Dupilumab-Associated Psoriasis and Psoriasiform Manifestations: A Scoping Review

Abstract

Background

Dupilumab is the first approved IL-4Rα inhibitor for the treatment of atopic dermatitis at present with good efficacy and safety. However, there have been several reports of psoriasis and psoriasiform manifestations occurring after dupilumab therapy in recent years, showing a new paradoxical cutaneous reaction associated with biologics.

Summary

This is a scoping review in order to summarize the demographics and epidemiology, clinical manifestations, diagnosis, potential pathogenesis, and promising management of dupilumab-associated psoriasis and psoriasiform manifestations.

Introduction

Dupilumab is a fully human monoclonal antibody that specifically targets the alpha subunit of the interleukin-4 receptor (IL-4Rα), blocking both IL-4 and IL-13 signaling pathways, which are key mediators of Th2-mediated diseases such as atopic dermatitis (AD). Dupilumab is the first biologic agent approved for the treatment of AD since 2017. It has also been approved for treating asthma and chronic rhinosinusitis with nasal polyposis. Phase 3 trials and real-world studies suggested dupilumab could markedly relieve the signs and symptoms of AD and improve patients’ quality of life [1, 2]. Dupilumab in treating patients with refractory AD and concomitant respiratory symptoms is extremely necessary due to the well-known atopic march theory, in which modifying the severity of AD might decrease the risk for the eventual development of asthma [3]. For AD in special population and anatomical sites, real-world studies have demonstrated that moderate-to-severe AD in the elderly and genital AD responded well to dupilumab therapy [4, 5]. Thus, dupilumab is gradually recommended as a first-line treatment for uncontrolled AD in many countries and areas, providing a new therapeutic option for moderate-to-severe AD.

Although dupilumab is recommended for AD with significant therapeutic effects, the long-term postmarketing surveillance is needed to assess the safety of dupilumab. Most side effects of dupilumab are mild. Conjunctivitis, injection-site reactions, nasopharyngitis, and headache are the most frequent side effects associated with dupilumab [1, 2, 6]. There have been other uncommon side effects associated with dupilumab reported in the literature. Tracey et al. [7] reported the first case of dupilumab-associated erythrodermic psoriasis in 2018. Since then, more and more cases of psoriasis and psoriasiform manifestations associated with dupilumab have been reported in recent years, showing a latent side effect which is not discovered before in phase 2 or 3 trials of dupilumab.

Herein, we conducted a literature review of dupilumab-associated psoriasis and psoriasiform manifestations (DAPs/PsM). A thorough search of the literature was performed in the PubMed using the title search term ([Psoriasis*] or [Psoriatic*] or [Psoriasiform*]) AND (dupilumab) from January 2018 to September 2022. Finally, 31 articles were found by hand searching for “case report” of “case series.” The selected articles were full-text reviewed to make sure the contents of article were relevant to DAPs/PsM. Results are summarized below and in Tables 1, 2.

Table 1.

Case reports and case series of DAPs/PsM

References	Age, years	Gender	Durationa, months	Family historyb	Type	Localization	Histological examination	Dupilumab interruption	Management	Outcome
De novo psoriasis in adult patients
Safa and Paumier, (2019) [8]	55	M	2	No	Plaque	Trunk	Parakeratosis, hyperkeratosis, acanthosis, dilated capillaries, and lymphocytic infiltrate in the upper dermis, consistent with psoriasis	No	Topical steroids	Improvement
Fowler et al., (2019) [9]	54	F	4	NA	Plaque	Bilateral upper and lower extremities, chest, back, neck, abdomen, soles, and palms	Acute spongiotic dermatitis with lymphocyte exocytosis	Yes	NA	Improvement
	49	F	18	NA	Plaque	Bilateral upper and lower extremities, nail	NA	No	Topical clobetasol	Improvement
Stout et al., (2019) [10]	59	F	1	NA	Plaque	Bilateral upper and lower extremities	Confluent parakeratosis with absent granular cell layer, regular acanthosis, and thinning of the suprapapillary plates, consistent with classic psoriasis vulgaris	Yes	Topical triamcinolone	Improvement
Gori et al., (2019) [11]	40	F	3.5	No	Guttate	Trunk and extremities	Parakeratosis, hyperkeratosis, acanthosis, dilated capillaries, and a lymphocytic infiltrate in the upper dermis	No	Topical calcipotriol betamethasone	Improvement
Napolitano et al., (2019) [12]	74	F	6	No	Plaque	Scalp	Parakeratosis, hyperkeratosis, Munro microabscess, and inflammatory dermal infiltrate composed mainly by lymphoplasma cells	No	Clobetasol lotion	Improvement
	50	M	5	No	Plaque	Scalp, hands, and upper limbs	Hyperkeratosis, parakeratosis, psoriasiform hyperplasia, and dermal infiltrate composed mainly by T lymphocytes and neutrophils	No	Calcipotriene/betamethasone foam	Improvement
	32	M	1	Yes	Plaque	Hands, trunk, and lower limbs	Parakeratosis, hyperkeratosis, Munro microabscess, and dermal infiltrate of lymphocytes, macrophages and neutrophils	Yes	Clobetasol ointment, prednisone tablets NB-UVB	Insufficient remission
Varma and Levitt, (2020) [13]	73	M	1	NA	Plaque	Bilateral forearms and right leg	NA	NA	NA	NA
Schrom et al., (2020) [14]	80	M	2.5	NA	Plaque	Trunk, arms, lower extremities	Orthokeratosis overlying parakeratosis, very mild spongiosis, lymphocyte exocytosis, and a mild superficial perivascular lymphocytic infiltrate	Yes	NB-UVB	Improvement
Ferrucci et al., (2020) [15]	42	M	3	No	Plaque	Trunk and limbs	Histological diagnosis of psoriasis	Yes	Topical calcipotriene and betamethasone dipropionate foam	Improvement
Kim and Yeung, (2020) [16]	36	F	5	No	Plaque	Knees and shins	Hyperkeratosis with confluent parakeratosis, uniformly elongated rete ridges, the absence of the granular layer, thinning of the suprapapillary plates, and collection of neutrophils in the stratum corneum consistent with Munro’s microabscesses, a superficial perivascular infiltrate of lymphocytes	Yes	Topical clobetasol propionate 0.05%	Recurrence
Gambichler et al., (2020) [17]	59	M	1	NA	Erythrodermic	Extremities	Psoriasiform hyperplasia with decreased granular layer and focal parakeratosis, mainly perivascular lymphocytic infiltrates in the dermis	Yes	NA	NA
Matsuda et al., (2020) [18]	60	M	3.5	NA	Plaque	Knees, right condyle to hands, elbows, face	Hyperkeratosis, thinning and disappearance of the stratum, granulosum, and neutrophilic infiltration into the stratum corneum	Yes	Topical steroids	Improvement
DeGrazia et al., (2020) [19]	32	F	1	No	Plaque	Scalp, bilateral inguinal folds	NA	No	Topical steroids	NA
	67	M	2	No	Plaque	Scalp	NA	No	Topical steroids	NA
	57	F	9	No	Plaque	Scalp	NA	No	Topical steroids	NA
D’Ambra et al., (2020) [20]	61	F	1	No	Guttate	Trunk and extremities	NA	No	Clobetasol propionate cream	Improvement
	56	F	2	No	Plaque	Scalp, elbows, arms	Hyperplastic epidermis with papillomatosis, hypogranulosis, parakeratosis, and presence of neutrophils in the corneum layer, a slight perivascular lymphocytic infiltrate in the upper dermis	No	Calcipotriene/betamethasone dipropionate foam	Improvement
	39	M	1	No	Plaque	Soles	NA	No	Topical corticosteroids	Improvement
Senner et al., (2020) [21]	40	M	1.5	NA	Plaque	Lower limbs and palms	Acanthosis, papillomatosis, extensive loss of stratum granulosum, parakeratosis, presence of neutrophils in the epidermis, an edema, meandering capillaries, and a lymphocytic infiltrate in the stratum papillary	Yes	Topical steroids, oral prednisone, topic salicylic acid, cyclosporine	Improvement
Al-Janabi et al., (2020) [22]	72	M	4	No	Seborrheic	Scalp, eyebrows, external auditory meatus	NA	No	Clobetasol propionate, salicylic acid 0.5%, distilled coal tar 1%	Improvement
Mirza et al., (2021) [23]	92	M	8	NA	Plaque	Extremities	Acanthosis, parakeratosis with abundant neutrophils, loss of the granular cell layer, minimal spongiosis, dilated capillary loops in the papillary dermis, and a perivascular lymphocyte predominant inflammatory infiltrate	No	Mycophenolate mofetil	Improvement
Beaziz et al., (2021) [24]	45	F	12	No	Plaque	Scalp	NA	No	Topical clobetasol propionate 0.05%	Improvement
Maiolini et al., (2021) [25]	22	M	5	NA	Plaque	Vertex region, left wrist and toes, nail pitting in the fingers	Psoriasiform dermatitis with confluent parakeratosis, spongiosis, exocytosis of lymphocytes, and extravasated red blood cells	NA	Topical betamethasone dipropionate and calcipotriol	Improvement
Russo et al., (2021) [26]	68	F	1	NA	Plaque	Arms and buttocks	Acanthosis, elongation of the epidermal rete ridges, parakeratosis associated with hypogranulosis, sterile intracorneal and subcorneal pustules, lymphohistiocytic and neutrophilic infiltrate in the edematous dermis, subcorneal spongiform pustules of Kogoj	Yes	Oral corticosteroids	Improvement
Kurihara et al., (2021) [27]	34	M	30	NA	Plaque	Arms and trunk	Psoriasiform acanthosis with a diminished granular layer and intracorneal microabscesses within a parakeratotic scale	No	Topical corticosteroids, tacrolimus ointment 0.1%, delgocitinib ointment	Improvement
	23	M	18	NA	Plaque	Face	Psoriasiform acanthosis with intracorneal microabscesses	No	Topical corticosteroids, tacrolimus ointment 0.1%, delgocitinib ointment	Improvement
Park et al., (2021) [28]	24	M	2	NA	Plaque	Palms and soles	Hyperkeratosis, parakeratosis, diffuse hypogranulosis, regular rete ridge elongation, suprapapillary thinning	No	Topical corticosteroids	Improvement
Flanagan et al., (2022) [29]	28	F	5	No	Plaque	Scalp, abdomen, proximal extremities	NA	Yes	Topical clobetasol	Improvement
Fan et al., (2022) [30]	25	F	2	No	Reverse	Armpits	NA	Yes	Topical hormonal cream, compound glycyrrhizin	Improvement
Incel Uysal and Gunhan, (2022) [31]	22	M	4	No	Pustular	Dorsal hands	Regular, psoriasiform acanthosis and parakeratosis of the epidermis with elongated rete ridges; subcorneal spongiotic pustule of neutrophil leucocytes, consistent with pustular psoriasis	Yes	Topical corticosteroid and calcipotriol	Improvement
Jia et al., (2022) [32]	23	M	2	NA	Pustular	Lower legs	Parakeratosis, hyperkeratosis, epidermal hyperplasia, dilated capillaries, and lymphocyte infiltrate in the upper dermis, dense neutrophil infiltration in the stratum corneum, and subcorneal zone forming spongiform abscesses	Yes	Topical steroids, cyclosporine	Improvement
Patruno et al., (2022) [33]	58	F	5.5	Yes	Plaque	Scalp, hands, and legs	Acanthosis, parakeratosis, exocytosis, hypogranulosis, dermal inflammatory infiltrate composed mainly of lymphoplasma cells, T lymphocytes and Langerhans cells and/or neutrophils, dilated vessels of the superficial derma	Yes	Upadacitinib	Improvement
Zhong et al., (2022) [34]	51	F	2	No	Pustular	Arms and trunk	Parakeratosis, psoriatic hyperplasia, dilated tortuous vessels in the papillary dermis; the superficial dermis was infiltrated by large quantities of perivascular lymphocytes and neutrophils	Yes	Methylprednisolone	Improvement
De novo psoriasis in pediatric patients
Parker et al., (2021) [35]	4	M	9–12	No	Plaque and Pustular	Trunk and legs	NA	Yes	Topical corticosteroid, ustekinumab	Improvement
	14	F	8	No	Plaque	Face and neck	NA	No	Triamcinolone 0.1% ointment	Improvement
	12	F	10	No	Plaque	Extensor knees	NA	No	Mometasone 0.1% ointment	Improvement
	18	M	7	No	Plaque	Scalp, forehead, neck	NA	No	Triamcinolone 0.1% ointment, betamethasone dipropionate shampoo, clobetasol 0.05% solution	Improvement
	16	M	7	No	Plaque	Left ankle, right knee	NA	No	Mometasone 0.1% ointment	Improvement
	18	F	6	No	Plaque	Abdomen, pubic area, ears, neck, and arms	NA	No	Triamcinolone 0.1% ointment, pimecrolimus cream	Improvement
Park et al., (2021) [28]	17	M	2	NA	Plaque	Palms and soles	Hyperkeratosis, parakeratosis, multifocal hypogranulosis, regular rete ridge elongation	Yes	Cyclosporine	Improvement
Ali et al., (2022) [36]	17 (twin)	M	5	No	Plaque	Scalp, face, abdomen, back, upper and lower extensor extremities	Psoriasiform hyperplasia, ectatic capillaries, perivascular lymphocytes infiltration acanthosis with thinning of suprapapillary plates, confluent parakeratosis with the absence of the granular cell layer	Yes	Baricitinib	Improvement
Dupilumab-associated flare of preexistent psoriasis
Tracey et al., (2018) [7]	50	F	2	NA	Erythrodermic	Scalp, trunk, bilateral upper and lower extremities	Psoriasiform hyperplasia with diminished granular layer and parakeratotic scale (arm) Acanthosis, mild spongiosis, and intraepidermal neutrophils forming subcorneal pustules (abdomen)	Yes	Methotrexate, topical steroids	Improvement
Dimitrov et al., (2020) [37]	35	M	5	NA	Plaque	Forehead, arms, lower leg	Characteristic changes of psoriasis	NA	NA	NA
Parker et al., (2021) [35]	9	F	3	NA	Plaque	Elbows	NA	No	Betamethasone dipropionate ointment 0.05%	Improvement

F, female; M, male; NA, not available.

^aTime from dupilumab treatment to onset of psoriasis.

^bFamily history of psoriasis.

Table 2.

Clinical characteristics of de novo psoriasis associated with dupilumab^a

Characteristics
Gender	n = 35
Male	19 (54.3%)
Female	16 (45.7%)
Age, years, mean (range)	48.6 (22–92)
Time to onset, months, mean (range)	n = 34b
	4.3 (1–18)
Lesion types	n = 35
Plaque psoriasis	27 (77.1%)
Pustular psoriasis	3 (8.6%)
Guttate psoriasis	2 (5.7%)
Erythrodermic psoriasis	1 (2.9%)
Reverse psoriasis	1 (2.9%)
Sebopsoriasis	1 (2.9%)
Lesion location
Extremities	27 (77.1%)
Trunk	13 (37.1%)
Scalp	11 (31.4%)
Face and neck	4 (11.4%)
Nail	2 (5.7%)
Dupilumab discontinuation	n = 33
	16 (48.5%)
Management	n = 32
Topical treatment
Topical corticosteroids	27 (84.4%)
Topical vitamin D derivatives	6 (18.8%)
Topical calcineurin inhibitors	2 (6.3%)
Phototherapy
NB-UVB	2 (6.3%)
Conventional systemic treatments
Oral corticosteroids	4 (12.5%)
Cyclosporine	2 (6.3%)
Mycophenolate mofetil	1 (3.1%)
JAK inhibitors
Delgocitinib ointment	2 (6.3%)
Upadacitinib	1 (3.1%)
Outcome	n = 30
Improvement	28 (93.3%)
Insufficient remission or recurrence	2 (6.7%)

^aCase reports of pediatric patients and flare of preexistent psoriasis are not summarized in table due to the small sample size, and detailed information can be found in Table 1.

^bOne case is excluded for a long onset time of 30 months.

Demographics and Epidemiology of DAPs/PsM

Thirty-one articles comprising 47 patients (37 adults and 10 children) met our final inclusion criteria, including 44 patients with de novo psoriasis and 3 patients suffering the flare of preexistent psoriasis after dupilumab treatment (Table 1). For de novo psoriasis, the average age of patients is 48.6 years (range, 22–92 years old) in the adult group, with a roughly equivalent number of males and females (Table 2). The mean time to onset of de novo psoriasis after dupilumab treatment is 4.3 months (range, 1–18 months) in adults, roughly consistent with previous studies [24, 38–40]. The mean time to onset in pediatric patients is slightly longer than in adults (6.4 months, ranging from 2 to 12 months). Besides, the flare of preexistent psoriasis after dupilumab treatment presents a relatively shorter onset time of 3.3 months on average (n = 3). Most of the patients (93.6%, 44/47) developed psoriasis or psoriasiform manifestations after initiation of dupilumab within 1 year, suggesting the first year of dupilumab treatment should be closely monitored and followed up by clinicians. However, there were some cases showing a long onset time of 1.5 years or even 2.5 years [9, 27]. The exact cause of long onset time is unclear, but a long-term follow-up after dupilumab treatment is recommended.

DAPs/PsM versus Classic Psoriasis

The largest cohort study performed by Jaulent et al. [38] showed a 1.88% (7/373) incidence of DAPs/PsM, while Napolitano et al. [2, 12] suggested an incidence of 3.33% (3/90) in 2019 and 3.03% (5/165) in 2021. These reported numbers seemed similar to the prevalence rate of classic psoriasis in the general population. However, it is hard to determine whether individuals with DAPs/PsM have the same genetic risk as general population, due to the variable prevalence rate of psoriasis in different regions ranging from 0.36% to 2.73% [41]. Surprisingly, a recent retrospective review of dupilumab for AD and dermatitis not otherwise specified showed a high incidence of psoriasis up to 7.0% (14/199), and 43% (6/14) patients with DAPs/PsM in this cohort had a distant history of psoriasis prior to starting dupilumab for AD/dermatitis not otherwise specified [42]. The history of psoriasis may explain such a high incidence of psoriasis in this cohort, and this result reminds us that dupilumab is not recommended to patients who have a history of psoriasis.

DAPs/PsM versus Concomitant AD and Psoriasis

AD and psoriasis were once considered as mutually antagonistic diseases because they required the activation of opposing inflammatory pathways [43]. However, there are many reports and systematic reviews that show AD and psoriasis can coexist in the same individuals, both simultaneously and/or consecutively. Cunliffe et al. [44] in a systematic review found the prevalence of AD in those with psoriasis varied from 0.17% to 20% (a pooled prevalence of 2%), while the prevalence of psoriasis in those with AD ranged from 0.3% to 12.6%, with a pooled prevalence of 2%. Barry et al. [45] also reported the prevalence of concomitant AD and psoriasis was 1.3% of the total population of patients diagnosed with either psoriasis or AD, and the number was pretty close to the incidence of DAPs/PsM mentioned above (ranging from 1.88% to 3.33%). In fact, systemic therapies may be a trigger to promote the processes that AD patients develop psoriasis or psoriasis patients develop AD. These processes can also happen regardless of whether a patient is undergoing systemic or topical therapies [46]. Thus, we hypothesize that dupilumab may act as a possible triggering factor, but not a decisive factor, to promote AD patients to develop psoriasis. This can explain why the prevalence of DAPs/PsM in patients with AD is roughly equal but slightly higher than the prevalence of concomitant AD and psoriasis.

In summary, the incidence of DAPs/PsM is at a relatively low level and almost equal to the prevalence of classic psoriasis and (or) concomitant AD and psoriasis. This result may imply that the occurrence of psoriasiform manifestations is dominated by intrinsic factors, and dupilumab contributes to the process as an extrinsic trigger.

Clinical Manifestations of DAPs/PsM

De novo Psoriasis: General Psoriasiform Manifestations Associated with Dupilumab

In general, DAPs/PsM show similar clinical features to classic psoriasis in many aspects. Plaque psoriasis (77.1% in adults and 100% in children) was the most common subtype of psoriasis reported in previous studies, which also accounts for the largest proportion of cases in classic psoriasis. The dupilumab-associated psoriatic plaques were often described as well-demarcated erythematous scaly plaques, showing no difference from classic psoriatic plaques in appearance. Guttate, erythrodermic, and pustular psoriasis have also been reported [7, 11, 17, 20, 31, 32, 34, 35], accounting for a small proportion. However, Jaulent et al. [38] reported a high proportion of pustular psoriasis (43%, 3/7) as a specific clinical feature in DAPs/PsM. Some specific variants of psoriasis, such as reverse psoriasis and sebopsoriasis, could also occur in patients with dupilumab therapy [22, 30]. Sebopsoriasis, as a combination of psoriasis and seborrheic dermatitis, was thought to result from the abnormal immune response to Malassezia induced by cytokine imbalances due to dupilumab [22].

Extremities (77.1% in adults and 77.8% in children) were the most common onset sites, especially bilateral extensor surfaces of upper and lower extremities, consistent with classic psoriasis. Additionally, trunk (37.1%) and scalp (31.4%) were other common locations in adults, while pediatric psoriasis was more common on the face and neck (55.6%). Palmoplantar and nail psoriasis have also been reported, occurring alone or in combination with lesions elsewhere [9, 20, 25, 28]. Recently, Fan et al. [30] reported a case of reverse psoriasis occurring in the armpits, indicating that flexural and intertriginous areas could also be affected by DAPs/PsM, especially easy to be confused with preexisting AD. Psoriatic plaques were mostly noticed in areas of skin that had not been affected by AD before, but a few cases revealed that psoriasis appeared on the original lesions, switching from AD to psoriasis directly [14, 32].

Scalp lesions were especially frequent in DAPs/PsM. Interestingly, alopecia areata (AA) could also be triggered by dupilumab, even coexisting with DAPs/PsM in the scalp [24]. Two different patterns of dupilumab-associated alopecia were described: classic AA and psoriatic alopecia plaques (AA-like reactions) associated with erythemas and scales. Psoriatic alopecia plaques could be confirmed by biopsy to distinguish from AA if necessary.

Flare of Preexistent Psoriasis: A More Severe Attack

In theory, it is unconventional that dupilumab should be applied to patients with psoriasis, but this condition can happen occasionally when preexistent psoriasis is misdiagnosed or mixed up with AD. Herein, we presented 3 cases of the flare of preexistent psoriasis. The earliest case reported was a patient with probable preexistent psoriasis who has developed severe erythrodermic psoriasis after dupilumab therapy [7]. Other cases showed a persistent or enlarged psoriatic plaque at the original site [35, 37]. These cases illustrated that dupilumab can indeed induce the flare of preexistent psoriasis, with more severe lesions and shorter time to onset (3.3 months on average compared with 4.3 months in de novo psoriasis).

Clinical Diagnosis of DAPs/PsM

The clinical diagnosis of DAPs/PsM was mainly based on typical psoriasiform lesions and the temporal relationship between dupilumab treatment. A full body examination should be checked for DAPs/PsM, particularly in areas of the scalp, palms, soles, and nails. For pediatric patients, the face, neck, and pubic area should also be examined carefully. A case of dupilumab-induced acute generalized exanthematous pustulosis on the second day after initiation of dupilumab was reported recently [47], suggesting that the clinical history is also crucial for differential diagnosis of acute generalized exanthematous pustulosis and dupilumab-associated generalized pustular psoriasis.

Skin biopsy can be helpful to diagnose DAPs/PsM but is rarely performed in pediatric patients when diagnosis and empiric treatment were allowed. The histopathological features of DAPs/PsM were not always consistent with classic psoriasis in some cases, showing an overlapping psoriasiform/spongiotic feature [14]. Classic psoriatic histopathological features include parakeratosis, hyperkeratosis, acanthosis of the epidermis, dilated capillaries, and lymphocytic infiltration in the dermis. These features were often found in DAPs/PsM, while mild spongiosis was also reported [14, 23, 25]. The overlapping psoriasiform/spongiotic feature may suggest that psoriasiform lesions associated with dupilumab still have a Th2-predominant background [48]. In addition, the occasional presence of eosinophils and (or) plasma cells has been reported in psoriasiform plaques induced by TNF-α inhibitors. It was considered as a clue to distinguish it from classic psoriasis, which also might be helpful to identify DAPs/PsM [49]. Interestingly, non-psoriasiform lesions could present psoriasiform changes histologically in some cases. de Wijs et al. [50] reported a case series of dupilumab-associated paradoxical head and neck erythema with less or no scaling, markedly different from psoriasis in clinical appearance, but histopathology showed epidermal hyperplasia, increased dilated capillaries, and a perivascular lymphocytic infiltration, suggesting psoriasiform changes.

In practice, differentiation between psoriasis and AD lesions can be difficult in some cases, both clinically and histologically, especially if areas of the scalp or hand/feet are affected. Therefore, it is a challenge for dermatologists to identify DAPs/PsM at an early stage, and a comprehensive judgment of clinical history, manifestations, and histopathology is crucial for clinicians to diagnose DAPs/PsM.

Pathogenesis of DAPs/PsM

Th2- and Th17-Mediated Disease: Two Poles of One Spectrum

Psoriasis and AD are both noncommunicable inflammatory skin diseases mediated by T cells, cytokines, chemokines, and other cells of the immune system. In the skin, T cells differentiate into specific subsets in response to distinct cytokines, then secrete cytokines to drive epidermal keratinocytes to alter growth and differentiation patterns, leading to the outcome of different inflammatory skin diseases [51]. Psoriasis is an inflammatory skin disease featured by Th1/Th17 cells with increased TNF-α, IL-17, and IL-23, while AD is a mainly Th2-mediated disease involving increased IL-4, IL-5, and IL-13 [52]. Recent studies have found that psoriasis and AD are not isolated diseases but two opposite poles of the same Th17-Th2 cell polarization spectrum where T cells can present variable polarization degrees and create some overlapping disease characteristics [53]. Moreover, blocking Th1 and Th17 pathways may result in the occurrence of Th2-mediated diseases. Paolino et al. [46] reported a case series of psoriatic patients who developed AD and/or eczematous-like eruptions after biologic treatments (4 patients with ustekinumab, 2 patients with adalimumab, 1 patient with ixekizumab, and 1 patient with guselkumab). Similarly, blocking of Th2 pathway may lead to T-cell polarization shift to Th17 subsets, explaining the phenomenon of DAPs/PsM in AD patients [7]. A recent unusual case reported secukinumab-induced AD in a patient with psoriasis that had resolved following several months of treatment with dupilumab, but subsequently, these patients had developed re-emergence of psoriatic lesions with dupilumab therapy [54]. These pieces of evidence strongly suggest that Th17 and Th2 pathways are one spectrum where immune conditions can reversibly switch from one pole to the other with the trigger of biologic therapy.

Psoriasis induced by dupilumab is not an accidental phenomenon. A large number of cases were provided to support that IL-4/IL-13 axis may act as a restraint toward Th17 pathway activation in some organs, and IL-4/IL-13 blockers may lead to an increased incidence of Th17-type disease (such as enthesitis/enthesopathy, seronegative arthritis, spondyloarthropathy, uveitis, psoriasis, and nail psoriasis) [55]. Interestingly, ankylosing spondylitis and inflammatory bowel disease, parts of the Th17 diseases, are not associated with dupilumab therapy [55]. Thus, further immunology studies are needed to refine the Th2-Th17 spectrum and related comorbidities driven by cytokines.

IL-23/IL-17: The Key Target of Immune Shift

Recent experimental studies have reported an increased IL-23A and de novo IL-17A expression in DAPs/PsM, suggesting the remarkable activation of IL-23/Th17 axis in psoriasiform lesions [23, 56]. The de novo IL-17A level of DAPs/PsM was even higher than classic psoriasis, suggesting a strong shift to Th17 induced by dupilumab. It is well known that IL-4 is a cytokine capable of negatively affecting Th17 lymphocyte function and upstream IL-23 production secreted by antigen-presenting cells [57]. Bridgewood et al. [58] also found that human enthesis contains IL-23-producing cells, and the production of IL-23 is attenuated by IL-4 and IL-13 treatment in vitro studies. Thus, IL-4/IL-13 blockers may increase IL-23 and downstream IL-17 production and consequently trigger Th17-mediated diseases.

IL-17 may act as the crucial intrinsic factor to activate Th17-mediated inflammation, which can be artificially upregulated by extrinsic IL-4/IL-13 blockers (dupilumab). Thus, patients with a high level of intrinsic IL-17 may be hypersensitive to DAPs/PsM. Specific subtypes of AD, including Asian and pediatric patients, have a prominent IL-17 component [53]. A case of Asian (Chinese) teenage twin brothers with a long history of AD since childhood has been reported. The twin brothers developed psoriasiform erythemas under the treatment of dupilumab, with a high IL-17A expression [36]. This result may indicate that Asian and pediatric patients have a higher possibility to develop DAPs/PsM because of the intrinsic Th17 component. Similarly, Flanagan et al. [29] summarized 18 cases of DAPs/PsM and found that most patients (83%) had AD since childhood, suggesting chronic AD is also more likely to develop psoriasis due to a partial Th1/Th17 shift in chronic AD. However, more strong evidence is needed to support that Asian, pediatric, and chronic AD patients have a higher incidence of DAPs/PsM than other patients.

In addition, DAPs/PsM had a higher IL-4 expression compared with classic psoriasis [56], and the IL-13 level was decreased after dupilumab treatment but not absent during the onset of DAPs/PsM in AD patients [23]. These results support that DAPs/PsM have a Th2 immune background, consistent with the specific histological features mentioned above. The coexistence of high IL-17/IL-23 and persistent IL-4/IL-13 expression seems paradoxical but reflects that DAPs/PsM is an inflammatory disease based on a specific intermediate state of Th2-Th17 spectrum both histologically and immunologically.

Besides the mechanism of T-cell polarization skewing, the common environmental factors and genetic backgrounds shared by AD and psoriasis may also contribute to the occurrence of DAPs/PsM. A population-based study by Simpson et al. [59] has found that Th1- and Th2-mediated diseases share common environmental risk factors to increase the likelihood of Th1- or Th2-mediated immune response to nonspecific antigens. Furthermore, a recent genome-wide study confirmed a high degree of genomic coincidence between AD and psoriasis, suggesting the overlapping of genetic backgrounds in these two diseases [60].

In summary, the T-cell polarization skewing theory may act as the key point of DAPs/PsM, and shared environmental and genetic factors between AD and psoriasis are involved. The disinhibition of IL-23/IL-17 axis suppressed by IL-4 can partly explain the occurrence of DAPs/PsM. However, many relevant questions, including the no correlation between partial Th17 diseases (inflammatory bowel disease and ankylosing spondylitis) and dupilumab, and whether patients with higher IL-17 component are hypersensitive to DAPs/PsM, are still not completely clear. Thus, more studies are needed to help us deepen the understanding of dupilumab and guide the clinical application in the future.

Management and Prevention of DAPs/PsM

At present, there is no high-quality evidence-based management guideline for DAPs/PsM. However, as a specific paradoxical reaction induced by the monoclonal antibody, the treatments can roughly refer to guidelines of classic psoriasis and other paradoxical reactions [39]. The aim of management is to alleviate psoriasiform lesions while maintaining control of AD, so weighing the severity of DAPs/PsM against the therapeutic effects of AD is essential in management.

General Practical Guidelines for de novo Psoriasis

For mild-to-moderate DAPs/PsM, topical therapies, phototherapy, and even systemic therapies can be considered. Discontinuation of dupilumab may not be necessary. Topical glucocorticoids (84.4%) or combinations of glucocorticoids and vitamin D derivatives (18.8%) were widely applied to these patients, consistent with the preferred conventional treatments of mild classic psoriasis. Phototherapy (narrow-band UVB) [12, 14] and systemic therapies (oral steroids [12, 21, 26, 34], cyclosporine [21, 28, 32], and mycophenolate mofetil [23]) were also reported for the treatment of mild-to-moderate DAPs/PsM. Most patients’ psoriasiform lesions could be completely cleared or partly improved after sufficient topical therapies. Parker et al. [35] suggested that DAPs/PsM in pediatric patients might be less refractory than in adults. Psoriasiform lesions could achieve acceptable clearance with topical glucocorticoids in all pediatric patients without discontinuation of dupilumab. Ustekinumab, an IL-12/IL-23 inhibitor, has also been applied in a pediatric patient [35], but whether recommending it as the first-line treatment of DAPs/PsM should be prudent considering the high cost for drugs and potential side effects.

For severe DAPs/PsM, discontinuation of dupilumab is recommended. We found that 48.5% adult patients chose discontinuation of dupilumab, and their psoriasiform lesions achieved various degrees of remission after discontinuation or combinations of discontinuation and additional treatments. Restarting of dupilumab after discontinuation is generally not advised due to the high risk of psoriasis recurrence. Kim et al. [16] reported a case of the recurrence of DAPs/PsM after restarting dupilumab, suggesting the recurrent and refractory features of DAPs/PsM.

Innovative Treatments for Concurrent Psoriasis and AD

Currently, Janus kinase (JAK) inhibitors are considered as potential treatments for patients presenting both AD and psoriasis, providing new ideas for the treatment of refractory DAPs/PsM [38]. Baricitinib, an oral selective JAK1 and JAK2 inhibitors, was applied to two seventeen-year-old teenagers with DAPs/PsM and showed a significant reduction in skin lesions [36]. Upadacitinib (selective JAK 1 inhibitor) was also reported in treating DAPs/PsM, resulting in complete remission of both psoriasiform eruptions and AD [33]. For topical treatments, Kurihara et al. [27] reported 2 cases of DAPs/PsM achieved remarkable improvement with the delgocitinib ointment after ineffective remission of topical corticosteroids and 0.1% tacrolimus ointment.

The combination of dupilumab with other monoclonal antibodies is another promising therapy strategy for concurrent psoriasis and AD. A short-term retrospective study reviewed 6 patients treated with biologic combination therapies (dupilumab and guselkumab) and found almost all of the patients (83.3%, 5/6) have presented significant improvement in both AD and psoriasis [61]. The safety of dupilumab associated with other monoclonal antibodies appears to be an important issue. Further studies summarized case reports of dupilumab in combination with other biologics (such as guselkumab, secukinumab, adalimumab, benralizumab, and omalizumab), presenting no or mild adverse drug reactions for a 2 to 22-month period of observation [62]. However, long-term monitoring is necessary to evaluate the safety of biologics in combination. The cost of multiple biologics is also of concern in clinical practice.

The principal prevention of DAPs/PsM is to strictly control the indications of dupilumab. Family or personal history of psoriasis may be risk factors for the occurrence and severity of psoriasis eruptions [12, 13], so dupilumab is not recommended for these patients. Furthermore, a long-term follow-up after initiating dupilumab therapy is especially important.

Conclusion

DAPs/PsM are relatively rare side effects triggered by dupilumab, mainly related to T-cell subset imbalance and multiple factors. This phenomenon is also a supplement of paradoxical reaction induced by biologic agents, providing strong evidence that AD and psoriasis are two poles of the same Th17-Th2 cell polarization spectrum. Clinicians should improve the awareness of this phenomenon since dupilumab has been widely used in clinical practice worldwide in recent years. Future research works are needed to clarify the detailed mechanism of DAPs/PsM in order to seek more effective management and prevention.

Key Message

The present review suggests that DAPs/PsM may occur in approximately 1.8–3.3% of AD patients after dupilumab therapy. In general, DAPs/PsM manifest similar clinical and histological features to classic psoriasis but not identical. T-cell polarization skewing between Th17 and Th2 spectrum may act as the core mechanism of DAPs/PsM, characterized by an upregulated IL-23/Th17 axis. Mild-to-moderate DAPs/PsM respond well to topical therapies, while discontinuation of dupilumab is recommended in severe cases. Currently, JAK inhibitors and the combination of dupilumab with other biologics are considered as potential treatments for concurrent AD and psoriasis. Future research works are needed to clarify the detailed mechanism of this phenomenon in order to seek more effective management and prevention.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was supported by National High Level Hospital Clinical Research Funding (2022-PUMCH-B-092).

Author Contributions

Zheng Su wrote the draft of the manuscript. Yue-Ping Zeng, M.D., supervised the work and critically revised the manuscript.

Funding Statement

This study was supported by National High Level Hospital Clinical Research Funding (2022-PUMCH-B-092).