone
Nieto101CR162/1MAda, Azacytidine, CsA, IFX, IVIG, Thalidomide, SCS90 Q8WComplete healingNone
Westerdahl102CS824–88/4M–4FSCS, Anti-TNFα, colchicine, Ixe, ATB,-3 patients: 90 Q8W; -1 patient: 90 Q12W; -2patients: 45 Q12W; -1 patient: 45 Q8W; -1 patient: 180 Q8WComplete healing 7/8, improvement 1/8None
de Risi-Pugliese38CS430–44/1FAZA, IFX, MTX, Ada, AZA, aminosalicylates, Mercaptopurine-2 patients: 90 Q8W; -1 patient: 90 Q2W then Q8W; -1 patient: 90 Q4W then Q8WComplete healing ¾; Significant improvement 1/4None
APF232 and 41/2FSCS, Dap, ISO, CsA, colchicine, Ana, ATB, Ada-1 patient: 90 Q8W; -1 patient: 90 week 0, 2 then Q8WSignificant improvement 2/2None
SS128/1MColchicine, MTX, SCS, Ada, Dap90 Q8WFail 1/1None
BDBaerveldt81CR139/1Fdiclofenac/misoprostol, colchicine, CsASD 45RemissionNone
Lopalco103CR136/1FSCS, colchicine, MTX, CsA, AZA, Anti-TNFα, AnaSD 45RemissionNone
Mirouse41Prospect-ive study1434–41/10M–4FColchicine, AZA, SCS, MMF, tocilizumab, tacrolimus-11 patients: SD 90; -3 patients: SD 45-Complete response: 9/14; -Partial response: 3/14; -Fail: 2/14None
Mirouse104open-label study3033–45/16M–14FColchicine, SCS, thalidomide, hydroxyl-chloroquine, MTX, cyclophosphamide, AZA, MMF, everolimus.SD 90-Complete response: 18/30; -Partial response: 9/30; -Fail: 3/30None
London105open-label study15NA/9M–6FColchicine, SCSSD 90-Complete response: 9/15; -Partial response: 2/15; -Fail: 4/15None
ADPuya106CR121/1FSCS, UVB, CsA, EfaSD 45Complete responseNone
Agusti-Mejias107CR116/1FSCS, phototherapy, AZA, CsASD 45Complete response: SCORAD 0None
Shroff108CR170/1FUVB, CsA, MMF45 week 0, 3, 11 and 19Complete response: SCORAD 0None
Fernández-Antón Martínez42CS423–29/4MSCS, phototherapy, AZA, CsA, MTX, MMFSD 45Significant improvementsNone
Lis-Święty109CR121/1MNoneSD 45ExacerbationNone
Ishiuji110CS259 and 39/1M and 1FNoneSD 45ExacerbationNone
Samorano111CS247 and 20/1M and 1Fphototherapy, SCS, CsA, MTX, MMF, Eta-1 patient: SD 45; -1 patient: 45 week 0, 6, 12Fail 2/2None
Nic Dhonncha112CS1020–50/8M–2Fphototherapy, AZA, CsA, MMF, Eta, EfaSD 45 or 90Significant improvements: 4/10; Fail: 6/10None
Saeki113RCT phase 252 vs 27 placebo20–57/36M–16Fphototherapy, SCS, CsASD 45 or 90No significant improvementNone
Wlodek114CR113/1FSCS, AZA, CsA, MTX, MMFSD 45Partial improvementNone
Khattri115RCT phase 216 vs 15 placeboNA/10M–16FNASD 45 or 90No significant improvementNone
Weiss116CS327–55/2M–1FSCS, phototherapy, CsA, MMF45 week 0, 4, 12 then Q8WImprovement 3/3None
AAGuttman-Yassky43CS3NA/2M–1FNASD 90 (3 doses)Improvement 3/3None
Aleisa44CS39–16/3FSCS,1 patient: 90 week 0, 12, 24; 2 patients: one dose 90Significant hair regrowth 3/3None
Ortolan117CS48–44/2M–2FSCS, CsA, MTX, ruxolitinib, tofacitinib1 patient: 45 week 0, 60 week 90 week 12, 20; 1 patient: 90 Q8W; 2patients: 90 week 0, 4, 12Fail 4/4None
Elkady34CR139/1FVitamines B complex90 week 0, 4 then Q8WHair regrowthNone
VitiligoNoneRepigmentation
SAPHOWendling46CS332–61/3FPhototherapy, MTX, CsA, Anti-TNFαSD 90Remission 1/3Paradoxical psoriasis
Firinu117CR1NA/1Fanti-TNF-α, AnaSD 90Significant improvementNone
LPSolimani47CS172/1FCsA, SCS, Aci,AZASD 45Significant improvementNone
Webster48CR170/1FHydroxychloroquineSD 45FailNone
LP pemphigoidesKnisley118CR171/1FCycline, nicotinamide, SCS, Dap, AZA, MMF HydroxychloroquineSD 45Significant improvementNone
BPLoget49CR188/1FNoneSD 45RemissionNone
antilaminin-γ1 pemphigoidMajima119CR169/1MSCS, AdaNARemissionNone
Cutaneous lupusDe Souza120CR158/1FNASD 45RemissionNone
Varada122CS168/1FNANARemissionNone
Dahl51CR179/1FSCS, hydroxychloroquine, AZA, thalidomide, MTX, IV IG45 week 0, 4, 16, 34ImprovementNone
Winchester50CR141/1MMTX, hydroxychloroquine, CsASD 45 then 90Significant improvementNone
Mazgaj122CR165/1FChloroquine, Aci, MTX, CsA, thalidomide, lenalidomide, alitretinoin.SD 45 then 90 Q8WRemissionNone

AA, alopecia areata; ACH, Acrodermatitis continua of Hallopeau; Aci, acitretine; AD, atopic dermatitis; Ada, adalimumab; AEs, adverse events; Ana, anakinra; anti-TNFα, tumor necrosis factor α inhibitor; APF, Amicrobial pustulosis of the folds; Apr, apremilaste; ATB, antibiotic; AZA, azathioprine; BD, Behçet disease; BP, bullous pemphigoid; CR, case report; CS, case series; CsA, cyclosporine; Dap, dapsone; Efa, efalusumab; EP, erythrodermic psoriasis; Eta, etanercept; GP, generalized psoriasis; GPP, generalized pustular psoriasis; HS, Hidradenitis suppurativa; IFX, infleximab; ISO, isotrétinoïne; IV IG, intravenous immunogolobulines; IV, intravenous; Ixe, ixekizumab; LP, lichen planus; MMF, mycophenolate mofetil; MTX, methotrexate; PG, pyoderma gangrenosum; PPP, palmoplantar pustuloses; PRP, Pityriasis rubra pilaris; Q(number)W, every (number) week; Ret, retinoid; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis; SC, subcutaneous; SCS, systemic corticosteroids; SD, ustekinumab at weeks 0, 4, and then every 12 weeks. Weight <100 kg, 45 mg/weight >100 kg, 90 mg; secu, secukinumab; SS, Sweet syndrome.

Ustekinumab for other subtypes of psoriasis

Psoriasis encompasses other infrequent variants namely guttate (GP), erythrodermic (EP), and pustular psoriasis (PP). GP accounts for nearly 2% of psoriatic patients and appears as red, scaly, small, raindrops-shaped papules that often erupt suddenly throughout the entire body.123 Although there is no consensus on the treatment of GP, severe forms of GP are commonly treated with topical corticosteroids, phototherapy, immunomodulatory drugs, or even biological therapy.124 Successful use of ustekinumab in recalcitrant GP has been reported in only a few of cases. For example, Brummer et al26 reported that treatment with ustekinumab successfully cleared lesions in six patients with resistant GP.

EP accounts for 1–2.25% of all cases and represents one of the most severe and potentially life-threatening subtypes of psoriasis. It manifests as erythema covering >75% of the entire skin surface.123 There is little scientific evidence that supports biological therapy in EP owing in part to the paucity of high-quality studies. However, the efficacy of ustekinumab in this rare form of psoriasis was highlighted in multiple clinical studies27–29,125,126 with impressive response despite the failure of a first-line anti-TNFα therapy. A multicenter retrospective study in Italy showed that 80% of EP patients achieved PASI 75 following treatment for seven months.27

PP is a rare form of psoriasis characterized by non-follicular small pustules on erythematous and edematous skin. There are three clinical forms of PP: generalized form (GPP), palmoplantar pustulosis form (PPP), and acrodermatitis continua of Hallopeau (ACH). It was postulated that the formation of pustules is caused by elevated levels of certain immune mediators, including IL-17F and IL-8, which can be targeted specifically by IL-23/IL-17 blockers. GPP (also known as von Zumbusch disease) can cause serious complications and can be life-threatening, especially if not diagnosed early and treated appropriately.123 There are only a few case reports30,31 and one case series32 of GPP that have been successfully treated with ustekinumab. Arakawa et al123 reported that ustekinumab therapy led to remission in four GPP cases for 17 months. PPP is a chronic, debilitating form of PP and is usually resistant to treatment. PPP manifests pustules as an erythematous base, hyperkeratosis, and scales, affecting both palms and soles.123 Despite the lack of sufficient evidence supporting ustekinumab use for PPP, there have been some reports of a satisfactory response among patients with PPP, including significant improvement in the QoL.127,128 ACH is an uncommon disease presenting with long-lasting sterile pustules specifically affecting the extremities of the digits.123 This form of PP has been found invariably recalcitrant to available antipsoriatic therapies. There are some case reports and one retrospective study on the efficacy of ustekinumab in the treatment of ACH.33–35 Treatment with ustekinumab effectively improved clinical symptoms in seven patients with ACH and cleared skin lesions in 75% of patients, similar to that of anti-TNFα therapy.

Ustekinumab for pityriasis rubra pilaris (PRP)

PRP is a rare disease characterized by erythematous and papulosquamous eruption and is classified into six major types depending on clinical aspects, age of disease onset, and outcome.129 The etiology of PRP is still not completely understood, and its management relies heavily on small clinical studies. There are diverse treatments for PRP with varying outcomes, including topical corticosteroids, phototherapy, systemic retinoids, and immunosuppressive drugs. In recalcitrant cases, anti-TNFα therapy can significantly improve clinical symptoms, supporting the immunological pathogenesis theory. In refractory PRP cases, ustekinumab has been reported to be valuable. A review of the PubMed database and the Cochrane Library until September 2017 by Kromer et al,130 included all studies that evaluated the risks and benefits of systemic treatments for PRP. There were about 182 studies (including 475 patients) on systemic treatment of PRP. Ustekinumab was successful in 62.5% of patients compared to adalimumab (46.4%), etanercept (53.3%), and infliximab (57.1%). The comparison between ustekinumab and acitretin (which is commonly considered as a reference treatment in PRP) showed a substantially elevated rate of excellent response in patients treated with ustekinumab (p = 0.001). The general AE reporting rate was 26.4%, but this was significantly elevated with retinoids (34.1%) then MTX (16.5%) and the lowest proportion was reported with biological agents (8.8%).

Ustekinumab for hidradenitis suppurativa (HS)

HS is a long-term inflammatory dermatosis that often causes serious morbidity and manifests mostly after puberty with inflamed nodules and painful deep-seated abscesses with sinus tracts mainly localized in body zones rich in apocrine glands including axillary and anogenital areas.131 Although some drugs have been proven to be successful in managing HS symptoms, there is a lack of solid evidence supporting them. The pathogenesis of HS is complex, but TNFα and IL-17 are recognized as central players in HS pathogenesis.132 One study suggests that gene polymorphisms in IL12Rβ1 may be linked to some severe forms of HS.133 Currently, adalimumab, a type of anti-TNFα antibody, is the only biological agent available for the treatment of HS.134 However, failure of treatment was common and consideration of second-line biological drugs, like ustekinumab, may be valuable for inhibiting Th17 responses. In this perspective, an open-label, uncontrolled trial was conducted in 17 patients with HS to determine the benefit of ustekinumab therapy. At week 40 when the clinical trial ended, 47% of patients achieved HiSCR-50 (50% improvement in HS inflammatory lesions), and >82% of cases obtained moderate or remarkable relief of their modified Sartorius score.36

Ustekinumab for neutrophilic diseases

Pyoderma gangrenosum (PG), Sweet syndrome (SS), subcorneal pustular dermatosis, and erythema elevatum diutinum are heterogeneous diseases that may be grouped as neutrophilic dermatoses (ND) hallmarked by a sterile, neutrophil-rich infiltrate on the skin.135 Clinical management of ND is challenging due to the lack of universally accepted and validated guidelines. The standard treatment for idiopathic PG and SS is systemic corticosteroids, whereas dapsone is the first line of treatment for subcorneal pustular dermatoses.136 However, the use of biological therapy, primarily TNFα blockers, anti-IL-1, anti-IL-17, and anti-IL-23, is rapidly expanding for the management of widespread and aggressive PG.137 Although detailed knowledge of how biological drugs work for ND is lacking, the expression of several cytokines, including TNFα, IL-8, IL-17, and IL-23, is up-regulated in PG, which may explain the favorable clinical results obtained with biological agents such as ustekinumab.37 A literature search found 21 out of 23 ND patients had responded positively to ustekinumab (17 PG, 4 amicrobial pustulosis of the folds, 1 Bowel-associated dermatosis-arthritis syndrome, and 1 SS), 16 (70%) were complete responders and 5 (21%) were partial responders, whereas no responses were seen in one PG and one chronic recurring Sweet syndrome.38–40,138

Ustekinumab for muco-cutaneous manifestations of Behçet disease (BD)

BD is a primary vasculitis that manifests specifically as repetitive attacks of oral-genital ulcers, cutaneous inflamed lesions, and uveitis with multiple organ system involvement, including the gastrointestinal, cardiopulmonary and nervous systems.139 Whereas systemic vasculitis may lead to worse outcomes, repetitive aphthous ulcers often lead to substantial QoL impairment. These mucocutaneous lesions could be managed with colchicine, azathioprine, thalidomide, and more recently apremilast, although with varying success and potential serious AEs. However, increased knowledge of the immune mechanisms responsible for BD has prompted the use of biological drugs to manage the more intractable mucocutaneous lesions. One randomized controlled, 4-week trial and several observational studies and case series have showed that TNF-α inhibitors are promising treatment options for recalcitrant mucocutaneous disease.140 Additionally, emerging evidence suggests that Th1 and Th17 responses may contribute to the pathogenesis and progression of BD. This, together with higher IL23 levels and Th17/Th1 ratios in BD patients, suggest that ustekinumab may be reasonable and effective for the management of BD. In support of this, ustekinumab has been demonstrated to be effective in ameliorating recalcitrant oral aphthous ulcers in BD patients in clinical trials.41,140

Ustekinumab for atopic dermatitis (AD)

AD is a frequent pruritic inflammatory dermatosis, which commonly follows a remitting-relapsing chronic course and commonly develops in a patient with atopic diathesis.141 The pathogenesis of AD is thought to be both skin barrier alteration and immune system dysfunction. The conventional treatments rely on topical anti-inflammatory drug medication and adequate skin hydration. However, systemic immunosuppressant medications are required for moderate to severe forms of the disease; although they are discouraged, owing to their transient efficacy and a poor AE profile.142 The identification of new immune targets involved in the process of AD has prompted the development of innovative therapeutics, including biological therapy and small molecules. Studies have showed that IL17 and IL22 expression are upregulated in AD lesions and represent therapeutic targets for ustekinumab treatment.42 Indeed, many studies have investigated the efficacy of IL-12/IL-23 inhibitors for patients with recalcitrant AD. Pan Y et al143 conducted a systematic review on the current scientific literature up to September 2017 concerning the benefits of ustekinumab in AD. They found that this biological drug has been administered in 8 case reports and 2 randomized placebo-controlled trials (RCTs) of 107 cases. In general, the observational studies have shown more clinically relevant effects, whereas RCTs have not shown a significant advantage of ustekinumab over the placebo.

Ustekinumab for Alopecia Areata (AA) and Vitiligo

AA is a common IMD that causes temporary and permanent non-scarring alopecia.144 Treatment of AA by conventional systemic therapy is hampered by its AEs and limited efficacy. Nevertheless, the discovery of the role of various immunological mediators, including Th1, Th2, and IL-23, in the pathological process of AA has opened a door to test the efficacy of ustekinumab for AA.145 There are some reports on the therapeutic efficacy of ustekinumab for new onset AA and some cases with hair regrowth.146 Guttman-Yassky et al43 demonstrated that treatment with ustekinumab for 20 weeks improved clinical symptoms in three moderate-to-severe AA patients without AEs. Likewise, ustekinumab has safely ameliorated clinical symptoms in three pediatric patients with mild, moderate, and severe AA.44

Vitiligo is also a long-lasting IMD and consists of depigmented skin macules. Like AA, Th17 cells are the major immune players in vitiligo pathogenesis.147 Therefore, it is reasonable to test the therapeutic efficacy and safety of ustekinumab for vitiligo. However, there is only one report on the use of ustekinumab for repigmentation in a patient with both psoriasis and vitiligo, and these findings contrast other observations.45,148,149

Miscellaneous

Ustekinumab has been reported for the treatment of miscellaneous cutaneous disorders, like SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis), lichen planus (LP), bullous pemphigoid (BP), and lupus erythematosus (LE). Some data have demonstrated an aberrant Th17 response in SAPHO patients, which suggests that ustekinumab may be promising for SAPHO syndrome.46 However, only 5 SAPHO cases have been treated with IL-12/IL-23 blockers with mixed results on cutaneous symptoms, as less than half of the patients had improved symptoms.150

There is little evidence on the efficacy of IL12/IL23 blocker for LP. Although treatment with ustekinumab was reported to remarkably improve extensive erosive oral LP in one report,47 ustekinumab treatment failed to show any efficacy in another report with concomitant psoriasis and erosive LP.48 There are controversial reports on the therapeutic effect and deteriorative outcomes of ustekinumab in BP patients.151,49

Regarding systemic LE, a phase II RCT conducted by Ronald van Vollenhoven et al152 to test the therapeutic effect of ustekinumab in 102 active systemic LE patients has revealed that addition of ustekinumab to standard therapy enhances therapeutic efficacy. Although peculiar cases of ustekinumab-induced lupus-like cutaneous reactions have been reported, many successful cases have been widely reported on the therapeutic efficacy of ustekinumab for cutaneous and discoid LE.50,51,153

AEs observed with ustekinumab

Most AEs associated with ustekinumab use are non-serious, occasional, and usually do not lead to drug discontinuation.154 The most commonly encountered AEs are headaches, asthenia, abdominal pain, and upper respiratory infections. Local injection site reactions are also usually mild in severity and infrequent, probably due to a minimal injection regimen.3 Moreover, there have been no reported differences in the frequency of AEs or abnormal laboratory tests between ustekinumab- and placebo-treated patients in clinical trials.154

IL-17 is a pro-inflammatory cytokine that can participate in immune responses against bacterial and fungus infections. Therefore, treatment with ustekinumab to block the IL-12/IL-17-related signaling may increase susceptibility to infections.155 However, the infectious risk due to ustekinumab was low in clinical trials. Furthermore, analysis of published register-based data did not show higher rates of severe infections when comparing ustekinumab to either anti-TNF agents or conventional systemic therapies.156,157 In particular, the potential risk of active tuberculosis infection due to ustekinumab seems to be reduced when compared to TNFα inhibitors.158 In addition to infectious hazards, the most reported AEs of ustekinumab treatment are the risk of major adverse cardiovascular events (MCCEs); a meta-analysis of RCTs in 2011 reported an increase in MCCEs during the first months of drug exposure, although there was no significant increase in the frequency of MACEs when compared to placebo.159 This report is correlated with experimental studies, in which the IL23/IL17 pathway negatively affects atherosclerotic plaques stability. Nonetheless, a case-control study of ustekinumab from the French National Health Insurance database involving more than 9,000 subjects during the period of 2010–2016, revealed a significant link between ustekinumab therapy and the onset of acute coronary syndrome, while stroke was identified only with high cardiovascular risk patients.160 Another important concern regarding ustekinumab use is its potential oncogenic effect. Animal-based studies have revealed that blockade of IL12/IL23 signaling may increase the risk of malignancies.161 However, despite scarce reports of malignant tumors, cancer incidence itself was low in clinical trials and in register-based data.157 There are neither observational studies, nor case reports on any increase of adverse outcomes in pregnant women.

Furthermore, ustekinumab treatment-related uncommon cutaneous and systemic AEs have been reported, including immune-mediated dermatological disorders. The most reported skin and systemic AEs associated with ustekinumab use are summarized in Tables 2 and 3, respectively.

Table 2

Skin adverse events associated with ustekinumab

Adverse event categoriesSpecific skin reactions
Skin lesions related to the administration of treatmentBruising, pruritus, pain, erythema, swelling, skin rash
Skin infectionsBacterial infections: cellulitis, mycobacterium abscessus, secondary syphilis, staphylococcal skin colonization; Viral infections: disseminated verrucae, condyloma acuminate, herpes zoster; Fungal infection: cutaneous candidiasis, Nocardia infection, disseminated sporotrichosis; Parasitic infections: plurifocal cutaneous leishmaniasis, cutaneous protothecosis
Skin neoplasiaNon melanoma skin tumors: basocellular carcinoma, spinocellular carcinoma; Malignant melanoma; Skin lymphomas/Lymphoproliferative disorders: Jessner-Kanof type, anaplastic large T cell lymphoma, mycosis fungoides; Multiple dermatofibromas
Immune mediated diseases«de novo» psoriasis and exacerbation of prior psoriasis or psoriasis subtypes; Atopic-dermatitis and its exacerbation; Lupus-like paradoxical reaction; Alopecia areata; Skin vasculitis; Vitiligo; Dermatomyositis; Localized scleroderma (morphea); Lichen or lichenoid reaction; Frontal fibrosing alopecia; Linear IgA bullous dermatosis; bullous pemphigoid; Erythema multiforme; Erythroderma, exfoliative dermatitis and hypersensitivity reaction; Erythematous annular eruptions; Fixed drug eruption; Urticaria
Other skin eventsHidradenitis suppurativa; Seborrhoeic keratosis; Thrombotic thrombocytopenic purpura; Sarcoidosis-like paradoxical reaction; Wells syndrome; Erythema annulare centrifugum; Cutaneous focal mucinosis; Lentigines; Spiny follicular hyperkeratosis

IgA, Immunoglobulin A.

Table 3

Adverse systemic reactions associated with ustekinumab

Adverse reaction categoriesSpecific systemic reactions
Systemic allergic reactions to the administration of treatmentFlushing, anaphylactoid reaction, nausea, vomiting, blurred vision and/or confusion, dizziness, difficulty in breathing
Whole body (general disorders)Asthenia, Flu-like symptoms, myalgia, anorexia, depression, sleep disturbance
InfectionsBacterial infections: latent tuberculosis reactivation, miliary tuberculosis, meningococcal meningitis, pneumonia, Clostridium difficile infection, Mycobacterium fortuitum ventriculoperitoneal shunt infection, perianal abscess, dental abcess, urinary tract infection, Staphylococcus aureus bacteremia with iliac artery endarteritis, Streptococcal sepsis; Viral infections: HSV-2 meningitis, Varicella zoster virus meningitis, acute hepatitis B, HBV reactivation, HCV reactivation, herpes simplex virus encephalitis, nasopharyngitis , Respiratory tract infections; Fungal infection: mycotic oesophagitis; Parasitic infections: Amoebic liver abscess, Ocular toxoplasmosis, severe acute toxoplasmosis
NeoplasiaAnal adenocarcinoma, cancer of anal fistula, endometrial cancer, esophageal cancer, hepatocellular carcinoma, pancreatic adenocarcinoma Malignant peritoneal mesothelioma, Gastric Mucosa-Associated Lymphoid Tissue Lymphoma, Exacerbation of Hodgkin’s lymphoma, chronic lymphocytic leukaemia, multiple myeloma, papillary thyroid cancer, breast cancer
Cardiovascular eventsHypertension, congestive heart failure, dilated cardiomyopathy, unstable angina, Vasculitis, central retinal vein and artery occlusion
Gastrointestinal events/Hepatobiliary eventsAcute hepatitis, elevated alanine transferase levels, fatty liver infiltration, diverticulitis, retroperitoneal fibrosis, pancreatitis
Musculoskeletal eventsParadoxical psoriatic arthritis, arthralgia, multifocal myositis, polymyositis, myasthenia gravis
Renal adverse eventsLupus nephritis, new-onset autoantibody-mediated nephritis, nephrotic syndrome, IgA nephropathy, focal segmental glomerulosclerosis
Nervous system eventsHeadache, neuropathic pain, memory loss, parkinsonism, benign intracranial hypertension, posterior reversible encephalopathy syndrome, demyelination, limbic encephalitis, Facial palsy, reversible cerebral vasoconstriction syndrome, ischaemic stroke, Guillain-Barré syndrome, peripheral neuropathy
Respiratory adverse eventsNoninfectious pneumonia, bronchospasm crisis, pneumothorax, sarcoidosis
Urogenital and obstetric eventsUrolithiasis; Epididymo-orchitis, erectile dysfunction; Foetal death and miscarriage;
Other systemic events-Monoclonal gammopathy of undetermined significance; Autoimmune thyroiditis

HBV, Hepatitis B Virus; HCV, Hepatitis C Virus; HSV-2, Herpes Simplex Virus-2.

Despite the reassuring data, the real-life, long-term safety of ustekinumab application still requires investigation across international, multicentric registry-based cohorts and from long-term outcome trials. Hence, greater vigilance should be applied when starting treatment: a thorough history, a holistic clinical examination with careful assessment for active infections (screening for possible tuberculosis, checking cardiovascular and neurological functions and ruling out any malignancy), along with laboratory workup (complete blood count and metabolic profile) should be considered before the initiation of ustekinumab. Subsequent laboratory tests and follow-up monitoring are recommended.

Future prospects

Currently, a myriad of biological drugs (either approved or used off label) are available for the treatment of skin diseases. For psoriasis, physicians have a plethora of biological drugs with different immunological mechanisms that could be used. Nonetheless, some patients can be resistant or show a declining response to biological agents over time.

Combination therapies with biological and conventional systemic drugs are well documented and have become a routine practice for many clinicians. However, for patients with a severe, debilitating skin disease, who do not respond to biological monotherapy and combination with conventional systemic agents, dual biological therapy (DBT) could be considered. However, uncertainty in the real safety profile of such a combination still exists, particularly for the high risk of opportunistic infection and MACEs, and data on the safety of such DBT in dermatology remain anecdotal. The limited number of case reports and case series mostly originated from gastroenterology and rheumatology-based studies and/or registries, but DBT has been used in many cases with PsA/psoriasis or inflammatory bowel diseases/psoriasis simultaneously. Available studies have shown that DBT ustekinumab/anti-TNFα blockers have better efficacy than each drug alone, although there are different safety profiles, without serious AEs. In dermatology, only one case of DBT of ustekinumab/adalimumab has been reported in a patient with a long-lasting, resistant PPP for a quasi-complete clearance over 4 months with a good overall tolerance. Thus, a window of opportunity does exist for the use of DBT with ustekinumab and other biological drugs for the treatment of psoriasis or other skin diseases, paving the way to a tailored, personalized treatment regimen. Despite the paucity of data, dermatologists can be inspired from the use of DBT in other fields, like gastroenterology and rheumatology. The main future challenges are to determine the optimal treatment dosing regimen and the best timing for DBT to result in the most effective and safest outcomes for patients.

Conclusions

Continual progression in psoriasis research has revealed the crucial role of Th17 responses in its pathogenesis. The successful treatment with IL-12/IL-23 blockers for moderate-to-severe psoriasis is considered a major scientific breakthrough, being the first non-TNFα targeted biological drug in the treatment of psoriasis and heralded as a new era of more precise biological therapy with higher efficacy and favorable safety profiles. Additionally, the recommended dosage regimen of ustekinumab is appropriate for most patients because its initial efficacy seems to be sustained fairly well over a 5-year treatment duration. The potential risk of infection or other AEs in patients with ustekinumab are mild, similar to that in placebo-treated patients, and there is no evidence of any overall increased risk in post-marketing reports. However, like other new biological drugs, high cost and unknown long-term effects limit the approval of this drug as a first-line treatment for moderate-to-severe psoriasis. Emerging data suggest that ustekinumab may be well tolerated and efficient for HS, PRP, and BD, as well as several other dermatological conditions, but there are few clinical trials to evaluate the therapeutic efficacy and safety of ustekinumab for these disorders.

This review highlights the significant progression during the past decade on the optimal use of ustekinumab for skin diseases beyond its labeled indications. However, there are some limitations, like the lack of RCTs and the limited amount of available data, especially regarding the off-label use of the biological drug. Further studies with larger cohorts of patients and robust designs are warranted to investigate ustekinumab’s efficacy, safety, and long-term effects in off-label uses for other skin diseases.

Abbreviations

ACH: 

acrodermatitis continua of Hallopeau

AD: 

Atopic dermatitis

AE: 

adverse event

BD: 

Behçet disease

BP: 

bullous pemphigoid

DBT: 

dual biological therapy

EMA: 

European Medicine Agency

EP: 

erythrodermic psoriasis

FDA: 

Food and Drug Administration

GP: 

guttate psoriasis

GPP: 

generalized pustular psoriasis

GWAS: 

genome-wide association studies

HS: 

hidradenitis suppurativa

IFN: 

interferon

IL: 

interleukin

IMD: 

immune-mediated disorders

JAK2: 

Janus kinase 2

LE: 

lupus erythematosus

LP: 

lichen planus

mAb: 

monoclonal antibody

MCVE: 

major adverse cardiovascular event

MTX: 

methotrexate

ND: 

neutrophilic dermatoses

PG: 

Pyoderma gangrenosum

PP: 

pustular psoriasis

PPP: 

palmoplantar pustulosis

PRP: 

pityriasis rubra pilaris

PsA: 

psoriatic arthritis

QoL: 

quality of life

RCT: 

randomized placebo-controlled trials

SAPHO: 

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis

SS: 

Sweet syndrome

STAT: 

sig­nal transduction activation of transcription

TNF: 

tumor necrosis factor

TYK2: 

tyrosine kinase

Declarations

Acknowledgement

None.

Funding

None.

Conflict of interest

Dr. Hakim Rahmoune has been an editorial board member of Journal of Exploratory Research in Pharmacology since June 2017. The authors have no other conflict of interests to declare.

Authors’ contributions

Contributed to study concept and design (ASC, NB, and HR), acquisition of the data (ASC and HR), data analysis (ASC), drafting of the manuscript (ASC and HR), critical revision of the manuscript (NB and HR), and supervision (ASC).

References

  1. Benson JM, Peritt D, Scallon BJ, Heavner GA, Shealy DJ, Giles-Komar JM, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs 2011;3(6):535-545 View Article PubMed/NCBI
  2. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008;371(9625):1665-1674 View Article PubMed/NCBI
  3. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008;371(9625):1675-1684 View Article PubMed/NCBI
  4. Tsai TF, Ho JC, Song M, Szapary P, Guzzo C, Shen YK, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci 2011;63(3):154-163 View Article PubMed/NCBI
  5. Young MS, Horn EJ, Cather JC. The ACCEPT study: ustekinumab versus etanercept in moderate-to-severe psoriasis patients. Expert Rev Clin Immunol 2011;7(1):9-13 View Article PubMed/NCBI
  6. Rawal S, Kianian S, Guo W, Marquez J, Ayasse M, Siamas KA, et al. Alternative uses of ustekinumab for non-indicated dermatological conditions: a systematic review. Arch Dermatol Res 2022;314(6):503-514 View Article PubMed/NCBI
  7. Hernández MV, Meineri M, Sanmartí R. Skin lesions and treatment with tumor necrosis factor alpha antagonists. Reumatol Clin 2013;9(1):53-61 View Article PubMed/NCBI
  8. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 2015;21(7):719-729 View Article PubMed/NCBI
  9. Zundler S, Neurath MF. Interleukin-12: Functional activities and implications for disease. Cytokine Growth Factor Rev 2015;26(5):559-568 View Article PubMed/NCBI
  10. Sun L, He C, Nair L, Yeung J, Egwuagu CE. Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine 2015;75(2):249-255 View Article PubMed/NCBI
  11. Wojkowska DW, Szpakowski P, Glabinski A. Interleukin 17A Promotes Lymphocytes Adhesion and Induces CCL2 and CXCL1 Release from Brain Endothelial Cells. Int J Mol Sci 2017;18(5):E1000 View Article PubMed/NCBI
  12. Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, et al. IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not. J Mol Med (Berl) 2009;87(5):523-536 View Article PubMed/NCBI
  13. Brembilla NC, Senra L, Boehncke WH. The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond. Front Immunol 2018;9:1682 View Article PubMed/NCBI
  14. Chyuan IT, Lai JH. New insights into the IL-12 and IL-23: From a molecular basis to clinical application in immune-mediated inflammation and cancers. Biochem Pharmacol 2020;175:113928 View Article PubMed/NCBI
  15. Kimmel GW, Lebwohl M. Psoriasis: Overview and Diagnosis. Evidence-Based Psoriasis 2018;1:1-16 View Article PubMed/NCBI
  16. Kimmel GW, Lebwohl M. Evidence-Based Psoriasis: Diagnosis and Treatment. Cham: Springer International Publishing; 2018, 1-16 View Article PubMed/NCBI
  17. Mattei PL, Corey KC, Kimball AB. Cumulative life course impairment: evidence for psoriasis. Curr Probl Dermatol 2013;44:82-90 View Article PubMed/NCBI
  18. Sarac G, Koca TT, Baglan T. A brief summary of clinical types of psoriasis. North Clin Istanb 2016;3(1):79-82 View Article PubMed/NCBI
  19. Rendon A, Schäkel K. Psoriasis Pathogenesis and Treatment. Int J Mol Sci 2019;20(6):E1475 View Article PubMed/NCBI
  20. Bianchi E, Rogge L. The IL-23/IL-17 pathway in human chronic inflammatory diseases-new insight from genetics and targeted therapies. Genes Immun 2019;20(5):415-425 View Article PubMed/NCBI
  21. Jeon C, Sekhon S, Yan D, Afifi L, Nakamura M, Bhutani T. Monoclonal antibodies inhibiting IL-12, -23, and -17 for the treatment of psoriasis. Hum Vaccin Immunother 2017;13(10):2247-2259 View Article PubMed/NCBI
  22. Rønholt K, Iversen L. Old and New Biological Therapies for Psoriasis. Int J Mol Sci 2017;18(11):2297 View Article PubMed/NCBI
  23. Fotiadou C, Lazaridou E, Sotiriou E, Ioannides D. Targeting IL-23 in psoriasis: current perspectives. Psoriasis (Auckl) 2018;8:1-5 View Article PubMed/NCBI
  24. Kimball AB, Papp KA, Wasfi Y, Chan D, Bissonnette R, Sofen H, et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol 2013;27(12):1535-1545 View Article PubMed/NCBI
  25. Chiu HY, Hui RC, Tsai TF, Chen YC, Chang Liao NF, Chen PH, et al. Predictors of time to relapse following ustekinumab withdrawal in patients with psoriasis who had responded to therapy: An 8-year multicenter study. J Am Acad Dermatol 2023;88(1):71-78 View Article PubMed/NCBI
  26. Brummer GC, Hawkes JE, Duffin KC. Ustekinumab-induced remission of recalcitrant guttate psoriasis: A case series. JAAD Case Rep 2017;3(5):432-435 View Article PubMed/NCBI
  27. Pescitelli L, Dini V, Gisondi P, Loconsole F, Piaserico S, Piccirillo A, et al. Erythrodermic psoriasis treated with ustekinumab: an Italian multicenter retrospective analysis. J Dermatol Sci 2015;78(2):149-151 View Article PubMed/NCBI
  28. Santos-Juanes J, Coto-Segura P, Mas-Vidal A, Galache Osuna C. Ustekinumab induces rapid clearing of erythrodermic psoriasis after failure of antitumour necrosis factor therapies. Br J Dermatol 2010;162(5):1144-1146 View Article PubMed/NCBI
  29. Wang TS, Tsai TF. Clinical experience of ustekinumab in the treatment of erythrodermic psoriasis: a case series. J Dermatol 2011;38(11):1096-1099 View Article PubMed/NCBI
  30. Storan ER, O’Gorman SM, Markham T. Generalized pustular psoriasis treated with ustekinumab. Clin Exp Dermatol 2016;41(6):689-690 View Article PubMed/NCBI
  31. Daudén E, Santiago-et-Sánchez-Mateos D, Sotomayor-López E, García-Díez A. Ustekinumab: effective in a patient with severe recalcitrant generalized pustular psoriasis. Br J Dermatol 2010;163(6):1346-1347 View Article PubMed/NCBI
  32. Arakawa A, Ruzicka T, Prinz JC. Therapeutic Efficacy of Interleukin 12/Interleukin 23 Blockade in Generalized Pustular Psoriasis Regardless of IL36RN Mutation Status. JAMA Dermatol 2016;152(7):825-828 View Article PubMed/NCBI
  33. Palacios-Álvarez I, Simal-Gómez G, Mas-Vidal A, Bernad-Alonso I. Treatment of acrodermatitis continua of Hallopeau with ustekinumab as monotherapy after failure of anti-TNF agents. J Dtsch Dermatol Ges 2018;16(5):611-613 View Article PubMed/NCBI
  34. Cymerman RM, Cohen DE. Treatment of Acrodermatitis Continua of Hallopeau With Ustekinumab as Monotherapy. JAMA Dermatol 2016;152(3):346-348 View Article PubMed/NCBI
  35. Husson B, Barbe C, Hegazy S, Seneschal J, Aubin F, Mahé E, et al. Efficacy and safety of TNF blockers and of ustekinumab in palmoplantar pustulosis and in acrodermatitis continua of Hallopeau. J Eur Acad Dermatol Venereol 2020;34(10):2330-2338 View Article PubMed/NCBI
  36. Blok JL, Li K, Brodmerkel C, Horvátovich P, Jonkman MF, Horváth B. Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum. Br J Dermatol 2016;174(4):839-846 View Article PubMed/NCBI
  37. Guenova E, Teske A, Fehrenbacher B, Hoerber S, Adamczyk A, Schaller M, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol 2011;147(10):1203-1205 View Article PubMed/NCBI
  38. de Risi-Pugliese T, Seksik P, Bouaziz JD, Chasset F, Moguelet P, Gornet JM, et al. Ustekinumab treatment for neutrophilic dermatoses associated with Crohn’s disease: A multicenter retrospective study. J Am Acad Dermatol 2019;80(3):781-784 View Article PubMed/NCBI
  39. Piqueras-García J, Sahuquillo-Torralba AJ, Torres-Navarro I, Botella-Estrada R. Pyoderma Gangrenosum With Ulcerative Colitis Successfully Treated With Ustekinumab. Actas Dermosifiliogr (Engl Ed) 2019;110(9):776-778 View Article PubMed/NCBI
  40. Petty AJ, Whitley MJ, Balaban A, Ellington K, Marano AL. Pyoderma gangrenosum induced by secukinumab in a patient with psoriasis successfully treated with ustekinumab. JAAD Case Rep 2020;6(8):731-733 View Article PubMed/NCBI
  41. Mirouse A, Barete S, Monfort JB, Resche-Rigon M, Bouyer AS, Comarmond C, et al. Ustekinumab for Behçet’s disease. J Autoimmun 2017;82:41-46 View Article PubMed/NCBI
  42. Fernández-Antón Martínez MC, Alfageme Roldán F, Ciudad Blanco C, Suárez Fernández R. Ustekinumab in the treatment of severe atopic dermatitis: a preliminary report of our experience with 4 patients. Actas Dermosifiliogr 2014;105(3):312-313 View Article PubMed/NCBI
  43. Guttman-Yassky E, Ungar B, Noda S, Suprun M, Shroff A, Dutt R, et al. Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism. J Allergy Clin Immunol 2016;137(1):301-304 View Article PubMed/NCBI
  44. Aleisa A, Lim Y, Gordon S, Her MJ, Zancanaro P, Abudu M, et al. Response to ustekinumab in three pediatric patients with alopecia areata. Pediatr Dermatol 2019;36(1):e44-e45 View Article PubMed/NCBI
  45. Elkady A, Bonomo L, Amir Y, Vekaria AS, Guttman-Yassky E. Effective use of ustekinumab in a patient with concomitant psoriasis, vitiligo, and alopecia areata. JAAD Case Rep 2017;3(6):477-479 View Article PubMed/NCBI
  46. Wendling D, Aubin F, Verhoeven F, Prati C. IL-23/Th17 targeted therapies in SAPHO syndrome. A case series. Joint Bone Spine 2017;84(6):733-735 View Article PubMed/NCBI
  47. Solimani F, Pollmann R, Schmidt T, Schmidt A, Zheng X, Savai R, et al. Therapeutic Targeting of Th17/Tc17 Cells Leads to Clinical Improvement of Lichen Planus. Front Immunol 2019;10:1808 View Article PubMed/NCBI
  48. Webster G. Failure of lichen planopilaris to respond to ustekinumab. Dermatol Online J 2015;21(11):13030/qt30z76472 View Article PubMed/NCBI
  49. Loget J, Plée J, Antonicelli F, Bernard P. A successful treatment with ustekinumab in a case of relapsing bullous pemphigoid associated with psoriasis. J Eur Acad Dermatol Venereol 2017;31(5):e228-e230 View Article PubMed/NCBI
  50. Winchester D, Duffin KC, Hansen C. Response to ustekinumab in a patient with both severe psoriasis and hypertrophic cutaneous lupus. Lupus 2012;21(9):1007-1010 View Article PubMed/NCBI
  51. Dahl C, Johansen C, Kragballe K, Olesen AB. Ustekinumab in the treatment of refractory chronic cutaneous lupus erythematosus: a case report. Acta Derm Venereol 2013;93(3):368-369 View Article PubMed/NCBI
  52. Amarnani A, Rosenthal KS, Mercado JM, Brodell RT. Concurrent treatment of chronic psoriasis and asthma with ustekinumab. J Dermatolog Treat 2014;25(1):63-66 View Article PubMed/NCBI
  53. Viguier M, Pagès C, Aubin F, Delaporte E, Descamps V, Lok C, et al. Efficacy and safety of biologics in erythrodermic psoriasis: a multicentre, retrospective study. Br J Dermatol 2012;167(2):417-423 View Article PubMed/NCBI
  54. Matsumoto A, Komine M, Karakawa M, Kishimoto M, Ohtsuki M. Adalimumab administration after infliximab therapy is a successful treatment strategy for generalized pustular psoriasis. J Dermatol 2017;44(2):202-204 View Article PubMed/NCBI
  55. Morales-Múnera C, Vilarrasa E, Puig L. Efficacy of ustekinumab in refractory palmoplantar pustular psoriasis. Br J Dermatol 2013;168(4):820-824 View Article PubMed/NCBI
  56. Au SC, Goldminz AM, Kim N, Dumont N, Michelon M, Volf E, et al. Investigator-initiated, open-label trial of ustekinumab for the treatment of moderate-to-severe palmoplantar psoriasis. J Dermatolog Treat 2013;24(3):179-187 View Article PubMed/NCBI
  57. Bulai Livideanu C, Lahfa M, Mazereeuw-Hautier J, Paul C. Efficacy of ustekinumab in palmoplantar psoriasis. Dermatology 2010;221(4):321-323 View Article PubMed/NCBI
  58. Bissonnette R, Nigen S, Langley RG, Lynde CW, Tan J, Fuentes-Duculan J, et al. Increased expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled trial. J Eur Acad Dermatol Venereol 2014;28(10):1298-1305 View Article PubMed/NCBI
  59. Adışen E, Özer İ, Temel B, Gürer MA. Ustekinumab for the treatment of acrodermatitis continua of Hallopeau refractory to anti-TNF agents. Dermatol Ther 2017;30(2):e12460 View Article PubMed/NCBI
  60. Saunier J, Debarbieux S, Jullien D, Garnier L, Dalle S, Thomas L. Acrodermatitis continua of Hallopeau treated successfully with ustekinumab and acitretin after failure of tumour necrosis factor blockade and anakinra. Dermatology 2015;230(2):97-100 View Article PubMed/NCBI
  61. Adas A, Dadban A, Arnault JP, Chaby G, Lok C. Acrodermatitis continua of Hallopeau response to optimized biological therapy. Dermatol Online J 2019;25(2):13030/qt93s9w1p3 View Article PubMed/NCBI
  62. Ruiz Villaverde R, Sánchez Cano D. Successful treatment of type 1 pityriasis rubra pilaris with ustekinumab therapy. Eur J Dermatol 2010;20(5):630-631 View Article PubMed/NCBI
  63. Byekova Y, Sami N. Successful response of refractory type I adult-onset pityriasis rubra pilaris with ustekinumab and acitretin combination therapy. J Dermatol 2015;42(8):830-831 View Article PubMed/NCBI
  64. Chowdhary M, Davila U, Cohen DJ. Ustekinumab as an alternative treatment option for chronic pityriasis rubra pilaris. Case Rep Dermatol 2015;7(1):46-50 View Article PubMed/NCBI
  65. Di Stefani A, Galluzzo M, Talamonti M, Chiricozzi A, Costanzo A, Chimenti S. Long-term ustekinumab treatment for refractory type I pityriasis rubra pilaris. J Dermatol Case Rep 2013;7(1):5-9 View Article PubMed/NCBI
  66. Eytan O, Sarig O, Sprecher E, van Steensel MA. Clinical response to ustekinumab in familial pityriasis rubra pilaris caused by a novel mutation in CARD14. Br J Dermatol 2014;171(2):420-422 View Article PubMed/NCBI
  67. Humme D, Beyer M, Röwert-Huber HJ, Sterry W, Philipp S. [CD30-positive anaplastic large cell T-cell lymphoma developing during immunosuppressive therapy of pityriasis rubra pilaris with ustekinumab]. Hautarzt 2013;64(3):190-194 View Article PubMed/NCBI
  68. Lernia VD, Ficarelli E, Zanelli M. Ineffectiveness of tumor necrosis factor-α blockers and ustekinumab in a case of type IV pityriasis rubra pilaris. Indian Dermatol Online J 2015;6(3):207-209 View Article PubMed/NCBI
  69. Lwin SM, Hsu CK, Liu L, Huang HY, Levell NJ, McGrath JA. Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14. Br J Dermatol 2018;178(4):969-972 View Article PubMed/NCBI
  70. Paganelli A, Ciardo S, Odorici G, Pellacani G, Conti A. Efficacy of ustekinumab after failure of infliximab CT-P13 in a HLA-Cw6-positive patient affected by pityriasis rubra pilaris: monitoring with reflectance confocal microscopy (RCM) and optical coherence tomography (OCT). J Eur Acad Dermatol Venereol 2017;31(5):e249-e251 View Article PubMed/NCBI
  71. Wohlrab J, Kreft B. Treatment of pityriasis rubra pilaris with ustekinumab. Br J Dermatol 2010;163(3):655-656 View Article PubMed/NCBI
  72. Aragón-Miguel R, Prieto-Barrios M, Calleja-Algarra A, Velasco-Tamariz V, Andres-Lencina JJ, Ortiz-Romero P, et al. Refractory pityriasis rubra pilaris with good response after treatment with ustekinumab. J Dtsch Dermatol Ges 2018;16(8):1022-1025 View Article PubMed/NCBI
  73. Feldmeyer L, Mylonas A, Demaria O, Mennella A, Yawalkar N, Laffitte E, et al. Interleukin 23-Helper T Cell 17 Axis as a Treatment Target for Pityriasis Rubra Pilaris. JAMA Dermatol 2017;153(4):304-308 View Article PubMed/NCBI
  74. Kalogeropoulos CI, Papathanasiou KA, Tsagkaraki I, Giannopoulos G, Bamias A, Boutati EI. A Case of Meningococcal and HSV-2 Meningitis in a Patient Being Treated with Ustekinumab for Pityriasis Rubra Pilaris. Eur J Case Rep Intern Med 2020;7(8):001615 View Article PubMed/NCBI
  75. Napolitano M, Lembo L, Fania L, Abeni D, Didona D, Didona B. Ustekinumab treatment of pityriasis rubra pilaris: A report of five cases. J Dermatol 2018;45(2):202-206 View Article PubMed/NCBI
  76. Craiglow BG, Boyden LM, Hu R, Virtanen M, Su J, Rodriguez G, et al. CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris. J Am Acad Dermatol 2018;79(3):487-494 View Article PubMed/NCBI
  77. Matsuda T, Yamazaki F, Ueda-Hayakawa I, Kambe N, Okamoto H. Case of pityriasis rubra pilaris progressed to generalized erythroderma following blockade of interleukin-17A, but improved after blockade of interleukin-12/23 p40. J Dermatol 2019;46(1):70-72 View Article PubMed/NCBI
  78. Volc-Platzer B. CARD14-mutations in pityriasis rubra pilaris and therapeutic response to ustekinumab - a hypothesis. J Dtsch Dermatol Ges 2020;18(11):1312-1315 View Article PubMed/NCBI
  79. Gulliver WP, Jemec GB, Baker KA. Experience with ustekinumab for the treatment of moderate to severe hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2012;26(7):911-914 View Article PubMed/NCBI
  80. Sharon VR, Garcia MS, Bagheri S, Goodarzi H, Yang C, Ono Y, et al. Management of recalcitrant hidradenitis suppurativa with ustekinumab. Acta Derm Venereol 2012;92(3):320-321 View Article PubMed/NCBI
  81. Baerveldt EM, Kappen JH, Thio HB, van Laar JA, van Hagen PM, Prens EP. Successful long-term triple disease control by ustekinumab in a patient with Behcet’s disease, psoriasis and hidradenitis suppurativa. Ann Rheum Dis 2013;72(4):626-627 View Article PubMed/NCBI
  82. Santos-Pérez MI, García-Rodicio S, Del Olmo-Revuelto MA, Pozo-Román T. Ustekinumab for hidradenitis suppurativa: a case report. Actas Dermosifiliogr 2014;105(7):720-722 View Article PubMed/NCBI
  83. Romaní J, Vilarrasa E, Martorell A, Fuertes I, Ciudad C, Molina-Leyva A. Ustekinumab with Intravenous Infusion: Results in Hidradenitis Suppurativa. Dermatology 2020;236(1):21-24 View Article PubMed/NCBI
  84. Scholl L, Hessam S, Garcovich S, Bechara FG. High-dosage ustekinumab for the treatment of severe hidradenitis suppurativa. Eur J Dermatol 2019;29(6):659-661 View Article PubMed/NCBI
  85. Takeda K, Kikuchi K, Kanazawa Y, Yamasaki K, Aiba S. Ustekinumab treatment for hidradenitis suppurativa. J Dermatol 2019;46(12):1215-1218 View Article PubMed/NCBI
  86. Montero-Vilchez T, Pozo-Román T, Sánchez-Velicia L, Vega-Gutiérrez J, Arias-Santiago S, Molina-Leyva A. Ustekinumab in the treatment of patients with hidradenitis suppurativa: multicenter case series and systematic review. J Dermatolog Treat 2022;33(1):348-353 View Article PubMed/NCBI
  87. Sánchez-Martínez EM, García-Ruiz R, Moneva-Léniz LM, Mateu-Puchades A. Effectiveness and safety of ustekinumab in patients with hidradenitis suppurativa using intravenous induction. Dermatol Ther 2020;33(6):e14054 View Article PubMed/NCBI
  88. Hollywood A, Murray G, Fleming S, Kirby B, Hughes R. Ustekinumab in the Management of Hidradenitis Suppurativa: A Retrospective Study. J Drugs Dermatol 2022;21(3):319-320 View Article PubMed/NCBI
  89. Smith J, Ezekwe N, Pourang A, Hamzavi I. Multifocal myositis and elevated creatine phosphokinase associated with the use of ustekinumab for hidradenitis suppurativa. Br J Dermatol 2021;184(6):1181-1182 View Article PubMed/NCBI
  90. Provini LE, Stellar JJ, Stetzer MN, Nguyen PD, Jen M. Combination hyperbaric oxygen therapy and ustekinumab for severe hidradenitis suppurativa. Pediatr Dermatol 2019;36(3):381-383 View Article PubMed/NCBI
  91. Valenzuela-Ubiña S, Jiménez-Gallo D, Villegas-Romero I, Rodríguez-Mateos ME, Linares-Barrios M. Effectiveness of ustekinumab for moderate-to-severe hidradenitis suppurativa: a case series. J Dermatolog Treat 2022;33(2):1159-1162 View Article PubMed/NCBI
  92. Goldminz AM, Botto NC, Gottlieb AB. Severely recalcitrant pyoderma gangrenosum successfully treated with ustekinumab. J Am Acad Dermatol 2012;67(5):e237-e238 View Article PubMed/NCBI
  93. Cosgarea I, Lovric Z, Körber A, Dissemond J. Successful treatment of refractory pyoderma gangrenosum with ustekinumab only after excision of renal cell carcinoma. Int Wound J 2016;13(5):1041-1042 View Article PubMed/NCBI
  94. Benzaquen M, Monnier J, Beaussault Y, Rouby F, Berbis P. Pyoderma gangrenosum arising during treatment of psoriasis with adalimumab: Effectiveness of ustekinumab. Australas J Dermatol 2017;58(4):e270-e271 View Article PubMed/NCBI
  95. Nunes G, Patita M, Fernandes V. Refractory Pyoderma Gangrenosum in a Patient With Crohn’s Disease: Complete Response to Ustekinumab. J Crohns Colitis 2019;13(6):812-813 View Article PubMed/NCBI
  96. Low ZM, Mar A. Treatment of severe recalcitrant pyoderma gangrenosum with ustekinumab. Australas J Dermatol 2018;59(2):131-134 View Article PubMed/NCBI
  97. Greb JE, Gottlieb AB, Goldminz AM. High-dose ustekinumab for the treatment of severe, recalcitrant pyoderma gangrenosum. Dermatol Ther 2016;29(6):482-483 View Article PubMed/NCBI
  98. Fahmy M, Ramamoorthy S, Hata T, Sandborn WJ. Ustekinumab for peristomal pyoderma gangrenosum. Am J Gastroenterol 2012;107(5):794-795 View Article PubMed/NCBI
  99. López González J, Lázaro Sáez M, Moreno Moraleda I, Hernández Martínez Á. Pyoderma gangrenosum solved by ustekinumab therapy. Gastroenterol Hepatol 2021;44(4):299-300 View Article PubMed/NCBI
  100. Vallerand IA, Hardin J. Ustekinumab for the treatment of recalcitrant pyoderma gangrenosum: A case report. SAGE Open Med Case Rep 2019;7:2050313X19845206 View Article PubMed/NCBI
  101. Nieto D, Sendagorta E, Rueda JM, Herranz P. Successful treatment with ustekinumab and vacuum-assisted closure therapy in recalcitrant myelodysplastic syndrome-associated pyoderma gangrenosum: case report and literature review. Clin Exp Dermatol 2019;44(1):116-119 View Article PubMed/NCBI
  102. Westerdahl JS, Nusbaum KB, Chung CG, Kaffenberger BH, Ortega-Loayza AG. Ustekinumab as adjuvant treatment for all pyoderma gangrenosum subtypes. J Dermatolog Treat 2022;33(4):2386-2390 View Article PubMed/NCBI
  103. Lopalco G, Fabiani C, Venerito V, Lapadula G, Iannone F, Cantarini L. Ustekinumab efficacy and safety in mucocutaneous multi-refractory Behçet’s disease. Clin Exp Rheumatol 2017;35 Suppl 108(6):130-131 View Article PubMed/NCBI
  104. Mirouse A, Barete S, Desbois AC, Comarmond C, Sène D, Domont F, et al. Long-Term Outcome of Ustekinumab Therapy for Behçet’s Disease. Arthritis Rheumatol 2019;71(10):1727-1732 View Article PubMed/NCBI
  105. London J, Régent A, Dion J, Jilet L, Jachiet M, Lidove O, et al. Efficacy and safety of ustekinumab in Behçet disease: Results from the prospective phase 2 STELABEC trial. J Am Acad Dermatol 2022;87(3):681-684 View Article PubMed/NCBI
  106. Puya R, Alvarez-López M, Velez A, Casas Asuncion E, Moreno JC. Treatment of severe refractory adult atopic dermatitis with ustekinumab. Int J Dermatol 2012;51(1):115-116 View Article PubMed/NCBI
  107. Agusti-Mejias A, Messeguer F, García R, Febrer I. Severe refractory atopic dermatitis in an adolescent patient successfully treated with ustekinumab. Ann Dermatol 2013;25(3):368-370 View Article PubMed/NCBI
  108. Shroff A, Guttman-Yassky E. Successful use of ustekinumab therapy in refractory severe atopic dermatitis. JAAD Case Rep 2015;1(1):25-26 View Article PubMed/NCBI
  109. Lis-Święty A, Skrzypek-Salamon A, Arasiewicz H, Brzezińska-Wcisło L. Atopic dermatitis exacerbated with ustekinumab in a psoriatic patient with childhood history of atopy. Allergol Int 2015;64(4):382-383 View Article PubMed/NCBI
  110. Ishiuji Y, Umezawa Y, Asahina A, Fukuta H, Aizawa N, Yanaba K, et al. Exacerbation of atopic dermatitis symptoms by ustekinumab in psoriatic patients with elevated serum immunoglobulin E levels: Report of two cases. J Dermatol 2018;45(6):732-734 View Article PubMed/NCBI
  111. Samorano LP, Hanifin JM, Simpson EL, Leshem YA. Inadequate response to ustekinumab in atopic dermatitis - a report of two patients. J Eur Acad Dermatol Venereol 2016;30(3):522-523 View Article PubMed/NCBI
  112. Nic Dhonncha E, Clowry J, Dunphy M, Buckley C, Field S, Paul L. Treatment of severe atopic dermatitis with ustekinumab: a case series of 10 patients. Br J Dermatol 2017;177(6):1752-1753 View Article PubMed/NCBI
  113. Saeki H, Kabashima K, Tokura Y, Murata Y, Shiraishi A, Tamamura R, et al. Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study. Br J Dermatol 2017;177(2):419-427 View Article PubMed/NCBI
  114. Wlodek C, Hewitt H, Kennedy CT. Use of ustekinumab for severe refractory atopic dermatitis in a young teenager. Clin Exp Dermatol 2016;41(6):625-627 View Article PubMed/NCBI
  115. Khattri S, Brunner PM, Garcet S, Finney R, Cohen SR, Oliva M, et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol 2017;26(1):28-35 View Article PubMed/NCBI
  116. Weiss D, Schaschinger M, Ristl R, Gruber R, Kopp T, Stingl G, et al. Ustekinumab treatment in severe atopic dermatitis: Down-regulation of T-helper 2/22 expression. J Am Acad Dermatol 2017;76(1):91-97.e3 View Article PubMed/NCBI
  117. Firinu D, Murgia G, Lorrai MM, Barca MP, Peralta MM, Manconi PE, et al. Biological treatments for SAPHO syndrome: an update. Inflamm Allergy Drug Targets 2014;13(3):199-205 View Article PubMed/NCBI
  118. Knisley RR, Petropolis AA, Mackey VT. Lichen planus pemphigoides treated with ustekinumab. Cutis 2017;100(6):415-418 View Article PubMed/NCBI
  119. Majima Y, Yagi H, Tateishi C, Groth S, Schmidt E, Zillikens D, et al. A successful treatment with ustekinumab in a case of antilaminin-γ1 pemphigoid associated with psoriasis. Br J Dermatol 2013;168(6):1367-1369 View Article PubMed/NCBI
  120. De Souza A, Ali-Shaw T, Strober BE, Franks AG. Successful treatment of subacute lupus erythematosus with ustekinumab. Arch Dermatol 2011;147(8):896-898 View Article PubMed/NCBI
  121. Varada S, Gottlieb AB, Merola JF, Saraiya AR, Tintle SJ. Treatment of coexistent psoriasis and lupus erythematosus. J Am Acad Dermatol 2015;72(2):253-260 View Article PubMed/NCBI
  122. Mazgaj M, Picard-Dahan C, Deschamps L, Marinho E, Estève E, Descamps V. Successful ustekinumab treatment in a patient with psoriasis and subacute cutaneous lupus erythematosus. Int J Dermatol 2020;59(4):e118-e120 View Article PubMed/NCBI
  123. Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker JNWN. Psoriasis. Lancet 2021;397(10281):1301-1315 View Article PubMed/NCBI
  124. Chalmers RJ, O’Sullivan T, Owen CM, Griffiths CE. Interventions for guttate psoriasis. Cochrane Database Syst Rev 2000:CD001213 View Article PubMed/NCBI
  125. Castiñeiras I, Fernández-Diaz L, Juárez Y, Lueiro M. Sustained efficacy of ustekinumab in refractory erythrodermic psoriasis after failure of antitumor necrosis factor therapies. J Dermatol 2012;39(8):730-731 View Article PubMed/NCBI
  126. Stinco G, Piccirillo A, Errichetti E, Bergamo S, Patrone P. Treatment of recalcitrant erythrodermic psoriasis with ustekinumab. Eur J Dermatol 2014;24(3):387-390 View Article PubMed/NCBI
  127. Freitas E, Rodrigues MA, Torres T. Diagnosis, Screening and Treatment of Patients with Palmoplantar Pustulosis (PPP): A Review of Current Practices and Recommendations. Clin Cosmet Investig Dermatol 2020;13:561-578 View Article PubMed/NCBI
  128. de Unamuno-Bustos B, Ballester-Sánchez R, Oliver-Martínez V, Alegre de Miquel V. [Ustekinumab for the treatment of palmar-plantar pustulosis]. Actas Dermosifiliogr 2011;102(10):833-835 View Article PubMed/NCBI
  129. Roenneberg S, Biedermann T. Pityriasis rubra pilaris: algorithms for diagnosis and treatment. J Eur Acad Dermatol Venereol 2018;32(6):889-898 View Article PubMed/NCBI
  130. Kromer C, Sabat R, Celis D, Mössner R. Systemic therapies of pityriasis rubra pilaris: a systematic review. J Dtsch Dermatol Ges 2019;17(3):243-259 View Article PubMed/NCBI
  131. View Article PubMed/NCBI
  132. Goldburg SR, Strober BE, Payette MJ. Hidradenitis suppurativa: Epidemiology, clinical presentation, and pathogenesis. J Am Acad Dermatol 2020;82(5):1045-1058 View Article PubMed/NCBI
  133. Saunte DML, Jemec GBE. Hidradenitis Suppurativa: Advances in Diagnosis and Treatment. JAMA 2017;318(20):2019-2032 View Article PubMed/NCBI
  134. Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa. N Engl J Med 2016;375(5):422-434 View Article PubMed/NCBI
  135. Prat L, Bouaziz JD, Wallach D, Vignon-Pennamen MD, Bagot M. Neutrophilic dermatoses as systemic diseases. Clin Dermatol 2014;32(3):376-388 View Article PubMed/NCBI
  136. Cohen PR. Neutrophilic dermatoses: a review of current treatment options. Am J Clin Dermatol 2009;10(5):301-312 View Article PubMed/NCBI
  137. Molinelli E, Brisigotti V, Paolinelli M, Offidani A. Novel Therapeutic Approaches and Targets for the Treatment of Neutrophilic Dermatoses, Management of Patients with Neutrophilic Dermatoses and Future Directions in the Era of Biologic Treatment. Curr Pharm Biotechnol 2021;22(1):46-58 View Article PubMed/NCBI
  138. Heard M, Zhang M, Jorizzo JL. A case of bowel-associated dermatosis-arthritis syndrome treated with ustekinumab: The importance of targeting underlying gastrointestinal disease. JAAD Case Rep 2020;6(6):506-508 View Article PubMed/NCBI
  139. Alpsoy E, Zouboulis CC, Ehrlich GE. Mucocutaneous lesions of Behcet’s disease. Yonsei Med J 2007;48(4):573-585 View Article PubMed/NCBI
  140. Alibaz-Oner F, Direskeneli H. Advances in the Treatment of Behcet’s Disease. Curr Rheumatol Rep 2021;23(6):47 View Article PubMed/NCBI
  141. Waldman AR, Ahluwalia J, Udkoff J, Borok JF, Eichenfield LF. Atopic Dermatitis. Pediatr Rev 2018;39(4):180-193 View Article PubMed/NCBI
  142. Johnson BB, Franco AI, Beck LA, Prezzano JC. Treatment-resistant atopic dermatitis: challenges and solutions. Clin Cosmet Investig Dermatol 2019;12:181-192 View Article PubMed/NCBI
  143. Pan Y, Xu L, Qiao J, Fang H. A systematic review of ustekinumab in the treatment of atopic dermatitis. J Dermatolog Treat 2018;29(6):539-541 View Article PubMed/NCBI
  144. Pratt CH, King LE, Messenger AG, Christiano AM, Sundberg JP. Alopecia areata. Nat Rev Dis Primers 2017;3:17011 View Article PubMed/NCBI
  145. Pourang A, Mesinkovska NA. New and Emerging Therapies for Alopecia Areata. Drugs 2020;80(7):635-646 View Article PubMed/NCBI
  146. Ortolan LS, Kim SR, Crotts S, Liu LY, Craiglow BG, Wambier C, et al. IL-12/IL-23 neutralization is ineffective for alopecia areata in mice and humans. J Allergy Clin Immunol 2019;144(6):1731-1734.e1 View Article PubMed/NCBI
  147. Speeckaert R, Lambert J, van Geel N. Learning From Success and Failure: Biologics for Non-approved Skin Diseases. Front Immunol 2019;10:1918 View Article PubMed/NCBI
  148. Méry-Bossard L, Bagny K, Chaby G, Khemis A, Maccari F, Marotte H, et al. New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases. J Eur Acad Dermatol Venereol 2017;31(1):181-186 View Article PubMed/NCBI
  149. Gedikli OK, Kilic G. New-onset vitiligo as an unusual cutaneous reaction under ustekinumab therapy in patients with psoriatic arthritis. Acta Reumatol Port 2020;45(4):301-303 View Article PubMed/NCBI
  150. Daoussis D, Konstantopoulou G, Kraniotis P, Sakkas L, Liossis SN. Biologics in SAPHO syndrome: A systematic review. Semin Arthritis Rheum 2019;48(4):618-625 View Article PubMed/NCBI
  151. Le Guern A, Alkeraye S, Vermersch-Langlin A, Coupe P, Vonarx M. Bullous pemphigoid during ustekinumab therapy. JAAD Case Rep 2015;1(6):359-360 View Article PubMed/NCBI
  152. van Vollenhoven RF, Hahn BH, Tsokos GC, Wagner CL, Lipsky P, Touma Z, et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 2018;392(10155):1330-1339 View Article PubMed/NCBI
  153. Tierney E, Kirthi S, Ramsay B, Ahmad K. Ustekinumab-induced subacute cutaneous lupus. JAAD Case Rep 2019;5(3):271-273 View Article PubMed/NCBI
  154. Rolston VS, Kimmel J, Popov V, Bosworth BP, Hudesman D, Malter LB, et al. Ustekinumab Does Not Increase Risk of Adverse Events: A Meta-Analysis of Randomized Controlled Trials. Dig Dis Sci 2021;66(5):1631-1638 View Article PubMed/NCBI
  155. Qian Y, Kang Z, Liu C, Li X. IL-17 signaling in host defense and inflammatory diseases. Cell Mol Immunol 2010;7(5):328-333 View Article PubMed/NCBI
  156. Li X, Andersen KM, Chang HY, Curtis JR, Alexander GC. Comparative risk of serious infections among real-world users of biologics for psoriasis or psoriatic arthritis. Ann Rheum Dis 2020;79(2):285-291 View Article PubMed/NCBI
  157. Papp K, Gottlieb AB, Naldi L, Pariser D, Ho V, Goyal K, et al. Safety Surveillance for Ustekinumab and Other Psoriasis Treatments From the Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Drugs Dermatol 2015;14(7):706-714 View Article PubMed/NCBI
  158. Cho SI, Kang S, Kim YE, Lee JY, Jo SJ. Ustekinumab does not increase tuberculosis risk: Results from a national database in South Korea. J Am Acad Dermatol 2020;82(5):1243-1245 View Article PubMed/NCBI
  159. Ryan C, Leonardi CL, Krueger JG, Kimball AB, Strober BE, Gordon KB, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. JAMA 2011;306(8):864-871 View Article PubMed/NCBI
  160. Poizeau F, Nowak E, Kerbrat S, Le Nautout B, Droitcourt C, Drici MD, et al. Association Between Early Severe Cardiovascular Events and the Initiation of Treatment With the Anti-Interleukin 12/23p40 Antibody Ustekinumab. JAMA Dermatol 2020;156(11):1208-1215 View Article PubMed/NCBI
  161. Santos-Juanes J, Coto P, GalacheF C. Ustekinumab. Neoplasias y otros aspectos de seguridadUstekinumab. Neoplasms and Other Safety Aspects. Actas Dermo-Sifiliográficas 2012;103(Suppl 2):39-44 View Article PubMed/NCBI

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