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Infections and Psoriasis Treatment: More “Real-World” Data Needed with Critical Appraisal

  • Luigi Naldi
    Correspondence
    Correspondence: Luigi Naldi, Unità di Dermatologia, Azienda Ospedaliera papa Giovanni XXIII, 24100 Bergamo, Italy.
    Affiliations
    Study Center of the Italian Group for Epidemiologic Research in Dermatology (GISED), Department of Dermatology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
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      Data from the Spanish registry BIOBADADERM suggest that the risks of any infectious episode in patients treated with biologics are limited, not exceeding the risks observed with a conventional treatment such as cyclosporine. The registry lacked enough statistical power to analyze risks for severe infections. These should be the focus of further research, although the difficulties of “real-world” data analysis should not be trivialized.
      • Infections are an issue of concern when deciding about psoriasis treatment.
      • The BIOBADADERM data are reassuring about the risk of any infections for biologics.
      • The risk of severe infection remains to be determined with certainty.
      • Dávila-Seijo P.
      • Dauden E.
      • Descalzo M.A.
      • Carretero G.
      • Carrascosa J.M.
      • Vanaclocha F.
      • et al.
      Infections in moderate to severe psoriasis patients treated with biological drugs compared to classic systemic drugs: Findings from the BIOBADADERM registry.
      present data from the Spanish registry BIOBADADERM concerning the risk of infections in patients treated systemically for psoriasis. Compared with methotrexate, the analyses documented a significant 71%, 58%, and 34% increased risk of overall infections for infliximab, cyclosporine, and etanercept respectively, and a significant 40% decreased risk of infection for acitretin. When looking at combination therapies, there was about a 2-fold increased risk of overall infection for adalimumab associated with methotrexate and a 58% increased risk for ustekinumab associated with methotrexate. Quite surprisingly, the association of methotrexate with infliximab or etanercept did not result in any significant increased risk, despite the risks documented when the latter two drugs were used as monotherapy. When restricting analyses to severe infection, defined as life-threating conditions leading to or prolonging hospitalization or causing persistent disability or death, a significant three times-higher risk of infection compared with methotrexate was observed for cyclosporine. Nonsignificant two to three times-higher risks were also documented for adalimumab in association with methotrexate and for infliximab alone or in combination with methotrexate; etanercept showed a nonsignificant 76% decrease in risk. Infliximab alone and adalimumab in combination with methotrexate had the highest significant risks of recurrent infection. At variance with studies in rheumatoid arthritis, which documented increased risks of infection for biologics limited to the first year of treatment, no consistent time dependency of risk was observed.
      The demand for so-called “real-world” data on a chronic disease like psoriasis is increasing, and this has paralleled the introduction of new targeted drugs. These drugs, which include several biologics and, more recently, a few small molecules, were proven to be effective or highly effective in the context of randomized clinical trials (RCTs). These RCTs typically exclude patients with selected comorbidities, have restricted time spans, and have sample sizes that are not adequate to rule out uncommon but relevant adverse events (e.g., those with an incidence of less than 1 in 100).
      A way of overcoming the statistical constraints of RCTs would be to combine them in a meta-analysis. A meta-analysis of RCTs of biologics in psoriasis has recently offered a reassuring picture concerning the risk of severe infection (
      • Yiu Z.Z.N.
      • Exton L.S.
      • Jabbar-Lopez Z.
      • Mustapa F.M.
      • Samarasekera E.J.
      • Burden A.D.
      • et al.
      Risk of serious infections in patients with psoriasis on biologic therapies: a systematic review and meta-analysis.
      ). Meta-analyses cannot, however, account for the stricter patient selection and closer monitoring criteria observed in RCTs when compared with real-world practice. Previous analyses of data from the BIOBADADERM registry documented that patients ineligible for RCTs may represent a large proportion of those receiving systemic therapy for psoriasis and that these patients have higher risk for severe adverse events. Biologics add to a higher baseline risk in patients who are ineligible for RCTs (
      • Garcia-Doval I.
      • Carretero G.
      • Vanaclocha F.
      • Ferrandiz C.
      • Dauden E.
      • Sanchez-Carazo J.L.
      • et al.
      Risk of serious adverse events associated with biologic and nonbiologic psoriasis systemic therapy: patients ineligible vs eligible for randomized controlled trials.
      ).
      Besides the above-mentioned BIOBADADERM study, I am aware of only one other published, registry-based, cohort study assessing the risk of severe infection in psoriatic patients treated with biologics, the Psoriasis Longitudinal Assessment and Registry (PSOLAR). That study showed an increased risk of serious infections for infliximab and adalimumab but not for other biologics when compared with a population that had received systemic retinoids or phototherapy (
      • Kalb R.E.
      • Fiorentino D.F.
      • Lebwohl M.G.
      • Toole J.
      • Poulin Y.
      • Cohen A.D.
      • et al.
      Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).
      ). Increasing age, diabetes mellitus, and smoking were additional factors influencing the risk of severe infection. Other registry-based studies focusing on the risk of infection for biologics have considered clinical conditions different from psoriasis or have pooled data from several indications, including psoriasis. These data may not be representative of psoriasis, because they have different profiles of co-medications and different baseline risks of infection for the conditions under consideration.

      Registries: a systematic data collection in the real world

      It is largely acknowledged that biologics are devoid, at least in the short term, of the typical organ-specific adverse events observed with small molecules. On the other hand, they may cause adverse events related to cytokine imbalance or impaired immune function (
      • Pichler W.J.
      Adverse side-effects to biological agents.
      ). The resulting clinical problems, for example, infection and/or cancer, may be difficult to differentiate from naturally occurring events, making the usual spontaneous surveillance systems rather inefficient at detecting relevant signals during the so-called postmarketing phase. A possible exception might be the triggering of very rare, unusual, or dramatic adverse events that would be more likely to prompt reporting, such as progressive multifocal leukoencephalopathy occurring with exposure to efalizumab (
      • Nijsten T.
      • Spuls P.I.
      • Naldi L.
      • Stern R.S.
      The misperception that clinical trial data reflect long-term drug safety: lessons learned from Efalizumab’s withdrawal.
      ).
      Registry-based cohort studies are one way to overcome the limitations of spontaneous surveillance, promoting a proactive attitude toward the identification of potential risks and to evaluate treatment effectiveness. A registry could be defined as “a systematic collection of information on all patients with a specific disease or other health-relevant condition,” whereas a cohort study is “a study where one or more samples (from the cohort population) with different levels of exposure to purported causal factors (e.g., drugs) are followed over time and assessed for the occurrence of one or more outcomes of interest.” A detailed overview of methods and experience with registries evaluating patient outcomes is prepared and regularly updated by the Agency for Healthcare Research and Quality of the US Department of Health and Human Services (
      ).

      Data analysis: a path with many traps

      The study of the relation between exposure to systemic treatment for psoriasis and infection offers a teaching example of the hurdles and complexities of the analysis of registry data (Figure 1). At variance with randomization, which tends to balance patient characteristics among different treatment groups, clinical practice requires that doctors adjust, as much as possible, treatments to the needs and characteristics of patients. As a consequence, patients managed by different treatment options in the real world may differ at baseline for several variables that may, unfortunately, be related to the outcome of interest. Therefore, a good prescribing doctor is responsible for reducing risks and, at the same time, confounding the comparisons of adverse events among several different therapies. A way to overcome the problem, at least partly, as reported in the BIOBADADERM article (
      • Dávila-Seijo P.
      • Dauden E.
      • Descalzo M.A.
      • Carretero G.
      • Carrascosa J.M.
      • Vanaclocha F.
      • et al.
      Infections in moderate to severe psoriasis patients treated with biological drugs compared to classic systemic drugs: Findings from the BIOBADADERM registry.
      ), is to use propensity score analysis. A propensity score is a statistical score that expresses the probability of treatment assignment conditionally on selected baseline characteristics. It summarizes multiple potentially confounding variables into a single score (
      • Moride Y.
      • Abenhaim L.
      Evidence of the depletion of susceptibles effect in non-experimental pharmacoepidemiologic research.
      ). Once the propensity score is developed, it can be used as a weight in a statistical model to calculate risks and to equalize patients for variables affecting drug prescriptions and, possibly, outcomes. It should be noted that a propensity score can adjust only for confounding variables that have been collected. If an important variable that affects treatment assignment and outcome is missing, then the propensity score cannot account for it. A previous history of infection may influence treatment choice and outcome. In the PSOLAR registry it was shown that a history of significant infection before enrollment into the registry was an independent predictor of subsequent serious infections (
      • Kalb R.E.
      • Fiorentino D.F.
      • Lebwohl M.G.
      • Toole J.
      • Poulin Y.
      • Cohen A.D.
      • et al.
      Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).
      ). I do not have information if a history of infection before entry into the registry was collected and analyzed within the BIOBADADERM study.
      Figure 1
      Figure 1Selected factors affecting risk assessment of infection with exposure to drugs in a registry-based cohort study. A summary representation of variables influencing risk evaluation being connected with different time points in a study: entry, follow-up and outcome.
      Once patients are enrolled into a registry, they should be followed up over time, keeping losses to follow-up to a minimum. One problem is the possible preferential loss to follow-up of those patients who experience adverse events, a phenomenon referred to in pharmacoepidemiology as depletion of susceptibles. The resulting situation is similar to the “healthy worker effect” observed in occupational epidemiology, which is a tendency for those who survive on a job (or on a drug) to have a more favorable morbidity experience than the reference population at large (
      • Moride Y.
      • Abenhaim L.
      Evidence of the depletion of susceptibles effect in non-experimental pharmacoepidemiologic research.
      ). Such an issue is particularly important when prevalent, rather than incident, treatment exposures are considered. Prevalent exposures occur when a patient is enrolled into a registry while already on a treatment for a period of time. In this case, it is quite possible that treatment survivors are more likely to be enrolled and that some adverse events that occurred before entry into the registry were missed (e.g., left truncation of survival data). It is reassuring that the BIOBADADERM study, at variance with the PSOLAR registry previously mentioned, considered only incident treatments, that is, new treatments started at the time of entry into the registry.
      A depletion of susceptibles effect in the BIOBADADERM study might at least partly explain the paradox of an increased risk of infection for etanercept and infliximab as monotherapy and a lack of risk for their combination with methotrexate. Methotrexate is frequently added for those patients receiving biologics who do not reach the desired level of improvement. It could be argued that those patients who have experienced an adverse event, such as infection, on a biologic drug as monotherapy are less likely to be considered suitable candidates for combination treatment. As discussed in the BIOBADADERM article, a depletion of susceptibles effect may have also biased risk estimates in the analysis of recurrent infections, because patients experiencing a first infectious episode on a drug, if not clinically trivial, may be offered alternative treatment options.
      When analyzing the exposure to outcome relationship, it is important to clearly define the time window of the exposure, that is, the period during which the exposure is expected to exert its effects. The definition should be based on pharmacokinetics and pharmacodynamic data, and it may include induction and latent periods. In the BIOBADADERM study, events were assigned to a drug if they occurred during drug therapy or within a 90-day period after the last dose. As an alternative, the time from discontinuation plus two half-lives of each drug was considered. The results for these two different criteria were almost identical. No minimum duration of exposure was defined for the drug to produce its effects.
      Infection is an imprecise term that includes a wide range of clinical conditions, with a large spectrum of severity levels. In the BIOBADADERM study the reported diagnoses encompassed rather trivial entities such as molluscum contagiousum and, at the same time, severe manifestations such as septic shock and disseminated tuberculosis. For mild clinical manifestations, the gathering of information may be influenced by exposure and comorbidities. Much more certain data are recorded with severe infections. These, however, are rare, and risk estimates may suffer from a lack of statistical power. In the BIOBADADERM study, the chance of documenting a 2-fold increase in risk, assuming an alpha error of 5%, was much lower than 60% for severe infections, whereas it was an acceptable 80% when considering any infectious episode. As a consequence, risk estimates for severe infections were unstable, with wide confidence intervals and with obvious uncertainties when interpreting them.

      Meta-analysis of registry data

      Psoriasis registries are active in several countries, but they are heterogeneous in terms of organization, study design, population coverage, and methods of data collection. It would be desirable for these registries to communicate with each other to harmonize procedures and to allow comparisons of data. Even better would be the possibility of combining data together, especially when considering uncommon or rare events.
      In Europe, several national psoriasis registries, including the Spanish BIOBADADERM registry, are now collaborating in a network termed the Psonet collaboration (Table 1). In parallel with the publication of the BIOBADADERM article, a meta-analysis of data from three registries contributing to Psonet was published. They include the Spanish registry, the Italian registry Psocare, and the Clalit Health Service database in Israel. The meta-analysis focused on anti-tumor necrosis factor drugs and compared them, pooled together, with conventional treatment. The analyses included a Charlson index, that is, an index summarizing the presence of selected comorbidities, but not a propensity score. No documentation of increased risks for severe infections or granulomatous infections was documented for the anti-tumor necrosis factor drugs when combined. When any infectious episode, irrespective of severity, was considered, the results were heterogeneous, with an increased risk in Spain but no risk documentation in the other two countries, probably reflecting differences in detection and reporting among the registries (
      • Garcia-Doval I.
      • Cohen A.D.
      • Cazzaniga S.
      • Feldhamer I.
      • Addis A.
      • Carretero G.
      • et al.
      Risk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti-tumor necrosis factor agents versus classic therapies: prospective meta-analysis of Psonet registries.
      ).
      Table 1Registries currently participating in the Psonet collaboration
      See also www.psonet.eu.
      CountryRegistry Name
      AustriaPsoRA (Psoriasis Registry Austria)
      AustraliaAustralasian Psoriasis Registry
      Czech RepublicPsoREP
      DenmarkDermBio
      FrancePsoBioTeq
      GermanyPsoBest
      IsraelClalit Health Service Database
      ItalyPsocare, Psodit, Psoreal
      SpainBIOBADADERM
      SwedenPsoReg
      SwitzerlandSwiss Dermatology Network for Biologicals SDNB
      The NetherlandsAMC psoriasis registry
      United KingdomBADBIR
      1 See also www.psonet.eu.
      The relationship between psoriasis treatment and infection remains an area in need of further research. Additional data are required concerning severe infections, looking at individual diagnoses, and assessing individual drugs. Risk modifiers and ways to reduce risks are additional aspects to be explored further. All in all, the data available suggest that current patient selection criteria and clinical monitoring procedures are effective measures to minimize risks of infection in patients treated systemically for psoriasis and that current standards of care should not be weakened (
      • Chirch L.M.
      • Cataline P.R.
      • Dieckhaus K.D.
      • Grant-Kels J.M.
      Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factor-alfa antagonists: Part I. Risks associated with tumor necrosis factor-alfa antagonists.
      ).

      Conflict of Interest

      During the last 5 years, Naldi has received consultant fees from Janssen-CILAG, Novartis, Abbvie, Lilly, Pfizer, Menarini, and Sanofi.

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      Linked Article

      • Infections in Moderate to Severe Psoriasis Patients Treated with Biological Drugs Compared to Classic Systemic Drugs: Findings from the BIOBADADERM Registry
        Journal of Investigative DermatologyVol. 137Issue 2
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          Information regarding the safety of biological drugs prescribed to psoriasis patients on daily and long-term bases is insufficient. We used data from the BIOBADADERM registry (Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases) to generate crude rates of infection during therapy with systemic drugs, including biological drugs (infliximab, etanercept, adalimumab, and ustekinumab) and nonbiological drugs (acitretin, cyclosporine, and methotrexate). We also calculated unadjusted and adjusted risk ratios (RRs) (with propensity score adjustment) of infection, serious infections, and recurrent infections of systemic therapies compared with methotrexate, using Poisson regression.
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