Adverse Effects of Biologic Therapy: A Retrospective Cohort Study

Abstract

Objective: To evaluate adverse effects associated with biologic therapy (Etanercept, Adalimumab, and Secukinumab) in patients with psoriasis, psoriatic arthritis, and hidradenitis suppurativa. Methods: This retrospective observational study included 58 patients receiving biologic therapy: 40 with generalized plaque psoriasis, 13 with psoriatic arthritis, and 3 with hidradenitis suppurativa. Eligibility was based on national treatment protocols (Psoriasis Area and Severity Index [PASI] > 10; Hurley stage II–III). Demographic data, treatment duration, therapy modifications, discontinuations, and adverse events were collected from medical records. Patients were monitored for both efficacy and safety outcomes. Results: Treatment discontinuation due to severe hepatotoxicity occurred in four patients (three receiving Etanercept and one Adalimumab), corresponding to 6.9% of the cohort. Adalimumab was discontinued in one patient due to cutaneous leishmaniasis after 24 months and in another due to pregnancy after 26 months. Upper limb edema was observed following a switch from Adalimumab to Secukinumab. One patient discontinued Etanercept due to lack of efficacy and subsequently died from a fatal methotrexate overdose. Treatment switches included Etanercept to Adalimumab for granulomatous uveitis (one case) and Adalimumab to Etanercept due to generalized urticaria (two cases). Conclusion: Adverse events were relatively infrequent, with an overall incidence below 10% (6.9% for the most common event and <2% for other events). Most adverse events were mild and reversible following dose adjustment or temporary discontinuation. No unexpected or fatal adverse events were directly attributable to biologic therapy.

1. Introduction

Biologic therapies have significantly transformed the management of chronic inflammatory and autoimmune diseases, including psoriasis, psoriatic arthritis, and hidradenitis suppurativa. Tumor necrosis factor-alpha (TNF-α) inhibitors, such as Adalimumab and Etanercept, as well as interleukin-17 (IL-17) inhibitors, such as Secukinumab, are widely utilized and have demonstrated substantial efficacy in reducing disease activity and improving patients’ quality of life. Despite their well-established efficacy, biologic agents are associated with a spectrum of potential adverse effects, necessitating careful monitoring during treatment. TNF-α inhibitors have been consistently associated with an increased risk of tuberculosis reactivation and other serious infections [1]. Furthermore, these agents, particularly Adalimumab, may predispose patients to severe, deep fungal, and atypical infections. Salmon-Ceron et al. [2] conducted a prospective study evaluating opportunistic infections, excluding tuberculosis, in patients with psoriasis, rheumatoid arthritis, ankylosing spondylitis, and other inflammatory disorders treated with biologic therapy. The most frequently reported infections included atypical mycobacteria, leishmaniasis, listeriosis, atypical salmonellosis, and disseminated cytomegalovirus infection. In addition to infectious complications, TNF-α inhibitors have been associated with rare but clinically significant adverse events, including new-onset or exacerbation of congestive heart failure, lupus-like syndrome, lymphoma, clinically relevant cytopenias, and demyelinating or other neurological disorders resembling multiple sclerosis [3]. Conversely, IL-17 inhibitors have been primarily associated with mucocutaneous candidiasis and inflammatory bowel disease, as well as rare adverse effects such as demyelinating disorders and hypersensitivity reactions [4]. Moreover, TNF-α inhibitors have been linked to an increased risk of cutaneous malignancies, particularly non-melanoma skin cancer. Askling et al. [5] performed a meta-analysis of 74 randomized controlled trials, including 15,418 patients treated with TNF-α inhibitors and 7486 controls, reporting a short-term risk of 2.02% for the development of non-melanoma skin cancer in patients receiving biologic therapy. The concomitant or prior use of other immunosuppressive treatments, such as methotrexate, cyclosporine, or PUVA therapy, may further increase the risk of both melanoma and non-melanoma skin cancers. Additionally, TNF-α inhibitors may induce paradoxical psoriatic eruptions or exacerbate pre-existing psoriasis [6]. These paradoxical manifestations may occur in previously unaffected individuals, suggesting de novo psoriasis, or may present as morphological variations in patients with established disease. For instance, patients with a history of plaque or guttate psoriasis may develop guttate lesions during treatment with TNF-α inhibitors. However, despite the growing body of evidence on the safety profile of biologic agents, real-world data on adverse effects in routine clinical practice remain limited, particularly in smaller cohorts and in patients with heterogeneous inflammatory conditions. To identify and evaluate adverse effects associated with biologic therapy (Etanercept, Adalimumab, and Secukinumab), we conducted a retrospective observational study in patients with psoriasis, psoriatic arthritis, and hidradenitis suppurativa.

2. Results

A total of 58 patients were included in the study, of whom 37 (63.8%) were male and 21 (36.2%) were female. The mean age was 51.7 years (range, 23–71 years). Among patients with psoriasis and psoriatic arthritis, the mean baseline Psoriasis Area and Severity Index (PASI) score was 32.2, indicating severe disease. Among patients with hidradenitis suppurativa, two were classified as Hurley stage III and one as stage II. At treatment initiation, 25 patients (43.1%) received Etanercept, 26 (44.8%) received Adalimumab, and 7 (12.1%) received Secukinumab.

Treatment modifications: Treatment modifications occurred in a subset of patients. One patient switched from Etanercept to Adalimumab after 5 months due to granulomatous uveitis, and another from Etanercept to Secukinumab after 12 months due to lack of efficacy. Two patients were switched from Adalimumab to Etanercept because of generalized urticaria. In two patients receiving Adalimumab, Methotrexate (7.5 mg/week) was added due to suboptimal clinical response. Additionally, one hepatitis B carrier was switched from Adalimumab to Secukinumab as a safer therapeutic option under strict viral monitoring (

Table 1. Treatment modifications and underlying reasons.

Modification	n (%)	Reason
Etanercept → Adalimumab	1 (1.7%)	Granulomatous uveitis
Etanercept → Secukinumab	1 (1.7%)	Lack of efficacy
Adalimumab → Etanercept	2 (3.4%)	Generalized urticaria

Abbreviations: n, number of patients.

).

No statistically significant association was observed between the type of initial biologic therapy and treatment modification (Fisher’s exact test, p = 0.18). Although modification rates were numerically higher among patients treated with Adalimumab (20%) compared to Etanercept (7.7%) and Secukinumab (0%), this difference did not reach statistical significance. Treatment discontinuation occurred in six patients. Four cases were attributed to severe hepatotoxicity (elevated transaminases AST and/or ALT levels ≥ 3 times the upper limit of normal), including three patients receiving Etanercept and one receiving Adalimumab. One patient treated with Adalimumab discontinued therapy after 24 months due to cutaneous leishmaniasis, and another after 26 months due to pregnancy. In one case, Etanercept was discontinued due to lack of efficacy; the patient was subsequently treated with Methotrexate and died from a fatal overdose (exitus), which was not considered directly related to biologic therapy (

Table 2. Treatment discontinuation.

Cause of Discontinuation	n	Therapy
Hepatotoxicity	4	3 Etanercept, 1 Adalimumab
Cutaneous Leishmaniasis	1	Adalimumab
Pregnancy	1	Adalimumab

Abbreviations: n, number of patients.

).

Although Adalimumab showed a numerically lower discontinuation rate (8%) compared to Etanercept (15.4%), no treatment discontinuations were observed among patients receiving Secukinumab in this cohort. However, no statistically significant association was found between biologic agent and treatment discontinuation (χ² = 0.69, df = 2, p = 0.70).

Adverse events according to biologic therapy are summarized in

Table 3. Adverse events according to biologic agent.

Adverse Event	Etanercept (n = 25)	Adalimumab (n = 26)	Secukinumab (n = 7)	Total (n = 58)
Hepatotoxicity	3 (12.0%)	1 (3.8%)	0 (0%)	4 (6.9%)
Generalized urticaria	1 (4.0%)	2 (7.7%)	0 (0%)	3 (5.2%)
Generalized rash	1 (4.0%)	0 (0%)	0 (0%)	1 (1.7%)
Diarrhea	0 (0%)	0 (0%)	1 (14.3%)	1 (1.7%)
Renal impairment	0 (0%)	1 (3.8%)	0 (0%)	1 (1.7%)
Severe anemia with leukopenia	1 (4.0%)	0 (0%)	0 (0%)	1 (1.7%)
Cutaneous leishmaniasis	0 (0%)	1 (3.8%)	0 (0%)	1 (1.7%)

Abbreviations: n, number of patients.

.

Hepatotoxicity (n = 4) was the most frequent adverse event and occurred predominantly in patients treated with Etanercept (n = 3) and Adalimumab (n = 1), leading to treatment discontinuation in all cases. Other adverse events included generalized urticaria (n = 3), observed in patients receiving Adalimumab (n = 2) and Etanercept (n = 1); generalized rash (n = 1) in a patient treated with Etanercept; diarrhea (n = 1) in a patient receiving Secukinumab; renal impairment (n = 1) in a patient treated with Adalimumab; and severe anemia with leukopenia (n = 1) in a patient receiving Etanercept. Cutaneous leishmaniasis (n = 1) was observed in a patient receiving Adalimumab and resulted in treatment discontinuation. Upper limb edema (n = 1) was reported following a switch from Adalimumab to Secukinumab. No statistically significant differences were identified (all p-values > 0.05), likely reflecting the limited sample size and low frequency of events. No clear drug-specific clustering of adverse events was observed beyond the higher frequency of hepatotoxicity in the Etanercept group.

3. Discussion

In this retrospective observational study of 58 patients with Psoriasis, Psoriatic Arthritis, and Hidradenitis Suppurativa, the overall incidence of adverse events was low, with hepatotoxicity being the most frequently observed (6.9%), which was the leading cause of treatment discontinuation. This finding suggests that liver toxicity, while relatively uncommon, remains clinically relevant and reinforces the importance of biochemical monitoring during biologic therapy. Biologic agents used in Psoriasis and Hidradenitis Suppurativa are generally considered to have a lower risk of hepatotoxicity compared with conventional systemic therapies such as methotrexate. However, Anti TNF-α therapy may cause hepatotoxicity, which can range from alteration of liver tests to severe liver failure, as reported in several studies that warrant clinical attention [7,8]. Hagel et al. published a case of a patient 44 with a history of Psoriasis without liver disease, who developed subacute liver failure 4 months after Adalimumab [9]. Also, Van der Heijde et al., in 208 patients with Ankylosing Spondylitis treated with Adalimumab, at week 12 of follow-up, reported elevated aminotransferases in six patients with ALT levels three times above the reference value [10]. The transaminase levels of our patients for whom we discontinued the treatment were three times above normal (in all three cases); although a recovery period was recommended, the levels did not change. Also, we discontinued therapy with Adalimumab in the case of a 32-year-old patient who was diagnosed with Cutaneous Leishmaniasis (acquired during travel to an endemic country) to start the appropriate antiparasitic treatment. Anti-TNF-α therapy is associated with an increased risk of Leishmaniasis, particularly in endemic areas. Gonzales et al. reported a case of a 49-year-old Caucasian man, treated with Adalimumab, who was also affected with mucocutaneous Leishmaniasis [11]. Also, Catala. A et al. reported a 59-year-old woman diagnosed with Cutaneous Leishmaniasis and her therapy with anti-TNF-α for Rheumatoid Arthritis [12]. Other events, including Generalized Urticaria, Cutaneous Rash, Granulomatous Uveitis, and laboratory abnormalities, were rare (<2%). Cutaneous eruptions complicating treatment with anti-TNF-α agents are common, occurring in around 20% of patients. Erythematous rash and urticaria have also been reported in other studies. Hadas et al. described four cases of hypersensitivity reactions in the form of Acute Urticaria as well as Erythema Multiforme during administration of Adalimumab and Ustekinumab [13]. Marques et al. presented a case of Henoch–Schonlein purpura vasculitis following treatment with the monoclonal anti-TNF antibody Adalimumab for Crohn’s disease. The reaction occurred after 18 months of Adalimumab therapy, and the discontinuation of the biologic resulted in rapid improvement of the condition [14]. Granulomatous Uveitis has also been reported as an adverse effect of Anti-TNF alpha therapy in other studies. Bonifazi et al. described a case of a 61-year-old psoriatic patient on long-term Etanercept therapy who developed induced Sarcoidosis with bilateral panuveitis [15]. Also, Sobolewska et al., in their study, reported 16 cases of new and recurrent Uveitis during treatment with Etanercept, Adalimumab and Abtacept [16]. Importantly, no unexpected or fatal adverse events directly attributable to biologic therapy were observed. Therapy modifications occurred in a minority of patients, most commonly due to adverse events or suboptimal response. Adalimumab showed numerically higher modification rates (20%) compared to Etanercept (7.7%) and Secukinumab (0%), although these differences were not statistically significant (Fisher’s exact test, p ≈ 0.18). Switching between biologic agents is a common strategy when treating inflammatory diseases, and the main reasons for this may include primary or secondary treatment failure, adverse effects (e.g., hepatotoxicity, infections, hypersensitivity reactions), development of paradoxical or immune-mediated reactions, and patient-related factors (e.g., pregnancy planning, intolerance). A recent real-world study analyzed switching patterns in psoriasis patients treated with biologics. Primary and secondary lack of efficacy were the most frequent reasons for switching, and anti-IL-17 agents (like Secukinumab) were commonly chosen after TNF inhibitors [17]. Switching can improve outcomes for many patients, though safety profiles and infection risks must be considered.

Overall, our findings support the favorable safety profile of biologic therapies in routine clinical practice, with a low incidence of adverse events and predominantly reversible outcomes. However, careful monitoring remains essential, particularly for hepatotoxicity and opportunistic infections. Despite these findings, several limitations of this study should be acknowledged. First, the retrospective design may introduce selection and information bias and limit the ability to establish causal relationships between biologic therapy and adverse events. Second, the sample size is relatively small, particularly for hidradenitis suppurativa, which restricts statistical power and limits the generalizability of the results; therefore, the study is not adequately powered to draw definitive conclusions regarding the overall safety of individual biologic agents. Third, the duration of follow-up varied among patients according to treatment initiation and discontinuation times, which may have resulted in underestimation of late-onset adverse events. Finally, although limited in size, this study provides real-world data from a tertiary center, contributing to the existing literature by reflecting everyday clinical practice in a regional setting where such data remain scarce. Larger prospective studies with standardized follow-up are warranted to further define the safety profile of biologic therapies.

4. Methods

This retrospective observational study was conducted between January 2022 and January 2026 at the Outpatient Consultation Center of the Departments of Dermatology and Rheumatology, University Hospital Center “Mother Teresa,” Tirana, Albania. The study included 58 consecutive adult patients receiving biologic therapy for psoriasis, psoriatic arthritis, or hidradenitis suppurativa. Eligibility for biologic therapy was determined according to national treatment protocols. For psoriasis, inclusion criteria were: (i) clinically and, when indicated, histopathologically confirmed chronic plaque or generalized psoriasis; (ii) moderate-to-severe disease defined by a Psoriasis Area and Severity Index (PASI) > 10; (iii) age ≥ 18 years; and (iv) inadequate response, intolerance, or contraindication to at least one conventional systemic therapy (e.g., methotrexate, cyclosporine, acitretin). For psoriatic arthritis, inclusion criteria were: (i) age ≥ 18 years; (ii) diagnosis confirmed by a rheumatologist according to the CASPAR criteria; and (iii) active disease despite treatment with at least one conventional disease-modifying antirheumatic drug (DMARD). Among patients with hidradenitis suppurativa, disease severity was classified according to the Hurley staging system: two patients were classified as stage III (diffuse or near-diffuse involvement, multiple interconnected sinus tracts, and extensive scarring), and one patient as stage II (recurrent abscesses with sinus tract formation and scarring, with widely separated lesions). Prior to initiation of biologic therapy, all patients provided written informed consent for treatment and for the use of their anonymized clinical data, in accordance with national regulations on personal data protection. Patient data were recorded in the national electronic registry to ensure standardized clinical monitoring and quality of care. Biologic therapies available through the public healthcare system included Etanercept (for psoriasis and psoriatic arthritis), Adalimumab (for psoriasis and hidradenitis suppurativa), and Secukinumab (for psoriasis and psoriatic arthritis). The choice of biologic agent was individualized based on disease severity, clinical phenotype, comorbidities, and route and frequency of administration. Data collected from medical records and follow-up documentation included demographic characteristics, diagnosis, duration of therapy, treatment modifications, discontinuation events, and adverse effects. Most patients received biologic therapy for prolonged periods according to the national 3-year treatment protocol, except for cases requiring earlier discontinuation due to adverse events. Patients were routinely monitored for both treatment efficacy and safety outcomes throughout the study period. Laboratory assessments were performed at baseline and every two months during treatment, while viral screening for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) was conducted every six months. Statistical analysis was performed using appropriate descriptive and inferential methods. Associations between biologic agents and treatment interruption or modification were evaluated using the Chi-square test or Fisher’s exact test, as appropriate. A p-value ≤ 0.05 was considered statistically significant.

5. Conclusions

Hepatotoxicity was the most frequently observed adverse event (6.9%) and represented the leading cause of treatment discontinuation, underscoring its clinical relevance despite the relatively small cohort size. Other adverse events occurred less frequently, including Generalized Urticaria, Granulomatous Uveitis, and laboratory abnormalities, which were rare (<2%). These findings highlight the importance of regular safety monitoring, particularly liver function surveillance, during biologic therapy. Owing to the study’s retrospective design and limited sample size, larger prospective studies are required to further clarify the incidence and clinical significance of adverse events associated with individual biologic agents.