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Abstract

Biologic therapies like adalimumab are the gold standard for psoriasis treatment with efficacy and safety profiles allowing for long-term treatment. However, adalimumab cannot be used in all patients and may cause adverse drug reactions. This study reviews conditions that might limit the use of adalimumab under real-life conditions. Local injection site reactions affect 12–37% of patients but rarely require specific therapy. Dermatological adverse events (AEs) include the paradoxical psoriasis and tend to respond to adequate therapy without adalimumab discontinuation. Adalimumab increases the risk for infections; latent chronic infections like tuberculosis or hepatitis B/C impose the highest risk for serious AEs. However, administration of adalimumab may still be possible under appropriate monitoring or prophylactic therapy. Some studies indicate an increased risk of malignancies in patients with psoriasis exposed to adalimumab. Here, the causal relationship is unclear since both psoriasis and some first-line therapies increase the risk of malignancies. Depression frequently coincides with psoriasis and may respond to adalimumab as well. Cardiovascular diseases are contraindications for adalimumab, but evidence suggests that adalimumab may still be a treatment option. Overall AE rates range from 245 to 399 per 100 patient years (serious AEs: 6–23; death: 1–2). Thus, adalimumab is slightly less safe than ustekinumab and infliximab but exhibits superior effectiveness and drug survival. Adalimumab is safe for pregnant women during the first trimester, for children up to 4 years and for the elderly. Thus, in spite of several conditions that require specific attention, the favourable safety and tolerability of adalimumab for the treatment of psoriasis is confirmed.

Keywords

adalimumab adverse drug reaction antidrug antibodies biologica local injection site reaction long-term safety opportunistic infection protected patient groups safety profile special patient populations tumour necrosis factor α

Introduction

Psoriasis is a chronic autoimmune skin disease characterized by keratinocyte hyperproliferation and chronic inflammation,¹ which affects 1–3% of the world’s population.² Until recently, predominant treatment strategies included methotrexate, cyclosporine, psoralen plus ultraviolet (UV)-A, oral retinoids and fumaric acid esters. Though these therapies exhibit good short-term efficacy, long-term use required for the treatment of a chronic disease may lead to a wide range of adverse effects like skin cancer, organ toxicity or hyperlipidaemia.³ Therefore, unrestricted long-term administration of these treatments is not recommended and has to be replaced by rotational, sequential, intermittent or combination treatments. However, these approaches may not provide continuous disease control or a stable treatment regimen,⁴ resulting in therapeutic challenges for the treating physician.

Tumour necrosis factor α (TNFα) is a potent proinflammatory cytokine expressed by activated macrophages, lymphocytes and inflammatory dendritic cells that induces diverse cellular responses varying from apoptosis to the expression of genes involved in early inflammatory and acquired immune responses.^5,6 Though the mechanism of keratinocyte activation is not properly understood yet, TNFα is definitely involved.¹ Thus, inhibition of TNFα by tailor-made antibodies as a therapy option was suggested as soon as the production of such antibodies became technically feasible.^7,8 Subsequently, recombinant antibodies (biologic agents or biologica) against TNFα were developed, including adalimumab, etanercept, infliximab and others. Though some of these substances were primarily licensed for the treatment of rheumatoid arthritis, their use for other autoimmune diseases like psoriasis arthritis or psoriasis was envisaged from the very beginning. Expectations included improved efficacy, reduced toxicity and adverse drug reactions (ADRs) and an overall profile enabling long-term use.^8,9

Now, more than one decade after the introduction of TNFα inhibitors, it can be concluded that these expectations have been fulfilled and that biologics are well established treatment options for moderate to severe psoriasis and a wide range of other autoimmune diseases ranging from Crohn’s disease¹⁰ to hidradenitis suppurativa.¹¹ Though the treatment costs for biologicals are considerably higher than for conventional therapies, a broad consensus exists that the prescription of biologicals is justified by their high efficacy and the gains in health-related quality of life. Due to reduced indirect disease effects, like sickness leave, premature retirement, presentism (i.e. reduced productivity in spite of presence at the workplace), among others, biologicals even provide a socioeconomic net benefit.^12,13 However, ADRs have been described for biologicals as well, and lack of effectiveness or discontinuation of treatment are frequent.¹⁴ Furthermore, various issues could not be addressed easily within the controlled environment of clinical market authorization studies, including long-term safety, tolerability for protected groups, or the reaction of patients suffering from concomitant diseases or receiving multiple medications. Now, after 15 years of experience with biologic treatment of psoriasis, data from clinical studies have been supplemented by a huge number of observational real-world studies and case reports, thus some of these open issues can now be addressed in more depth.

This paper discusses recent real-world data and expert opinions on the use of a well established TNFα inhibitor, adalimumab, in the treatment of psoriasis, focusing on safety and tolerability in the broadest sense, including ADRs, the formation of antibodies against TNFα inhibitors, the occurrence of infections and malignancies, and the treatment of patients belonging to protected groups or suffering from concomitant diseases. Contraindications and safety signals identified by controlled clinical trials and already considered by the summary of product characteristics (SmPC) are not the focus of this review.

Method

A PubMed database search was conducted for publications until November 2017. The search strategy used MeSH and keyword headings, using the search string ‘psoriasis’ AND ‘adalimumab’, resulting in 1495 matches. These publications were screened manually for content referring to the research questions formulated above, primarily focusing on real-life studies published since 2015. This study does not aim at a systematic review of registry data.

Adverse drug reactions

In general, adalimumab is considered a safe and well tolerated treatment option for psoriasis.¹⁵ The overall safety profile of adalimumab is well known and is not repeated here in detail. Typically, ADRs can be classified as infections and oncological disorders (described separately below), and dermatologic disorders including vesiculobullous erythema multiforme major, nodular hypodermitis, secondary erythroderma, hives and others.¹⁶ A survey of adverse events related to adalimumab carried out in the United States, Canada, and the Netherlands covering three different studies² found adverse event rates ranging from 245 to 399 per 100 patient years, with serious adverse events in the range from 6 to 23 per 100 patient years. Death occurred at a rate of 1–2 per 100 patient years. Though the studies used by these authors are not perfectly comparable among each other, the risk profile of adalimumab seems to be less favourable than for etanercept (rates per 100 patient years: 57–274 adverse events, 7–9 serious adverse events, 0.1–0.5 deaths), usketimab (rates per 100 patient years: 70–233 adverse events, 4–7 serious adverse events, 0.2–0.3 deaths) and especially infliximab (rate per 100 patient years: 28–38 adverse events, 4–8 serious adverse events and <0.6 deaths).

Adalimumab is suitable for long-term treatment. In patients with moderate to severe psoriasis treated with adalimumab, drug survival rates after 16 weeks, 6 months and 1 year of treatment were 64%, 58% and 53%, respectively. Effectiveness (PASI90 after 6 months) was the only independent predictor of drug survival, rather than safety issues.¹⁷ Another study¹⁸ found 1- and 2-year survival rates of 77% and 67% with a median drug survival of 2 years; again, discontinuations were rather due to lack of efficacy than to safety issues. Overall, adalimumab is considered a safe option for long-term treatment¹⁹ in spite of the possibility of adverse events.

According to the administration route of adalimumab, local injection site reactions (including erythema, pruritus, pain, inflammation, rash, induration, itching, and oedema) are relatively common and affect 12–37% of patients. Such reactions usually occur within the first month of treatment, last for 3–5 days, and usually resolve without additional therapy. Combination with methotrexate or other drugs instead of monotherapy seems to be a promising strategy to reduce local injection site reactions.²⁰ There is little evidence that the pattern of local reactions caused by adalimumab differs significantly from other TNFα inhibitors administered subcutaneously; infliximab, however, seems to cause fewer local reactions, probably due to the intravenous administration. Though local injection site reactions obviously affect the patient by inducing pain, stress and reduced quality of life, their clinical relevance is not clear yet.²⁰ A case study,²¹ however, suggests that gradually increasing intensity of local reactions might be correlated with a reduced effectiveness. In this specific case, effectiveness was regained as soon as local reactions were prevented by combining adalimumab with cyclosporine.

Cutaneous adverse events sensu lato are distinct from local injection site reactions. These events tend to emerge months to years after the initiation of treatment and include xerosis cutis, eczema, cutaneous infections, alopecia, and even dermatological malignancies (see below). Most frequently, dermatological findings are observed which are summarized in clinical practice as ‘orange-red psoriasiform eczema’. These eczemas may affect the flexures, genitalia, scalp, or face, and are susceptible to bacterial superinfection with Staphylococcus aureus. The pathophysiology is poorly understood, but epidermal permeability barrier dysfunction, increased susceptibility to bacterial superinfection and cytokine formation appear to be involved. Though some of these cutaneous adverse events may be severe, they usually respond to specific treatment and do not require discontinuation of adalimumab. Detailed information on these events is provided by a recent review.²²

A rare paradoxical treatment effect has been described for adalimumab as well, for example, the development of psoriasis-like conditions after the administration of adalimumab for other indications in 2–5% of the patients, called paradoxical psoriasis.²³ Here, plaques develop with histological findings consistent with psoriasis; involvement of nails is possible as well, the phenotype may vary between pustular, flexural or guttate. These reactions may arise in spite of successful treatment of the original condition. Adalimumab-induced psoriasis usually responds to biologic discontinuation or to conventional topic treatment.^22,24,25 Recent research showed that paradoxical psoriasis is clearly different from conventional psoriasis on the molecular level²⁶ characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells but reduced T-cell numbers, leading to an ongoing overactive innate inflammatory process without T-cell autoimmunity.²³

Finally, a variety of rare and extraordinary events have been described after adalimumab administration, including repigmentation of age-related grey hair,²⁷ autoimmune haemolytic anaemia,²⁸ medically significant cytopenia, and worsening or initiation of a multiple sclerosis or other neurological diseases.²⁹ In these rare events, the causal relationship to adalimumab treatment is difficult to determine.

Remarkably, little evidence of cumulative organ-specific toxicity has been found yet.² Furthermore, the safety profile of adalimumab-naïve patients does not differ significantly from patients switching to adalimumab from another biologic treatment.³⁰

Immune reaction towards TNFα inhibitors

As a foreign protein, adalimumab is able to trigger reactions of the immune system. The formation of antibodies against adalimumab can be expected to lower drug levels and therefore reduce effectiveness. These hypotheses were tested in 53 Chinese patients suffering from psoriasis.³¹ Antibodies against adalimumab were detected in 51% of the patients, resulting in a statistically significant reduction of serum adalimumab levels. Accordingly, only 44% of the patients with adalimumab antibodies achieved PASI75 (75% reduction in the psoriasis area and severity index) compared with 89% of those patients in whom no such antibodies were detected. Treatment interruption, low trough adalimumab concentration, absence of concomitant methotrexate use and biologics switching were identified as risk factors for the formation of antibodies. A similar study comparing adalimumab and etanercept but focusing on arthritis and related diseases³² suggests that antibody formation strongly contributes to treatment failure in adalimumab but not etanercept and concludes that determination of antibody titres may contribute to treatment optimization only in adalimumab, which is likely to apply in the case of psoriasis as well.

A meta-analysis on the formation of antibodies towards TNFα inhibitors³³ in general comprising 34 studies with 4273 patients revealed a less pronounced risk for antibody formation (<20%) but confirmed reduced effectiveness in patients forming antidrug antibodies and formation of injection site reactions, especially in the case of adalimumab. Thus, measures should be taken in order to detect antibodies against adalimumab in a timely manner. Though efficient analytical techniques are available, their implementation into clinical routine is still a challenge.

Antibodies against anti-TNFα have also been described from foetuses as well mothers who have been exposed to adalimumab.³⁴

Lack of efficacy due to the formation of antibodies must not be confused with lack of efficacy in another subset of patients with psoriasis who do not respond to any TNFα inhibitor but may be highly receptive to ustekinumab, another monoclonal antibody directed against interleukin 21 and 23. Thus, there seems to be a form of psoriasis not involving TNFα but other signal cascades.³⁵ Evidence has been found that six types of single nucleotide polymorphisms might be associated with PASI75 after 3 or 6 months of treatment with adalimumab or infliximab: rs6661932 (IVL), rs2546890 (IL-12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A), rs645544 (SLC9A8) and rs1061624 (TNFR1B). However, additional evidence is required before implementing these biomarkers into clinical practice.³⁶

Infections

Since TNFα plays an important role in defence against pathogens,⁶ its inhibition can be expected to affect the proper functioning of the immune system. This risk cannot be avoided due to the very nature of TNFα inhibitors and has to be balanced against the expected treatment benefit in each individual case. In general, the use of adalimumab is not recommended if active infections are present.²⁹ In industrialized countries, a rate of 1.5–2.0 serious infectious events per 100 patient years has been described.²

Due to prolonged latent states without symptoms, tuberculosis infections appear to be prone to reactivation due to anti-TNFα therapy since TNFα seems to be involved in activating phagosome maturation TNFα inhibitors, especially adalimumab and infliximab, which can affect the host response to mycobacteria including Mycobacterium tuberculosis.³⁷ Indeed, numerous case studies have been published in which patients developed active tuberculosis during anti-TNFα treatment, in some cases even despite negative tuberculin tests prior to treatment and in the absence of known risk factors.³⁸ Thereby, military or extrapulmonary tuberculosis presentation is frequent,³⁹ and lesions may be formed in the brain.⁴⁰ A nationwide retrospective French study identified 12 cases of tuberculosis (two of these with deadly outcome) from 2006 to 2014;³⁹ for other western countries, a incidence rate of 0.1–0.2 per 100 patient years was estimated.² However, a much higher risk has been identified for countries with a high prevalence of tuberculosis, for example, Taiwan.⁴¹ Here, a retrospective study from 2007 to 2011 reported 86 cases of tuberculosis after adalimumab treatment despite the smaller population of Taiwan compared with France and the shorter study period. Thereby, adalimumab showed a worse safety profile compared with etanercept (1.6 events per 100 patient years compared with 0.6 events per 100 patient years). Therefore, screening for latent tuberculosis infection is recommended prior to initiation of systemic biologic agents; repeated, for example, annual screening, however, seems not to be required, at least in regions with low tuberculosis incidence and in the absence of known risk factors. Furthermore, such annual tests may be of limited use due to the possibility of false-negative findings.⁴² Both tuberculin skin tests⁴³ and QuantiFERON-B Gold In-Tube (QFT-GIT) in vitro assays which do not require any clinical, radiological or microbiological evidence of active tuberculosis⁴⁴ have both been used successfully. In the case of positive findings, prophylaxis with isoniazid was shown to be effective in preventing tuberculosis reactivation under biologics therapy.⁴⁴

Hepatitis is another chronic disease for which the risk of reactivation needs to be considered prior to the administration of anti-TNFα. However, adalimumab seems to be a reasonably safe treatment option for patients with hepatitis B or C, as no case of relapse was reported for 37 Italian patients during a mean follow-up period of 40 months.⁴⁵ Again, the situation is more severe in countries with a higher incidence of hepatic diseases. In Taiwan, for example, 1.6 serious hepatic events leading to hospitalization per 100 patient years were reported for adalimumab from 2007 to 2011.⁴¹ As in the case of tuberculosis, the risk of infections was lower for etanercept (0.4 serious hepatic events per 100 patient years). A retrospective study⁴⁶ identified seven inactive hepatitis carriers treated with anti-TNFα, including three patients receiving adalimumab. All patients received lamivudine starting 2 weeks before anti-TNFα and lasting throughout the anti-TNFα treatment without worsening of liver function or viral load. Another retrospective study on hepatitis B carriers⁴⁷ only applied monitoring of viral load and liver function. Here, reactivation of the virus during anti-TNFα treatment was observed in three of seven cases but was controlled by antiviral treatment without leading to hepatitis. In 37 patients who were hepatitis B or C carriers treated with adalimumab, no case of reactivation was observed.⁴⁵ Thus, adalimumab can be used for the treatment of hepatitis carriers, provided appropriate precautions like close monitoring of viral load and liver function and possible prophylactic antiviral treatment are taken.

For human immunodeficiency virus (HIV), the situation is similar, though no controlled studies are available for this subpopulation of patients. However, these patients are often susceptible to debilitating inflammatory disorders that are refractory to standard treatment. Given the recent advances in antiviral therapy, reliable seropositive patients, who are adherent to medication regimens and frequent monitoring and have failed to respond to other treatment modalities, need not be excluded from TNFα inhibitor therapy.⁴⁸ One typical case report,⁴⁹ for example, describes 30 months of adalimumab treatment in a patient who was HIV positive with severe plaque psoriasis without the occurrence of adverse events.

Some case studies have been published on patients presenting with other infections emerging during adalimumab treatment, including lyme neuroborreliosis,⁵⁰ infective endocarditis,⁵¹ histoplasmosis,⁵² deep fungal and other serious and atypical infection.²⁹ However, in all these cases, the causal relationship between biologics and these rare infections remains dubious.

In spite of these constraints, a study assessing serious infections in a large sample of 5617 patients receiving biologics⁵³ did not find a significantly increased infection risk for adalimumab and other TNFα inhibitors compared with conventional treatment. An earlier registry including 11,466 patients,⁵⁴ however, found a risk of serious infections of 1.97 per 100 patient years for adalimumab, considerably more than for methotrexate (1.28), other systemic nonbiologic treatments (1.05) and even more than for the biologics ustekinumab (0.83) and etanercept (1.47). Increasing age, diabetes mellitus, smoking, significant infection history, infliximab exposure, and adalimumab exposure were each associated with an increased risk of serious infection. Therefore, it remains uncertain if the risk of serious infection should be the key discriminator when choosing between conventional systemic and biologic therapies for the treatment of psoriasis.

Formation of malignancies

Early on, malignancies have been reported as part of the safety profile of all TNFα inhibitors.⁵⁵ However, psoriasis itself also coincides with an increased risk of malignancies.⁵⁶ Thus, any findings on the development of malignancies after TNFα inhibitor treatment of psoriasis have to be treated carefully. A survey comprising 12 years of research therefore did not find evidence of an increased risk in patients treated with adalimumab.⁵⁷ Other studies^2,58 acknowledge an increased risk of nonmelanoma skin cancer in patients with psoriasis treated with adalimumab. However, nonmelanoma skin cancer tends to appear very early after the introduction of adalimumab, and is only rarely found in patients receiving adalimumab for the treatment of rheumatoid arthritis. Therefore it may be concluded that nonmelanoma skin cancer is not necessarily caused by adalimumab therapy, but by previous psoriasis therapies, most likely by phototherapy using UV light.⁵⁸

Besides skin cancer, other malignancies like B-cell lymphoma,⁵⁹ squamous intraepithelial neoplasm of the conjunctiva⁶⁰ or multiple eruptive squamous cell carcinoma⁶¹ have been described as well. In all these case studies, causal relationships to adalimumab cannot be established since the patients have not only been exposed to an increased malignancy risk due to psoriasis itself, but usually also exhibit a long history of psoriasis treatments, which typically includes both conventional immunosuppressants and one or several TNFα inhibitors. In spite of these ambiguities, experts have suggested chemoprophylaxis with, for example, acitetrin prior to the initiation of TNFα inhibitors⁶¹ or close monitoring⁶² in patients with a known risk of nonmelanoma cancers.

Concomitant diseases

Unlike the situation in controlled clinical trials, concomitant diseases are frequent under real-world conditions. Whereas the presence of infections may form a major contraindication for the administration of adalimumab (see above), the drug can be expected to show a beneficial effect in the case of a wide range of other autoimmune diseases, including arthritis, psoriasis arthritis, hidradenitis suppurativa, Crohn’s disease and other diseases listed in the SmPC.

There are some diseases which are frequently observed together with psoriasis. Without necessarily assuming a causal relationship, clinical studies have been carried out in order to determine if the administration of adalimumab, resulting presumably in psoriasis improvement, may also contribute to a mitigation of these concomitant diseases. Due to the well known psychological and social impact of psoriasis,⁶³ up to 50% of patients with psoriasis have depression. After 12 weeks of adalimumab, a mean change in Zung Self-Rating Depression Scale of −6.7 with adalimumab was observed, compared with −1.5 with placebo. Similar results have been achieved for etanercept and ustekinumab, though the use of different rating scales for these drugs does not allow for a direct comparison.⁶⁴ In the case of obstructive sleep apnoea, another condition frequently coinciding with psoriasis, no evidence was found that the administration of adalimumab would influence the disease in either way by a small clinical trial involving 20 patients.⁶⁵

Cardiovascular events have also been found to be associated with psoriasis, though the evidence is less unambiguous than in the case of arthritis. The underlying mechanism seems to be based on the constant elevation of circulating inflammatory proteins, including C-reactive protein, interleukins and soluble endothelial adhesion proteins, which are associated with an increased risk of acute cardiovascular events.^66,67 The use of adalimumab is contraindicated in the case of moderate or severe heart failure according to the SmPC. However, TNFα inhibitors in psoriasis were shown to reduce the risk of myocardial infarct compared with topical agents.⁶⁸ The same study suggests that TNFα inhibitors also seems to be superior to methotrexate, though this difference was not shown to be significant yet. The cardiovascular effect was more pronounced in patients with psoriasis responding to TNFα inhibitors compared with nonresponders, therefore suggesting a causal relationship. In a review of 24 earlier studies, Brezinski and colleagues⁶⁹ found evidence that patients with psoriasis and psoriatic arthritis exhibit significantly increased arterial stiffness, impaired endothelial-dependent vasodilation, increased carotid intima media thickness, and decreased aortic elasticity compared with the general population. The conclusion that TNF inhibitors improve not only the underlying psoriatic disease but also endothelial function is supported in part by the present data, but additional studies are needed in order to clarify this contradiction to the SmPC.

In the case of renal failure, adalimumab has been demonstrated to be safe without interfering with the course of disease. Concomitant renal failure is described in a recent Japanese case study.⁷⁰ Here, adalimumab treatment led to improvement of psoriasis plaques without severe side effects on renal functions. Remarkably, in this patient infliximab had to be discontinued due to the formation of pulmonary oedema, which emerged after each administration of infliximab treatment since the start of haemodialysis. No such effect was observed for adalimumab.

Pregnancy, lactation, children and the elderly

Good clinical practice defines vulnerable groups with a protected status for children and pregnant women, thereby restricting their participation in clinical trials. Accordingly, little data are known on the use of adalimumab in these groups. However, since cutaneous psoriasis is well known to reduce quality of life and personal social interactions,⁶³ physicians may opt for this therapeutic option even if data are insufficient for a specific subset of patients.

The number of pregnant or lactating women receiving adalimumab or other TNFα inhibitors for the treatment of psoriasis is limited, however no specific safety signals have been described for these groups yet.⁷¹ In 38 women exposed to anti-TNFα for any reason during conception or pregnancy, no significant differences compared with the untreated control group were found concerning pregnancy outcome. In one woman receiving adalimumab, however, the foetus exhibited congenital diaphragmatic hernia and obstructive megaureter.⁷² Another study, however, reported decreased birth weight and increased risks of preterm birth and major birth defects in patients receiving TNFα inhibitors compared with a healthy control group. Thus, this study cannot differentiate between the effects of the disease and of anti-TNFα.⁷³ Adalimumab is transferred from the mother to the foetus⁷⁴ and immunological changes have been described in newborns following parental exposition to adalimumab and infliximab, including a more immature B and helper T phenotype that normalized within 12 months. Immunoglobulin production and vaccine responses, however, were not affected.³⁴ At present, expert opinion suggests that anti-TNFα drugs could be safe when administered during conception or the first trimester.⁷² Similarly, safety data concerning biologics use during lactation are reassuring as well.⁷⁵

Survey data showed that approximately 80% of the physicians do not object to the administration of adalimumab during pregnancy and lactation (indication was not restricted to psoriasis), compared with only 56% for infliximab and 3% for methotrexate.⁷⁶ However, the Australasian Psoriasis Collaboration generally recommends conventional drugs for pregnant or breastfeeding patients, instead of using newer alternatives with less foetal safety data.⁷⁷

Adalimumab has been approved by the European Medicines Agency as a first-line treatment for severe chronic plaque psoriasis in children (⩾4 years old) and adolescents.⁷⁸ A review of 77 juvenile patients (mean age 13 years) treated with adalimumab for psoriasis showed that PASI75 response rates at 16 weeks were significantly greater for standard dose (0.8 mg/kg) but not for low dose (0.4 mg/kg) compared with methotrexate. Observed quality of life changes were inconsistent across different measures. A total serious adverse event rate of 5.9 events per 100 years of treatment at the standard dose was reported. All serious adverse events were considered as unrelated or probably unrelated to adalimumab with the exception of one case of eye naevus, which was assessed as ‘possibly related’. Reasons for discontinuation included urticaria and psoriasis flares. Compared with methotrexate treatment, ADRs were less frequent in children treated with biologicals.^79,80 A recent clinical trial⁸¹ found PASI75 in 58% of the children exposed to adalimumab compared with 32% in the children exposed to methotrexate. Safety data gave no evidence of drug-related serious adverse events or organ toxicity. In spite of this evidence for effectiveness and the favourable safety profile, the overall performance of adalimumab in children seems to be inferior to etanercept and ustekinumab.^79,81

Elderly patients are another distinct population requiring specific attention. A retrospective study in 89 patients aged at least 65 years treated with anti-TNF-α agents⁸² found PASI50 in 82% of the patients receiving adalimumab at week 156. Another study¹⁹ confirmed the safety profile of adalimumab in elderly patients aged over 65 years. Local injection site reactions even become less frequent with age, especially in patients aged 70 years and over.²⁰ Therefore, adalimumab and other anti-TNFα agents are appropriate, safe and efficient in the long-term management of elderly patients.

Conclusions

Due to their favourable safety profiles and excellent efficacy, biologic agents are considered the gold standard for moderate to severe psoriasis.⁸³ Among these biologic agents, adalimumab and infliximab exhibit superior short-term effectiveness compared with etanercept, whereas drug survival is superior in adalimumab and infliximab compared with etanercept.^17,84 Therefore, adalimumab is one of the most frequently prescribed biologics, as demonstrated by recent counts from Germany (717 prescriptions, followed by 598 prescription for secukinumab). However, adalimumab prescriptions are dwarfed by the use of conventional treatments, for example, 2258 prescriptions of fumaric acid esters and 1649 prescriptions of methotrexate.⁸⁵ These numbers, however, probably underestimate the true relevance of adalimumab, which is usually prescribed only in case of high disease activity, if treatment goals cannot be met by the use of cheaper conventional drugs, or if these drugs have to be discontinued for any reason.

In spite of a favourable safety profile, TNFα inhibitors including adalimumab cannot be used in all patients and may cause adverse drug reactions. A review of the literature on conditions that may limit the use of TNFα inhibitors revealed the following constraints:

Adverse reactions frequently include local injection site reactions which rarely require a specific therapy; sometimes the use of combination instead of monotherapies is beneficial. Dermatological adverse events including the paradoxical formation of psoriasis-like plaques tend to respond to adequate therapy without the need for adalimumab discontinuation.

Due to their mode of action, which involves interference with the immune system, anti-TNFα drugs inevitable increase the risk of infections. The highest risk for serious or severe events was found for chronic infections like tuberculosis or hepatitis B or C. However, the respective benefit risk ratio depends on many factors, especially the prevalence of the above-mentioned diseases in the respective geographic region. Thus, the conduct of appropriate monitoring and specific tests prior to treatment is recommended.^42,45 Considering the limitations of such tests, etanercept may be a safer alternative for the treatment of patients exposed to increased risk of hepatitis or tuberculosis.⁴¹

Some studies identify an increased risk of malignancies, especially nonmelanoma skin cancer, in patients with psoriasis exposed to adalimumab or other TNFα inhibitors. However, both psoriasis itself and several common first-line therapies are known to increase the risk of malignancies as well. Additional long-term studies are required in order to establish or exclude a causal role of adalimumab.

Some diseases typically coinciding with psoriasis tend to respond to adalimumab treatment as well. This is especially the case for depression and cardiovascular diseases. For a variety of other concomitant diseases, ranging from renal failure and sleep apnoea to hepatitis and HIV, adalimumab seems to be a safe treatment option for psoriasis, provided that intense monitoring is carried out.

Observations on pregnant or lactating women did not result in the identification of novel safety signals. Thus, expert opinion and the majority of physicians agree that adalimumab is a safe treatment option at least for the first trimester of pregnancy. The foetus, however, can develop antibodies against TNFα. Given the well known heredity of psoriasis,⁸⁶ their future response to TNFα may be affected if they happen to develop psoriasis by themselves.

Adalimumab has been approved for children 4 years of age or older. Though the majority of data have been produced in older children, adalimumab can be considered as a safe treatment option for children.

Adalimumab is one of the most commonly prescribed TNFα inhibitors for the treatment of psoriasis, but several safety data suggest inferiority to etanercept or infliximab. This, however, seems to be balanced by superior effectiveness.⁸⁴

This study aimed to provide a broad overview on conditions which may be detrimental to the use of adalimumab for the treatment of psoriasis. Some of these conditions are well established and appropriate measures have been integrated into clinical routines. In others, current data allow for little more than educated guesses. Finally, some present contraindications may deserve review. Thus, the ongoing establishment and the evaluation of registries collecting nationwide real-life data from a significant portion of adalimumab users can be expected to close the gaps still present in the current safety profile.⁵⁶

Footnotes

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for writing assistance was provided by AbbVie.

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Patel

Tsilioni

Weng

et al . TNF stimulates IL-6, CXCL8 and VEGF secretion from human keratinocytes via activation of mTOR, inhibited by tetramethoxyluteolin. Exp Dermatol 2018; 27: 135–143.

Mansouri

Goldenberg

Biologic safety in psoriasis: review of long-term safety data. J Clin Aesthet Dermatol 2015; 8: 30–42.

Shear

NH.

Fulfilling an unmet need in psoriasis: do biologicals hold the key to improved tolerability?

Drug Saf 2006; 29: 49–66.

van de Kerkhof

PC.

Consistent control of psoriasis by continuous long-term therapy: the promise of biological treatments. J Eur Acad Dermatol Venereol 2006; 20: 639–650.

Lowes

Chamian

Abello

et al . Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc Natl Acad Sci USA 2005; 102: 19057–19062.

Rahman

McFadden

Modulation of tumor necrosis factor by microbial pathogens. PLoS Pathog 2006; 2: e4.

Andreakos

Foxwell

Brennan

et al . Cytokines and anti-cytokine biologicals in autoimmunity: present and future. Cytokine Growth Factor Rev 2002; 13: 299–313.

Saini

Tutrone

Weinberg

JM.

Advances in therapy for psoriasis: an overview of infliximab, etanercept, efalizumab, alefacept, adalimumab, tazarotene, and pimecrolimus. Curr Pharm Des 2005; 11: 273–280.

Scheinfeld

Adalimumab (HUMIRA): a review. J Drugs Dermatol 2003; 2: 375–377.

10.

Tanaka

Kamata

Yamada

et al . Long-term retention of adalimumab treatment and associated prognostic factors for 1189 patients with Crohn’s disease. J Gastroenterol Hepatol 2018; 33: 1031–1038.

11.

Martin-Ezquerra

Masferrer

Pujol

RM.

Use of biological treatments in patients with hidradenitis suppurativa. G Ital Dermatol Venereol 2017; 152: 373–378.

12.

Greiner

Braathen

LR.

Cost-effectiveness of biologics for moderate-to-severe psoriasis from the perspective of the Swiss healthcare system. Eur J Dermatol 2009; 19: 494–499.

13.

Nelson

Pearce

Fleischer

et al . Cost-effectiveness of biologic treatments for psoriasis based on subjective and objective efficacy measures assessed over a 12-week treatment period. J Am Acad Dermatol 2008; 58: 125–135.

14.

Warren

Smith

Yiu

et al . Differential drug survival of biologic therapies for the treatment of psoriasis: a prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol 2015; 135: 2632–2640.

15.

Burness

McKeage

Adalimumab: a review in chronic plaque psoriasis. Drugs 2015; 75: 2119–2130.

16.

Brănişteanu

Voicu

Creţu

et al . Adverse reactions of biological therapy for psoriasis. Rev Med Chir Soc Med Nat Iasi 2015; 119: 38–44.

17.

López-Ferrer

Vilarrasa

Gich

et al . Adalimumab for the treatment of psoriasis in real life: a retrospective cohort of 119 patients at a single Spanish centre. Br J Dermatol 2013; 169: 1141–1147.

18.

Soubrier

Bele-Philippe

Cortet

et al . Treatment response, drug survival and safety of anti-tumour necrosis factor α therapy in 193 patients with psoriatic arthritis: a twelve-year ‘real life’ experience. Joint Bone Spine 2015; 82: 31–37.

19.

Chiricozzi

Zangrilli

Bavetta

et al . Real-life 9-year experience with adalimumab in psoriasis and psoriatic arthritis: results of a single-centre, retrospective study. J Eur Acad Dermatol Venereol 2017; 31: 304–311.

20.

Matsui

Umetsu

Kato

et al . Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015. Int J Med Sci 2017; 14: 102–109.

21.

Nakamizo

Miyachi

Kabashima

Addition of cyclosporine to adalimumab improved psoriasis and adalimumab-induced injection site reaction. Indian J Dermatol 2014; 59: 522–523.

22.

Segaert

Hermans

Clinical signs, pathophysiology and management of cutaneous side effects of anti-tumor necrosis factor agents. Am J Clin Dermatol 2017; 18: 771–787.

23.

Conrad

Di Domizio

Mylonas

et al . TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis. Nat Commun 2018; 9: 25.

24.

Sfikakis

Iliopoulos

Elezoglou

et al . Psoriasis induced by anti-tumor necrosis factor therapy: a paradoxical adverse reaction. Arthritis Rheum 2005; 52: 2513–2518.

25.

Matthews

Rogers

FitzGerald

Development of new-onset psoriasis while on anti-TNFalpha treatment. Ann Rheum Dis 2006; 65: 1529–1530.

26.

Stoffel

Maier

Riedl

et al . Analysis of anti-TNF-induced skin lesions reveals strong Th1 activation with some distinct immunological characteristics. Br J Dermatol 2018; 178: 1151–1162.

27.

Tintle

Dabade

Kalish

et al . Repigmentation of hair following adalimumab therapy. Dermatol Online J 2015; 21: pii: 13030/qt6fn0t1xz.

28.

Harada

Yamamoto

Sato

et al . Autoimmune hemolytic anemia during adalimumab treatment for plaque psoriasis. Intern Med 2015; 54: 1103–1104.

29.

Scheinfeld

Adalimumab: a review of side effects. Expert Opin Drug Saf 2005; 4: 637–641.

30.

Sator

Richter

Saxinger

et al . Adalimumab in the treatment of moderate-to-severe chronic plaque psoriasis in patients switching from other biologics. J Eur Acad Dermatol Venereol 2015; 29: 1742–1749.

31.

Chiu

Wang

Chan

et al . Risk factor analysis for the immunogenicity of adalimumab Aassociated with decreased clinical response in Chinese patients with psoriasis. Acta Derm Venereol 2015; 95: 711–716.

32.

Bandrés Ciga

Salvatierra

López-Sidro

et al . An examination of the mechanisms involved in secondary clinical failure to adalimumab or etanercept in inflammatory arthropathies. J Clin Rheumatol 2015; 21: 115–119.

33.

Pecoraro

De Santis

Melegari

et al . The impact of immunogenicity of TNFα inhibitors in autoimmune inflammatory disease. A systematic review and meta-analysis. Autoimmun Rev 2017; 16: 564–575.

34.

Esteve-Solé

Deyà-Martínez

Teixidó

et al . Immunological changes in blood of newborns exposed to anti-TNF-α during pregnancy. Front Immunol 2017; 8: 1123.

35.

Viguier

Livideanu

Beylot-Barry

et al . Observational case series on a group of psoriasis patients who failed to respond to any TNF blockers. J Dermatolog Treat 2014; 25: 75–77.

36.

Ovejero-Benito

Prieto-Pérez

Llamas-Velasco

et al . Polymorphisms associated with adalimumab and infliximab response in moderate-to-severe plaque psoriasis. Pharmacogenomics 2018; 19: 7–16.

37.

Harris

Hope

Keane

Tumor necrosis factor blockers influence macrophage responses to Mycobacterium tuberculosis. J Infect Dis 2008; 198: 1842–1850.

38.

Gilbert

Manalo

et al . Active tuberculosis in a psoriasis patient treated with tumor necrosis factor inhibitors despite an initial negative tuberculin skin test and no known risk factors. Dermatol Online J 2016; 22: pii: 13030/qt45d4x70k.

39.

Guinard

Bulai Livideanu

Barthélémy

et al . Active tuberculosis in psoriasis patients treated with TNF antagonists: a French nationwide retrospective study. J Eur Acad Dermatol Venereol 2016; 30: 1336–1341.

40.

Tanaka

Sekine

Tsunoda

et al . Central nervous system manifestations of tuberculosis-associated immune reconstitution inflammatory syndrome during adalimumab therapy: a case report and review of the literature. Intern Med 2015; 54: 847–851.

41.

Chiu

Tang

Hung

et al . A real-world risk analysis of biological treatment (adalimumab and etanercept) in a country with a high prevalence of tuberculosis and chronic liver disease: a nationwide population-based study. Scand J Rheumatol 2017; 46: 236–240.

42.

Johnson

Bialas

Hall

et al . Should all patients undergoing treatment with biologic agents be screened annually for latent tuberculosis infection with an interferon gamma release assay? J Dermatolog Treat 2016; 27: 378–380.

43.

Cagatay

Bingol

Kıyan

et al . Follow-up of 1887 patients receiving tumor necrosis-alpha antagonists: tuberculin skin test conversion and tuberculosis risk. Clin Respir J 2018; 12: 1668–1675.

44.

Gisondi

Pezzolo

Lo Cascio

et al . Latent tuberculosis infection in patients with chronic plaque psoriasis who are candidates for biological therapy. Br J Dermatol 2014; 171: 884–890.

45.

Piaserico

Dapavo

Conti

et al . Adalimumab is a safe option for psoriasis patients with concomitant hepatitis B or C infection: a multicentre cohort study of 37 patients and review of the literature. J Eur Acad Dermatol Venereol 2017; 31: 1853–1859.

46.

Fotiadou

Lazaridou

Ioannides

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. J Eur Acad Dermatol Venereol 2011; 25: 471–474.

47.

Cho

Chen

Chiu

et al . Use of anti-tumor necrosis factor-α therapy in hepatitis B virus carriers with psoriasis or psoriatic arthritis: a case series in Taiwan. J Dermatol 2012; 39: 269–273.

48.

Gallitano

McDermott

Brar

et al . Use of tumor necrosis factor (TNF) inhibitors in patients with HIV/AIDS. J Am Acad Dermatol 2016; 74: 974–980.

49.

Lindsey

Weiss

Lee

et al . Treatment of severe psoriasis and psoriatic arthritis with adalimumab in an HIV-positive patient. J Drugs Dermatol 2014; 13: 869–871.

50.

Merkac

Tomazic

Strle

Lyme neuroborreliosis in a patient treated with TNF-alpha inhibitor. Infection 2015; 43: 759–762.

51.

Haque Hussain

Wallace

Belham

et al . Infective endocarditis complicating adalimumab therapy for psoriasis. Clin Exp Dermatol 2014; 39: 555–556.

52.

Muñoz-Oca

Villarreal Morales

Nieves-Rodriguez

et al . Concomitant disseminated histoplasmosis and disseminated tuberculosis after tumor necrosis factor inhibitor treatment: a case report. BMC Infect Dis 2017; 17: 70.

53.

Yiu

Smith

Ashcroft

et al . Risk of serious infection in patients with psoriasis on biologic therapies: a prospective cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol 2018; 138: 534–541.

54.

Kalb

Fiorentino

Lebwohl

et al . Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol 2015; 151: 961–969.

55.

Fleischmann

Yocum

Does safety make a difference in selecting the right TNF antagonist?

Arthritis Res Ther 2004; 6(Suppl. 2): S12–S18.

56.

Lockwood

Prens

Kimball

AB.

Adverse reactions to biologics in psoriasis. Curr Probl Dermatol 2018; 53: 1–14.

57.

Burmester

Panaccione

Gordon

et al . Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis 2013; 72: 517–524.

58.

van Lümig

Menting

van den Reek

et al . An increased risk of non-melanoma skin cancer during TNF-inhibitor treatment in psoriasis patients compared to rheumatoid arthritis patients probably relates to disease-related factors. J Eur Acad Dermatol Venereol 2015; 29: 752–760.

59.

Nosotti

Baiocchini

Bonifati

et al . Unusual case of B cell lymphoma after immunosuppressive treatment for psoriasis. World J Hepatol 2015; 7: 814–818.

60.

Lezcano Carduz

Mingo Botín

Durán Poveda

SP.

Squamous cell neoplasm of the ocular surface in a patient with psoriasis treated with tumor necrosis factor-alpha inhibitors. Cornea 2015; 34: 833–834.

61.

Simpkin

Oakley

Multiple eruptive squamous cell carcinoma in a patient with chronic plaque psoriasis on adalimumab. Australas J Dermatol 2013; 54: 55–58.

62.

Asgari

Ray

Geier

et al . Malignancy rates in a large cohort of patients with systemically treated psoriasis in a managed care population. J Am Acad Dermatol 2017; 76: 632–638.

63.

Winterfield

Menter

Gordon

et al . Psoriasis treatment: current and emerging directed therapies. Ann Rheum Dis 2005; 64(Suppl. 2): ii87–ii90; discussion ii91–ii92.

64.

Fleming

Roubille

Richer

et al . Effect of biologics on depressive symptoms in patients with psoriasis: a systematic review. J Eur Acad Dermatol Venereol 2015; 29: 1063–1070.

65.

Maari

Bolduc

Nigen

et al . Effect of adalimumab on sleep parameters in patients with psoriasis and obstructive sleep apnea: a randomized controlled trial. J Dermatolog Treat 2014; 25: 57–60.

66.

Dattilo

Cardiovascular risk in psoriasis: current state of the art. Curr Vasc Pharmacol. Epub ahead of print 16 November 2017. DOI: 10.2174/1570161115666171116163816

67.

Bathon

Giles

Solomon

DH.

TNF antagonists: Killing two ‘birds’ with one biologic ‘stone’. Arthritis Rheumatol (Hoboken, N.J.) 2018; 70: 326–329.

68.

Shaaban

Al-Mutairi

. The effect of tumor necrosis factor inhibitor therapy on the incidence of myocardial infarction in patients with psoriasis: a retrospective study. J Dermatolog Treat 2017: 1–5.

69.

Brezinski

Follansbee

Armstrong

et al . Endothelial dysfunction and the effects of TNF inhibitors on the endothelium in psoriasis and psoriatic arthritis: a systematic review. Curr Pharm Des 2014; 20: 513–528.

70.

Kusakari

Yamasaki

Takahashi

et al . Successful adalimumab treatment of a psoriasis vulgaris patient with hemodialysis for renal failure: a case report and a review of the previous reports on biologic treatments for psoriasis patients with hemodialysis for renal failure. J Dermatol 2015; 42: 727–730.

71.

Lund

Thomsen

SF.

Use of TNF-inhibitors and ustekinumab for psoriasis during pregnancy: a patient series. Dermatol Ther 2017; 30. DOI: 10.1111/dth.12454

72.

Hoxha

Calligaro

Di Poi

et al . Pregnancy and foetal outcomes following anti-tumor necrosis factor alpha therapy: a prospective multicentre study. Joint Bone Spine 2017; 84: 169–173.

73.

Weber-Schoendorfer

Oppermann

Wacker

et al . Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study. Br J Clin Pharmacol 2015; 80: 727–739.

74.

Seow

Leung

Vande Casteele

et al . The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease. Aliment Pharmacol Ther 2017; 45: 1329–1338.

75.

Porter

Lockwood

Kimball

AB.

Update on biologic safety for patients with psoriasis during pregnancy. Int J Womens Dermatol 2017; 3: 21–25.

76.

Huang

Chang

Kroeker

et al . Management of inflammatory bowel disease during pregnancy and breastfeeding varies widely: a need for further education. Can J Gastroenterol Hepatol 2016; 2016: 6193275.

77.

Rademaker

Agnew

Andrews

et al . Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis Collaboration. Australas J Dermatol 2018; 59: 86–100.

78.

Fortina

Bardazzi

Berti

et al . Treatment of severe psoriasis in children: recommendations of an Italian expert group. Eur J Pediatr 2017; 176: 1339–1354.

79.

Duarte

Mebrahtu

Goncalves

et al . Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation. Health Technol Assess 2017; 21: 1–244.

80.

Bronckers

IMGJ

Seyger

MMB

West

et al . Safety of systemic agents for the treatment of pediatric psoriasis. JAMA Dermatol 2017; 153: 1147–1157.

81.

Di Lernia

. Adalimumab for treating childhood plaque psoriasis: a clinical trial evaluation. Expert Opin Biol Ther 2017; 17: 1553–1556.

82.

Esposito

Giunta

Mazzotta

et al . Efficacy and safety of subcutaneous anti-tumor necrosis factor-alpha agents, etanercept and adalimumab, in elderly patients affected by psoriasis and psoriatic arthritis: an observational long-term study. Dermatology 2012; 225: 312–319.

83.

Oussedik

Patel

Cash

et al . Severe and acute complications of biologics in psoriasis. G Ital Dermatol Venereol 2017; 152: 586–596.

84.

Inzinger

Wippel-Slupetzky

Weger

et al . Survival and effectiveness of tumour necrosis factor-alpha inhibitors in the treatment of plaque psoriasis under daily life conditions: report from the Psoriasis Registry Austria. Acta Derm Venereol 2016; 96: 207–212.

85.

Augustin

PsoBest: Das deutsche Psoriasis-Register. Aktuelle Einschlusszahlen, https://www.psobest.de/ (2017, accessed 12 September 2017).

86.

Wuepper

Coulter

Haberman

Psoriasis vulgaris: a genetic approach. J Invest Dermatol 1990; 95: 2S–4S.

Safety and tolerability of adalimumab for the treatment of psoriasis: a review summarizing 15 years of real-life experience

Abstract

Keywords

Introduction

Method

Adverse drug reactions

Immune reaction towards TNFα inhibitors

Infections

Formation of malignancies

Concomitant diseases

Pregnancy, lactation, children and the elderly

Conclusions

Footnotes

Funding

Conflict of interest statement

References