Targeting interleukin 4 and interleukin 13: a novel therapeutic approach in bullous pemphigoid

Figures & data

Table 1. Case reports and studies of BP patients treated with dupilumab.

	Year of publication	Number of patients	Sex	Age (years)	Patients’ comorbidities	Concomitant medication	Systemic BP medication before dupilumab (overall)	Response to medication before dupilumab	Disease duration before dupilumab initiation (months)	Dosage of dupilumab	Concurrent therapies with dupilumab	Response to dupilumab	Last follow-up condition
Cao et al. [28]	2022	26	15 M, 18 F, 3 Not Reported	74.3 Mean	Not reported	Not reported	Corticosteroids (N = 24/36); Methotrexate (N = 8/36); Mycophenolate Mofetil (N = 5/36); Azathioprine (N = 2/36); Cyclosporine (N = 1/36); Cyclophosphamide (N = 1/36); Dapsone (N = 1/36); Doxycycline (N = 6/36); Nicotinamide (N = 5/36); Intravenous immunoglobulin (N = 5/36); Antihistamines (N = 1/36); Rituximab (N = 2/36); Omalizumab (N = 5/36)	Failed to control disease	19.2 Average	Not mentioned	Corticosteroids (N = 26/36); Methotrexate (N = 3/36); Mycophenolate mofetil (N = 2/36); Azathioprine (N = 9/36); Cyclosporine (N = 0/36); Cyclophosphamide (N = 1/36); Dapsone (N = 0/36); Doxycycline (N = 2/36); Nicotinamide (N = 1/36); Intravenous immunoglobulin (N = 0/36); Antihistamines (N = 0/36); Omalizumab (N = 1/36); None (N = 3/36); Not reported (N = 1/36)	Complete remission (N = 86/122); Partial remission (N = 29/122); No remission (N = 6/122); Deteriorated (N = 1/122); Average remission time: 5.7 months	Mean follow-up time: 21.9 months; Recurred (N = 25/122); Did not recur (N = 86/122); Did not report (N = 4/122)
Velin et al. [29]	2022	8	4 M, 4 F	79.5 Mean	Not reported	Not reported	Topical corticosteroids (N = 8); Systemic corticosteroids (N = 1); Methotrexate (N = 3); Omalizumab (N = 2)	Unresponsive	17.2 Mean	600 mg SC initially; 300 mg Q2W	Topical corticosteroids (N = 7); Systemic corticosteroids (N = 5)	Complete response (N = 3); Partial response (N = 1); Poor response (N = 1); Non-treatment-related deaths (N = 2); Intolerance with burning sensation (N = 1)	/
Yang et al. [19]	2022	20 in dupilumab and methylprednisolone group (dupilumab group); 20 in methylpre­dnisolone alone group (control group)	10 M and 10 F in dupilumab group; 8 M and 12 F in control group	72 Median in both group	Hypertension (n1 = 6) (n2 = 7); Cardiovascular disease (n1 = 3) (n2 = 4); Diabetes mellitus (n1 = 4) (n2 = 3); Chronic renal insufficiency (n1 = 3) (n2 = 3); Neurologic disorder (n1 = 5) (n2 = 6); Interstitial lung disease (n1 = 5) (n2 = 4); Tumor (n1 = 1) (n2 = 3)	Not reported	3 patients with dupilumab had previously undergone systemic therapy; 37 patients were newly diagnosed and received no prior treatment	The 3 patients reached complete remission off therapy, but relapsed without treatment	5 Median in both group	600 mg SC initially; 300 mg Q2W	Equivalent dose of methylprednisolone at <0.4 mg/kg/day for patients in dupilumab group; Equivalent dose of methylprednisolone at 0.4 mg/kg/day in moderate patients or at 0.6–0.8 mg/kg/day in patients with extensive disease in control group	Shorter time to reach disease control in the dupilumab group than the control group (14 vs. 19 days, p = 0.043); Lower control dose and cumulative dosage of methylprednisolone in the dupilumab group than the control group (24.6 vs. 48.8 mg, 376.8 vs. 985.6 mg, both p < 0.01); Less adverse events in the dupilumab group	/
Takamura and Teraki [30]	2022	1	F	72	Diabetes mellitus	Dipeptidyl peptidase-4 inhibitors	Minocycline and nicotinic acid amide; Patients refuse treatment with oral corticosteroids	No improvement	1.5	600 mg SC initially; 300 mg Q2W	Not reported	Complete improvement of pruritus within 2 weeks; Complete improvement of skin blisters within 4 weeks; Anti-BP180 antibodies became negative at 7 months	No recurrence of BP for at least 12 months
Pop et al. [21]	2022	1	F	59	Cervical cancer	Pembrolizumab	Methylprednisolone, prednisone, doxycycline, niacinamide, dapsone, and topical corticosteroids	Numerous flares of BP	12	300 mg Q2W	Steroid 60 mg daily (0.75 mg/kg/day) tapered down to 5 mg daily after 2 months;	Cessation of new BP lesions after 2 months; Relapsed after missed 4 doses of dupilumab at month 5; Re-initiation of dupilumab, doxycycline 100 mg twice daily, and prednisone 60 mg daily (tapered down to 10 mg/day over 4 weeks) reached disease clearance	Remained clear for an additional 6 months
Wang et al. [17]	2022	1	M	72	Type 2 diabetes mellitus	Not reported	Methylprednisolone and methotrexate	Absence of improvement	Not reported	300 mg SC twice	Not reported	Significant improvement of pruritus the next day; Improvement of skin lesions after 2 weeks	Not reported
Wang et al. [17]	2022	1	M	88	Tuberculosis	Not reported	Methylprednisolone at high dose	Absence of skin lesions improvement	12	300 mg SC twice	Not reported	Significant improvement of skin lesions after 2 weeks	Not reported
Shan and Zuo [20]	2022	1	M	32	Tuberculosis	Isoniazid, rifampicin, and ethambutol	Corticosteroid 15 mg daily (later increased to 35 mg daily)	Two flares of disease and later diagnosed of pulmonary tuberculosis	18	600 mg SC initially; 300 mg Q2W	Prednisolone	Improvement of pruritus within 1 week; Cessation of new vesicles within 1 week; Clearance of vesicles within 2 weeks	Discontinued of prednisolone; Remained stable after treated with dupilumab for 12 times
Jendoubi et al. [22]	2022	1	F	76	Hypertension, diabetes, obesity, and atrial fibrillation	Not reported	Topical corticosteroids	Flare of disease during tapering of topical corticosteroids	Not reported	600 mg SC initially; 300 mg Q2W	Not reported	Clearance of pruritus and lesions in 4 months	No recurrence for at least 6 months
Bruni et al. [23]	2022	1	M	76	Melanoma	Nivolumab	Systemic and topical corticosteroids, and doxycycline	Flare of disease during tapering of corticosteroids	Not reported	300 mg Q2W	Methylprednisolone 20 mg daily	Significant clinical improvement after 2 months; Cessation of new blisters within 4 months; Clearance of BP lesions in 6 months	/
Li et al. [18]	2022	1	M	85	Asthma and ulcerative colitis	No need for drugs	Topical corticosteroids, tofacitinib, antihistamines, and omalizumab,	Absence of improvement	2	600 mg SC initially; 300 mg Q2W	Not reported	Improvement of pruritus within 1 week; Clearance of BP lesion after 6 weeks	No recurrence for at least 6 months
Valenti et al. [33]	2022	1	M	63	Atopic dermatitis and allergic rhino-conjunctivitis	Not reported	Methylprednisolone, azathioprine, dapsone, and colchicine	Unsatisfactory response	6	600 mg SC initially; 300 mg Q2W	Not reported	Remarkable improvement of skin lesions after 1 month	In clinical remission at month 6
Bal et al. [31]	2022	1	M	74	Diabetes mellitus and hypertension	Metoprolol	Systemic and topical corticosteroids	Minimal improvement	5–6	600 mg SC initially; 300 mg Q2W	Not reported	Improvement of pruritus within 1–2 weeks; Clearance of BP lesion in 4 weeks	No flares or recurrence for at least 12 months
Zhang et al. [14]	2021	8	3 M, 5 F	64.50 Median	Cardiovascular disease (N = 3); Neurologic disorders (N = 1); Hyperlipidemia (N = 3); Cancers (N = 2)	Not reported	Not reported	Not reported	2 Median	600 mg SC initially; 300 mg Q2W	Methylprednisolone (0.6 mg/kg/day) and azathioprine (2 mg/kg/day)	Median time of cessation of new BP lesions: 8 days; 62.5% of patients reached complete remission	/
Klepper and Robinson [26]	2021	1	F	79	Melanoma	Nivolumab, levothyroxine, hydrochlorothiazide/losartan, atorvastatin	Doxycycline, fexofenadine, dapsone, and topical steroids	Intolerance of prednisone	Not reported	600 mg SC initially; 300 mg Q2W	Not reported	Clearance of pruritus after 4 weeks; Cessation of new blisters within 4 weeks;	Maintain clearance after 24 doses of dupilumab
Seyed Jafari et al. [15]	2021	1	M	70	Obesity, type 2 diabetes mellitus, and hypertension	Not reported	Topical corticosteroids, dapsone, methotrexate, mycophenolate-mofetil, and omalizumab	Constant mild itch with transient prurigo-like lesions	24	600 mg SC initially; 300 mg Q2W	Mycophenolate-mofetil, omalizumab and topical steroids	Clearance of pruritus and cessation of new BP lesions within 3 months	In clinical remission at month 7; Stopped mycophenolate-mofetil and topical corticosteroids at month 7
Zhang et al. [24]	2021	1	F	61	Not reported	Not reported	Methylprednisolone and azathioprine	Two flares of disease during tapering of methylprednisolone and 3 months of azathioprine failed to control disease	Not reported	600 mg SC initially; 300 mg QW	Methylprednisolone, azathioprine, and topical steroids	Clearance of pruritus within 1 month; Cessation of new BP lesions within 1 month	In clinical remission at month 5; No flare was observed during tapering of methylprednisolone; Stopped azathioprine at month 5
Saleh et al. [25]	2021	1	M	80	Not reported	Not reported	Prednisone, doxycycline, niacinamide, and mycophenolate mofetil	Flare of disease during tapering of prednisolone; Intolerance of mycophenolate mofetil	Not reported	600 mg SC initially; 300 mg Q2W	Prednisone, doxycycline	Significant improvement in BP lesions in 2 weeks; Reached disease clearance	Remain disease clearance on dupilumab and doxycycline
Liu et al. [32]	2021	1	F	54	Psychiatric disorder	Not reported	Methylprednisolone, dexamethasone, intravenous immunoglobulin, cyclophosphamide and topical corticosteroids	Poor response; psychosis progression	17	600 mg SC initially; 300 mg Q2W for twice	Methylprednisolone, CTX, and Topical corticosteroids,	Disease clearance within 1 month	No flare was observed during tapering of methylprednisolone for 12 weeks
Liu et al. [32]	2021	1	M	50	HBsAg (+) with high copies of HBV	Not reported	Methylprednisolone, intravenous immunoglobulin, methotrexate, cyclosporine and topical corticosteroids	Poor response	3	600 mg SC once	Methylprednisolone, methotrexate, cyclosporine and topical corticosteroids	Disease controlled within 1 week	No flare was observed during tapering of methylprednisolone over 2 months
Liu et al. [32]	2021	1	F	68	Hypertension, type 2 diabetes mellitus, stroke, arrhythmias with sustained atrial fibrillation, and HBsAg (+) with high copies of HBV	Not reported	Prednisone, cyclophosphamide, topical corticosteroids	Poor response; Developed gastric ulcer	>36	600 mg SC initially; 300 mg Q2W for twice	Topical corticosteroids	Improvement of pruritus within 1 week and maintained for 2 months; No improvement in bulla	/
Abdat et al. [13]	2020	13	8 M, 5 F	76.8 Average	Not reported	Not reported	None (N = 1); Prednisone (N = 3); Methotrexate (N = 1); Doxycycline (N = 1); Prednisone and methotrexate (N = 2); Prednisone, doxycycline, and niacinamide (N = 1); Prednisolone, methotrexate, intravenous immunoglobulin (N = 1); Prednisone, mycophenolate, rituximab, and intravenous immunoglobulin (N = 1); Prednisone, mycophenolate, doxycycline, and niacinamide (N = 1); Rituximab, intravenous immunoglobulin, doxycycline, nicotinamide, and azathioprine (N = 1);	Failed to control disease	28.8 Average	600 mg SC initially (N = 13); 300 mg Q2W (N = 10); 300 mg QW (N = 2); every 12 days (N = 1)	None (N = 6), Prednisone (N = 3), Methotrexate (N = 3), Intralesional and topical steroids (N = 1)	Absence of both bullae and pruritus (N = 7); Resolved bullae with residual pruritus (N = 10); Objective improvement of pruritus (N = 11); Complete resolution of pruritus (N = 7); Improvement in pruritus with persistent bulla (N = 1); No improvement in pruritus or bulla (N = 1)	/
Seidman et al. [27]	2019	1	M	89	Type 2 diabetes mellitus	Metformin	Prednisone, doxycycline, nicotinamide, mycophenolate mofetil, and omalizumab	Flare of disease during tapering of prednisone; Flare of disease 6 months after starting omalizumab	24	Dupilumab every other week (dosage not reported)	Prednisone 2.5 mg daily mycophenolate mofetil 500 mg twice daily, doxycycline 100 mg twice daily, nicotinamide 500 mg twice daily and topical steroids	Improvement of pruritus within 2 weeks; Complete BP lesions resolution after 7 weeks	Continued benefit from dupilumab at 1 year
Kaye et al. [16]	2018	1	M	80s	Mycobacterium tuberculosis and hepatitis B core laboratory positivities	Not reported	Prednisone	Two flares of disease during tapering of prednisone	1.5	600 mg SC initially; 300 mg QW	Not reported	Improvement in pruritus within a week; Clearance of all blisters after 3 months; Undetectable levels of BP180 and BP230 antibodies after 3 months	Remained clear of lesions after 10 months of dupilumab monotherapy

n1: dupilumab and methylprednisolone group = dupilumab group; n2: methylprednisolone group = control group.

Figure 1. IL-4 and IL-13 receptor structure IL-4 can bind to both type I and type II receptors. (A) Type I receptors consist of IL-4Rα and γc, whereas type II receptors consist of IL-4Rα and IL-13Rα1. When IL-4 binds to a type I receptor, Janus kinase (JAK) 1 and JAK3 are activated; both can induce tyrosine phosphorylation of the type I receptor intracellular domain, forming docking sites for downstream signaling molecules, such as signal transducer and activator of transcription (STAT) 6 and insulin receptor substrate-2 (IRS-2). Homodimers of STAT6 then translocate to the nucleus to facilitate transcription of IL-4- and IL-13-dependent genes. IRS-2 can activate signaling molecules, such as PI3K to induce gene transcription. (B) IL-13 binds to IL-13Rα2 with greater affinity than IL-13Rα1; the IL-13Rα2 receptor is considered a decoy receptor because it lacks a cytoplasmic signaling tail. However, the cytoplasmic domain of IL-13Rα2 may attenuate IL-4 signaling by inhibiting dimerization with γc or IL-13Rα1. (C) When IL-4 or IL-13 binds to a type II receptor, JAK1 and JAK2/TYK2 are activated.

Figure 2. Mechanism of pruritus in BP Sources of IL-4 and IL-13 may include T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s), and follicular helper T (Tfh) cells. IL-4 and IL-13 can activate basophils that produce IL-31, a cytokine that induces pruritus by stimulating IL-31Rα on sensory neurons. Additionally, basophils can produce IL-4 and IL-13; IL-31 can recruit eosinophils to lesion sites, contributing to the formation of a positive feedback loop that exacerbates pruritis. In addition to IL-31, IL-4, and IL-13 can directly cause chronic pruritus by interacting with IL-4Rα and IL-13Rα on sensory neurons. Furthermore, IL-4 can induce upregulation of IL-31Rα on dermal dendritic cells. The augmented IL-31/IL-31Rα interaction can lead to increased production of CCL17 and CCL22, thus promoting Th2-related immune response.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.