Introduction

Historically, physicians have treated the symptoms of disease, however with increasing technology and knowledge, biological agents are used in the current times to target the root cause of diseases and thus not only treat the symptoms but with the aim of re-educating the immune system and putting diseases into remission. In the last few years this shift in treatment has grown from a new understanding of the immunopathophysiological basis of the underlying disease conditions, allowing the development of newer technologies that use organisms to create new drugs. Biological agents are thus defined as ‘A substance that is made from a living organism or its products and is used in the prevention, diagnosis, or treatment of diseases. Biological drugs include antibodies, interleukins, and vaccines’ [1].

Currently there are limited data on biological agents being used for paediatric dermatological conditions. This is due to lack of multicentre, randomized, placebo-controlled studies, but also more importantly to the majority of dermatological conditions in children being treated topically, rather than submitting the whole body, including vital organs, to the exposure of powerful chemicals. Psoriasis, however, is one exception and biological therapies are indicated if more conventional therapies have failed. Closely related to dermatological diseases, with overlap into this area, are the rheumatological conditions where these treatments are slowly becoming familiar practice. This chapter will present each therapy using the knowledge gained from paediatric rheumatological conditions, and discuss in turn the differential diagnoses that may benefit from such therapies.

The tumour necrosis factor α (TNF-α) therapies are used most frequently and are presented first. The structure, pharmacokinetics, dosage, efficacy and side-effects will all be described and supported by current literature where appropriate. At the end of this section, the most important issues related to their use in paediatric patients, such as how to encourage compliance of painful injections, or how to instill realistic hopes and expectations, will be discussed. The extended family of biological therapies such as anakinra, tocilizumab and rituximab will then be covered.

Reference

1 National Cancer Institute. www.cancer.gov/dictionary.

Anticytokine Therapies

Tumour Necrosis Factor α

Tumour necrosis factor is one of the main cytokines involved in stimulating the inflammatory process. TNF receptors are the body’s natural way of controlling excess TNF. However, in many autoimmune conditions, such naturally occurring TNF receptors cannot adequately regulate TNF activity, leading to an imbalance. It is thought that TNF-α resides at the apex of an inflammatory cytokine cascade that is responsible for the pathophysiology of some autoimmune conditions. TNF-α can be produced by numerous cell types, but in inflammatory conditions is usually produced by activated macrophages. TNF-α may contribute to the pathogenesis of inflammatory conditions inducing other proinflammatory cytokines (e.g. interleukin 1 (IL-1), IL-6) and chemokines (e.g. IL-8); by enhancing leukocyte migration, by increasing endothelial layer permeability and adhesion molecule expression; and by improving the function and induction of synthesis of acute-phase reactants and other proteins [1]. It was proved in animal studies initially that the inhibition of TNF-α with soluble TNF receptor constructs ameliorated the signs of inflammation and prevented joint damage and destruction [2].

With tools from molecular biology, different compounds have been created, all of which bind strongly to TNF-α and inhibit its proinflammatory activities. Etanercept is a fusion protein made up of two recombinant p75 TNF receptors fused with the Fc portion of a human immunoglobulin 1 (IgG-1). Infliximab and adalimumab are both monoclonal antibodies; the first is a chimeric molecule (composed of the variable region of a murine antibody grafted to the constant region of a human antibody); the second is a human-derived antibody [3].

Etanercept

Structure

Etanercept is a human TNF receptor p75–Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary mammalian expression system. Etanercept is a dimer of a chimeric protein genetically engineered by fusing the extracellular ligand-binding domain of a human TNF receptor 2 (TNF-R2/p75) to the Fc domain of human IgG-1. This Fc component contains the hinge, CH₂ and CH₃ regions but not the CH₁ region of IgG-1 [4]. The resultant molecule binds both TNF-α and LT-β (lymphotoxin β, previously termed TNF-β) with high affinity and specificity.

Pharmacokinetics

Etanercept is slowly absorbed from the site of subcutaneous injection, reaching a maximum concentration approximately 48 h after a single dose. With twice weekly doses it is anticipated that steady-state concentrations are approximately twice as high as those observed after single doses. Etanercept is cleared slowly from the body, with a half-life of approximately 70 h. There is no apparent pharmacokinetic difference between males and females; the presence of renal or hepatic impairment should not require a change in dosage. Methotrexate has no effect on the pharmacokinetics of etanercept [4]. In a polyarticular juvenile idiopathic arthritis (JIA) trial with etanercept, 69 patients were administered 0.4 mg etanercept/kg twice weekly for 3 months. Serum concentration profiles were similar to those seen in adult rheumatoid arthritis patients. The youngest children (4 years of age) had reduced clearance (increased clearance when normalized by weight) compared with older children (12 years) and adults. Simulation of dosing suggests that while older children (10–17 years) will have serum levels close to those seen in adults, younger children will have appreciably lower levels [4–6].

Drug Dose

Juvenile Idiopathic Arthritis

In JIA (age 4 years and above, although it has FDA (Food and Drug Administration) approval from 2 years and above in the United States) 0.4 mg/kg (up to a maximum of 25 mg per dose) is given twice weekly as a subcutaneous injection with an interval of 3–4 days between doses. Whilst the license is for twice weekly etanercept in paediatrics, many physicians find that once weekly (at 0.8 mg/kg per dose) is as efficacious. In patients who are well controlled on twice weekly doses, the move to once weekly often improves patient and family satisfaction [5].

Paediatric Plaque Psoriasis

In paediatric plaque psoriasis (age 8 years and above) 0.8 mg/kg (up to a maximum of 50 mg per dose) is given once weekly for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks. If retreatment with etanercept is indicated, the above guidance on treatment duration should be followed. The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.

Efficacy

Juvenile Idiopathic Arthritis

Etanercept was the first TNF-α antagonist to be approved for use in treating JIA in 1999, and has recently received FDA approval for treating children as young as 2 years old with severe polyarticular JIA. The one and only randomized controlled trial of etanercept for the treatment of refractory polyarticular JIA enrolled 69 patients in a multicenter, placebo-controlled trial employing a drug withdrawal design, followed by an open-label extension phase. Patients were aged 4–17 years with moderately to severely active polyarticular JIA refractory to or intolerant of methotrexate. Patients were randomized to placebo or active drug after an initial 3-month treatment with etanercept. The results showed that patients randomized to continue drug therapy had a significant longer median time to disease flare than those randomized to placebo [5]. The open-label extension phase results were published recently providing information on 318 patient years of etanercept therapy, including up to 8 years of continuous therapy for some. Whilst the results of the 11 patients who continued etanercept therapy for 8 years were impressive, only 20 out of the initial 69 patients continued into the open-label extension trial. Eleven of the patients who failed to respond during the initial phase and a further 38 withdrew for a variety of reasons including lack of efficacy, adverse events, physician decision or patient refusal [6].

Registries aim to capture information about all patients receiving the same drug or type of drug; this often includes age, sex, drug doses, other medications and side-effects experienced. The initial data of 322 patients with JIA and 12 with non-JIA rheumatic diseases were published from the German and Austrian JIA/etanercept registry in 2004. Of 592 patient treatment years there were 69 reports of adverse events in 56 patients and treatment was discontinued in only 53 JIA patients, in 25 because of lack of efficacy [7]. More recently, the German registry set up in 2001 presented data on a total of 722 patients with JIA. Data were examined on those available at 12 months and they found 81% of those on etanercept and methotrexate met the criteria for a 30% improvement and 70% of those on etanercept alone [8]. Similar results have been observed in the Dutch registry of 146 JIA/etanercept patients, although the response waned after 2 years of treatment. This could be explained by a high percentage of patients with systemic-onset JIA, who have been shown to respond less well than patients with other subtypes of JIA [9–11].

Psoriasis

A group of 211 paediatric patients aged 4–17years old with moderate to severe plaque psoriasis (as defined by a static physicians global assessment (sPGA) score of ≥3, involving ≥10% of the body surface area, and PASI ≥12) were enrolled into a randomized, double-blind, placebo-controlled study. The primary endpoint was 75% or greater improvement from baseline in the psoriasis area-and-severity index (PASI 75) at week 12. Secondary endpoints included PASI 50, PASI 90, a physician’s global assessment of clear or almost clear of disease, and safety assessments. Eligible patients had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy. Patients received etanercept 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomized to etanercept had positive efficacy responses (e.g. PASI 75) than those randomized to placebo (57% and 11%, respectively). After the initial phase, all patients received etanercept 0.8 mg/kg (up to 50 mg) once weekly for a further 24 weeks and the results were similar to those seen in the initial phase. At week 36, 138 patients underwent a second randomisation to placebo or etanercept to investigate the effects of withdrawal and retreatment. At week 48, response was lost by 29 of the 69 patients assigned to placebo. Four serious adverse events (three infections) occurred in three patients during treatment with open-label extension; all resolved without sequelae [12].

Uveitis

Chronic uveitis occurs in up to 30% of children with JIA, especially in those with oligoarticular forms, below the age of 7 years old, of female gender and with antinuclear antibody (ANA) positivity. As Schmeling and Horneff discuss, TNF-α has been implicated in the pathogenesis of uveitis and has been extensively studied in animal models [13]. The question as to whether etanercept is good for uveitis has been researched for many years now. In 2001, Reiff et al. suggested that etanercept has a beneficial effect on treatment-resistant uveitis as observed in their cohort of 10 paediatric patients with uveitis (seven due to JIA) in a prospective study over 3 months [14]. In a retrospective study, 229 questionnaires were returned out of 310 sent to paediatric rheumatologists enquiring about uveitis and etanercept administration. Thirty-one patients had a history of uveitis (13.5%) before etanercept addition. Upon starting etanercept, 32 courses of uveitis occurred in 19 patients and in two further patients (1%) in whom uveitis occurred for the first time. The study concluded that during treatment with etanercept there were both relapses and first occurrences of uveitis, and that the frequency and severity of flares was not influenced by etanercept [13].

A more recent study compared 24 patients with JIA taking etanercept and 21 taking infliximab. Of these 45 patients, uveitis improved in 14 (31%), no change was observed in 14 (31%), and the activity of uveitis increased in 17 (38%). However, inflammatory activity improved more frequently in those taking infliximab than etanercept. Uveitis developed for the first time in four patients taking etanercept and one taking infliximab. In conclusion, uveitis improved in one-third of patients on anti-TNF treatment and infliximab may be more effective than etanercept [15].

It is only fair to say that case reports have been published postulating whether etanercept could in fact cause uveitis in patients rather than affecting the natural progression of the disease itself [16,17]. However, so far these remain only as case reports and until the data from the registries are published, this question can not be answered.

Orphan Diseases

Anti-TNF agents as a whole have been used in a variety of autoimmune conditions, including juvenile-onset spondyloarthropathies [17–20], TRAPS (TNF receptor superfamily 1A-associated periodic fever syndrome) [21,22], chronic recurrent multifocal osteomyelitis [23], Behcet disease [24–26], inflammatory myopathies [27–29] and various types of vasculitis [30–33]. Whilst etanercept is not licensed for such conditions, physicians will try these medications in an acutely unwell child who has failed conventional treatment, producing interesting results that are published as case reports.

Contraindications

• Patients who are hypersensitive to the active substance.
  
• Patients with sepsis.
  
• Patients with active infections.
  
• Premature babies or neonates as the solvent contains benzyl alcohol.
  
• Must not be administered with abatacept, anakinra and other anti-TNFs.

Live vaccines should not be given with etanercept, and adolescents should use contraception whilst taking the drug.

Side-Effects

Injection Site Reactions

Compared to placebo, patients with rheumatic diseases treated with etanercept had a significantly higher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the first month. Mean duration was approximately 3–5 days. No treatment was given for the majority of injection site reactions, and those who were given treatment received topical preparations such as corticosteroids or oral antihistamines. Additionally, some patients developed recall injection site reactions characterized by a skin reaction at the most recent site of injection along with the simultaneous appearance of injection site reactions at previous injection sites. These reactions were generally transient and did not recur with treatment [4].

Infections and General Side-Effects

The types of infections seen in clinical trials in JIA patients aged 2–18 years were generally mild to moderate and consistent with those commonly seen in outpatient paediatric populations. Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae, appendicitis, gastroenteritis, oesophagitis/gastritis, group A streptococcal septic shock, and soft tissue and postoperative wound infection. Severe non-infectious adverse events reported included depression/personality disorder, cutaneous ulcer, oesophagitis/gastritis and type I diabetes mellitus [4].

In one study in children with JIA arthritis aged 4–17 years, 43 of 69 (62%) children experienced an infection while receiving etanercept during 3 months of the study (part 1 open label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types and proportion of adverse events in JIA patients were similar to those seen in trials of etanercept in adult patients with rheumatoid arthritis, and the majority were mild. Several generalized adverse events were reported more commonly in 69 JIA patients receiving 3 months of Enbrel compared to 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 events per patient year), abdominal pain (19%, 0.74 events per patient year) and vomiting (13%, 0.74 events per patient year) [4].

In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with etanercept developed injection site reactions compared with 3.4% of placebo-treated patients during the first 12 weeks of treatment [4].

Malignancies

Malignancies have been reported whilst patients have been receiving anti-TNF agents [4]; 48 reported cases of paediatric malignancies over an 8-year period (2001–2008) have been investigated by the FDA, from all over the globe. The highest number of one type of cancer to occur were 10 anti-TNF-associated hepatosplenic T-cell lymphomas reported in juvenile inflammatory bowel disease patients. There were seven non-Hodgkin lymphomas, six Hodgkin lymphomas and six leukaemias; the rest were a variety of single cases of cancers. Patient treatment years were estimated to be 22,645 treatment years for infliximab for patients aged 0–16 years and for etanercept to be 26,800 treatment years for patients aged 0–17 years. Twenty-one of the malignancies were reported in children with Crohn disease, 15 in children with JIA and four in ulcerative colitis. It is currently unclear whether this risk of malignancy is increased in children with JIA as there are no data for JIA children on alternative treatments, unlike the data from adults that indicate an increased risk of lymphoma in patients with rheumatoid arthritis [34].

Tuberculosis

One of the major concerns with TNF-α blockers is their potentially pro-infective action. The reactivation of tuberculosis has become less of a concern with careful screening and prophylaxis before starting therapy. However there are two case reports in the literature of two systemic patients dying whilst on anti-TNF – one on infliximab and the other receiving etanercept [35].

Infliximab

Structure

Infliximab is a chimeric human–murine IgG-1 monoclonal antibody produced by recombinant DNA technology. After reconstitution each millilitre contains 10 mg of infliximab [36].

Infliximab binds with high affinity to both soluble and transmembrane forms of TNF-α but not to lymphotoxin α (TNF-ß). Infliximab inhibits the functional activity of TNF-α in a wide variety of in vitro bioassays. Infliximab prevented disease in transgenic mice that developed polyarthritis as a result of constitutive expression of human TNF-α and, when administered after disease onset, it allowed eroded joints to heal. In vivo, infliximab rapidly forms stable complexes with human TNF-α, a process that parallels the loss of TNF-α bioactivity [36].

Pharmacokinetics

Single intravenous infusions of 1, 3, 5, 10 or 20 mg/kg of infliximab yielded dose-proportional increases in the maximum serum concentration (C_max) and area under the concentration–time curve (AUC). The volume of distribution at steady state (median V_d of 3.0–4.1 L) was not dependent on the administered dose and indicated that infliximab is predominantly distributed within the vascular compartment. No time dependency of the pharmacokinetics was observed. The elimination pathways for infliximab have not been characterized. Unchanged infliximab was not detected in urine. No major age- or weight-related differences in clearance or volume of distribution were observed in rheumatoid arthritis patients. The pharmacokinetics of infliximab in elderly patients has not been studied, and studies have not been performed in patients with liver or renal disease [36].

In combination therapy with methotrexate, serum infliximab concentrations tend to be slightly higher than when administered alone [1].

Overall, serum levels in paediatric patients with Crohn disease (53 patients aged 6–17 years; 8 patients aged 6–10 years) were similar to those in adult Crohn disease. The median terminal half-life for the 5 mg/kg dose in paediatric patients with Crohn disease is 10.9 days [36].

Drug Dose

• Adult rheumatoid arthritis: the dose is 3 mg/kg IV given as an intravenous infusion over a 2 h period followed by an additional 3 mg/kg infusion at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter [36]. When administered in conjunction with methotrexate there is an enhanced clinical response and also a decrease in its immunogenicity [1].
  
• Adult psoriatic arthritis: the dose is 5 mg/kg given as an intravenous infusion over a 2 h period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter [36].
  
• Adult psoriasis: the dose is 5 mg/kg given as an intravenous infusion over a 2 h period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no response after 14 weeks (i.e. after four doses), no additional treatment with infliximab should be given [36].
  
• Crohn disease (6–17 years): the dose is 5 mg/kg given as an intravenous infusion over a 2 h period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longer dosing interval may be sufficient. Available data do not support further infliximab treatment in paediatric patients not responding within the first 10 weeks of treatment [36]. Infliximab has not been studied in patients with Crohn disease aged less than 6 years. Due to insufficient data on safety and efficacy, infliximab is not recommended for use in any other paediatric indication [36].

Efficacy

Whilst other areas of the discussion on infliximab have been extrapolated from adult evidence, this section will only detail paediatric studies to provide a concise report.

Paediatric Crohn Disease (6–17 Years)

In the REACH study, 112 patients (aged 6–17 years, median age 13.0 years) with moderate to severe active Crohn disease (median paediatric Crohn disease activity index of 40) and an inadequate response to conventional therapies received 5 mg/kg infliximab at weeks 0, 2 and 6. All patients were required to be on a stable dose of 6 mercaptopurine, azathioprine (AZA) or methotrexate (MTX) (35% were also receiving corticosteroids at baseline). Patients assessed by the investigator to be in clinical response at week 10 were randomized and received 5 mg/kg infliximab at either 8 weeks or 12 weeks as a maintenance treatment regimen. If response was lost during maintenance treatment, crossing over to a higher dose (10 mg/kg) and/or shorter dosing interval (q8 weeks) was allowed. Thirty-two evaluable paediatric patients crossed over (nine subjects in the q8 week and 23 subjects in the q12 week maintenance groups). Twenty-four of these patients (75.0%) regained clinical response after crossing over.

The proportion of subjects in clinical response at week 10 was 88.4% (99/112). The proportion of subjects achieving clinical remission at week 10 was 58.9% (66/112). At week 30, the proportion of subjects in clinical remission was higher in the q8 week (59.6%, 31/52) than the q12 week maintenance treatment group (35.3%, 18/51; P = 0.013). At week 54, the figures were 55.8% (29/52) and 23.5% (12/51) in the q8 week and q12 week maintenance groups, respectively (P <0.001).

Data about fistulas were derived from paediatric CDAI scores. Of the 22 subjects that had fistulas at baseline, 63.6% (14/22), 59.1% (13/22) and 68.2% (15/22) had incomplete fistula responses at week 10, 30 and 54, respectively, in the combined q8 week and q12 week maintenance groups.

In addition, statistically and clinically significant improvements in quality of life and height, as well as a significant reduction in corticosteroid use, were observed versus baseline.

Juvenile Idiopathic Arthritis

An international, multicentre, randomized, placebo-controlled, double-blind study enrolled 122 children with persistent polyarticular JIA (aged 4–17 years) despite prior methotrexate use. Patients received 3 or 6 mg/kg infliximab as a three-dose induction regimen (weeks 0, 2 and 6 or weeks 14, 16 and 20, respectively) followed by maintenance therapy every 8 weeks, in combination with methotrexate. Disappointingly, while infliximab at 3 and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy endpoint at 3 months did not differ significantly between infliximab-treated and placebo-treated patients [37]. The study concluded that the results warranted further investigation in children with JIA and thus a licence has never been sought.

Orphan Diseases

There are many case reports of infliximab use in other paediatric diseases with good efficacy, for example JIA-associated uveitis [15,38–40], juvenile dermatomyositis [41], juvenile psoriasis [42,43], juvenile spondyloarthropathies and vasculitic paediatric disorders, but there are no published trials.

Side-Effects

Infusion Reactions

In clinical trials in both polyarticular and systemic JIA approximately 3–5% of patients have demonstrated infusion reactions or frank allergic reactions and 9% developed new autoantibodies [44]. In the poly-JIA international, multicentre, randomized, placebo-controlled, double-blind study infusion reactions occurred in 35% of patients with juvenile rheumatoid arthritis receiving 3 mg/kg compared with 17.5% of patients receiving 6 mg/kg. In the 3 mg/kg infliximab group, four out of 60 patients had a serious infusion reaction and three patients reported a possible anaphylactic reaction (two of which were among the serious infusion reactions). In the 6 mg/kg group, two out of 57 patients had a serious infusion reaction, one of whom had a possible anaphylactic reaction [36].

Overall, in the paediatric Crohn study (REACH), 17.5% of randomized patients experienced one or more infusion reactions. There were no serious infusion reactions, and two subjects in REACH had non-serious anaphylactic reactions.

Immunogenicity

Related posts:

12 Collodion Baby 57 Mycobacterial Infections of the Skin 96 Knuckle Pads 140 Skin Gene and Cell Therapy 58 Bartonella Infections: Bacillary Angiomatosis, Cat Scratch Disease and Bartonellosis 168 Kawasaki Disease

Stay updated, free articles. Join our Telegram channel

Join