Eczematoid paradoxical reaction in psoriasis patients following secukinumab

To the Editor: Biologics have been used successfully for the treatment of psoriasis; however, some patients develop paradoxical reactions, particularly psoriasiform and eczematoid reactions. Eczematoid paradoxical reactions (EPRs) occur in 1%–6% of cases treated with tumor necrosis factor (TNF)-α inhibitors, 2.4% with interleukin (IL)-12/23 inhibitors, 3.5% with IL-17 inhibitors, and 0.01% with IL-23 inhibitors.[1] In practice, the incidence of EPRs induced by IL-17A inhibitors varies widely[2–4] and biologicals may have to be discontinued in some severe cases.[5] We conducted a retrospective, single-centered, case-control study enrolling 1308 patients aged 18 years and older with plaque psoriasis who were treated with secukinumab between May 2019 and December 2022. This study was reviewed and approved by the Institutional Review Board of Peking University People’s Hospital (No. 2022PHB410-001). Patient data included baseline characteristics and demographics, comorbidities, initiation and duration of secukinumab, onset, treatment, and outcome of EPR, and laboratory profiles, including peripheral blood eosinophils, basophils, total serum IgE, and cytokines (IL-2, IL-4, IL-5, IL-10, IL-17A, IL-17F, IL-22, TNF-α, and interferon-γ). Sixty patients (4.6%) developed EPRs (male 37; female 23), including 36 (60.0%) mild, 21 (35.0%) moderate, and three (5.0%) severe cases. Twenty-five patients with EPR (41.7%) had a history of atopic diseases. A personal or family history of atopic diseases was more common in patients with an EPR compared with those without an EPR (41.7% vs. 4.8% and 25.0% vs. 1.7%, respectively; P <0.001). The incidence of nail involvement was significantly lower in patients with EPR than in those without (21.7% vs. 44.3%, P = 0.001). There was no significant difference in the incidence of joint involvement between patients with and without EPR (13.3% vs. 16.3%, P = 0.536), and the incidences of hypertension and metabolic disorders were similar between the two groups [Table 1]. Table 1 - Demographic and clinical characteristics of psoriasis patients with EPR and non-EPR. Items EPR (N = 60) Non-EPR (N = 1248) P-value Gender (M/F) 37/23 858/390 0.249 Age (years) 45.4 ± 12.9 42.9 ± 14.3 0.422 Body mass index (kg/m2) 25.9 ± 4.4 25.2 ± 4.0 1.000 Smoking 15 (25.0) 371 (29.7) 0.433 Drinking 9 (15.0) 292 (23.4) 0.131 Personal atopic history 25 (41.7) 60 (4.8) <0.001 Family atopic history 15 (25.0) 21 (1.7) <0.001 Duration of psoriasis 18.0 (10.0, 24.0) 13.0 (8.0, 20.0) 0.098 BSA 20.0 (14.8, 30.0) 18.0 (9.0, 35.6) 0.290 PASI 18.9 (13.0, 25.5) 16.8 (10.4, 26.0) 0.176 Psoriatic arthritis 8 (13.3) 204 (16.3) 0.536 Nail involvement 13 (21.7) 553 (44.3) 0.001 Family history of psoriasis 17 (28.3) 306 (24.5) 0.503 Overweight/obesity 32 (53.3) 605 (48.5) 0.462 Hypertension 13 (21.7) 184 (14.7) 0.143 Diabetes 6 (10.0) 115 (9.2) 0.838 Dyslipidemia 26 (43.3) 516 (41.3) 0.760 Hyperuricemia 14 (23.3) 282 (22.6) 0.894 After EPR occurrence EASI 4.5 (1.5, 11.1) PP-NRS 9.0 (6.5, 10.0) PP-NRS ≥4 54 (90.0) S-NRS 8.0 (5.0, 10.0) S-NRS ≥4 51 (85.0) Lesions location Scalp and face 53 (88.3) Upper extremities 26 (43.3) Trunk 26 (43.3) Lower extremities 27 (45.0) Data are expressed as mean ± standard deviation, median (Q1, Q3) or n (%). BSA: Body surface area affected by psoriasis; EASI: Eczema Area and Severity Index; EPR: Eczematoid paradoxical reaction; PASI: Psoriasis area severity index; PP-NRS: Peak Pruritus Numerical Rating Scale; S-NRS: Sleep Numerical Rating Scale. Overweight and obesity were defined as body mass index ≥25.0 and 30.0 kg/m2, respectively. Hypertension was defined as systolic/diastolic blood pressure ≥140 mmHg/90 mmHg based on the 2010 Chinese Guidelines for the Management of Hypertension. Diabetes was defined as fasting plasma glucose ≥6.1 mmol/L and/or 2-h post-load glucose ≥7.8 mmol/L. Dyslipidemia was defined as triglycerides ≥1.7 mmol/L, total cholesterol ≥6.2 mmol/L, low-density lipoprotein cholesterol ≥4.1 mmol/L, or high-density lipoprotein cholesterol <0.9 mmol/L (male) or <1.0 mmol/L (female) based on the 2016 Chinese Guideline for the Management of Dyslipidemia in Adults. The PP-NRS was used to measure peak pruritus or “worst” pruritus in the past 24 h based on the following question: On a scale of 0–10, where 0 is “no pruritus” and 10 is “worst pruritus imaginable,” how would you rate your pruritus at the worst time during the past 24 h? 0 ≤PP-NRS <4 is considered mild pruritus, 4 ≤PP-NRS <7 is considered moderate pruritus, and 7 ≤PP-NRS ≤10 is considered severe pruritus. The S-NRS was used to assess the degree of sleep disturbance in patients with EPR and atopic dermatitis, where 0 indicates no effect and 10 indicates unable to sleep. 0 ≤S-NRS score <4 is considered mild, 4 ≤S-NRS score <7 is considered moderate, and 7 ≤S-NRS score ≤10 is considered severe. The onset of EPRs ranged from 3 days to 24 months after the start of secukinumab treatment (median 2.0 months). Twenty-seven patients (45.0%) had localized lesions, most commonly on the head and face (88.3%), followed by the lower limbs (45.0%), upper limbs (43.3%), and trunk (43.3%). The median Eczema Area and Severity Index was 4.5 (1.5, 11.1). Pruritus was present in all patients with an EPR and the median Peak Pruritus Numerical Rating Scale (PP-NRS) score was 9.00 (6.5, 10.0) and the median Sleep Numerical Rating Scale (S-NRS) score was 8.0 (5.0, 10.0) [Table 1]. Serum total IgE and eosinophil levels were elevated after EPR in 22 (36.7%) and six patients (10.0%) in the EPR group, respectively, and both were higher than in the non-EPR group (36.7% vs. 5.1%, P <0.001 and 10.0% vs. 3.8%, P = 0.045, respectively), but the incidence of elevated total serum IgE before EPR was similar in the EPR and non-EPR groups (6/60 = 10.0% vs. 64/1248 = 5.1%, P = 0.179). The proportion of patients with elevated total serum IgE before and after EPR was higher in the EPR group (10.0% vs. 36.7%, P <0.001). Serum cytokine levels before and after initiation of EPR in six patients showed elevated IL-5 levels in one patient and elevated IL-22 levels in another patient after EPR. Logistic regression analysis showed that a personal or family history of atopy was a risk factor for EPR, whereas nail psoriasis was a protective factor. A predictive model constructed using personal and family history of atopy and nail psoriasis had an area under the curve of 0.74 (95% confidence interval 0.67–0.81), specificity of 0.87, sensitivity of 0.57, and an F1 score of 0.74, indicating that the model had a better fit. Forty-two (70.0%) patients with EPR continued to receive secukinumab with dose reduction or an extended interval to every 6–8 weeks, topical treatment, and antihistamines, and their EPR gradually improved; however, three patients (7.1%) experienced psoriasis relapse. Ten patients (16.7%) discontinued secukinumab after which their EPR improved rapidly, but psoriasis relapsed in seven patients. Eight (13.3%) patients switched to other biologics, including three patients who switched to adalimumab, two patients who switched to ustekinumab, and three patients who switched to ixekizumab, with improvement in all patients except the three who switched to ixekizumab. EPR induced by IL-17A inhibitors tended to have a shorter onset time compared with EPR induced by TNF-α inhibitors. Th2 skewing and IL-17 family cytokines have been implicated in EPR and may be responsible for its occurrence; however, the mechanism remains unclear.[6] In this study, the lesions in most patients with EPR were mild or moderate; however, most patients had severe pruritus, suggesting that the mechanism of pruritus in EPR may differ from that of psoriasis. Blockade of IL-17A can lead to upregulation of IL-23, IL-17F, TNF-α, and IL-22, and IL-22 may in turn be involved in the activation of the pruritus-specific signaling pathway (gastrin-releasing peptide receptor).[7] Caldarola et al[2] found that a high number of patients had a personal or family history of atopic disease, with an increase in total IgE and eosinophils. In this study, although personal and family histories of atopic disease were independent risk factors for EPR, there was no significant difference in total serum IgE between the EPR and non-EPR groups at baseline. Serum total IgE and peripheral blood eosinophil levels are elevated in patients who develop EPR, and physicians should thus question patients with psoriasis carefully regarding their personal and family history of atopic diseases before starting biologic therapy. Total serum IgE and peripheral blood eosinophil levels should be monitored during the biologic therapy. In this study, the lesions in most patients with EPR were mild and responded well to topical treatment, and 70.0% of patients achieved remission with appropriate interventions. These patients were accordingly able to continue treatment with secukinumab, which is an important consideration in clinical practice. Further studies are needed to confirm if interventions prior to the use of biologics could prevent EPR in patients with a personal or family history of atopic disease. Acknowledgements We would like to thank Dr. Yin Su and Dr. Yuan Jia from the Department of Rheumatology and Immunology, Peking University People’s Hospital, for their help in diagnosing psoriatic arthritis, and all the patients who participated in this study. Funding This work was supported by a grant from Bethune Charitable Foundation (No. J202301E036). Conflicts of interest None.