Long-term data in the treatment of psoriasis

Moderate-to-severe plaque psoriasis is associated with a considerable disease burden and treatment needs are often unmet. Several conventional systemic drugs are available as treatments, including methotrexate, ciclosporin, retinoids and psoralen ultraviolet A, which, although effective, are associated with considerable toxicity that limits their long-term use. Recent developments in more targeted therapies involving biological agents, such as anti-T-cell agents and inhibitors of tumour necrosis factor-alpha, offer an alternative treatment approach with the possibility of longer continuous therapy, which may translate into disease control and improved quality of life. Although the majority of data supporting the use of biological agents have been obtained in short-term studies of 3–6 months' duration, some agents have been evaluated for longer periods of continuous administration. Comparison of efficacy among these agents may better define their role as long-term therapy. This article discusses the data currently available on both conventional and biological systemic therapies for psoriasis, in terms of short-term and long-term use.     

Biological therapies for psoriasis: Adherence and outcome analysis from a clinical perspective

We evaluated and compared patients' long‐term adherence to biological therapies in a real‐life clinical setting. Secondary aims included weight changes on biological therapy and reporting adverse effects. This prospective case‐note review included 58 patients, undergoing 84 treatment series including etanercept (21), adalimumab (24), infliximab (14) and ustekinumab (25). Patients' adherence was greatest with ustekinumab (being 6.7‐fold less likely to withdraw from treatment than etanercept, P = 0.014), while the difference in treatment adherence of adalimumab and infliximab compared to etanercept was not statistically significant. Adalimumab and infliximab were associated with an increase in weight, while ustekinumab was associated with weight loss compared with etanercept (not statistically significant). Long‐term patient adherence to biologic therapy in patients with psoriasis is greatest with ustekinumab.     

Biologic therapies for psoriasis: practical experience in a U.K. tertiary referral centre

Summary Background Large‐scale clinical trials provide clear evidence of the efficacy and short‐term toxicity of biologic therapies for psoriasis. However, to date, there are few reports of the practical use of these therapies outside of the trial setting and, to our knowledge, none from a U.K. cohort of patients with psoriasis. Objectives (i) To assess efficacy and safety of efalizumab, etanercept and infliximab in a U.K. cohort of patients with psoriasis, with mean Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index 21·8 and 21·7, respectively, outside of the clinical trial setting. (ii) To examine our approach to the processes involved in the initiation of biologic therapies in the era of National Institute for Health and Clinical Excellence guidance. Methods A retrospective case‐note review to identify all patients initiated on biologic therapies for psoriasis in a U.K. tertiary referral centre. Results At 3 months of treatment the efficacy of efalizumab (n = 28), etanercept (n = 70) and infliximab (n = 20), as assessed by PASI 75 (75% decrease from baseline score), was 24%, 35% and 85%, respectively. All three biologics used were well tolerated. Combination therapy with traditional systemic agents was required either at transition to, or to counter relapse while established on, a biologic therapy in 30% of cases. Streamlined approaches to screening and funding significantly (P ≤ 0·05) hastened the initiation of biologic therapies. Conclusions In a cohort of U.K. patients with severe psoriasis, biologic therapies have proved to be a significant step forward in expanding the therapeutic armamentarium for psoriasis. Pharmacovigilance, in the form of registries, is essential to assess the long‐term safety of such drugs.     

Cost-effectiveness analysis of TNF-α blockers for the treatment of chronic plaque psoriasis in the perspective of the Italian health-care system

The cost-effectiveness of biological treatments for psoriasis is not well determined and may vary from country to country. The objectives of this study was to perform a cost-effectiveness analysis of infliximab compared with other anti-tumor necrosis factor-α agents for the treatment of psoriasis in Italy. The incremental cost-effectiveness ratio per patients achieving at least 75% improvement in the psoriasis area and severity index assessed over 24- and 48–50-week periods was calculated. Efficacy data were drawn from randomized controlled trials when available or from open label studies. Considering patients achieving psoriasis area and severity index at week 24 and 48–50, infliximab was dominant (more effective and less costly) over etanercept given at 50 mg twice weekly. In contrast, infliximab was not dominant over etanercept at other dosages or over adalimumab. When considering the impact of therapy on quality of life at Week 12 using the Dermatology Life Quality Index equal to zero, infliximab resulted more effective and less costly than etanercept. Therefore, infliximab seems to be cost-effective in the therapy of psoriasis. Further cost-efficacy evaluations based on head-to-head trials are necessary to address health economic considerations.     

Presence of antidrug antibodies correlates inversely with the plasma tumor necrosis factor (TNF)‐α level and the efficacy of TNF‐inhibitor therapy in psoriasis

Antidrug antibodies have been shown to be associated with a loss of response during biologic therapy. Despite the potential association, there has been no report on the simultaneous monitoring of the following parameters in psoriasis: presence of neutralizing antibodies, plasma tumor necrosis factor (TNF)‐α concentration, TNFi concentration and disease activity. Plasma concentrations of adalimumab, infliximab, etanercept and their respective antidrug antibodies, as well as plasma concentrations of TNF‐α were measured in 77 psoriasis patients receiving biologic therapy, and the values were correlated with the clinical activity of the skin disease. Antidrug antibodies were identified in the plasma of 25% of infliximab‐treated patients and 29.6% of adalimumab‐treated patients, but not in the etanercept group. Clinical severity scores were significantly higher in the antibody‐positive patients. In patients receiving infliximab or adalimumab therapy, the presence of antidrug antibodies was directly associated with reduced plasma TNF‐inhibitor concentration and elevated plasma TNF‐α level.     

Is there truly a risk of lymphoma from biologic therapies?

The treatment of psoriasis has undergone a revolution with the advent of biologic therapies, including infliximab, etanercept, adalimumab, efalizumab, and alefacept. Biologics are generally safe and well tolerated. However, there has been concern over the risk of lymphoma with use of these agents because of their immunosuppressive properties. This review summarizes the current evidence in regards to lymphoma risk with biologic therapy obtained from case reports and case series, observational studies, clinical trials, and meta-analyses. The majority of data for T-cell inhibitors comes from case reports and relatively small, short-term clinical trials. In addition to published case reports and case series, TNF-α inhibitors have also been studied extensively in large cohort studies and meta-analyses of clinical trials derived primarily from the rheumatoid arthritis population. Current data are neither sufficient to completely rule out an increased risk of lymphoma associated with biologics, nor to firmly establish a causal relationship between biologics and lymphoma. Short- to intermediate-term treatment with biologics (e.g., up to 4 years) appears to be very safe with respect to lymphoma risk, especially with TNF-α inhibitors in which their potential risks appear to be well defined. Continued vigilance is warranted; however, in the appropriate patient, the risk-to-benefit profile of psoriasis treatment with respect to lymphoma risk appears highly favorable.     

Etanercept decreases the innate immune wounding response in psoriasis

Cathelicidin is increased when normal skin is injured and in psoriasis lesions where it has been suggested to play a pivotal role in inflammation through interactions with self‐DNA and toll‐like receptor 9 (TLR‐9) in keratinocytes and plasmacytoid dendritic cells. Because of etanercept's success in treating psoriasis, we hypothesized that etanercept may suppress TLR‐9 and cathelicidin induction. Examination of experimentally induced wounds of psoriatic lesional and non‐lesional skin, and comparison with wounded normal skin, shows that the induction of cathelicidin and TLR‐9 is greatly enhanced in lesional psoriatic skin. Six weeks of etanercept appears not to affect the baseline expression of cathelicidin or TLR‐9, but does blunt the induction of cathelicidin in psoriasis with wounding. These findings support the role of cathelicidin in the enhancement of local inflammation in psoriasis and may partially explain one of the mechanisms enabling TNF‐α inhibitors to successfully treat this disorder.     

Use of biological drugs in patients with psoriasis and psoriatic arthritis in Italy: Results from the PSONG survey

This Italian multicenter retrospective study compared the drug survival and efficacy of different anti‐TNF agents in psoriasis (PsO) and psoriatic arthritis (PsA) patients. A database of PsO/PsA patients treated with adalimumab, etanercept, and infliximab from May 2013 to May 2014 was analyzed. PASI 75, 90, and 100 was calculated at each time point to evaluate efficacy. Drug survival rate and probability of maintaining PASI response were evaluated. The impact of dependent variables on probability of PASI 75 loss was evaluated by logistic regression. 1,235 patients were included, 577 with PsO and 658 with PsA. Highest survival rates were observed with adalimumab followed by etanercept and infliximab in PsO and PsA patients. The probability of maintaining PASI response was significantly higher for adalimumab followed by infliximab. For PsO patients, the odds of losing PASI 75 was higher in etanercept‐treated patients (OR: 8.1; 95% CI: 4.2–15.6, p < .001) or infliximab (OR: 6.6; 95% CI: 2.6–16.3, p < .001) vs. adalimumab. Likewise, for PsA patients the odds of losing PASI 75 was higher in etanercept‐treated patients (OR: 2.3; 95% CI: 1.4–3.8, p = .01) or infliximab (OR: 2.2; 95% CI: 1.1–4.1, p = .018) vs. adalimumab. Adalimumab could be the best therapeutic option over other anti‐TNF agents for the treatment of PsO and PsA patients.     

Etanercept for the treatment of psoriasis and psoriatic arthritis

Etanercept is a fully human soluble recombinant p75 TNF receptor that blocks the binding of TNF to cell surface receptors, thereby neutralizing its biologic activity. Data supporting the FDA's approval of etanercept for controlling signs and symptoms and for inhibiting XRAY progression of psoriatic arthritis will be presented. Data supporting the FDA filing of etanercept for the treatment of moderate to severe psoriasis will also be presented. Long term safety data of etanercept in the over 231,000 adults and children with rheumatoid arthritis who have been treated worldwide will be briefly summarized.     

Safety of anti‐tumour necrosis factor‐α agents in psoriasis patients who were chronic hepatitis B carriers: a retrospective report of seven patients and brief review of the literature

Background Issues concerning the potential risks of reactivating chronic hepatitis B virus arise when the use of anti‐Tumour Necrosis Factor‐α (TNFα) agents is imperative in patients with concurrent psoriasis and hepatitis B virus infection. Objective The aim of this study was to report the experience regarding safety in the management of patients with coexisting psoriasis and chronic hepatitis B with the anti‐TNFα agents: infliximab, etanercept and adalimumab. Methods The psoriasis outpatient database of our dermatological department was searched for psoriasis and hepatitis B diagnoses and the medical records of these patients were reviewed for use of anti‐TNFα agents. Results Seven cases (four women and three men) were identified, with mean age of 51 years (34–65 years). Three patients received adalimumab, three patients were given etanercept and one infliximab. All patients received lamivudin, 100 mg/day, which started 2 weeks before the initiation of anti‐TNFα medication and went on during the whole treatment period. Follow‐up period extended from 6–24 months. All patients were inactive HbsAg (+) carriers. Liver function tests – at baseline and at the end of follow‐up period – were within the normal range. There was no considerable rise in the viral load in any case, from baseline until the last available measurement, although a patient receiving infliximab showed an increase that reached 600 IU/mL. Conclusion Successful treatment of psoriasis with anti‐TNFα agents in patients who are inactive HBsAg carriers is possible and could be safe under the conditions of concomitant lamivudin administration and intensive monitoring. Larger randomized controlled studies are needed to confirm these findings.     

Fluctuations in serum levels of adalimumab and infliximab in patients on stable treatment for psoriasis

Many patients with psoriasis fail to respond to biologic drugs either initially or lose response over time, the latter having predominantly been linked to low circulating drug levels. We examined how serum drug levels varied over three treatment cycles of stable maintenance therapy with either adalimumab or infliximab among a total of 28 patients with psoriasis (22 men, mean age 48.6 years, mean treatment time 6.2 years) and whether there was an association with various patient‐specific factors. The range for all concentrations was 1.1 to 24.3 μg/mL for adalimumab and 0.0 to 180.6 μg/mL for infliximab. There was a consistent inverse association between body mass index (BMI) and trough and maximum serum concentrations of adalimumab (P < .05 for all comparisons) and a positive, less consistent, association between age and maximum serum concentration of infliximab (P < .05 for both comparisons). Patient‐specific factors, such as BMI and age, can help predict fluctuations in serum concentrations of biologics used for psoriasis.     

An Italian shared dermatological and rheumatological proposal for the use of biological agents in psoriatic disease

Background As psoriatic disease (PD) is a condition characterized by the combination of inflammatory skin (psoriasis) and osteo‐articular manifestations (psoriatic arthritis), its treatment should cover both its clinical components. Objective The objective of this study was to propose a flexible framework for the use of biological agents in PD. Methods The proposal was drawn up by a group of dermatologists and rheumatologist expert in PD and was based on existing evidence and personal opinion. Results The three TNF‐α inhibitors (adalimumab, etanercept, infliximab) are effective in all of the psoriatic manifestations and should be used in the case of moderate/severe disease refractory to systemic treatment with non‐biological drugs. We propose the following definitions of moderate/severe disease: PASI > 10 or BSA > 10 or DLQI > 10 for plaque‐psoriasis; BSA ≥ 10 or DLQI ≥ 10 for the other psoriatic skin lesions; DLQI ≥ 10 or meaningful values of the NAPSI or mNAPSI for psoriatic nail involvement; ≥ 1 inflamed joint + patient global VAS³4 + physician's judgement or arthritic joint deformities or radiographic joint damage plus ≥ 5 inflamed small joints or ≥ 1 large joints for peripheral joint involvement; ≥ 1 digit with dactylitis and ≥ 1 enthesitic sites + patient global VAS³4 + physician's judgement for dactylitis and enthesitis. BASDAI ≥ 4 + physician's judgement for spondylitis; recurrent flares or risk of developing irreversible damage for uveitis. Other assessment instruments can be used if the physician is more familiar with them and if they have been validated. Conclusion We provide a shared dermatological and rheumatological proposal for the use of biological agents in PD.     

Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-γ release assay vs. tuberculin skin test

Background Antitumour necrosis factor (anti‐TNF) treatments may reactivate latent tuberculosis infection (LTBI). For detecting LTBI, the tuberculin skin test (TST) has low sensitivity and specificity. Interferon‐γ release assays (IGRA) have been shown to be more sensitive and specific than TST. Objective To compare the TST and the T‐SPOT.TB IGRA for identifying LTBI in patients with psoriasis before anti‐TNF treatment. Methods A retrospective study was carried out over a 4‐year period on patients with psoriasis requiring anti‐TNF treatment. All were subjected to the TST, T‐SPOT.TB and chest X‐ray. Risk factors for LTBI and history of bacillus Calmette–Guérin (BCG) vaccination were recorded. The association of T‐SPOT.TB and TST results with risk factors for LTBI was tested through univariate logistic regression models. Agreement between tests was quantified using kappa statistics. Treatment for LTBI was started 1 month before anti‐TNF therapy when indicated. Results Fifty patients were included; 90% had prior BCG vaccination. A positive T‐SPOT.TB was strongly associated with a presumptive diagnosis of LTBI (odds ratio 7·43; 95% confidence interval 1·38–39·9), which was not the case for the TST. Agreement between the T‐SPOT.TB and TST was poor, κ = 0·33 (SD 0·13). LTBI was detected and treated in 20% of the patients. In 20% of the cases, LTBI was not retained in spite of a positive TST but a negative T‐SPOT.TB. All patients received an anti‐TNF agent for a median of 56 weeks (range 20–188); among patients with a positive TST/negative T‐SPOT.TB, no tuberculosis was detected with a median follow‐up of 64 weeks (44–188). One case of disseminated tuberculosis occurred after 28 weeks of adalimumab treatment in a patient with LTBI in spite of treatment with rifampicin. Conclusion This study is the first to underline the frequency of LTBI in patients with psoriasis (20%), and to support the use of IGRA instead of the TST for its detection. Nevertheless, there is still a risk of tuberculosis under anti‐TNF therapy, even if LTBI is correctly diagnosed and treated.     

Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma

The efficacy and safety of infliximab in patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type) and psoriatic erythroderma were assessed in clinical practice. Without washout of the existing treatment of psoriasis, treatment was switched to infliximab, which was given at a dose of 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks up to week 46. The primary end-points were 75% improvement in Psoriasis Area and Severity Index score (PASI 75 response rate) for plaque psoriasis, 20% improvement in American College of Rheumatology criteria (ACR 20 response rate) for psoriatic arthritis, and global improvement in pustular psoriasis and psoriatic erythroderma. The PASI 75 response rate in plaque psoriasis was 72.2% at week 10 and 53.6% at week 50. The ACR 20 response rate in psoriatic arthritis was 66.7% at week 14 and 80.0% at week 46. The response defined as global improvement in pustular psoriasis was between 66.7% and 100.0% during the 2–50-week period. The response defined as global improvement in psoriatic erythroderma was between 75.0% and 100.0% during the week-2–50 period. There were 14 discontinued patients. The most frequently reported reason for discontinuation was the development of adverse events. However, there were no serious respiratory diseases, infections or infusion reactions. In patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma, infliximab was well tolerated, regardless of prior treatment, and also showed superior efficacy over a period of approximately 1 year.