Use of biologics in the era of COVID-19: Where do we stand?

To the Editor: The novel coronavirus disease 2019 (COVID-19) has been spreading for more than 5 months since the World Health Organization declared the COVID-19 pandemic in March 2020. As of August 26, the pandemic had resulted in 23 million confirmed cases and 810,000 deaths worldwide. As the likelihood of prolonged spread without sudden termination of this situation increases, the topic of infection risk in patients treated with biologics is becoming crucial in the dermatologic field. Therefore, we conducted a PubMed search for articles reporting biologics exposure and reviewed guidelines on biologics use published during this pandemic.

Although according to phase 2 and 3 clinical trials the most frequently experienced adverse effects of biologics include upper respiratory tract infection, nasopharyngitis, or both, no significant increase in the risk of infection has been observed in treated groups compared with control groups., However, in most clinical studies, data on the incidence of lower respiratory tract infection (main pathogenicity of COVID-19) for each drug are insufficient, probably because of lack of investigator interest and low incidence (less than 5%).

The risk of COVID-19 infection in dermatologic patients treated with biologics can be assessed, focusing on areas in which COVID-19 has spread rapidly (Table I). Although the control for biologics-treated groups is the general population rather than patients treated without biologics, the proportion of polymerase chain reaction–confirmed cases in the biologics-treated group is low (approximately 0%-1.8%). Given that the proportion of suspected (not confirmed but symptomatic) cases in the biologics-treated group varies by study, with up to 18% suspected cases being reported, it is important to distinguish and manage high-risk patients. To properly interpret these data, it is necessary to face the limitations of remarkably low proportions of infected patients in the biologics-treated group, limited adjustment of clinical parameters, and heterogeneity of design between studies.

Table I

Cohort studies for incidence of coronavirus disease 2019 infection in patients treated with biologics for dermatologic disease (listed in sample number)

Author	Country	Biologics-treated group						Control group (general population)
		Patients	Count	Age, years	Sex ratio (M:F)	Type of biologics (%)	No. of COVID-19–infected patients (%)	Count	No. of COVID-19–infected patients (%)
Gisondi P et al1	Italy	Psoriasis	5206	53.2 ± 11.2	1:0.84	Anti–TNF-α antibody (32.2)Anti–IL-12/23 antibody (26.7)Anti–IL-23 antibody (2.7)Anti–IL-17 antibody (38.3)	6 (0.12)
Damiani G et al2	Italy	Psoriasis	1193	55	1:0.47	Anti–TNF-α antibody (19.9)Anti–IL-12/23 antibody (45.4)Anti–IL-17 antibody (5.2)	22 (1.84)	10,060,574	54,801 (0.54)
Gisondi P et al3	Italy	Psoriasis	980	56.4 ± 12.4	1:0.72	Anti–TNF-α antibody (50.0)Anti–IL-12/23 antibody (17.0)Anti–IL-23 antibody (0.0)Anti–IL-17 antibody (28.0)	0	257,353	3199 (1.24)
Carugno A et al4	Italy	Psoriasis	159	51.5 ± 14.0	1:0.39	Anti–TNF-α antibody (33.3)Anti–IL-12/23 antibody or anti–IL-23 antibody (18.9)Anti–IL-17 antibody (47.8)	29 (18.24)∗
Giulia R et al5	Italy	Hidradenitis suppurativa	96	35	ND	Anti–TNF-α antibody (47.9)Anti–IL-17 antibody (11.5)	0
Carungo A et al6	Italy	Atopic dermatitis	30	35.5 ± 11.9	1:0.5	Anti–IL-4/13 antibody (100.0)	0

COVID-19, Coronavirus disease 2019; F, female patients; IL, interleukin; M, male patients; ND, not described; TNF, tumor necrosis factor.

Estimated for patients with suspected COVID-19 (not polymerase chain reaction confirmed). 1. Gisondi P et al. The impact of the COVID-19 pandemic on patients with chronic plaque psoriasis being treated with biological therapy: the Northern Italy experience. Br J Dermatol. 2020;183(2):373-374. 2. Damiani G et al. Biologics increase the risk of SARS-CoV-2 infection and hospitalization, but not ICU admission and death: real-life data from a large cohort during red-zone declaration. Dermatol Ther. 2020;e13475. 3. Gisondi P et al. Risk of hospitalization and death from COVID-19 infection in patients with chronic plaque psoriasis receiving a biologic treatment and renal transplant recipients in maintenance immunosuppressive treatment. J Am Acad Dermatol. 2020;83(1):285-287. 4. Carugno A et al. COVID-19 and biologics for psoriasis: a high-epidemic area experience-Bergamo, Lombardy, Italy. J Am Acad Dermatol. 2020;83(1):292-294. 5. Giulia R et al. Experience in patients with hidradenitis suppurativa and COVID-19 symptoms. Dermatol Ther. 2020. https://doi.org/10.1016/j.jaad.2020.06.986. 6. Carungo A et al. No evidence of increased risk for coronavirus disease 2019 (COVID-19) in patients treated with dupilumab for atopic dermatitis in a high-epidemic area - Bergamo, Lombardy, Italy. J Eur Acad Dermatol Venereol. 2020. https://doi.org/10.1111/jdv.16552.

Although conventional guidelines prohibit the use of biologics for acute severe infection, the need for recommendation with detailed risk stratification has been raised in preparation for various conditions that fit the current situation. Several expert opinions or consensus statements have been reported recently (Table II). It is generally recommended that asymptomatic low-risk patients continue treatment based on dosing schedule interruption, dysregulated immunogenicity (eg, antidrug antibody), and proven safety, whereas infected patients should discontinue treatment. Furthermore, dermatologists should make sound judgments depending on the circumstances (withholding, down-dosing, or postponement) for patients with exposure history or those at high risk. However, the definitions of high-risk factors vary, and information on restarting treatment for patients who have terminated treatment or initiating treatment for biologics-naive patients is limited.

Table II

Expert opinion∗ or official statement for recommendation of biologics use in dermatologic patients

Author/organization	Subjects for recommendation	Current risk of patients for COVID-19 infection	Recommendation for current treatment	Initiation for biologic-naive patients	Remarks
International Psoriasis Council1	Treated for psoriasis with any biologics	COVID-19 infected	Discontinuation
		High risk, no CSS	Depends on situation		High risk: >60 y, comorbidities (CVD, DM, hepatitis B, COPD, CKD, cancer)
Price KN et al2	Treated with anti–TNF-α antibody	No CSS or mild CSS	Continuation
		CSS worsening or high fever	Discontinuation
	Treated with anti–IL-4/13 antibody	Mild to moderate CSS	Continuation
		Severe CSS	Discontinuation
	Treated with anti–IL-17, anti–IL-12/23, and anti–IL-23 antibody	No CSS or mild CSS	Continuation
		CSS worsening or high fever	Discontinuation
American Academy of Dermatology3	Treated with any biologics	No CSS	Continuation
		High risk, no CSS	Depends on situation	Postponement or change to alternative agent	High risk: >60 y, comorbidities (CVD, DM, severe HTN, liver disease, kidney disease, pulmonary disease, cancer), current smoker
		COVID-19 infected	Discontinuation or postponement
Australian Medical Dermatology Group4	Treated with any biologics	No CSS	Continuation	Depends on situation
		High risk, no CSS	Discontinuation or dose reduction		High risk: >60 y, uncontrolled or multiple comorbidities (CVD, CKD, DM, HTN, cancer), high dose or multiple use of other immunosuppressive agent, history of severe/recurrent respiratory tract infection
		CSS	Discontinuation or dose reduction
		COVID-19 infected	Discontinuation or postponement (if next injection is scheduled within 31 d)
Brownstone ND et al5	Treated for psoriasis with any biologics	High risk, no CSS	Discontinuation or dose reduction		High risk: elderly, CVD, HTN, lung disease, DM, cancer, concomitant use of other immunosuppressive agent, immunosuppressive state (HIV), history of infection during biologics treatment
		Exposure to COVID-19–infected patient	Discontinuation or dose reduction
		COVID-19 infected	Holding a dose
Amerio P et al6	Treated with any biologics	No CSS	Continuation
		High risk and CSS	Discontinuation		High risk: elderly with comorbidities (HTN, DM, obesity)
		High risk and exposure to COVID-19–infected patient	Discontinuation		High risk: elderly with comorbidities (HTN, DM, obesity)
Reynolds SD et al7	All biologics-treated children	No CSS	Continuation
		CSS	Depends on situation		For dupilumab, 50% of experts agree to continue
		High risk and exposure to COVID-19–infected patient	Discontinuation or depends on situation		For dupilumab, 50% of experts agree to continue
		COVID-19 infected	Discontinuation		For dupilumab, 16% of experts agree to continue
Conforti C et al8	All biologics treated	COVID-19 infected	Discontinuation
Patruno C et al9	Anti–IL-4/13 antibody treated	No CSS	Continuation
Sanchez DP et al10	All biologics treated	CSS	Holding a dose
		No CSS	Continuation		Change to self-injectable agent/home infusion (if possible)Enhancement of self-isolation for patients treated with secukinumab and adalimumab
Galimberti F et al11	All biologics treated	No CSS	Continuation	Postponement
		CSS	Discontinuation
		COVID-19 infected	Discontinuation
Ricardo JW et al12	Anti–TNF-α antibody treated	COVID-19 infected	Discontinuation
		No CSS	Change to alternative agent
	Anti–IL-17 antibody treated	No CSS	Continuation
		COVID-19 infected	Discontinuation
	Anti–IL-12/23 antibody treated	No CSS	Continuation		Refrain from changing to anti–IL-23 antibody if possible
		COVID-19 infected	Discontinuation
	Anti–IL-23 antibody treated	No CSS	Continuation	Possible
		COVID-19 infected	Discontinuation
	Anti–IL-4/13 antibody treated	No CSS	Continuation	Possible
Karadag AS et al13	Anti–IL-12/23 and Anti–IL-23 antibody treated	No CSS	Continuation		Use the lowest dose (if possible)
International League of Dermatological Societies14	All biologics for psoriasis and atopic dermatitis treated	No CSS	Continuation
		High risk, no CSS	Depends on situation		High risk: elderly, comorbidities (DM, COPD, HTN, CKD, liver disease, cancer except for keratinocyte carcinoma)
		CSS	Change to alternative agent	Postponement
		COVID-19 infected	Discontinuation

CKD, Chronic kidney disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CSS, COVID-19 suspected symptom; CVD, cardiovascular disease; DM, diabetes mellitus; HTN, hypertension; IL, interleukin; TNF, tumor necrosis factor.

Search of PubMed with following keywords: biologics (“anti–TNF-α antibody,” “etanercept,” “infliximab,” “adalimumab,” “certolizumab pegol,” “anti–interleukin-12/23 antibody,” “anti–interleukin-23 antibody,” “ustekinumab,” “guselkumab,” “tildrakizumab,” “risankizumab,” “anti–interleukin-17 antibody,” “secukinumab,” “ixekizumab,” “brodalumab,” “anti–interleukin-4/13 antibody,” “dupilumab,” “anti-IgE antibody,” “omalizumab,” or “biologic”) and COVID-19 (“SARS-CoV2,” “novel coronavirus infection,” or “COVID-19”). Listed in order of publication date. 1. International Psoriasis Council. IPC Statement on the coronavirus (COVID-19) outbreak (accessed 26th Jul 2020, updated Mar 2020). https://www.psoriasiscouncil.org/blog/Statement-on-COVID-19-and-Psoriasis.htm. 2. Price KN et al. COVID-19 and immunomodulator/immunosuppressant use in dermatology. J Am Acad Dermatol. 2020;82(5):e173-e175. 3. American Academy of Dermatology. Recommendations for dermatologists (accessed 26th Jul 2020, updated Apr 2020). https://www.aad.org/member/practice/coronavirus/clinical-guidance/recommendations. 4. Australian Medical Dermatology Group. COVID-19 and the use of immunomodulatory and biologic agents for severe cutaneous disease: an Australian/New Zealand consensus statement. Australas J Dermatol. 2020;61(3):210-216. 5. Brownstone ND et al. Novel coronavirus disease (COVID-19) and biologic therapy in psoriasis: infection risk and patient counseling in uncertain times. Dermatol Ther (Heidelb). 2020;10(3):1-11. 6. Amerio P et al. COVID-19 and psoriasis: should we fear for patients treated with biologics? Dermatol Ther. 2020. https://doi.org/10.1111/dth.13434. 7. Reynolds SD et al. Systemic immunosuppressive therapy for inflammatory skin diseases in children: expert consensus-based guidance for clinical decision-making during the COVID-19 pandemic. Pediatr Dermatol. 2020;37(3):424-434. 8. Conforti C et al. Biologic therapy for psoriasis during the COVID-19 outbreak: the choice is to weigh risks and benefits. Dermatol Ther. 2020. https://doi.org/10.1111/dth.13490. 9. Patruno C et al. Dupilumab and COVID-19: what should we expect? Dermatol Ther. 2020. https://doi.org/10.1111/dth.13502. 10. Sanchez DP et al. Clinical considerations for managing dermatology patients on systemic immunosuppressive or biologic therapy, or both, during the COVID-19 pandemic. J Am Acad Dermatol. 2020;83(1):288-292. 11. Galimberti F et al. Evidenced-based best practice advice for patients treated with systemic immunosuppressants in relation to COVID-19. Clin Dermatol. 2020. https://doi.org/10.1016/j.clindermatol.2020.05.003. 12. Ricardo JW et al. Considerations for safety in the use of systemic medications for psoriasis and atopic dermatitis during the COVID-19 pandemic. Dermatol Ther. 2020. https://doi.org/10.1111/dth.13687. 13. Karadag AS et al. Immunosuppressive and immunomodulator therapy for rare or uncommon skin disorders in pandemic days. Dermatol Ther. 2020. https://doi.org/10.1111/dth.13686. 14. International League of Dermatological Societies. Guidance on the use of systemic therapy for patients with psoriasis/atopic dermatitis during the Covid-19 (Sars-Cov-2, coronavirus) pandemic (accessed 26th Jul 2020, updated May 2020). https://ilds.org/covid-19/guidance-psoriasis-atopic-dermatitis.

In conclusion, with advances in the understanding of COVID-19 pathogenesis and opposing suggestions of certain biologics as an alternative treatment option for COVID-19 disease,, it will be necessary for guidelines about biologics use to be consistently modified and integrated at the pannational level in the COVID-19 era. Moreover, the guidelines need to be tailored to each condition, considering the differences in the prevalence of COVID-19, the incidence of pulmonary complications, quarantine policy, and insurance coverage of biologics between countries.