Individualized Algorithm of Systemic Treatment in Moderate to Severe Atopic Dermatitis

Dear Editor:

We have reviewed the manuscript "Atopic Dermatitis (AD) Therapeutic Algorithm of JAK-Inhibitors (iJAK) and IL-4/IL-13 Antagonists Utilizing Patient Profiles and Drug Efficacy" published in the Journal of Clinical and Aesthetic Dermatology in the month of February.1

We thank the authors for their contribution, as we were lacking a review of all recently approved iJAK and biologic drugs for AD depending on patients profile, having no algorithm to assist dermatologists in choosing the most appropriate one. However, we would like to add some observations on the review and algorithm that has been proposed.

There is still a considerable lack of data, and plenty of ongoing clinical trials that will keep the scenario changing in the future years. This is, any algorithm will be liable to change in the short term, since some drugs may have not achieved yet approval for the treatment of AD (e.g. lebrikizumab) or comorbidities (e.g. iJAKs for prurigo nodularis). In addition, differences between countries do appear, regarding governmental agencies (FDA, EMA) approvals (e.g. baricitinib is not approved for AD in UE), and thus restrict available treatment options in some countries. Consequently, we hereby propose a modified review (Table 1) and algorithm (Figure 1) of all available treatments for AD, pointing out some details and including all available data as accurately as we were able to summarize.

TABLE 1.

Comparison of available therapeutic options for atopic dermatitis, clinical development, dosage, contraindications and special situations, safety profile and adverse effects, and review of efficacy data.

DRUG TYPE		Abrocitinib	Upadacitinib	Baricitinib	Dupilumab	Tralokinumab
DRUG CLASS		JAK inhibitor; Preferentially JAK1	JAK inhibitor; Preferentially JAK1	JAK inhibitor; Inhibits JAK1 and JAK2	Monoclonal Antibody; IL-4 alpha subunit receptor antagonist	Monoclonal antibody; IL 13 antagonist
DRUGS PRESENTATION		CIBINQO® 50mg tablets CIBINQO® 100mg tablets CIBINQO® 200mg tablets	Rinvoq® 15mg tablets Rinvoq® 30mg tablets Rinvoq® 45mg tablets	Olumiant® 2mg tablets Olumiant® 4mg tablets	Dupixent® 200mg pre-filled syringe/pen Dupixent® 300mg pre-filled syringe/pen	Adtralza® 150mg pre-filled syringe
ROUTE OF ADMIN.		Oral	Oral	Oral	Subcutaneous	Subcutaneous
ATOPIC DERMATITIS CLINICAL TRIALS AND COMORBIDITIES	ATOPIC DERMATITIS THERAPY	JADE MONO 1 – Monotherapy (>12y) JADE MONO 2 – Monotherapy (>12y) JADE TEEN – Adolescents (12-18y) JADE DARE – vs Dupilumab HEAD TO HEAD JADE COMPARE – vs Dupilumab + TCS JADE REGIMEN – vs Dose reduction	MEASURE UP-1 – Monotherapy (12-75y) MEASURE UP-2 – Monotherapy (12-75y) RISING UP – Upadacitinib + TCS AD UP – Upadacitinib + TCS HEADs UP –vs Dupilumab (Head-to Head)	BREEZE-AD1 – Monotherapy (>18y) BREEZE-AD2 – Monotherapy (>18y) BREEZE-AD5 and AD6 – Monotherapy in United States (2mg, 1mg, placebo) BREEZE-AD7 – Baricitinib + TCS	SOLO-1 – Monotherapy (>18y) SOLO-2 – Monotherapy (>18y) SOLO-CONTINUE – Confirm SOLO 1-2 CHRONOS – Long term LIBERTY AD – Dupilumab + TCS (6m-6y) NCT-02612454 – Children and adolescents (6-18y)	ECZTRA-1,2 – Monotherapy (>18y) ECTRZA-3,4 – Tralokinumab + TCS ECTRZA-6 – Adolescentes (12-18y) ECZTEND – Long term TRAPEDS – Pediatrics (2-12y)
	FDA APPROVAL	FDA: January 2022, >18 years, February 2023, 12-18 years EMA: December 2021, > 18 years	FDA: January 2022, >12 years EMA: July 2022, > 12 years	FDA: N/A EMA: September 2020, > 18 years	FDA: March 2017, >18 years; October 2018, > 12 years; June 2022, > 6 months EMA: October 2017, > 12 years; March 2023, > 6 months	FDA : December 2022, > 18 years EMA : June 2021, >18 years; September 2022, >12 years
	ASTHMA	–	–	–	Venture	STRATOS, TROPOS, MESO
	CRSWNP	–	–	–	Sinus-52	–
	EOE	–	–	–	NCT03633617	–
	PN	–	–	–	LIBERTY-PN PRIME, PRIME-2; Liberty-PN Prime, Prime-2	–
SUMMARY OF OTHER EMA LABELED INDICATIONS		–	Psoriatic arthritis Rheumatoid arthritis Axial spondyloarthritis Ulcerative colitis	Rheumatoid arthritis Alopecia areata	Moderate to severe Eos asthma Chronic rhinosinusitis with NP Eosinophilic Esophagitis Prurigo Nodularis	–
ATOPIC DERMATITIS DOSAGE	Infants (<6y.)	–	–	–	5 to 15 kg: - Initial: 200mg - Subsequent: 200 mg, Q4W 15 to 30kg: - Initial: 300mg - Subsequent: 300 mg, Q	–
ATOPIC DERMATITIS DOSAGE	Pediatric (<12y.)	–	–	–	15 to 60kg: Initial: 300mg Day15: 300mg Subsequent: 300 mg, Q4W (starting 4 weeks after D15 dose) >60 kg: Initial: 600mg (300mg x2) Subsequent : 300mg, Q2W	–
	Adolescent (12-18y.)	100 mg daily	(weighing >30 kg) 15 mg daily	–	<60 kg: Initial: 400mg (200mg x2) Subsequent : 200mg, Q2W >60 kg: Initial: 600mg (300mg x2) Subsequent : 300mg, Q2W	–
	Adult (>18y)	Initial: 100 mg. Maintenance: 100 mg once daily, increase to 200 mg if no improvement after 12 weeks	Initial: 15 mg Maintenance: 15 mg once daily, increase to 30mg mg if inadequate response	Initial: 4mg Maintenance: 2mg daily	Initial: 600mg (300mg x2) Subsequent: 300mg, Q2W	Initial: 600mg (150mg x4) Subsequent: 300mg (150mg x2), Q2
	Elderly (>65y)	100 mg daily	15 mg daily	2 mg daily (>75y)	Same as adult	Same as adult
CONTRAINDICATIONS and REPRODUCTIVE SPHERE	Contraindications	Absolute neutrophil count <1,000/mm3 Absolute lymphocyte count <500/mm3 Hemoglobin <8g/dL			–	–
		Active tuberculosis Treat latent tuberculosis prior to treatment initiation
		Severe active infection		Consider benefits over risk before initiation if there is an active infection; careful monitoring and interrupt if there is no response to standard therapy
		Severe hepatic impairment (Child Pugh C)		–
	Fertile desire	Abandon 1 month prior to conception	Abandon 1 month prior to conception	Abandon 1 week prior to conception	No fertility impairment	No fertility impairment
	Pregnancy	Contraindicated			Limited data Use only if potential benefits justify potential risks	Limited data Preferably avoid
	Breast Feeding	Contraindicated			Discontinue either DUPI or breast feeding
DRUG TYPE	Abrocitinib	Upadacitinib	Baricitinib	Dupilumab	Tralokinumab
ADVERSE EVENTS
MOST COMMONLY REPORTED AES (%)	Nausea (15.1) Headache (7.9) Acne (4.8) Herpes simplex (4.2) Blood CK increased (3.8) Vomiting (3.5) Herpes zoster (1.2)	Upper resp. tract infections (25.4) Acne (15.1) Herpes simplex (8.4) Headache (6.3) Blood CPK increased (5.5) Herpes zoster (4.0) Cough (3.2) Foliculitis (3.2) Abdominal pain (2.9) Nausea (2.7) Neutropenia (2.3) Pyrexia (2.1) Influenza (2.1)	Increased LDL cholesterol (26) Upper resp. tract infections (16.9) Headache (5.2) Blood CPK increased (3.4) Herpes simplex (3.2) Urinary tract infections (2.9) Blood CPK increased (2.9) Foliculitis (2.1) Acné (<2)	Local injection site reaction (15.0) Conjunctivitis (14.0) Allergic conjunctivitis Arthralgia Herpes simplex (3) Oral herpes (4) Eosinophilia (<3)	Upper resp. tract infections (23.4) Local injection site reaction (7.2) Conjunctivitis (5.4) Allergic conjunctivitis (2.0) Eosinophilia (1.2)
INFECTIOUS AND OTHER SIGNIFICANT AES	Reactivation of herpes simplex and zoster; Patients screened (+) for active or latent HBV or HCV were excluded from trials. Serious infections: 2.43 per 100 pat.-year (100mg) 2.46 per 100 pat.-year (200mg) Deep vein thrombosis: 0 per 100 pat.-year (100mg) 0.11 per 100 pat.-year (200mg) Pulmonary embolism: 0.08 per 100 pat.-year (100mg) 0.17 per 100 pat.-year (200mg)	Reactivation of herpes simplex and zoster; Patients screened (+) for active or latent HBV or HCV were excluded from trials Serious infections: 2.3 per 100 pat.-year (15mg) 2.8per 100 pat.-year (30mg) Deep vein thrombosis: <0.1 per 100 pat.-year (15 and 30mg) Pulmonary embolism: <0.1 per 100 pat.-year (15 and 30mg)	Reactivation of herpes simplex and zoster; Patients with past HBV or HCV infection were allowed to participate; monitoring HBV DNA or HCV RNA Serious infections: 2.1 per 100 pat.-year (any dose) Deep vein thrombosis N/A Pulmonary embolism 0.06 per 100 pat.-year (2 and 4mg)	Serious allergic (hypersensitivity) reaction; Patients with known helminth infections were excluded from participation Serious infections (Data from CHRONOS): 0.6% in pats. treated with placebo 0.2% in pats. treated with dupilumab	Serious allergic (hypersensitivity) reaction; Patients with known helminth infections were excluded from participation Serious infections (Data from ECZTEND): 0.4% in pats. treated with tralokinumab
BLACK BOX LABEL RECOMMENDATIONS	Based on the ORAL Surveillance Study (tofacitinib in patients with RA and cardiovascular risk factors), EMA concludes that the identified risks apply to all JAK inhibitors approved for the treatment of chronic inflammatory disorders. Thus, these should only be used in the following patients if no suitable alternatives are available: Patients aged 65 years or above Current or past long-time smokers Personal history of atherosclerotic cardiovascular disease or other cardiovascular risk factors Patients with malignancy risk factors Other risk factors for VTE (cautious use) If JAK inhibitors are needed in patients with risk factors: a lower dose may be recommended.			–	–
ADVERSE EVENTS
DRUG INTERACTIONS	Coadministration with: CYP-2C19 inhibitors (e.g. fluconazole): reduce dose to 50 or 100mg daily Except for low-dose aspirin (≤81 mg daily): no antiplatelet therapies during the first 3 months Anti-acids (e.g. omeprazole): consider 200mg daily dose		Coadministration with: CYP-3A4 inhibitors (e.g. ketocona-zole): use 15 mg daily with caution, 30mg is not recommended CYP-3A4 inducers (e.g. rifampicin): monitor disease activity Anti-acids (e.g. omeprazole): no effect		Coadministration with: CYP-3A4 inducers or inhibitors: no meaningful changes OAT3 inhibitors (e.g. probenecid): 2 mg daily is recommended Anti-acids (e.g. omeprazole): no effect		None reported	Effects of tralokinumab on CYP1A2, CYP2C9, CYPD26, CYP2C19, CYP3A substrates were evaluated: CYP1A2, CYP2C9: no effect CYPD26, CYP2C19, CYP3A: small changes were observed with no expected clinical relevancy
	Inactivated or live vaccines are not recommended Response to non-live vaccines can be satisfactory (e.g. pneumococcal)						Inactivated or live vaccines are not recommended Response to non-live vaccines can be satisfactory (e.g. Tdap, meningococcal)
	Do not use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs, or with potent immunosuppressants (e.g. azathioprine and cyclosporine)						–
PARAMETERS TO MONITOR	Prior to therapy: same as UPA and BARI During therapy: same as UPA and BARI, but 4 weeks after initiation; further monitoring same as UPA and BARI.		Prior to therapy: complete blood count including platelet, absolute lymphocyte and neutrophil count with hemoglobin, lipid parameters, active/latent tuberculosis, hepatitis virus. During therapy: repeat complete blood count and lipid parameters no later than three months; further monitoring according to the patient’s risk for cardiovascular disease and clinical guidelines for hyperlipidemia.				–	–
	Plus clinical monitoring of symptoms of: infection and thrombosis.						–	–
EFFICACY (16W)
DRUG TYPE	COMPARE ABRO + TCS		AD UP UPA + TCS		BRREZE AD7 BARI + TCS		CHRONOS DUPI + TCS	ECZTRA 3 TRALO + TCS
DRUG DOSAGE	200mg (n=226)	100mg (n=238)	30mg (n=297)	15mg (n=300)	4mg (n=106)	2mg (n=109)	600mg + 300mg Q2W (n=106)	600mg + 300mg Q2W (n=252)
IGA 0/1	47.5	34.8	59	40	30.6	23.9	38.7	38.9
NRS4	62.8	47	64	52	44	38.1	56.6	45.4
EASI 75	71	60.3	77	65	47.7	43.1	68.9	56
EASI 90	46.1	36.6	63	43	-	-	39.6	33

Acronyms and abbrevations: ABRO: abrocitinib. AD: atopic dermatitis. AEs: Adverse effects. BARI: baricitinib. BSA: body surface area (%). CRSwNP: Chronic Rhinosinusitis with Nasal Polyps. dL: deciliters. DUPI: dupilumab. DVT: deep vein thrombosis. EASI: eczema area severity index. eGFR: estimated glomerular filtration rate. Eg: For example. EMA: European Medicines Agency. EoE: Eosinophilic Esophagitis. FDA: Food and Drug Administration. g: grams. HBV: Hepatitis B virus. HCV: Hepatitis C virus. m: months. mg: milligrams. NRS: Numerical Rating Scale. y: year. IGA: Investigator Global Assessment. iJAK: janus kinase inhibitor. Pat: Patients. PN: Prurigo Nodularis. Q2W: Once every 2 weeks. Q4W: Once every 4 weeks. RA: Rheumatoid arthritis. SCORAD: scoring atopic dermatitis. TCS: Topical corticosteroids. TRALO: tralokinumab. UPA: upadactinib. VTE: Venous thromboembolism. w: weeks.

Clinical trials: Only efficacy and safety clinical trials have been included, excluding pharmakokinethics. Complete clinical trials with results (endopoints achieved and endpoints failed) have been included among those considered relevant by the authors. Efficacy data come from the clinical trials referenced in the table (for further and complete data, consult http://clinicaltrials.gov.

For detailed information, please refer to the FDA and EMA Medication Guide of Dupilumab, Tralokinumab, Upadacitinib, Baricitinib and Abrocitinib.

FIGURE 1.

Atopic dermatitis therapeutic algorithm depending on patient profiles

First of all, prior to receiving any of these new advanced therapies, most patients require to be treated for their moderate or severe AD with any of the following: systemic steroids, systemic immunosuppressants (e.g. cyclosporine A) or methotrexate. Systemic steroids provide a rapid but unsustained improvement, while methotrexate’s use, though it may be beneficial, is off-label. Cyclosporine A is an approved and effective therapy, yet it should not be maintained over a year’s time. It is mandatory to know that both systemic steroids (Category B) and cyclosporine (Category C) are not prohibited during pregnancy, and it is necessary to always balance their benefits over the risk of their use. Meanwhile, methotrexate is strictly prohibited (Category X). As a result, only some of these systemic therapies should also be regarded in a treatment algorithm prior to the use of any advanced therapy, in any kind of patient (e.g. in Spain, it is compulsory to first treat a patient with cyclosporine to get access to another advanced therapy).

Secondly, it is well known that AD is often associated with asthma, allergic rhinoconjunctivitis and nasal polyposis, eosinophilic esophagitis or phenotypically can also appear as prurigo nodularis. For the treatment of all of these, dupilumab has been proved to be effective (Table 1), as well as in AD1. Thus, all mentioned AD related comorbidities, if present, should be taken into account when making a decision, being dupilumab so far the leading option. While tralokinumab failed to demonstrate efficacy for asthma in clinical trials, other biologic drugs have not been studied for these indications, so their utility for these indications cannot be denied. Likewise, patients with concomitant inflammatory diseases such as rheumatoid or psoriatic arthritis, ankylosing spondylitis, ulcerative colitis or alopecia areata can benefit from treatment with specific iJAKs, as some of them are already licensed for some of these indications.3–5 It is true in the case of an adult without any cardiovascular risk factor, severe renal or hepatic impairment, history of malignancy or cytopenia, all available treatments could be an option; and AD patients are mostly young, without any accompanying diseases and unmedicated. As said before, comorbidities should be kept in mind.

Additionally, in the case where all treatment options could be used, the dermatologist's criteria and the patient's characteristics and needs will lead to the choice of the drug. For example, in the case when a rapid response or pruritus relief would be needed, an iJAK could be a preferred option;3–5 while to avoid analytical monitoring or in the presence of any risk factors, anti-IL4/IL13 or anti-IL13 drugs would be the leading option.2,6 In our opinion, needle phobia, though it may be taken into account, might not be relevant enough to be included in a treatment algorithm.

Lastly, the proposed algorithm obviously excludes the use of iJAKs during pregnancy. Nevertheless, these can be used safely prior to conception, as long as a washout period of one week for baricitinib and four weeks for upadacitinib and abrocitinib is observed.3–5 Additionally, pregnancy in women under 18 years old is an scenario that is also plausible and must be beheld. Dupilumab, though it has no assigned category for pregnancy, has proved to be safe in some reported cases, while the same profile of security for tralokinumab during pregnancy could be assumed.2,6

We would also like to note that it might be early and risky to talk about efficacy when comparing different clinical trials, as it is well known that there are always methodological differences between them, regarding e.g. length and follow-up during studies, responding criteria or characteristics of the patients included. Indeed, only two head-to-head clinical trials have been carried out so far: JARE DARE (abrocitinib vs dupilumab) and HEADS UP (upadacitinib vs dupilumab). Therefore, we have little comparative data of efficacy regarding these new treatments, and a lack of efficacy and safety data for most of them (except for dupilumab) in real clinical practice.

As a result, we hereby propose a modified summary and algorithm (Table 1 and Figure 1) to assist dermatologists in the choice of an AD treatment, taking into account every aspect highlighted by the authors of the annotated manuscript, as well as our remarks discussed above.

With regard,