Key Points
Question
What are the clinical and histopathologic features of dupilumab-associated lymphoid reactions in patients with atopic dermatitis?
Findings
This case series presents 11 patients with atopic dermatitis who developed a dupilumab-associated lymphoid reaction with deterioration of symptoms (eg, burning sensation, itch) after initial response, which mimics a cutaneous T-cell lymphoma but has distinctive histopathologic features (a sprinkled distribution of small hyperchromatic lymphocytes in the upper epidermal section, a dysregulated CD4:CD8 ratio, CD30 overexpression, and no loss of pan-T-cell antigens [CD2, CD3, and CD5]).
Meaning
Clinical and histopathologic recognition of a lymphoid reaction is important, and dupilumab discontinuation is recommended in these patients.
This case series presents and describes 11 patients with atopic dermatitis who developed a lymphoid reaction during treatment with dupilumab.
Abstract
Importance
Since the increased use of dupilumab for atopic dermatitis (AD) in daily practice, several cases have been reported on the development of cutaneous T-cell lymphomas (CTCL) and lymphoid infiltrates.
Objective
To provide insight in the clinical and histopathologic features of patients with AD clinically suspected for CTCL during dupilumab treatment.
Design, Setting, and Participants
This retrospective observational case series included adult (≥18 years) patients with AD treated with dupilumab between October 2017 and July 2022 at the University Medical Center Utrecht in the Netherlands.
Main outcomes and measures
Relevant patient, disease, and treatment characteristics were evaluated. Skin biopsies before, during, and after treatment were collected and reassessed.
Results
Fourteen patients (54.5% male) with a median (IQR) age of 56 (36-66) years suspected for CTCL with deterioration of symptoms during dupilumab treatment were included. Of 14 patients, 3 were retrospectively diagnosed with preexistent mycosis fungoides (MF). Eleven patients with AD were eventually diagnosed with a lymphoid reaction (LR). These patients showed MF-like symptoms; however, histopathologic findings were different, and included sprinkled distribution of small hyperchromatic lymphocytes in the upper epidermal section, a dysregulated CD4:CD8 ratio, and CD30 overexpression, without loss of CD2/CD3/CD5. The median time to clinical worsening was 4.0 months (IQR, 1.4-10.0). Posttreatment biopsies showed complete clearance of the LR in all patients.
Conclusions and relevance
This study found that dupilumab treatment can cause a reversible and benign LR, which mimics a CTCL, though has distinctive histopathologic features.
Introduction
Atopic dermatitis (AD) is a T-helper 2 (Th2)-mediated, chronic, inflammatory skin disease characterized by recurrent pruritic erythematosquamous lesions.1 Dupilumab, a monoclonal antibody that blocks the interleukin (IL)-4 receptor α, and thereby inhibits IL-4/13 signaling, is a new targeted AD treatment. It has proven to be effective and overall safe for the treatment of moderate to severe AD.2 However, since the increased use of dupilumab in daily practice, several cases have been published on cutaneous adverse effects, such as the development of (atypical) lymphoid infiltrates and cutaneous T-cell lymphomas (CTCL).3,4,5
The most common type of CTCL is mycosis fungoides (MF), which is still a relatively rare condition.4,6 Worldwide prevalence rates range between 4.8 and 6.6 per 100 000 people.7 Due to a comparable clinical presentation and often indolent course of the disease, it might be challenging to differentiate between some presentations of early-stage MF and AD.6,8 In addition, patients with chronic and persistent AD are known to have an increased risk of developing a CTCL in a later disease stage, especially patients with severe AD.9,10 Similar to AD, MF is a primarily Th2-driven skin disease. It has been shown that IL-13 and its receptor are expressed by tumor cells in the clinically involved skin of patients with CTCL, suggesting that this might be a possible therapeutic target for the treatment of CTCL.11 Therefore, dupilumab was proposed to be used off-label in the management of CTCL.12 However, several cases were described with disease progression of MF during treatment with dupilumab.3,5 Moreover, treatment with dupilumab unmasked a misdiagnosed MF in some patients with AD.4
Given the malignant character of CTCL, it is important to distinguish this condition from benign lymphoid infiltrates. In this study we present and describe 11 patients with AD who developed a lymphoid reaction (LR) during treatment with dupilumab. We aimed to provide insight into the clinical and histopathologic characterization of these LRs.
Methods
Study Design and Patient Cohort
This retrospective observational case series included adult patients (aged ≥18 y), with a primary diagnosis of AD, clinically suspected of having CTCL during dupilumab treatment. The study was performed at the Department of Dermatology of the University Medical Center Utrecht (UMCU) in the Netherlands, from October 2017 to July 2022. Most patients participated in the BioDay Registry, a prospective multicenter registry in which patients with AD treated with new advanced systemic treatments in daily practice are enrolled. Several patients started treatment with dupilumab in another hospital and were referred to our hospital due to uncontrolled AD despite dupilumab treatment. All patients had received, as per protocol, a loading dose of dupilumab of 600 mg subcutaneously, followed by the standard dosage of 300 mg every other week. No specific exclusion criteria were applied. Of the included patients, relevant patient, disease, and treatment characteristics were collected. Patients provided written and/or oral informed consent.
The BioDay registry was considered a noninterventional study by the local medical ethics committee (METC 18/239) and was conducted in accordance with the Declaration of Helsinki.
Material Collection and Histopathologic Examination
Of the included patients, all relevant skin biopsies were evaluated including biopsies before, during, and after (≥3 months) dupilumab treatment (Figure 1A). The Palga database, a Dutch nationwide network and registry that includes all pathology results, was used to identify available biopsies from other hospitals.13 If relevant biopsies were available, pathology slides of these biopsies were collected and reassessed. Histopathologic examination was performed by an experienced pathologist (M.R.vD.) specialized in the dermatopathological field. The biopsies were evaluated based on specific histopathologic features and included: predominant histologic patterns, absence/presence of intraepithelial T-cell lymphocytes, composition and distribution of cellular infiltrates, and characteristics of lymphocytes; CD2, CD3, CD4, CD5, CD8 and CD30 immunohistochemical stainings (IHC) were performed on (most) biopsies.
Figure 1. Study Flowchart and Clinical Presentation of Dupilumab-Associated Lymphoid Reactions.
A, Flowchart of number of biopsies performed before, during, and after dupilumab treatment. B, Images of the clinical presentation of dupilumab-associated lymphoid reactions. LR indicates lymphoid reaction; MF, mycosis fungoides.
Results
Of 530 adult patients with AD treated with dupilumab at the UMCU, we found 14 patients (2.6%) clinically suspected for CTCL during treatment. Of these 14 patients, 3 (3/530 [0.6%]) patients were eventually diagnosed with MF during dupilumab treatment, which was initially indicated for their AD. Two of these patients had been diagnosed with AD since their childhood (Table 1). From all patients with MF, a biopsy prior to dupilumab treatment was available, which was retrospectively assessed as MF instead of AD (eTable 1 in Supplement 1). In these patients the longest misdiagnosis was almost 14 years (confirmed by histopathologic analysis). In 11 of 530 patients (2.1%) we found lymphoid infiltrates that were slightly different compared with the histopathologic characteristics of MF. In 6 patients (54.5%), a biopsy before the start of dupilumab was available (eTable 1 in Supplement 1). These biopsies were reassessed and the diagnosis of AD was reconfirmed. Because the lymphoid infiltrate in these 11 patients did not meet all histopathologic CTCL criteria (eTable 2 in Supplement 1), we will from now on refer to this condition as a lymphoid reaction (LR).
Table 1. Patient and Disease Characteristics.
| Characteristic | Patients with MF (n = 3) | Patients with LR (n = 11) |
|---|---|---|
| Sex, No (%) | ||
| Female | 3 (100) | 3 (27.3) |
| Male | 0 | 8 (72.7) |
| Age, median (IQR), y | 57 (55-57) | 52 (31-69) |
| Age at AD onset, No. (%) | ||
| Childhood | 2 (66.7) | 5 (45.5) |
| Adolescence | 0 | 2 (18.2) |
| Adult | 1 (33.3) | 4 (36.4) |
| Atopic comorbidities, No. (%) | 1 (33.3) | 7 (63.6) |
| Allergic asthma | 0 | 4 (36.4) |
| Allergic rhinitis | 1 (33.3) | 7 (63.6) |
| Allergic conjunctivitis | 0 | 5 (45.5) |
| Food allergy | 0 | 3 (27.3) |
| ≥2 Atopic comorbidities | 0 | 6 (54.5) |
| Previous use of immunosuppressive drugs, No. (%) | 2 (66.7) | 11 (100) |
| Cyclosporin A | 2 (66.7) | 7 (63.6) |
| Methotrexate | 1 (33.3) | 7 (63.6) |
| Azathioprine | 0 | 2 (18.2) |
| Mycophenolate mofetil | 1 (33.3) | 1 (9.1) |
| Oral tacrolimus | 0 | 1 (9.1) |
| History ≥2 systemic immunosuppressive drugs, No. (%) | 2 (66.7) | 4 (36.4) |
| Disease characteristics, median (IQR) | ||
| EASI score at baseline | NA | 17.1 (9.8-22.9) |
| Missing, No. (%) | 3 (100) | 4 (36.4) |
| Time to deterioration of symptoms, mo | 4.0 (2.0-5.0) | 4.0 (1.4-10.0) |
| TARC levels at deterioration of symptoms, pg/mL | NA | 2866 (1730-15.598) |
| Missing, No. (%) | 3 (100) | 3 (27.3) |
| Clinical symptoms, No. (%)a | ||
| Painful/burning sensation | 2 (66.7) | 7 (63.6) |
| Worsening of itch | 1 (33.3) | 6 (54.5) |
| Few excoriations | 1 (33.3) | 8 (72.7) |
| Lichenification trunk/extremities | 2 (66.7) | 7 (63.6) |
| Suberythrodermicb | 2 (66.7) | 5 (45.5) |
| Erythematous maculopapular plaques | 3 (100.0) | 8 (81.8) |
Abbreviations: AD, atopic dermatitis; EASI, Eczema Area and Severity Index; LR, lymphoid reaction; MF, mycosis fungoides; NA, not available; TARC, thymus and activation-regulated chemokine.
Not all patients were specifically asked or examined on these symptoms, so therefore the numbers presented are likely underreported.
Suberythrodermic was defined as 50% to 90% body surface area involvement.
Patient Characteristics and Clinical Presentation
All 14 patients suspected for CTCL experienced deterioration of symptoms after an initial adequate response to dupilumab treatment. In both MF and LR groups, patients were in their mid-50s and the median time from dupilumab initiation to clinical worsening was 4 months, with a broad range up to almost 1 year in the LR group (Table 1). In the MF group only 1 patient had allergic rhinitis, whereas in the LR group, 7 patients (63.6%) had 1 or more allergic comorbidities. Patients reported new symptoms (eg, burning/painful sensation of the skin) and, although they reported itch, excoriations were mild or absent in all patients (Table 1). Several patients reported that their skin lesions were different compared with their usual lesions during an AD flare. Although findings on physical examination were somewhat heterogeneous in LR, most common findings were the (generalized) erythematous maculopapular plaques, sometimes with (severe) lichenification in the lower trunk and upper thighs (Figure 1B). Some patients were suberythrodermic.
Histopathologic Features
All biopsies, from those with MF and those with LR, showed a variety of eczematous characteristics including spongiosis, acanthosis, and parakeratosis. In addition, all biopsies showed a lymphoid infiltrate with lichenoid or perivascular distribution and intraepithelial T-cell lymphocytes (Table 2, Figure 2A). In MF, atypical small/medium hyperconvoluted, and cerebriform lymphocytes were lined up in the basal layer of the epidermis at the dermoepidermal junction. In LR, similar small, hyperchromatic, and cerebriform lymphocytes were found, laying in a sprinkled pattern in the upper epidermal section (Figure 2B). Regarding IHC, we found a dysregulated CD4:CD8 ratio in both MF and LR. In most patients with LR we found monotypical CD4 expression, which is also most commonly seen in those with MF (Table 2, Figure 2 C and D).14 In all LR cases there was no loss of CD2, CD3, and C5 (Table 2, Figure 2E). On the contrary, among the patients with MF there was varying loss of CD2 and CD5. Loss of CD5 is frequently a sign of early-stage MF with eventual loss of CD2 and/or CD3 in a later disease stage.6 Furthermore, a characteristic feature of LR was CD30 overexpression, which is in general negative in early-stage MF (Figure 2F). In patient 14, the CD30 staining was positive, indicating an advanced stage of MF, which corresponds with the misdiagnosis of almost 14 years. Remarkably, patient 13 had a biopsy that showed MF- and LR-like features, indicating that this patient had both skin conditions (Table 2).
Table 2. Histopathologic Findings of the Biopsies During Dupilumab Treatment.
| Finding | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Patient 7 | Patient 8 | Patient 9 | Patient 10 | Patient 11 | Patient 12 | Patient 13 | Patient 14 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Diagnosis | LR | LR | LR | LR | LR | LR | LR | LR | LR | LR | LR | MF | MF/LR | MF |
| Eczematous features | ||||||||||||||
| Acanthosis | Moderately present | Mildly present | Severely present | Mildly present | Moderately present | Moderately present | Moderately present | Mildly present | Moderately present | Mildly present | Mildly present | Mildly present | Moderately present | Mildly present |
| Spongiosis | Moderately present | Mildly present | Severely present | Mildly present | Moderately present | Mildly present | Moderately present | Mildly present | Moderately present | Mildly present | Mildly present | Absent | Mildly present | Mildly present |
| Parakeratosis | Moderately present | Mildly present | Severely present | Mildly present | Moderately present | Mildly present | Mildly present | Moderately present | Moderately present | Mildly present | Mildly present | Mildly present | Mildly present | Moderately present |
| Presence of lymphoid infiltrate | Moderately present | Moderately present | Moderately present | Moderately present | Moderately present | Moderately present | Severely present | Moderately present | Severely present | Moderately present | Moderately present | Mildly present | Moderately present | Severely present |
| Distribution lymphoid infiltrate stratum papillare | ||||||||||||||
| Perivascular | Mildly present | Mildly present | Mildly present | Absent | Mildly present | Moderately present | Moderately present | Moderately present | Mildly present | Mildly present | Mildly present | Absent | Mildly present | Mildly present |
| Lichenoid | Moderately present | Moderately present | Moderately present | Severely present | Absent | Absent | Mildly present | Mildly present | Absent | Absent | Absent | Mildly present | Mildly present | Mildly present |
| Intraepithelial T-cell lymphocytes | Mildly present | Mildly present | Mildly present | Mildly present | Moderately present | Mildly present | Severely present | Moderately present | Severely present | Moderately present | Mildly present | Mildly present | Moderately present | Mildly present |
| Lining of cells in basal layer | Mildly present | Absent | Absent | Absent | Absent | Absent | Absent | Absent | Absent | Absent | Mildly present | Mildly present | Moderately present | Mildly present |
| Sprinkled pattern in epithelial layer | Moderately present | Moderately present | Moderately present | Mildly present | Moderately present | Mildly present | Moderately present | Moderately present | Mildly present | Moderately present | Moderately present | Absent | Mildly present | Absent |
| IHC | ||||||||||||||
| CD2, CD3, CD5 | No loss | No loss | No loss | No loss | No loss | No loss | No loss | No loss | No loss | No loss | No loss | CD5a | CD2,a CD5a | CD2a |
| CD4/CD8 ratio | CD4>CD8 | CD4>>>CD8 | CD4>CD8 | CD4>CD8 | CD4<CD8 | CD4>CD8 | CD4<<CD8 | CD4:CD8 | CD4>CD8 | CD4<CD8 | CD4>CD8 | CD4>CD8 | CD4>CD8 | CD4>>>CD8 |
| CD30 expression | Mildly present | Severely present | Moderately present | Moderately present | Mildly present | Mildly present | Moderately present | Moderately present | Mildly present | Mildly present | Moderately present | Absent | Mildly present | Severely present |
Abbreviations: IHC, immunohistochemical staining; LR, lymphoid reaction; MF, mycosis fungoides.
IHC decreased.
Figure 2. Histopathologic Images of Dupilumab-Associated Lymphoid Reactions (LRs) From Different Patients.
Clinical and Histopathologic Follow-Up
Dupilumab treatment was discontinued in all patients with MF and LR. In all patients with LR, improvement of clinical symptoms was reported. However, as the burning sensation and the maculopapular exanthema disappeared, AD lesions emerged and patients reported more itch. Posttreatment biopsies showed clearance of the LR with negative CD30 staining (Figure 3 A and B; eTable 3 in Supplement 1). The median follow-up time after the development of an LR was 24.8 months in which most patients experienced mild AD while treated with other systemic therapies (eTable 4 in Supplement 1). In patient 12 with MF, a posttreatment biopsy was available in which MF features were more subtle (without marker loss) after dupilumab discontinuation (eTable 3 in Supplement 1). The patient showed temporal clinical improvement; however, due to an increase in MF symptoms, psoralen UV-A light (PUVA) therapy was started. Of the other 2 patients with MF, there was no follow-up data available because 1 patient died due to sepsis and the other patient was referred to a secondary care hospital for PUVA therapy. An overview of overlapping and differences in histopathologic findings between AD, LR, and MF is shown in Figure 3C.
Figure 3. Images of Posttreatment Biopsies After the Development of a Dupilumab-Associated Lymphoid Reaction and Summary of Histopathologic Features.
A, Overview slide with complete clearance of the lymphoid infiltrate. B, Complete clearance of the lymphoid reaction and negative CD30 staining results. C, Overlapping and differences in histopathologic features of atopic dermatitis, lymphoid reactions, and mycosis fungoides.
Discussion
This case series study characterizes histopathologic features of LRs developing during dupilumab treatment in patients with AD who were clinically suspected to have CTCL. We found 11 of 530 patients (2.1%) who developed an LR with deterioration of symptoms (eg, burning sensation, itch) after initial response to dupilumab treatment. Striking histopathologic features were the small hyperchromatic lymphocytes with a sprinkled distribution in the upper epidermal section, a dysregulated CD4:CD8 ratio, CD30 overexpression, and no loss of pan–T-cell antigens (CD2, CD3, and CD5). Posttreatment biopsies showed clearance of the LR. Three of 530 patients (0.6%) had a misdiagnosed MF who also experienced clinical worsening after initial response to dupilumab treatment.
Recognition of an LR can be challenging for various reasons. First of all, the clinical and histopathologic presentation of LRs include several eczematous features (eg, itch, burning of the skin [although uncommon in patients with AD], erythematous lesions, spongiosis, parakeratosis). Clinical worsening during dupilumab treatment can therefore easily be misdiagnosed as an AD flare. However, several patients with LR described that their skin lesions were different than an AD flare and reported burning and/or pain as a new symptom. Clinically, we observed less squamous and excoriated lesions and a more (diffuse) maculopapular exanthema, with lichenification in the lower trunk/upper thighs in some patients. We found a relatively broad interpatient variability in time between clinical improvement and development of LR lesions after the start of dupilumab, which might hamper early diagnosis as well. Notably, in more than half of the patients, skin biopsies were taken prior to dupilumab treatment, suggesting a more atypical presentation of AD because AD is usually diagnosed clinically.
Furthermore, LRs seem to mimic an early-stage CTCL in both clinical symptoms and histopathologic findings. Overlapping features are pruritic erythematous lesions, sometimes specifically on the lower trunk/upper thighs and the lymphoid infiltrate with a dysregulated CD4:CD8 ratio (mostly CD4>CD8).14,15,16 Another similarity is the presence of intraepithelial T-cell lymphocytes.6,17 However, features that can potentially distinguish LR from MF are the lack of pan–T-cell markers loss and the presence of small cerebriform lymphocytes sprinkled in the upper epidermal section, whereas in early-stage MF these cerebriform lymphocytes are lined up in the basal layer of the epidermis.17 Also, CD30 expression is usually not seen in early-stage MF and can therefore be a distinctive feature in recognizing LR. The coexistence of MF and LR in 1 of these patients highlights the complexity of accurate diagnosis. Furthermore, some features of LRs are similar to primary cutaneous CD30-positive T-cell lymphoproliferative disorders (CD30+ T-LPDs), the second most common type of CTCL, which account for approximately 25% of all CTCLs.14 Overall, CD30+ T-LPD includes 2 main skin conditions; lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). Their common hallmark and matching feature with LRs is the expression of CD30 by atypical lymphocytes.15,16 However, these lymphocytes are medium to large in size instead of small, and intraepithelial T-cell lymphocytes are usually absent or subtle. Also, in most cases of pcALCL and LyP there is variable loss of pan–T-cell antigens, which is not seen in those with LR.16 Furthermore, the clinical presentation is different from LR. Overall, pcALCL is characterized by solitary or grouped nodules that rapidly grow to tumorous and sometimes ulcerated lesions, whereas LyP presents with recurring disseminated or grouped papules and small nodules.14,15,16 In both conditions, there is or can be spontaneous regression of the lesions.15 Clinical practice has shown that continuation of dupilumab treatment in our first LR cases with a relatively late diagnosis (because this was not directly recognized as such), led to clinical progression of skin lesions. This raises the question if LRs might evolve into a CTCL if dupilumab treatment is not permanently stopped, which hypothesis is strengthened by the patient with both MF and LR.
The role of dupilumab in the unmasking and progression of CTCLs has previously been discussed in several case series. Our findings on patients with MF are in line with these studies.3,4,5,17,18 The study by Espinosa et al3 reported that dupilumab seemed to temporarily relieve pruritus and erythema, but was associated with progression of CTCL after long-term use. They theorized that the initial improvement might be caused by transient blockage of the Th2 pathway, leading to a shift toward a Th1 tumor-suppressive effect via interferon-y.3 However, because early-stage MF is Th1-mediated and late-stage MF has a Th2 predominance, it is plausible that dupilumab treatment accelerates a disturbed Th1/2 balance in an early stage of CTCL.19 The transition of AD, an inflammatory disease, into an lymphoid infiltrate and/or neoplasia is complex, and the exact pathomechanism remains unknown. Sokumbi et al4 described 7 patients who developed an atypical lymphoid infiltrate or MF during dupilumab treatment. All of these patients had a biopsy-proven AD before the start of dupilumab treatment.4 Exogenous and endogenous factors on a molecular level (eg, viral or nonviral, self-altered or cross-reactive antigens) may drive lymphocytes from a chronic inflammatory condition into a reactive cell proliferation, subsequently leading to genomic instability (genotraumatic lymphocytes) and therefore neoplastic processes.19 It was hypothesized that dupilumab, by targeting the IL-4/13 signaling pathway, might be a trigger for the progression of initially benign lymphoid infiltrates, leading to clonal expansion of T lymphocytes and possibly to malignant transformation.4 The presence of LRs might be part of this transformational process, though the exact outcome remains unknown because dupilumab treatment was discontinued in these patients.
Next to CTCLs, there are other skin conditions with histopathologic features similar to LR, such as cutaneous B-cell lymphomas and various inflammatory and infectious diseases (eg, herpes simplex, scabies, Epstein-Barr virus, perniosis, and drug reactions). A common feature are the CD30-positive–presenting immune cells.16,20,21 However, as emphasized before, it is important to correlate clinical presentation with histopathologic findings. In patients with LR, both clinical and histopathologic presentation showed several comparable findings with cutaneous drug reactions (ie, [generalized] maculopapular erythema, a perivascular [atypical] lymphoid infiltrate, CD30 expression). Moreover, Etesami et al22 reported on 89 cases in which drug-induced cutaneous pseudolymphomas (CPL) were found. In these patients (epi)dermal lymphoid infiltrates were found together with CD30 expression in 87.5% of the patients. Magro et al23 even reported on atypical lymphocytes in the superficial layers of the epidermis. The most common drugs associated with these CPLs were antihypertensive medications, anticonvulsants, monoclonal antibodies, and antidepressants, which were only used by 2 of the 11 patients in the present study. In 12 of 89 patients with CPL, a monoclonal antibody triggered the skin reaction (eg, infliximab, adalimumab, secukinumab), of which 5 patients had a dysregulated CD4:CD8 ratio.22 Because dupilumab is a monoclonal antibody, though with a different therapeutic mode of action, these drug-induced CPLs strengthen our findings on dupilumab-associated LRs and therefore it might be a subtype of CPLs.
This study highlights the need for caution in continuing dupilumab treatment in patients with AD with clinical worsening and newly reported symptoms (eg, burning sensation) after initial adequate response because these patients might develop an LR. We hypothesize that these benign LRs may evolve into CTCL if dupilumab treatment is not permanently stopped. So, as dupilumab treatment might reveal a misdiagnosed MF, histopathologic evaluation including IHC is advised in specific patients (eg, late-onset AD, nonatopic elderly with an atypical and/or severe [progressive] presentation).24,25,26
Limitations
The current study may be biased because all included patients were treated in a tertiary referral hospital, indicating a difficult-to-treat AD subpopulation. Also, reassessment of the biopsies was performed by the same pathologist. Another limitation is the relatively small sample size and the retrospective design. Other case reports/series are therefore needed to confirm our findings on dupilumab-induced LRs.
Conclusions
Dupilumab treatment may cause a reversible and most likely benign LR in patients with AD that mimics a CTCL, though it has distinctive histopathologic features. Clinical and histopathologic recognition of an LR is important, and treatment discontinuation is recommended in these patients.
eTable 1. Histopathologic findings of biopsies before dupilumab treatment
eTable 2. Clinical features of patients with a lymphoid reaction or mycosis fungoides based on diagnostic criteria for MF
eTable 3. Histopathologic findings of the biopsies after dupilumab treatment
eTable 4. Clinical follow-up of patients with lymphoid reactions up to 4 years after treatment discontinuation
Data Sharing Statement
References
- 1.Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023):1109-1122. doi: 10.1016/S0140-6736(15)00149-X [DOI] [PubMed] [Google Scholar]
- 2.Ariëns LFM, van der Schaft J, Spekhorst LS, et al. Dupilumab shows long-term effectiveness in a large cohort of treatment-refractory atopic dermatitis patients in daily practice: 52-Week results from the Dutch BioDay registry. J Am Acad Dermatol. 2021;84(4):1000-1009. doi: 10.1016/j.jaad.2020.08.127 [DOI] [PubMed] [Google Scholar]
- 3.Espinosa ML, Nguyen MT, Aguirre AS, et al. Progression of cutaneous T-cell lymphoma after dupilumab: Case review of 7 patients. J Am Acad Dermatol. 2020;83(1):197-199. doi: 10.1016/j.jaad.2020.03.050 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sokumbi O, Shamim H, Davis MDP, Wetter DA, Newman CC, Comfere N. Evolution of dupilumab-associated cutaneous atypical lymphoid infiltrates. Am J Dermatopathol. 2021;43(10):714-720. doi: 10.1097/DAD.0000000000001875 [DOI] [PubMed] [Google Scholar]
- 5.Hashimoto M, Miyagaki T, Komaki R, Takeuchi S, Kadono T. Development of nodular lesions after dupilumab therapy in erythrodermic mycosis fungoides with interleukin-13 receptor alpha2 expression. Acta Derm Venereol. 2022;102:adv00766. doi: 10.2340/actadv.v102.2234 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Amorim GM, Niemeyer-Corbellini JP, Quintella DC, Cuzzi T, Ramos-E-Silva M. Clinical and epidemiological profile of patients with early stage mycosis fungoides. An Bras Dermatol. 2018;93(4):546-552. doi: 10.1590/abd1806-4841.20187106 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Maguire A, Puelles J, Raboisson P, Chavda R, Gabriel S, Thornton S. Early-stage Mycosis Fungoides: Epidemiology and Prognosis. Acta Derm Venereol. 2020;100(1):adv00013. doi: 10.2340/00015555-3367 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kołkowski K, Trzeciak M, Sokołowska-Wojdyło M. Safety and Danger Considerations of Novel Treatments for Atopic Dermatitis in Context of Primary Cutaneous Lymphomas. Int J Mol Sci. 2021;22(24):13388. doi: 10.3390/ijms222413388 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Legendre L, Barnetche T, Mazereeuw-Hautier J, Meyer N, Murrell D, Paul C. Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: A systematic review and meta-analysis. J Am Acad Dermatol. 2015;72(6):992-1002. doi: 10.1016/j.jaad.2015.02.1116 [DOI] [PubMed] [Google Scholar]
- 10.Mansfield KE, Schmidt SAJ, Darvalics B, et al. Association Between Atopic Eczema and Cancer in England and Denmark. JAMA Dermatol. 2020;156(10):1086-1097. doi: 10.1001/jamadermatol.2020.1948 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Geskin LJ, Viragova S, Stolz DB, Fuschiotti P. Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation. Blood. 2015;125(18):2798-2805. doi: 10.1182/blood-2014-07-590398 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Saulite I, Hoetzenecker W, Weidinger S, Cozzio A, Guenova E, Wehkamp U. Sézary Syndrome and Atopic Dermatitis: Comparison of Immunological Aspects and Targets. Biomed Res Int. 2016;2016:9717530. doi: 10.1155/2016/9717530 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Public Palga Pathology Database . https://www.palga.nl/data/openbare-databank
- 14.Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;133(16):1703-1714. doi: 10.1182/blood-2018-11-881268 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Guitart J, Querfeld C. Cutaneous CD30 lymphoproliferative disorders and similar conditions: a clinical and pathologic prospective on a complex issue. Semin Diagn Pathol. 2009;26(3):131-140. doi: 10.1053/j.semdp.2009.09.001 [DOI] [PubMed] [Google Scholar]
- 16.Kempf W. A new era for cutaneous CD30-positive T-cell lymphoproliferative disorders. Semin Diagn Pathol. 2017;34(1):22-35. doi: 10.1053/j.semdp.2016.11.005 [DOI] [PubMed] [Google Scholar]
- 17.Hollins LC, Wirth P, Fulchiero GJ Jr, Foulke GT. Long-standing dermatitis treated with dupilumab with subsequent progression to cutaneous T-cell lymphoma. Cutis. 2020;106(2):E8-E11. doi: 10.12788/cutis.0074 [DOI] [PubMed] [Google Scholar]
- 18.Poyner EFM, Bacon CM, Osborne W, Frew JA, Weatherhead SC. Dupilumab unmasking cutaneous T-cell lymphoma: report of a fatal case. Clin Exp Dermatol. 2022;47(5):974-976. doi: 10.1111/ced.15079 [DOI] [PubMed] [Google Scholar]
- 19.Burg G, Dummer R, Haeffner A, Kempf W, Kadin M. From inflammation to neoplasia: mycosis fungoides evolves from reactive inflammatory conditions (lymphoid infiltrates) transforming into neoplastic plaques and tumors. Arch Dermatol. 2001;137(7):949-952. [PubMed] [Google Scholar]
- 20.Werner B, Massone C, Kerl H, Cerroni L. Large CD30-positive cells in benign, atypical lymphoid infiltrates of the skin. J Cutan Pathol. 2008;35(12):1100-1107. doi: 10.1111/j.1600-0560.2007.00979.x [DOI] [PubMed] [Google Scholar]
- 21.Kempf W. CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators. J Cutan Pathol. 2006;33(suppl 1):58-70. doi: 10.1111/j.0303-6987.2006.00548.x [DOI] [PubMed] [Google Scholar]
- 22.Etesami I, Kalantari Y, Tavakolpour S, Mahmoudi H, Daneshpazhooh M. Drug-induced cutaneous pseudolymphoma: A systematic review of the literature. Australas J Dermatol. 2023;64(1):41-49. doi: 10.1111/ajd.13951 [DOI] [PubMed] [Google Scholar]
- 23.Magro CM, Daniels BH, Crowson AN. Drug induced pseudolymphoma. Semin Diagn Pathol. 2018;35(4):247-259. doi: 10.1053/j.semdp.2017.11.003 [DOI] [PubMed] [Google Scholar]
- 24.Adam DN, Gooderham MJ, Beecker JR, et al. Expert consensus on the systemic treatment of atopic dermatitis in special populations. J Eur Acad Dermatol Venereol. 2023;37(6):1135-1148. doi: 10.1111/jdv.18922 [DOI] [PubMed] [Google Scholar]
- 25.Vakharia PP, Silverberg JI. Adult-Onset Atopic Dermatitis: Characteristics and Management. Am J Clin Dermatol. 2019;20(6):771-779. doi: 10.1007/s40257-019-00453-7 [DOI] [PubMed] [Google Scholar]
- 26.Pimpinelli N, Olsen EA, Santucci M, et al. ; International Society for Cutaneous Lymphoma . Defining early mycosis fungoides. J Am Acad Dermatol. 2005;53(6):1053-1063. doi: 10.1016/j.jaad.2005.08.057 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Histopathologic findings of biopsies before dupilumab treatment
eTable 2. Clinical features of patients with a lymphoid reaction or mycosis fungoides based on diagnostic criteria for MF
eTable 3. Histopathologic findings of the biopsies after dupilumab treatment
eTable 4. Clinical follow-up of patients with lymphoid reactions up to 4 years after treatment discontinuation
Data Sharing Statement