Safety of Biologic Therapies in Patients with Moderate-to-Severe Plaque Psoriasis and Concomitant Viral Hepatitis: A Monocentric Retrospective Study

Psoriasis is a chronic skin disease that affects about 2–4% of the world population [1]. Typically, psoriasis presents with erythematous and scaly plaques and patches diffused to the trunk and to upper and lower limbs. Frequently, plaque psoriasis can also involve scalp, palms/soles, genitals, and nails, significantly impairing patients’ quality of life. It is now well known that psoriasis also plays a crucial role in the development of different types of comorbidities, including psoriatic arthritis (PsA), cardiovascular diseases, arterial hypertension, and metabolic syndrome [2]. Biologic drugs have changed the management of moderate-to-severe chronic plaque psoriasis with their effectiveness and safety profiles, and they appear also to have an impact on the natural history of this disease [3]. However, there is a lack of strong evidence regarding the treatment with biologics (especially for the most recent anti-IL-17 and anti-IL-23 drugs) of patients with concomitant viral hepatitis B or C. These more recent biologics treatments appear to have better safety profiles, based on data from both randomized clinical trials and real-life experiences [4, 5]. On the other hand, several reports suggest that anti-TNF-α monoclonal antibodies should be avoided in those patients because of the higher risk of serious infections compared with nonbiologic therapies [6].

In the absence of clear evidence, most clinicians decide to prescribe prophylaxis with lamivudine or other antiviral drugs before starting therapy in patients with evidence of viral hepatitis B. On the other hand, drug resistance due to the use of prophylactic antivirals is increasingly developing, raising concerns about their overuse [7].

The aim of this retrospective real-life single center study is to assess the efficacy and the safety of biologic drugs in a cohort of 20 patients affected by severe plaque type psoriasis and concurrent chronic viral hepatitis (both chronic inactive hepatitis and occult cases) with no clinical signs and/or lab indication of active liver disease) who did not receive antiviral prophylaxis before starting treatment.

This is a non-interventional retrospective single-center real-life study analyzing the psoriasis database of our dermatology department.

The inclusion criteria are:

Moderate-to-severe psoriasis was defined by the “rule of 10” before starting biologic therapies [PASI > 10, Body Surface Area (BSA)  > 10 or Dermatology Life Quality Index (DLQI) > 10] [8]. The efficacy of biologic treatments was defined by assessing Psoriasis Area and Severity Index (PASI) during all visits. All patients were evaluated by a hepatologist and underwent testing for viral load before obtaining approval to start biologic treatment. According to the hepatologist’s indications, patients were regularly monitored for reactivation of viral hepatitis with liver enzymes, viral DNA load and viral RNA load (for HBV and HCV viruses, respectively), and viral markers (every 3 months). They also underwent periodical hepatologic visits. None of our patients received antiviral therapies before the start of the biologic drug.

Active hepatitis was defined as transaminases enzyme elevation at least five times the upper normal limit [9]. HBV reactivation was defined as an increase in HBV replication of > 1 log₁₀ copies/mL or seroconversion from negative to positive HBsAg [9].

Institutional review board approval was exempted as the study protocol did not deviate from standard clinical practice. All included patients had provided written consent for retrospective study of data collected during routine clinical practice.

Of the 794 patients with psoriasis or psoriatic arthritis treated with a biologic drug at our department, 20 (2.52%) patients had positive markers of HBV or HCV before starting the treatment. Seventeen patients had positive markers of HBV infection and four patients had positive antibodies for HCV, but HCV-RNA was undetectable in all patients (one patient had serologic evidence of both HBV and HCV infection).

Regarding patients with HBV infection, 12 were male (70.59%) and 5 were female (29.41%). All were affected by plaque psoriasis, and their median age was 57 years. Four patients received more than one biologic drug. Anti-IL-23 biologics were the most used in our population, with risankizumab being the most prescribed drug (n = 11), followed by tildrakizumab, ustekinumab, ixekizumab, secukinumab (n = 2 each), brodalumab, adalimumab, and etanercept (n = 1 each). Median PASI at baseline was 15. Two patients were also affected by psoriatic arthritis, and the most common comorbidity was arterial hypertension (n = 8), followed by type 2 diabetes (n = 2). All patients were followed through at l east 52 weeks, with six patients completing at least 2 years of treatment. Five patients had a serologic status suggestive for a previous resolved HBV infection (with negative HbsAg and positive HbsAb and HbcAb), while 11 patients had a positivity for HbcAb only. Just one patient was an inactive HBV carrier, with positive HbsAg (256,66 mIU/mL), negative antibodies, and undetectable viral load (Table 1). No patient received the indication of prophylaxis from our hepatologists. During follow-up, each patient underwent blood testing for HBV viral load and HbsAg, along with transaminases, every 3 months for the first year of therapy and then every 6 months. No patient had evidence of viral reactivation during our study. At the last available observation, PASI 100 was achieved by 12 patients (70.59%), while 15 patients (88.24%) maintained a PASI 90 response, at least (Table 1). To date, all patients are still under treatment with a biologic drug, as none of them has experienced neither adverse events leading to discontinuation nor therapeutic ineffectiveness.

Four patients had serological evidence of HCV infection (three men and one woman), with a median age of 54.5 years (Table 2). Viral HCV load was undetectable for all of them. All patients were followed for at least 52 weeks. One patient was treated with ustekinumab for more than 4 years, another patient received risankizumab, achieving a PASI 100 response. The third patient also reached PASI 100 during treatment with ixekizumab. The fourth patient, who also had a diagnosis of PsA, was treated with adalimumab, before being switched to secukinumab and then to brodalumab, achieving good control of both psoriasis and PsA. Each patient was tested for HCV-RNA every 3 months, and none of them showed sign of viral reactivation.

Since biologic therapies are becoming the standard of care for the treatment of moderate-to-severe plaque psoriasis, it is very important to assess the safety of this drugs in patients with serology suggestive for viral hepatitis. Reports regarding the safety profile of biologic drugs in patients affected by viral hepatitis show contrasting data. However, the vast majority of these studies focused on anti-TNF-α drugs and ustekinumab, and those studies included mostly patients with rheumatic diseases [10].

Regarding viral hepatitis B, none of our patients (including the one individual with positive HbsAg) experienced viral reactivation despite not receiving antiviral prophylaxis, supporting the safety of biologics in this population. Although the risk of HBV reactivation during the course of biologic therapy is considered to be low, especially for HbsAg-negative patients, it is relevant to underline that viral load was persistently undetectable in all patients in our experience, strongly decreasing the risk of a possible viral reactivation. A retrospective study by Sanz-Bueno et al. [11] on 20 patients treated for psoriasis with a TNF inhibitor or ustekinumab, having evidence of prior infection with hepatitis B (defined as the positivity for anti-HBc, the absence of HBsAg, and the presence or absence of anti-HBs), did not report any case of hepatitis B reactivation. As in our experience, none of the patients received prophylaxis before starting treatment. A study by Viganò et al. [12] recommended HBV prophylaxis in patients with positive HBsAg before therapy with anti-TNF drugs, while they agreed that patients seropositive for anti-HBc should be closely monitored. In our study, we found the presence of HbsAg in only two patients: they were both treated with risankizumab after a hepatologic visit, which recommended only monitoring for reactivation of viral hepatitis with liver enzymes and viral DNA load testing. In a systematic review by Snast et al. [13], only 1.14% (2/175) of patients with positive HbcAb had viral reactivation. Regarding patients with chronic HBV infection (positive HbsAg regardless of serological status), reactivation was experienced by 3/26 patients (11.54%) receiving prophylaxis compared with 5/14 (35.71%) patients without prophylaxis. This review included 312 patients with evidence of hepatitis B, all treated with either ustekinumab or anti-TNF-α therapies [13]. According to a review article by Kaushik and Lebwohl [14], biologic therapy can be initiated in all patients affected by chronic (or past) infection from hepatitis B, under close laboratory and clinical monitoring with a hepatologist. According to their experience, IL-17 inhibitors appear safe if used after antiviral prophylaxis in patients with positive HbsAg, while no data were reported on anti-IL-23 drugs. On the other hand, they approved the use of anti-TNF-α, ustekinumab, and anti-IL-17 in patients with positive HbcAb. No data were available on anti-IL-23 treatments in this population.

Regarding chronic HCV infection, the risk of reactivation in patients with positivity for HCV-ab but undetectable HCV-RNA is considered to be very low [13]. Moreover, several studies have demonstrated that TNF-α inhibitors are associated with a decrease in viral load. The previously mentioned review by Snast et al. [13] reports a yearly rate of viral reactivation of 2.42% in patients treated with either adalimumab or etanercept. According to Kaushik and Lebwohl [14], regarding biologic therapies, IL-17 inhibitors and apremilast appear to have a favorable safety profile, while patients receiving TNF-α inhibitors should receive antiviral therapy and be monitored closely. However, in their review, only limited data on IL-23 inhibitors were available. Our study included only four patients, and none of them experienced viral reactivation during the course of therapy.

Our study has several limitations, the first being its retrospective nature, which does not allow us to generalize our conclusions. Second, a follow-up of 52 weeks may be too short to assess the safety profile of biologics in our population, despite half of our patients reaching at least 104 weeks of observation. Moreover, we included patients with different serological status receiving different biologic drugs, which may make it difficult to generalize our data. However, our retrospective study has the particularity of including only patients treated with anti-IL-12/23, anti-IL-17, or anti-Il-23 therapies, which now represent the standard of care for moderate-to-severe plaque psoriasis.

In conclusion, our data show that none of our patients experienced reactivation of viral hepatitis, during treatment with anti-IL12/23, anti-IL-17, and anti-IL-23 biologic drugs for at least 52 weeks, despite not receiving antiviral prophylaxis. Since no strong evidence is available yet, we recommend strict monitoring for HbsAg and HBV/HCV viral load during the course of therapy with biologics for psoriasis. Further prospective studies, with larger cohorts of patients and longer follow-up periods, are needed to assess the risk of viral reactivation in patients receiving biologic therapies.