© Springer Science+Business Media Singapore 2017
Sujata Sawhney and Amita Aggarwal (eds.)Pediatric Rheumatology10.1007/978-981-10-1750-6_88. Biologic Response Modifiers in Pediatric Rheumatology
(1)
Istituto Giannina Gaslini, University of Genova and Second Division of Pediatrics, Genova, Italy
(2)
Istituto Giannina Gaslini, Pediatric Rheumatology International Trials Organization and Second Division of Pediatrics, Genova, Italy
Learning Objectives
- 1.
To introduce the concept of biologic response modifiers (BRMs)
- 2.
To discuss the safety issues with BRMs including infections, risk of malignancies, and pregnancy during therapy
- 3.
To discuss the mode of action, trial data, registry data, and safety profile of individual BRMs (anti-TNF agents, anti-IL-1 agents, tocilizumab, and abatacept)
Introduction
Over the last two decades, the treatment of juvenile idiopathic arthritis (JIA) has been dramatically changed by the use of novel biologic agents that have greatly improved patients’ outcomes. Currently available biologic medications for the treatment of JIA patients include tumor necrosis factor (TNF) blockers, agents targeting interleukin (IL)-1 and the IL-6 receptor, T-cell costimulation inhibitors, and antibodies to the B-lymphocyte antigen CD20. This chapter will focus on the efficacy and safety data related to all the biologic medications currently available for the treatment of JIA.
Biologic agents are molecules that specifically target cytokines or cell surface antigens. Biologic agents have dramatically changed the way children with JIA are treated. Biologic agents are different from traditional immunosuppressive or disease-modifying antirheumatic drugs (DMARDs), as they target to selectively block only one inflammatory pathway such as TNF blockers (etanercept, adalimumab, infliximab,golimumab, and certolizumab pegol), IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-6 receptor blockers (tocilizumab), or costimulation blocker that block T-cell activation via B7-CD28 pathway (abatacept). In contrast traditional DMARDs act on multiple pathways and cause generalized immune suppression. The efficacy profile of most of these drugs is similar, and they are usually administered concomitantly with MTX.
Safety Considerations
The safety profile seems to be favorable and overlapping with what has been observed in adults with rheumatoid arthritis. However, more long-term data is needed for severe adverse events such as serious infections, autoimmune events, response to vaccination, or malignancies [1–3]. Thus, it is important to insist on patient/parent information and prophylactic measures, such as vaccinations (knowing that live-attenuated vaccines are only recommended before starting the treatment, while other vaccinations can be performed on treatment).
Biologic agents are associated with an increased risk of tuberculosis. An analysis of the administrative claims in the United States showed that among 8,479 children with JIA patients, there was an increased rate of infection compared to children with attention deficit hyperactivity disorder. This increased rate was not due to MTX or TNF inhibitor use, but was due to high-dose glucocorticoid use [4]. Screening for tuberculosis (tuberculosis skin test or PPD) is mandatory for patients in whom biologic treatment is considered. In general, whenever an infection occurs, the therapy with a biologic agent should be at least temporarily discontinued. Discontinuation should be however always discussed with the family on a case by case basis.
In 2008 the FDA issued a black box warning about the possible increase of lymphomas associated with the use of anti-TNF agents (infliximab, etanercept, and adalimumab) in children (19 out of 48 cases were JIA) [5]. Five cases of cancer out of 1260 patients have been reported from the German registry [6, 7]. In a biologic-naive population of patients with JIA and matched healthy controls from the Swedish patient registry, JIA patients with disease onset before 1987 were not at increased risk of cancer, while in the period 1987–1999, there was a significant increase of incident lymphoproliferative malignancies (relative risk 4.2, 95 % confidence interval 1.7–10.7) and cancers overall (relative risk 2.3, 95 % confidence interval 1.2–4.4) [8]. In a study evaluating US administrative database of 7,812 children with JIA versus children without JIA, the standardized incidence ratio (SIR) was 4.4 (95 % confidence interval, 95 % CI 1.8–9.0) for probable and highly probable malignancies. For those taking MTX without TNF inhibitor use, the SIR was 3.9 (95 % CI 0.4–14). Following any use of TNF inhibitors, no probable or highly probable malignancies were identified (SIR 0, 95 % CI 0–9.7). The authors concluded that children with JIA appeared to have an increased rate of incident malignancy compared to children without JIA. However, the treatment for JIA, including TNF inhibitors, did not appear to be significantly associated with the development of malignancy [9]. Similar conclusions were reached with the analysis of the PharMetrics Patient-Centric Database [10], where the JIA cohort had a standardized incidence ratio of 4.0 and non-JIA cohort of 1.4 as compared to the mean values observed in United States. In the phase III abatacept withdrawal trial, which enrolled 190 patients in the open-label phase, a case of acute lymphoblastic leukemia has been reported, but no new cases were seen in the long-term extension [11]. No cases of malignancy have been reported so far in the clinical trials with anti-IL-1 or anti-IL-6 inhibitors [12–15]. Thus at present there is no clear evidence that biologic therapy increases risk of malignancy [3].
The data on the use of biologic drugs during pregnancies is limited, but in general it is recommended to discontinue the drugs. Since the experience with biologic drugs is recent, real long-term safety data are still lacking. It is important that the doctors openly discuss the issue with the families, the risk and benefit associated with the use of these drugs.
Route and Frequency of Administration
While efficacy and safety are so far largely overlapping among biologics, they differ from each other in the frequency and route of administration. This varies from daily (anakinra) to weekly or biweekly (etanercept, adalimumab, or tocilizumab for systemic JIA), monthly (abatacept or tocilizumab for polyarticular-course JIA and canakinumab), or bimonthly (infliximab).Tocilizumab and infliximab are given intravenously, the others by the subcutaneous route.
Which Is Biologic?
Usually anti-TNF agents are administered for the majority of the JIA categories with the exception of systemic JIA where IL-1- or IL-6-targeted therapies are used. Persistent oligoarthritis is normally not treated with biologic agents unless it is unresponsive to corticosteroid injection and MTX. As with all other second level drugs, they must be administered under strict medical control.
Anti-TNF Agents
Etanercept (ETN)
Elevated levels of TNF are found in tissues and fluids of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. Etanercept (ETN) binds specifically to TNF and blocks its interaction with cell surface TNF receptors. There are two distinct receptors for TNF (TNFRs), a 55 kilodalton (kD) protein (p55) and a 75 kD protein (p75). The biological activity of TNF is dependent upon binding to either cell surface receptor (p75 or p55).
Etanercept is a fully human soluble TNF receptor. It binds to both TNF-α and TNF-β, preventing their binding to the receptors on cell surface. ETN dimeric fusion protein consists of the extracellular ligand-binding portion of the human 75 kD (p75) TNF receptor linked to the Fc portion of human IgG1. ETN is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids.
ETN is administered by a subcutaneous injection, weekly (0.8 mg/kg with a maximum of 50 mg) or twice a week (0.4 mg/kg, with a maximum of 25 mg) from the age of 2 years. Injections can be self-administered by the patient.
The efficacy of ETN treatment in JIA was first demonstrated to be effective in a multicenter, randomized, placebo-controlled clinical trial involving 69 patients with polyarthritis not responding to methotrexate alone [16]. In the first, open-label, phase, where all patients were given ETN, 74 % of patients reached at least an ACR Pediatric 30 improvement. In the double-blind phase, ETN-treated patients had a reduced rate of flare (28 % vs. 81 %) and a longer time to flare (116 days vs. 28 days) in comparison to placebo. In the extension phase, 63 % of patients reached clinical remission within 2 years. Long-term extension studies of the original trial cohort and several national registries have subsequently confirmed the sustained clinical benefit and acceptable safety profile of the drug [17–19]. In the German registry, 47.6 % and 26.6 % of 787 patients reached the criteria for inactive disease or clinical remission on medication, respectively [20]. Among 262 patients included in the Dutch registry, the frequency of excellent response, defined as fulfillment of adapted inactive disease criteria, was 32 % after 15 months of therapy. This rate increased from 37 to 49 % in a secondary longer-term follow-up analysis, 4–7 years after initiation of ETN [21]. Together, the results indicate that around half of children with JIA who are treated with ETN in real-life clinical settings are able to attain good clinical response. It is also associated with improvement of functional ability and quality of life [22, 23], recovery of growth velocity and bone status [24, 25], and reduction in the progression of radiographic joint damage [26]. Several studies, including two registry reports, have shown that anti-TNF agents are less effective in the systemic subset of JIA [6, 19–21, 27–30]. This phenomenon has been attributed to interleukin 1 (IL-1) and IL-6 playing a greater pathogenic role than TNF-α in systemic arthritis [31–33].
The safety profile of ETN has been evaluated both in the original trial and in national registries. In the controlled trial, there were three cases of primary varicella infection with a complicated course. In a registry run by the PRCSG in North America, among 397 patients treated with ETN alone or in combination with methotrexate for 3 years, the rates of adverse events, serious adverse events, medically important infections, and autoimmune events were similar in those treated with methotrexate alone, ETN alone, and the combination of ETN and methotrexate with no cases of demyelinating disease, tuberculosis, malignancy, or death reported [34, 35].
In the German registry of 604 ETN-treated patients with JIA, 190 adverse events were reported [6, 36]. Four malignancies, including two cases of lymphoma and no deaths, were recorded. In the Dutch registry, in 146 JIA patients (313 patient-years of exposure), there were nine serious adverse events; treatment was permanently stopped due to adverse events in six. Three new autoimmune diseases were noted: one case each of sarcoidosis, ulcerative colitis, and Crohn’s disease. One case of tuberculosis was also described, and three deaths were recorded [28].In the British registry, in 483 JIA patients treated with ETN (941 patient-years of exposure), 21 patients discontinued the ETN due to toxicity: five discontinued due to infections, ten due to noninfectious central nervous system (CNS) events, and six due to other events. One patient developed inflammatory bowel disease (IBD) [29]. Both the Dutch and German national biologics registries have reported a decrease in the rate of adverse events (AEs) over time [28, 36], from 0.20 AEs/patient during the first year of treatment reducing to 0.12 AEs/patient/year thereafter [36].
Treatment with ETN does not prevent the onset of uveitis in JIA patients; it is still debatable whether ETN contributes to the occurrence of uveitis [1]. The two national registries [28, 36] and other case series [27, 37–39] suggest that uveitis starts or flares up after treatment, whereas another study did not find any difference in patients treated or not treated with anti-TNF medications [40]. The most commonly reported side effects are local reactions at injection site (red spot, itching, swelling) that are usually of short duration and of mild intensity.
Infliximab
Infliximab (IFX) is a chimeric human-murine anti-TNF monoclonal antibody that binds to TNF-alpha. IFX does not neutralize TNF-β (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNF-α.
IFX is administered intravenously every 2 weeks for the first three administrations and then every 4–8 weeks at the dosage of 3–6 mg/kg at each infusion. IFX is administered in association with methotrexate in order to reduce the frequency of side effects. The safety and efficacy of IFX in the treatment of JIA was first assessed in a controlled trial involving 122 patients [45]. Children were randomized to receive methotrexate and IFX (at 3 mg/kg) or methotrexate and placebo. The trial failed to demonstrate a statistically significant difference in its primary outcome at 3 months, which was the achievement of an ACR Pediatric 30 improvement. After 14 weeks, patients in the placebo arm were switched to receive higher-dose IFX (6 mg/kg). By week 52, ACR Pedi 50 and ACR Pedi 70 responses were seen in 69.6 % and 51.8 % patients, respectively, similar to that observed with ETN. During the open-label extension phase of this study, 42/78 patients discontinued IFX after 1–4 years. After nearly 4 years of treatment, the proportion of patients with ACR Pediatric 30, 50, 70, and 90 responses or inactive disease was 44 %, 40 %, 33 %, 24 %, and 13 %, respectively [46].
Of note, although the two dosages used were of comparable efficacy, patients receiving 3 mg/kg had more frequent occurrences of serious adverse events, infusion reactions, antibodies to IFX, and newly induced ANA and anti-DNA antibodies. There were 24 serious adverse events including 6 serious infections (1 case of pulmonary TB) and 3 mild opportunistic infections (2 cases of thrush and 1 case of herpes zoster). During the infusion, allergic reaction may occur going from mild reactions (shortness of breath, red skin rash, itching) that are easily treated to serious allergic reactions with hypotension (lowering of the blood pressure) and risk for shock. These allergic reactions occur more often after the first infusions and are due to an immunization against a portion of the molecule, which is of mouse origin, leading to the production of anti-IFX antibodies. If an allergic reaction occurs, the drug has to be withdrawn. Of the 122 children enrolled in the original trial, 25 % developed antibodies to IFX (38 % in the low-dose group and 12 % in the high-dose group). An infusion reaction was seen in 31 of 117 patients treated with IFX (serious in 6 patients).
IFX is not registered for use in JIA; however IFX is frequently prescribed in refractory polyarticular JIA, with good clinical results [47].
Adalimumab
Adalimumab (ADA) is a fully human monoclonal antibody against TNF-α that binds to TNF-α and blocks its interaction with the p55 and p75 cell surface TNF receptors. ADA is administered by subcutaneous injection and is registered for JIA patients from the age of 4 years both in the United States and in Europe with a different dose schedule. In the United States, a fixed dose of 20 mg every 2 weeks for children <30 kg and 40 mg/every 2 weeks for children ≥30 kg is recommended, whereas in Europe 24 mg/m2/every 2 weeks is recommended for all children.
The efficacy of ADA in the treatment of polyarticular JIA was assessed in a controlled trial with a withdrawal design, comparing ADA in monotherapy or in combination with methotrexate in 171 patients [48]. In the open-label phase, 74 % of patients not receiving methotrexate and 94 % of those receiving methotrexate had at least an ACR Pediatric 30 response at week 16. In the double-blind phase, patients treated or not treated with methotrexate were randomized separately to receive ADA or placebo. Flares were significantly more frequent in those treated with methotrexate and placebo or placebo alone (primary outcome). However, at 48 weeks, the percentages of patients who achieved an ACR Pediatric 30, 50, 70, or 90 responses were significantly greater for those receiving ADA than for those receiving placebo only among patients concomitantly treated with methotrexate. At the end of the 2-year open-label extension phase, 40 % of patients were in remission.
Among the 171 patients enrolled in the trial, 14 children experienced a serious adverse event. Of these, 7 were serious infections (bronchopneumonia, herpes simplex virus infection, pharyngitis, pneumonia, and unspecified viral infection and two cases of herpes zoster). Anti-ADA antibodies were developed in 16 % of patients during the open-label and double-blind phases: 5 of 85 (6 %) receiving methotrexate and 22 of 86 (26 %) not receiving methotrexate. Development of anti-ADA antibody did not lead to a greater rate of discontinuation of the study drug, nor did it increase the incidence of serious adverse events.
Long-term data on safety is still scarce as it is in use for only a decade. The FDA collated the data from 1,500 pediatric patients treated with ADA, of whom 330 had JIA [49]. Three fatal cases, 105 other serious adverse events (including three cases of Mycobacterium infection and one case of Hodgkin lymphoma), and 1 death in a patient with JIA due to macrophage activation syndrome and interstitial pneumonia were reported.
Anti-interleukin-1 Agents
IL-1β is a powerful pro-inflammatory cytokine that plays a key role in innate and adaptive immunity.
Dysregulated production of IL-1 plays a critical role in the pathogenesis of systemic JIA: it has been demonstrated that the expression of IL-1α, IL-1β, and other innate immunity genes is upregulated in the serum of SoJIA patients; moreover, the patient’s peripheral blood mononuclear cells produce an excess of IL-1beta upon activation, and treatment with IL-1 receptor antibody (IL-1Ra) efficiently treats the disease [31].
According to the pattern of response to anti-IL-1 therapy, two subpopulations of systemic JIA patients can be identified: one with a pronounced, complete response to IL-1 blockade and another that is resistant to treatment or has an intermediate response [52]. These two subpopulations do not differ in IL-1 in vitro production or in serum cytokine concentrations, but only in the number of joints affected and in neutrophil counts. Patients with fewer joints affected or with a higher neutrophil count have an increased probability of responding to anti-IL-1 treatment. Thus, systemic JIA can be stratified into at least two subgroups on the basis of the response to IL-1-blocking agents and therefore on the possible pathogenic relevance of this cytokine.
Anakinra
Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1Ra) that blocks the biologic activity of IL-1 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI). Anakinra is composed of 153 amino acid residues and is produced by using the Escherichia coli expression system.
Anakinra is administered subcutaneously everyday. In systemic JIA, the usual dosage is 1–2 mg/kg, but it can be increased up to 5 mg/kg in some low-weight children with severe disease activity; rarely the dose exceeds 100 mg per day at each daily infusion. Anakinra is not currently licensed for use in JIA.
Anakinra was first demonstrated to be effective in the treatment of systemic JIA in a multicenter controlled trial, in which 8 out of 12 patients on anakinra and 1 out of 12 on placebo achieved an ACR Pediatric 30 response [13]. Patients treated with placebo in the first phase of the trial were switched to anakinra, and 90 % of them had an improvement. In polyarticular JIA, anakinra has not demonstrated a significant benefit over placebo [15].
Two recent open-label studies have demonstrated the efficacy of anakinra monotherapy without any use of corticosteroids in new onset systemic JIA patients [53–55]. Following the hypothesis that by targeting more specifically some key immunologic features of systemic JIA very early in the disease course, it could be possible to achieve high rates of response to recombinant IL-1Ra with a shorter treatment course, Vastert et al. treated 20 consecutive systemic JIA patients with anakinra as a first-line agent [54]. At 3 months 18 patients treated with anakinra in monotherapy reached at least an ACR Pediatric 90 response and started tapering the drug. This encouraging result needs to be confirmed in a larger sample of patients, in order to assess if patients treated with anakinra have a better long-term outcome and are exposed to a lower risk of side effects [56].
Safety of anakinra treatment was the primary outcome of the controlled trial on 86 polyarticular JIA patients treated for up to 40 weeks. Only one serious adverse event thought to be due to anakinra (nephrosis) was reported. In the ANAJIS trial, of the 22 patients receiving anakinra for 1 year, 5 patients had serious adverse events, including one patient developing Crohn’s disease [13]. In a cohort of 33 patients treated with anakinra for systemic JIA in the United States, one developed macrophage activation syndrome and another Epstein-Barr virus infection [57].
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