Pharmacology: Biologics




Biologics are different from nonbiologic disease-modifying antirheumatic drugs (DMARDs) in that they are produced by biologic processes rather than chemical syntheses and target specific, well-defined molecules expressed on cells or secreted into the extracellular space. The terms “nonbiologic,” “conventional,” and other descriptors were used to identify the agents discussed in Chapter 12 . This chapter focuses on the mechanism of action, pharmacokinetics, pharmacodynamics, dosing, and safety of various biologic as well as targeted synthetic therapies, also known as “small molecules.” For information related to efficacy of these agents in pediatric rheumatic diseases, please consult the chapter that discusses the specific disorder.


General Considerations


In general, affinity is a major determinant of the pharmacokinetic (PK) and pharmacodynamic (PD) profile of monoclonal antibodies (mAbs) and receptors (Cepts). Higher affinity allows efficacy to be maintained at lower serum concentrations. That is why proteins with similar half-lives and sizes can have very different duration of efficacy. Essentially, all biologic agents are immunogenic because they are nonself. Even humanized and fully human mAbs and Cepts can elicit antibody responses. The effects of human antichimeric antibodies (HACAs) or human antihuman antibodies (HAHAs) include reduction in serum levels, neutralization of biologic activity, anaphylactoid reactions, and loss of clinical efficacy. Their generation appears to be related to dose, route, and frequency of administration, as well as host-related factors. The interactions with Fc receptors also affect the PD of those mAbs and Cepts that are fusion proteins that include the Fc portion of IgG. The system of naming monoclonal and receptor biologics is shown in Table 13-1 . Information (molecule, target, route of administration, dose, and toxicity) regarding the major mAbs and Cepts used in pediatric rheumatology is shown in Table 13-2 .



TABLE 13-1

Naming of Monoclonal Antibody and Receptor Biologic Therapies (United States Adopted Names System)








  • All monoclonal antibodies’ names end in “mab”



  • Source identifiers




    • u = human (e.g., adalim u mab, golim u mab)



    • o = mouse



    • a = rat



    • zu = humanized (e.g., tocili zu mab, certoli zu mab)



    • e = hamster



    • i = primate



    • xi = chimeric (e.g., ritu xi mab, infli xi mab)



    • axo = rat/mouse



    • xizu = combination of humanized and chimeric chains




  • All receptors end in “cept” (e.g., etanercept, rilonacept, abatacept)



TABLE 13-2

Molecule, Target, Half-Life, Route of Administration, Indications, Dose, and Major Toxicities of Biologic Agents in Pediatric Rheumatology


























































































































































BIOLOGIC MOLECULE TARGET T1/2 C/H
IV/SC/PO
INDICATION/OTHER USE DOSE MAJOR TOXICITY COMMENTS
Etanercept TNFRII/FcIgG1 TNF-α,β 4 d H
SC
RA, PsA, Ps, AS, JIA 0.8 mg/kg q wk or 0.4 mg/kg twice weekly; max 50 mg TB, fungal, lymphoma, MS With or without MTX
Adalimumab mAb to TNF-α TNF-α 2 weeks H
SC
RA, PsA, Ps, AS, JIA, CD, UC/uveitis 15-30 kg-20 mg q2 wk
>kg-40 mg q2 wk
rTB, fungal, lymphoma, MS With or without MTX
Infliximab mAb to TNF-α TNF-α 12.4 d (a)
13.2 d (p)
C
IV
RA, PsA, Ps, AS,J IA, IBD/uveitis 6-10 mg/kg q
2 wk-2 mo
Infusion rxns
TB, fungal, lymphoma, MS
With MTX
pre-med with corticosteroid, acetaminophen, antihistamine
Golimumab mAb to TNF-α TNF-α 2 wk H
SC
RA, PsA, AS, UC 50 mg q mo adult
30 mg/m 2 ch
TB, fungal, lymphoma, MS With MTX
Certolizumab Peg mAb to TNF-α TNF-α 14 d H
SC
CD, RA, PsA 400 mg initially, wks 2 and 4 then 200 mg q2 wk or 400 mg q 4 wks (adult doses) TB, fungal, lymphoma, MS With or without MTX
Anakinra IL-1Ra IL-1 4-6 h H
SC
RA/SJIAC, CAPS 1 mg/kg, max 100 mg daily Injection site rxns, liver Don’t use with other biologics other than abatacept
Rilonacept IL-1R/IL-1AcP/FCIgG1 IL-1 7.72 d H
SC
CAPS/SJIA 4.4 mg/kg (max 320 mg) loading dose then 2.2 mg/kg q week (max 160 mg) Injection site rxns, liver, lipids Don’t use with other biologics
Canakinumab mAb to IL-1 IL-1 26 d adults
23-26 d child
H
SC
CAPS/SJIA 150 mg q8 wk (adult dose CAPS)
4 mg/kg q 4 wks SJIA
Injection site rxns, liver, neutropenia Don’t use with other biologics
Abatacept CTLA4-Ig CD80/86 13 d IV
14.3 d SC
H
IV
SC
RA/JIA, uveitis <75 kg-10 mg/kg wk 0, 2, 4 then q4 wk
75-100 kg-750 mg
>100 kg-1000 mg
Injection site rxns Don’t use with other biologics other than anakinra
Rituximab mAb to CD20 CD20 +
B cells
6-62 d C
IV
RA/RF + polyJIA
RF
375-500 mg/m 2 IV q2 wk × 2 doses Infusion rxns
Progressive multifocal encephalopathy
With MTX
Pre-med with glucocorticoid, acetaminophen, antihistamine
Tocilizumab mAb to IL-6 receptor IL-6 11-13 d IV RA, SJIA, pJIA Poly JIA >2 yr, <30 kg 10 mg/kg q4 wk
>2 yr, >30 kg 8 mg/kg
SJIA >2 yr, <30 kg 12 mg/kg q2 weeks
>2 yr, >30 kg 8 mg/kg q2 weeks
Infection, TB, malignancy, GI perforation, hypersensitivity rxn, anaphylaxis/anaphylactoidrxns
MS lipids
With or without MTX; dose interruptions for liver toxicity, neutropenia, thrombocytopenia
Belimumab mAb to BLyS B cells 19.5 d IV SLE 10 mg/kg q2 wk × 3 then q4 wk Infections, anaphylaxis, infusion rxns Observe for 1 hour after infusion is complete
Ustekinumab mAb to p40 subunit of IL-12 and IL-23 Th17 cells 15-46 d SC Ps, PsA 45 mg SC wk 0, wk 4, then q12 wk (PsA; <100 kg)
90 mg SC wk 0, wk 4, then q12 wk (>100 kg)
Infection, malignancy, hypersensitivity rxn, anaphylaxis, PRES, cardiovascular events With or without MTX
Tofacitinib Small molecule Jak 1,2,3 3 hr PO RA 5 mg PO BID Infections, viral reactivation, neutropenia, lymphopenia, anemia, malignancy, GI perforation Dose adjustments for toxicity; avoid use in severe liver impairment

AS , Ankylosing spondylitis; C , chimeric; CAPS , cryopyrin-associated periodic syndrome; CD , Crohn’s disease; Fungal , reactivated fungal infection; H , humanized; IV , intravenous infusion; JIA , polyarticular course juvenile idiopathic arthritis; mAb , monoclonal antibody; MS , multiple sclerosis/demyelinating disease; MTX , methotrexate; P , pegylated; PRES , posterior reversible encephalitis syndrome; Ps , psoriasis; PsA , psoriatic arthritis; RA , rheumatoid arthritis; rTB , reactivated tuberculosis; rxns , reactions; SC , subcutaneous injection; SJIA , systemic JIA; T1/2 , half-life; UC , ulcerative colitis.


For some biologics, interpretation of safety data is difficult due to the randomized withdrawal study design that results in subjects in both arms of the studies being exposed to the agent with no suitable comparator group of nonexposed subjects. There are concerns that targeting the immune system may result in an increase in serious infections, malignancies, and autoimmune disease, in addition to complications of HACAs and HAHAs. A recent review showed different frequencies of these complications for various biologics and small molecules used in the treatment of juvenile idiopathic arthritis (JIA) ( Table 13-3 ).



TABLE 13-3

Rates of Serious Infections Malignancies, Autoimmune Diseases, Antibiologic Antibodies Per 100 Patient-Years Exposed to Biologics in JIA












































































SERIOUS INFECTIONS MALIGNANCIES AUTOIMMUNE DISEASES ANTI-BIOLOGIC ANTIBODIES
Normal children 1.0 .032 .0069 new-onset uveitis
.0083 IBD
.00015 optic neuritis
.0001 MS
JIA without MTX, steroids, or anti-TNF 2.2 .025 2.5 new-onset uveitis
JIA with MTX 3.3 .033-0.046 .83 uveitis
JIA with steroids 6.9 ND ND
Abatacept 1.3 ND .22 uveitis flare
.22 MS
23 no AEs
Adalimumab 2.9 ND 0 7.6 with MTX within 1 year
25.3 without MTX within 1 year
Anakinra 8.7 ND ND 75.0 nonneutralizing within 1 year
81.8 after 1 year
6.3 neutralizing within 1 year
0 neutralizing after 1 year
Etanercept 2.7 0.015 .44 new-onset uveitis
.57 flares of uveitis
.31 new-diagnosis IBD
.15 new-onset SLE
.64 new-diagnosis sarcoid
2.9 nonneutralizing
Infliximab 1.0 ND 5.1 new-onset uveitis
25.9 new ANA ≥1 : 320 no symptoms
6.6 new anti-dsDNA no symptoms
36.6 positive
32.4 inconclusive
Infusion reaction related
Rituximab 14.5 ND ND ND
Tocilizumab 11.6 ND ND 7.1
1 anaphylactoid reaction

Adapted from J.F. Swart, S. de Roock, N.M. Wulffraat, Arthritis Res. Ther. 15 (2013) 213.


Clinical trials powered for efficacy are underpowered to determine whether rare, serious, or adverse events are associated with treatment (e.g., malignancy, serious infections, autoimmune diseases), and thus safety data are difficult to interpret. Large, long-term, multicenter disease-specific registries are more likely to find a significant association of these events with treatment.


The safety, immunogenicity, and effects of vaccines on the underlying rheumatic disease is of great concern in patients on biologic therapy. The 2011 European League Against Rheumatism (EULAR) recommendations state that nonlive vaccines are safe and can be administered to patients on corticosteroids and/or biologic therapy; however, responses may be somewhat lower than in normal children. Live-attenuated vaccines generally have a good safety profile in children with rheumatic diseases who are on biologic therapy, especially with booster doses. It is recommended that an individual without a history of varicella zoster virus infection or vaccination be assessed before the initiation of immunosuppressive therapy and, if possible, vaccination before initiation of therapy be performed when required. In considering the use of biologics, one should weigh the risk of the wild-type infection against the possible side effects of vaccination and the risk of disease flare should treatment be withheld for a period after vaccination. In a study of attenuated measles-mumps-rubella (MMR) boosters in 137 patients, antibody titers were similar in the 15 patients on biologic therapies and the rest of the cohort, and there were no effects on disease activity.




Intravenous Immunoglobulin


Intravenous immunoglobulin (IVIG) is prepared from pooled human plasma. More than 75% of IVIG in the United States is administered to patients with autoimmune or inflammatory conditions. The doses used in inflammatory conditions are many-fold higher than the doses used for replacement therapy in immunodeficient patients, usually 2 g/kg (total dose) administered over a period of 1 to 5 days. Upon intravenous administration, IgG enters the vascular compartment at high concentration, redistributes rapidly into tissue compartments (the α phase involving rapid lysosomal degradation due to saturation of neonatal Fc receptors), and then is slowly catabolized (the β phase when the neonatal Fc receptors are not saturated and IVIG is recycled back to the surface of the cell).


IVIG is relatively safe, but anaphylactoid reactions, thromboembolic events, renal complications including osmotic nephrosis and renal failure, hemolysis, and acute meningeal inflammation do occur. Ideally, IgA deficiency should be excluded before administration because of the associated presence of anti-IgA antibodies, but this is not routine practice. Anaphylactoid, thromboembolic, hemolytic, and meningeal (aseptic meningitis) events can be minimized by slower infusion or changing preparations; renal complications can be minimized by better hydration and use of sugar-free stabilizers. Current preparation protocols purify the product so that it is not contaminated with human immunodeficiency virus (HIV), hepatitis C virus, and other known viruses. However, there is always a risk of transmission of as-yet unidentified pathogens. Guidelines for IVIG administration are listed in Table 13-4 . The mechanisms whereby IVIG exerts its therapeutic effects are not clear and may differ in each disease state. IVIG has many effects beyond antibody replacement. Potential mechanisms are listed in Table 13-5 .



TABLE 13-4

Guidelines for Use of Intravenous Immunoglobulin











Dose



  • Up to 2 g/kg (max 75 g)



  • Preparation



  • Start IV with normal saline



  • Administration



  • Give IVIG at rate of 0.5 mL/hr for 30 min, then 1.0 mL/kg/hr for 30 min, then 2.0 mL/kg/hr for the remainder

Clinical Monitoring



  • Blood pressure and pulse rate every 15 min for first hour, every 30 min for second hour, every 60 min thereafter



  • Observe



  • Sudden fall in blood pressure (anaphylaxis)



  • Headache, vomiting 18-36 hours after infusion (aseptic meningitis)



TABLE 13-5

Antiinflammatory and Immunomodulatory Activities of IVIG











Fab Mediated Activities



  • Suppression or neutralization of autoantibodies



  • Suppression or neutralization of cytokines



  • Neutralization of activated complement components



  • Restoration of idiotypic, antiidiotypic networks



  • Blockade of leukocyte adhesion molecule binding



  • Targeting of specific immune cell-surface receptors



  • Modulation of maturation and function of dendritic cells

Fc-Dependent Activities



  • Blockade of the FcRn



  • Blockade of activating FcγR



  • Upregulation of inhibitory FcγRRIIB



  • Immunomodulation by sialylated IgG





Inhibition of the Costimulatory Pathway


CTLA-4Ig (Abatacept).


In order to activate resting T cells, two molecular signals are required: (1) the interaction of the T-cell receptor (TCR) with processed peptide, presented in the appropriate major histocompatibility complex (MHC) setting; and (2) interaction of CD28 on T cells with CD80/86 on the surface of the antigen-presenting cell. Another high-affinity receptor, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), can also bind to CD80/86 with a higher avidity than CD28, thereby preventing the second signal required for T-cell activation. Abatacept is a fully human, soluble fusion protein comprising the extracellular domain of CTLA-4 and the Fc component of IgG1, which selectively inhibits the costimulatory signal necessary for full T-cell activation ( Fig. 13-1 ). By binding to CD80/86, it can prevent T-cell activation. In an international, multicenter prospective study of 190 subjects with polyarticular course JIA using a randomized, double-blind, placebo-controlled withdrawal design, adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients ( P = 0.47). Abatacept was well tolerated in this trial, and there were no serious adverse events. Abatacept is approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in polyarticular course JIA in children age 6 or older. Time to response can be as long as 6 months. In the open-label extension of this study, there were 1.33 serious infections per 100 patient-years among 153 patients. Five patients developed six infections, including dengue fever, erysipelas, gastroenteritis, herpes zoster, bacterial meningitis, and pyelonephritis. Guidelines for abatacept’s use in children are shown in Table 13-6 .




FIGURE 13-1


Biologic therapies currently used in JIA and uveitis. A, Mechanism of action of abatacept. Abatacept binds the CD80 and CD86 family of B proteins on antigen-presenting cells, thereby preventing the costimulatory signaling needed to activate T cells via CD28. B, Structure of the three anti-TNF biologics used in the treatment of JIA and uveitis. Adalimumab and infliximab are both anti-TNF monoclonal antibodies but differ in that infliximab is a chimeric antibody whose antigen-binding region uses a mouse component. Etanercept is a fusion protein containing a human FcIgG1 linked with a TNF receptor. C, Mechanism of action of etanercept. TNF exerts its action on immunoinflammatory cells by binding to cell-bound TNF receptors, resulting in cell activation. Etanercept binds circulating TNF-α, thus preventing cellular binding and cell activation. D, Mechanism of action of anakinra. Anakinra binds to the IL-1 receptor and thereby prevents binding of the IL-1 receptor accessory protein (IL-1R-AcP) and subsequent cell signaling. E, Mechanism of action of tocilizumab. Tocilizumab is a genetically engineered, humanized, mAb to the IL-6 receptor that is produced by grafting the complementarity-determining region of mouse antihuman IL-6 receptor antibody to human IgG1. Tocilizumab competes with both the soluble and the membrane-bound IL-6 receptor preventing cell signaling.


TABLE 13-6

Guidelines for the Use of Abatacept in the Treatment of JIA















Dose



  • <75 kg: 10 mg/kg intravenously over 30 minutes on weeks 0, 2, 4 then every 4 weeks



  • >75 kg: 750 mg intravenously over 30 minutes on weeks 0, 2, 4, then every 4 weeks

Clinical Monitoring



  • Document absence of latent or active tuberculosis before starting



  • Improvement should be seen by the third to fourth dose, but may be delayed



  • Monitor every 1-2 months initially, then every 3-6 months, depending on course



  • Hold if suspected bacterial infection, varicella

Laboratory Monitoring
CBC with WBCC, differential, and platelet count; AST, ALT, albumin every 4-12 weeks


Subcutaneous dosing of abatacept has been approved by the FDA for rheumatoid arthritis (RA), and studies are under way in JIA. Overall immunogenicity to abatacept is low. Interruption and reintroduction did not affect the safety or efficacy of the drug. The incidence of autoimmune disorders was similar in patients with RA treated intravenously and subcutaneously. In a meta-analysis, abatacept-treated subjects had more serious infections than patients receiving placebo. In adults with hepatitis B no reactivation occurred if they were on antiviral therapy. Reactivation did occur in patients not treated with antiviral therapy.




B-Cell Targeted


Rituximab.


Rituximab is a chimeric mouse–human monoclonal antibody that binds to the B-cell CD20 receptor, which is present on pre-B and mature B cells but not on stem cells or plasma cells. It was developed initially for the treatment of relapsed Hodgkin’s B-cell lymphoma. Rituximab exerts its effect by removing CD20 + B cells from the circulation, both by antibody-dependent and complement-dependent cellular cytotoxicity, and by the induction of apoptosis of B cells. Although the antibody-producing plasma cells are not removed from the circulation, B cells that may act as antigen-presenting cells, produce cytokines, and infiltrate tissues are removed for a prolonged period. Memory B cells, which are also responsible for antibody production, may be removed as well.


Rituximab is theoretically beneficial in diseases in which autoantibodies may be pathogenic. It was first used in patients with idiopathic thrombocytopenic purpura and more recently in a variety of other autoimmune diseases. In lymphoma, a dose of 375 mg/m 2 administered weekly for four infusions dramatically reduces B cells for a period of 6 to 9 months. This regimen was also used in treatment of antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitis. Alternative dosing in RA is 1000 mg intravenously in divided two doses, 2 weeks apart. Studies in ANCA-associated vasculitis have shown it to be as effective as cyclophosphamide for remission induction and perhaps better for treatment of disease flares. Rituximab induced a profound depletion of all peripheral blood B-cell populations in patients with RA. Repopulation occurred mainly with naïve mature and immature B cells. Patients whose RA relapsed upon the return of B cells tended to show repopulation with higher numbers of memory B cells.


Recommendations for rituximab’s use in children are shown in Table 13-7 and are based primarily on adult data, as there is only limited information about the use of rituximab in children. Binstadt and colleagues reported four children with multisystem autoimmune illnesses who received rituximab after the failure of multiple other agents, noting improvement in their neurologic manifestations. Nadirs of IgG levels were seen at 4 to 6 months, and three of the patients required immunoglobulin replacement therapy. Leandro and associates reported improvement in five of six patients with systemic lupus erythematosus (SLE) treated with a combination of two rituximab infusions of 500 mg, two infusions of cyclophosphamide at 750 mg, and high-dose oral corticosteroids. Eleven girls with severe SLE, including eight with class IV or class V lupus nephritis, two with severe autoimmune cytopenia, and one with antiprothrombin antibody with severe hemorrhage, were treated with 2 to 12 intravenous infusions of rituximab (350-450 mg/m 2 /infusion) and with corticosteroids. Depletion of B cells paralleled remission in seven of eight patients. Severe adverse events were seen, including two patients with septicemia and four with severe hematologic toxicity. The authors concluded that rituximab was effective but noted the incidence of severe adverse events. Treatment with rituximab was reported in 18 patients with lupus who showed improvement in double-stranded DNA antibodies, renal function, and proteinuria, but some patients required repeated courses, and one died of endocarditis. In a study of nine children with SLE manifesting as autoimmune cytopenias, rituximab resulted in complete B-cell depletion, which was seen in all the children in the study. No serious infections occurred, but one patient had an infusion reaction. In another study of 19 patients, 5 developed herpes zoster infections.



TABLE 13-7

Guidelines for Use of Rituximab















Dose



  • 500 mg/m 2 (maximum 1000 mg) intravenously on weeks 0, 2; or 375 mg/m 2 weekly for 4 doses at 50 mg/hr initially



  • If no infusion reaction occurs, escalate dose at 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If the first infusion was tolerated well, subsequent infusions can be give over a shorter period of time with an initial rate of 100 mg/hr and every 100 mg/hr increments every 30 minutes.



  • Premedicate with methylprednisolone 100 mg intravenously 30 minutes prior to infusion



  • Observe for infusion during therapy. Discontinue and treat with corticosteroids and antihistamines if infusion reaction occurs

Clinical Monitoring



  • Improvement should be seen within a month of initial infusion



  • Monitor every 1-2 months initially, then every 3 months, depending on course

Laboratory Monitoring



  • Screen for hepatitis B virus



  • Check B-cell numbers before and 1 month after infusion



  • Quantitative immunoglobulins every 3 months



  • Follow liver transaminases



In a study of 125 adult and pediatric patients with anti- N -methyl- d -aspartate (NMDA) receptor encephalitis unresponsive to first-line therapy, one anaphylactic reaction and one infection were attributed to rituximab treatment.


Side effects include flushing and itching, usually with the first dose. These manifestations are probably allergic in nature and may be alleviated with pretreatment with an antihistamine and corticosteroids. Infusion reactions, including severe mucocutaneous reactions, are most common with the first infusion. Pretreatment with cortico­steroids reduces the incidence and severity. Prolonged reduction of immunoglobulin levels is more common and significant in children than in adults and may require immunoglobulin replacement therapy, especially in patients who have developed serious infection or who are on other immunosuppressive therapy such as cyclophosphamide, mycophenolate, or azathioprine. Reduced baseline immunoglobulin levels may be associated with increased susceptibility to infection. HACAs may develop in one third of patients after treatment and are associated with lower serum levels of rituximab at 2 months, and less effective B-cell depletion. Rituximab is contraindicated in patients with hepatitis B, as reactivation has occurred, resulting in fulminant hepatitis, hepatic failure, and death; thus all patients must be screened for hepatitis B virus prior to treatment. In occult infection with hepatitis B, serum transaminases should be monitored. Rituximab should not be given in the presence of a severe or opportunistic infection. B-cell numbers can be used to time repeated courses of therapy in some diseases.


Patients must be observed closely for development of viral infections, because post-rituximab infections with parvovirus, varicella-zoster virus, cytomegalovirus, and enterovirus have been reported. Serious infections were seen at a rate of 14.5 per 100 patient-years in 55 children with JIA, 46 of whom had systemic juvenile idiopathic arthritis (SJIA). Pneumonias were caused by Pneumocystis jirovecii, but the patients were on multiple concomitant medications, including methotrexate, corticosteroids, and cyclosporine, all of which could have contributed to susceptibility to this organism.


A systematic review identified 52 patients with underlying lymphoproliferative disorders who developed progressive multifocal leukoencephalopathy (PML) after treatment with rituximab and other agents (two patients with SLE, one patient with RA, one patient with idiopathic autoimmune pancytopenia, and one with immune thrombocytopenia). Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and one patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from the last rituximab dose to PML diagnosis was 5.5 months. Four patients with RA treated with rituximab developed PML. Although PML is a rare adverse event associated with rituximab therapy, its devastating nature mandates continued vigilance, particularly in patients with current or prior exposure to an alkylating agent. Baselines screening for JC virus is not required. These data tend to implicate the other treatments as the cause of PML rather than rituximab alone, but further study is necessary. There are insufficient data to require tuberculosis screening, but physicians should be vigilant.


Belimumab.


Belimumab is a human IgG1 neutralizing monoclonal antibody against B-lymphocyte stimulating factor (also known as B-lymphocyte stimulator [BLyS]). BLyS, a member of the tumor necrosis factor (TNF) ligand superfamily, is synthesized as a 285-amino acid type II membrane protein and exists in both membrane and cleaved 152-amino acid soluble forms. Expressed on monocytes, macrophages, and monocyte-derived dendritic cells, BLyS is upregulated in response to interferon (IFN)-γ and interleukin (IL)-10, enhancing B-cell proliferation and immunoglobulin secretion. Belimumab binds with high affinity to BLyS and inhibits binding of BLyS to its three receptors, inhibiting BLyS-induced proliferation of B cells and decreasing survival of autoreactive B cells, which are particularly dependent on soluble BLyS. Treatment results in decreasing serum anti-double-stranded DNA antibody levels.


Safety data from 1458 adult SLE patients from one phase II study and two phase III studies were analyzed. Serious adverse events included infections, hypersensitivity reactions, anaphylaxis, and infusion reactions. Serious cases of pyrexia and anemia occurred more frequently in the highest dosage (10 mg/kg) than in the placebo group (approximately 1%). The number of adverse events was similar across the groups on three dosing regimens of belimumab and placebo (between 13% and 20%). Most infusion reactions occurred during the first two infusions and consisted of headache, nausea, pruritus, and rash; these were not dose related. Serious and/or severe hypersensitivity reactions were reported in four patients receiving belimumab. None had anti-belimumab antibodies. Patients should be observed for at least 1 hour after each infusion, particularly early in the course; however, some reactions were seen 3-5 hours after infusion. Three malignancies occurred in the placebo group and three in the 10 mg/kg group. Belimumab has been given continuously for more than 5 years in a minority of patients. A trial in childhood lupus is under way. Recommendations for the use of belimumab are shown in Table 13-8 .



TABLE 13-8

Guidelines for Use of Belimumab in the Treatment of Systemic Lupus Erythematosus











Dose



  • 10 mg/kg via intravenous infusion via intravenous infusion over 1 hour at 2-week intervals for the first 3 doses, then at 4 week intervals thereafter.



  • Vital signs once at 15 minutes and then at 45 minutes

Laboratory Monitoring
Monitor for leukopenia and elevated transaminases with each infusion




Interference with cytokines


TNF inhibitors


The biologic effects of T cell–derived and monocyte-derived cytokines can explain much of the clinical syndrome of synovitis as well as the systemic manifestations associated with JIA. Cytokines are critical in perpetuating and damping the immune response, and as such they are important targets for therapeutic manipulation. TNF inhibitors have now been proven to be effective in the treatment of a number inflammatory conditions, including polyarticular course JIA, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease ( Table 13-2 ).


Anti-TNF agents currently in use or under study in children are etanercept, infliximab, adalimumab, golimumab, and certolizumab ( Table 13-2 ).


Etanercept


Etanercept is a fully human, dimeric protein containing the extracellular domain of the human p75 TNF receptor fused to the Fc region of human IgG1. By binding to trimers of TNF-α in the circulation, etanercept prevents the interaction of TNF-α with its cell surface receptor, thereby preventing cell activation and perpetuation of the inflammatory cascade. It can also modulate biologic responses that are mediated by TNF, such as expression of adhesion molecules, serum concentration of matrix metalloproteinases (MMPs), and cytokines. Although soluble forms of the TNF-α receptor occur naturally, they are generally inadequate to block TNF activity in systemic inflammatory disorders. The dimeric form of the TNF-α receptor is much more efficient at binding TNF because it binds at a much greater affinity (50 to 1000 times higher) than that of the naturally occurring form. Etanercept also binds lymphotoxin (formerly called TNF-β). The role of lymphotoxin in the pathogenesis of arthritis is not as well understood as that of TNF-α. The half-life of etanercept, administered subcutaneously, is approximately 4 days. Etanercept was initially given twice weekly but is as effective using the same total dose once a week. In adults with RA, steady-state concentrations are achieved in about 2 weeks. Etanercept has been used extensively in children with JIA since the initial report of its effectiveness in 2000. It is currently indicated for children age 2 and above for polyarticular JIA in both North America and Europe. In Europe it is also approved for use in children ages 12-17 with psoriatic arthritis or enthesitis-related arthritis. A study of nearly 600 subjects demonstrated its relative safety over 3 years. Long-term continuous treatment up to 10 years appears to be safe with little evidence of tachyphylaxis. Guidelines for the use of etanercept are shown in Table 13-9 .



TABLE 13-9

Guidelines for Use of Etanercept in the Treatment of Juvenile Idiopathic Arthritis















Dose



  • 0.4 mg/kg twice weekly or 0.8 mg/kg per week subcutaneously



  • Max 50 mg/week

Clinical Monitoring



  • Document absence of latent or active tuberculosis before starting



  • Improvement should be seen by the third or fourth dose



  • Monitor every 1-2 months initially, then every 3-6 months, depending on course



  • Hold if suspected bacterial infection, varicella

Laboratory Monitoring
CBC with WBCC, differential and platelet count; AST, ALT, albumin every 4-12 weeks


To date, etanercept has been very well tolerated. The placebo-controlled study showed an increase in symptoms of upper respiratory tract infection as well as injection site reactions, although these were generally mild. Injection site reactions may be treated with topical corticosteroids. However, postmarketing studies have reported a variety of unusual side effects; most importantly, systemic infection must be closely watched for. This includes bacterial infection, viral infection such as varicella with or without superimposed bacterial infection, and granulomatous infection. Although these infections are more common in elderly patients, physicians must be attuned to their development in any age group. Two patients in the pivotal trial developed aseptic meningitis secondary to varicella zoster, prompting the recommendation that JIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to starting etanercept. Patients with a significant exposure to varicella virus should temporarily discontinue etanercept and be considered for prophylaxis with varicella zoster immune globulin. Live virus vaccination is contraindicated, but concurrent methotrexate and etanercept did not appear to decrease the rate of seroconversion to MMR vaccination.


A variety of other side effects have been noted. Although rare enough to be the subject of case reports, there may be an association between treatment with etanercept and the development of vasculitic skin rash, and systemic or drug-induced lupus. The associations with pancytopenia and aplastic anemia are less clear. Several cases of diabetes mellitus after etanercept treatment have been reported in children with JIA. Patients experiencing changes in mood, weight gain, autoimmune hepatitis, thymic enlargement, sterile cholecystitis, tuberculous uveitis, and macrophage activation syndrome while being treated with etanercept have been reported.


Infliximab


Infliximab is a chimeric anti–TNF-α antibody consisting of a mouse Fab′ fragment antibody and the constant region of the human IgG1. In contradistinction to Cepts such as etanercept, monomers of infliximab bind not only to monomers of soluble TNF-α but also to membrane-bound TNF-α, leading to both antibody-dependent and complement-dependent cytotoxicity. It seems to be more efficacious than etanercept in granulomatous inflammatory disorders (e.g., sarcoidosis) and uveitis but also seems to be associated with the development of granulomatous opportunistic infections. Administration of infliximab is through the intravenous route ( Table 13-10 ). Dose and frequency vary somewhat with the clinical response. Initial doses in adults usually start at 3 mg/kg and are given at time 0, at 2 weeks, at 6 weeks, and then every 8 weeks depending on clinical response. Starting doses in children should be 6 mg/kg routinely (see the next paragraph). Doses often require escalation, and doses up to 20 mg/kg have been used occasionally in children. Alternatively, the length of time between infusions can be shortened. Administration with methotrexate (MTX) is recommended to prevent the development of anti-infliximab antibodies, which seem to correlate with infusion reactions and accelerated clearance of infliximab. It is not certain, however, that these antibodies actually reduce the effectiveness. Similar to etanercept, combination treatment with MTX seems to improve the response to infliximab in patients with RA.



TABLE 13-10

Guidelines for Use of Infliximab in the Treatment of Juvenile Idiopathic Arthritis















Dose



  • 6-10 mg/kg /infusion over approximately 2 hours on weeks 0, 2, and 6, then every 4-8 weeks thereafter, depending on course; dose may be increased up to 10 mg/kg



  • Start at 10 cc/hour for 15 minutes, double rate every 15 minutes until 160 cc/hour for 30 minutes, then 250 cc/hour until finished



  • Usually given with methotrexate



  • Consider premedication with diphenhydramine, acetaminophen

Clinical Monitoring



  • Document absence of latent or active tuberculosis before starting



  • Improvement should be seen by the third or fourth dose



  • Monitor every 1-2 months initially, then every 3-6 months, depending on course



  • Hold if suspected bacterial infection, varicella

Laboratory Monitoring
CBC with WBCC, differential and platelet count; AST, ALT, albumin every 4-12 weeks.


Ruperto et al. reported the results of a randomized, double-blind, placebo-controlled trial of infliximab in patients with polyarticular-course JIA. The clearance of the drug was more rapid in children with juvenile rheumatoid arthritis (JRA) than was observed in adults with RA, resulting in lower trough levels before the next dose. Infliximab was generally well tolerated, but the safety profile of infliximab at a dose of 3 mg/kg appeared less favorable than that of infliximab at a dose of 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double-stranded DNA observed with the 3 mg/kg dose, perhaps related to the lower trough levels in the 3-mg/kg group.


Treatment with infliximab resulted in reduced serum concentrations of interleukin (IL)-6, myeloperoxidase, and soluble adhesion molecules ICAM-1, and E-selectin. TNF-α levels tended to increase while the concentrations of endogenous TNF antagonists (sTNF-RI and sTNF-RII) were reduced.


Infection remains the major concern with the use of infliximab. Many more cases of tuberculosis have been reported in patients treated with infliximab than in those treated with etanercept, probably because of the destabilization of previously formed granulomata. Other infections that have occurred with greater than expected frequency include histoplasmosis, coccidioidomycosis, and listeriosis. One case of optic neuritis has been reported in a child. IgA and IgM anti-double-stranded DNA antibodies can occur with infliximab therapy, but only 1 of 156 patients with these antibodies developed lupus. In addition to the side effects noted with etanercept, infusion reactions ranging from mild allergic reactions to anaphylactic reactions may occur, more commonly on the second or third infusions. Therefore, infliximab must be administered under close observation. See Table 13-10 for guidelines regarding administration.


Adalimumab


Adalimumab is a recombinant human IgG1 mAb that acts in a similar fashion to infliximab and golimumab by binding to the TNF both in the circulation and on the cell surface. Therefore, it may result in cell lysis in the presence of complement. Adalimumab, but not etanercept, has been shown to induce immunosuppressive T reg cells. It is administered subcutaneously with a half-life of approximately 2 weeks. Initial recommended dosing in children was 24 mg/m 2 every second week. In North America the tendency is to administer 20 mg every second week for patients weighing less than 30 kg, and 40 mg every second week for patients weighing more than 30 kg. As with other anti-TNF agents, the effects are seen quickly, but the dose may need to be given once a week for sustained improvement. Injection site reactions can be problematic. Some practitioners add lidocaine into the syringe. The combination of adalimumab and MTX is safe and results in increased efficacy in RA.


A pivotal study resulted in FDA approval for the use of adalimumab for polyarticular JIA. ( Table 13-11 ). Serious adverse events possibly related to adalimumab occurred in 14 patients; 7 of these patients had serious infections (bronchopneumonia, herpes simplex virus infection, pharyngitis, pneumonia, viral infection, and 2 cases of herpes zoster). Twelve patients discontinued treatment because of adverse events. No deaths, malignant conditions, opportunistic infections, tuberculosis, demyelinating diseases or lupuslike reactions occurred. Sixteen percent of patients (6% on MTX; 26% not on MTX) had at least one positive test for anti-adalimumab antibodies. Development of anti-adalimumab antibodies did not affect the incidence of serious adverse events.



TABLE 13-11

Guidelines for Use of Adalimumab in the Treatment of Juvenile Idiopathic Arthritis















Dose



  • 15-30 kg: 20 mg subcutaneously every second week



  • >30 kg: 40 mg subcutaneously every second week



  • Can be given with or without methotrexate

Clinical Monitoring



  • Document absence of latent or active tuberculosis before starting



  • Improvement should be seen by the second or third dose



  • Monitor every 1-2 months initially, then every 3-6 months depending on course



  • Hold if suspected bacterial infection, varicella exposure or infection, hepatitis B infection

Laboratory Monitoring
CBC with WBC count, differential and platelet count, AST, ALT, albumin every 4-12 weeks


Golimumab


Golimumab is a recombinant human IgG monoclonal antibody to TNF-α. The constant regions of the heavy and light chains of this monoclonal antibody are identical in amino acid sequence to the corresponding constant regions of the human–mouse chimeric mAb infliximab. However, in contrast to infliximab, the heavy and light variable regions are of human sequence. The recommended dosage is 50 mg subcutaneously once a month in combination with MTX. The FDA approved golimumab in 2009 for the treatment of moderately to severely active adult RA, psoriatic arthritis, and ankylosing spondylitis. In the pivotal trial, one patient died after developing nausea, diarrhea, ileus, aspiration pneumonia, and sepsis. The most frequent adverse events were infection and injection site reaction. Antinuclear antibodies may occur, and their development may correlate with higher doses of golimumab or the absence of MTX. Antibodies to golimumab were observed in 2.1% of the subjects and were not significantly associated with decreased efficacy or injection site reaction. Pediatric studies are under way, but there are no published pediatric data to date.


Certolizumab


Certolizumab pegol is a pegylated (i.e., conjugated with polyethylene glycol) humanized Fab′ fragment of a monoclonal antibody that binds TNF-α. Pegylation increases its half-life. As opposed to infliximab, adalimumab, and golimumab—which are full-length bivalent IgG mAbs—certolizumab is a monovalent Fab antibody fragment. It has a higher affinity for TNF-α, is devoid of the Fc portion of the antibody, and does not induce complement activation, antibody-dependent cellular cytotoxicity, or apoptosis. Its efficacy and safety in active RA have now been assessed in three phase III, multicenter, randomized, double-blind, placebo-controlled clinical trials. In the most recent study of 619 subjects, certolizumab pegol plus MTX were more efficacious than placebo plus MTX, rapidly and significantly improving signs, symptoms, and physical function in patients with RA, and inhibiting radiographic progression. The dose was 200 mg or 400 mg subcutaneously every 2 weeks. Five patients developed tuberculosis. Pediatric studies are under way.


Common issues with anti-TNF agents


With the increasing use of anti-TNF agents, a number of common concerns have arisen, one of which is the increased risk of infection, particularly tuberculosis; fungal infections, including histoplasmosis; and other opportunistic infections. Children with JIA had a higher rate of opportunistic infections, including an increased rate of coccidioidomycosis, salmonellosis, and herpes zoster. Among children with JIA, the rate of infection was not increased with MTX or TNF-inhibitor use but was significantly increased with high doses of corticosteroids. In general, before starting treatment with any of these agents, the following approach is recommended: patients should be screened for the presence of latent tuberculosis with a tuberculosis skin test or a blood-based diagnostic assay (e.g., Quantiferon-Gold). The latter may have higher specificity particularly in patients who have had bacillus Calmette-Guérin (BCG) vaccination. A chest radiograph is probably unnecessary unless the purified protein derivative (PPD) result is positive. If the skin test or blood-based assay is positive, thorough investigation of the patient and family for active tuberculosis must be undertaken, and the patient must be treated accordingly. If the investigations prove negative, the patient should be given isoniazid (INH). Treatment with anti-TNF agents may be initiated 1 month after starting INH, although some give INH simultaneously with TNF-inhibitor therapy. The FDA advises close monitoring of patients for signs and symptoms of potential fungal infection, especially in endemic areas, both during and after treatment with anti-TNF drugs. Patients in whom fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates on chest radiographs, or serious systemic illness develop should undergo a complete diagnostic workup appropriate for immunocompromised patients. The decision to initiate empiric antifungal therapy in at-risk symptomatic patients should be made in conjunction with an infectious diseases specialist, taking into account both the risk for severe infection and the risks of antifungal therapy. TNF inhibitors should be withheld for serious infection or sepsis. Anti-TNF treatment should not be used in patients with active infection and should be discontinued in the case of a serious infection. Mild upper respiratory tract or urinary tract infections are not a reason to stop anti-TNF agents. Patients with hepatitis B who were treated with a TNF inhibitor had worsening symptoms, viral load, or hepatic function, and although hepatitis B reactivation has been added to the label, concomitant antiviral treatment can be given.


Concern remains regarding the development of malignancy, particularly lymphoma. Patients must be observed closely for the occurrence of malignancies. However, any association is difficult to decipher because of the known increased incidence of malignancy in patients with rheumatoid arthritis. Aggressive and fatal hepatosplenic T-cell lymphomas, a rare malignancy, have been reported in patients receiving TNF blockers. Most cases occurred in patients getting infliximab for Crohn’s disease or ulcerative colitis who had received concomitant treatment with azathioprine or 6-mercaptopurine; the majority involved adolescent boys and young adult men.


In information obtained from manufacturers of TNF inhibitors approved for use in children (etanercept, infliximab, adalimumab), 48 cases of malignancies in children and adolescents were identified. It was estimated that 14,837 children received infliximab, 9200 received etanercept, and 2636 received adalimumab during the studied period. Approximately half of the malignancies were lymphomas. Others included leukemia, melanoma, and solid organ cancers. Eleven of the patients died (nine from hepatosplenic T-cell lymphoma, and one from T-cell lymphoma). The rates of malignancy were higher with infliximab than expected rates, but the primary use of infliximab was for inflammatory bowel disease in contrast to etanercept, where patients with JIA represented the majority. Eighty-eight percent of cases were in patients taking other immunosuppressive medications such as azathioprine, 6-mercaptopurine, or contradistinction MTX. It was concluded that there is an increased risk of malignancy with TNF-inhibitor exposure, but that the strength of the association, or a definite causal relationship could not be assigned. Some major problems with these conclusions were that the precise denominator for users was not known, and treated patients were not compared to a control group of JIA patients not treated with biologics. Bernatsky et al., using data from three Canadian centers, did not find an increased incidence of malignancy in patients with JIA. In contrast, Simard et al., using comprehensive administrative data from Sweden, showed that the incidence of malignancy in patients with JIA had increased in the years 1987 to 1999 (before the use of biologics) compared to the preceding two decades. Using national Medicaid data from 2000 through 2005, Beukelman et al. showed that children with JIA in the United States appeared to have an increased incidence of malignancy compared with children without JIA and that the treatment for JIA, including TNF inhibitors, did not appear to be significantly associated with the development of malignancy. Similar data were reported by Nordstrom et al. Thus the role of anti-TNF agents in increasing the risk of malignancy in patients with JIA is not yet clear. A meta-analysis in adults concluded that etanercept is safer than anakinra, adalimumab, or infliximab.


The safety of anti-TNF therapy during pregnancy is unknown, and it is classified as a category B medication, meaning that there is no evidence of risk in humans or if human studies have not been done, no evidence in animals that show risk. Many reports have documented lack of teratogenicity with healthy pregnancy outcomes. Similarly, breast-feeding appears to be safe. Consideration should be given to avoiding live viral vaccines for 6 months in children who have been exposed to biologic therapy during pregnancy.


Similar concerns exist for the development of demyelinating syndromes, especially multiple sclerosis, with anti-TNF therapy. Early postmarketing studies suggested that demyelinating syndromes, including multiple sclerosis, might be more common in patients treated with etanercept. In a trial of lenercept, another TNF antagonist, used to treat patients with multiple sclerosis, those taking the active drug had more exacerbations than those who did not. Patients with JIA have developed demyelinating syndromes, as have adults with RA. Guillain-Barré syndrome developed in 15 patients identified from the FDA database. In children, four cases of optic neuritis have been reported. On the other hand, large studies have failed to demonstrate an occurrence greater than what would have been expected. Patients with previous demyelinating syndromes should not be treated with TNF antagonists, and those with a strong family history should be observed carefully for the development of symptoms that may be suggestive of demyelination. Performing a baseline central nervous system MRI should be considered in patients with a family history of multiple sclerosis.


TNF antagonist therapy has been rarely associated with SLE-like syndromes and antiphospholipid antibody syndrome. The development of leukocytoclastic vasculitis had been reported in 35 patients; the disease resolved in the majority after discontinuation of anti-TNF therapy. New-onset psoriasis and Crohn disease have been reported.


In trials in patients with congestive heart failure (CHF), neither infliximab nor etanercept was effective, and the drugs may have even worsened the CHF. These agents might exacerbate, or even induce, CHF in patients with no previous risk factors. A meta-analysis in adults with plaque psoriasis found no effect of TNF inhibitors on cardiovascular events. A systematic review showed that TNF inhibition did not lead to significant changes in intima-media thickness, endothelial function, or lipid profiles over 52 weeks.


It does not seem that any specific laboratory monitoring is required routinely for any of these agents. Although the induction of antinuclear antibodies is common (up to approximately 15% of patients), screening for them is necessary only if suspicion of a developing autoimmune disease (e.g., drug-induced lupus) is raised.


As with most safety signals from postmarketing surveillance, it is difficult to know whether or not these cases are related to anti-TNF therapy, concomitant therapy, the underlying diseases, or demographics of the patients being treated, but caution is required when considering offering this therapy to candidate patients. It may not be entirely correct to lump all TNF inhibitors together as their mechanisms, pharmacokinetics, and hosts may differ, particularly with the nonmonoclonal antibody etanercept.


Guidelines developed for adults suggest withholding biologic DMARDs for at least 1 week before and after surgery. No specific recommendations regarding the use of biologic DMARDs during pregnancy or breast-feeding were made because of conflicting evidence.


IL-1 inhibitors


Anakinra.


IL-1 plays a prominent role in RA by stimulating synoviocytes and chondrocytes to produce small inflammatory mediators (e.g., prostaglandins) and matrix metalloproteases (MMPs) that lead to cartilage destruction and bone erosions. IL-1 also increases the expression of receptor-associated NF-κB ligand (RANK ligand), leading to osteoclast differentiation and activation and bone destruction. It exerts its effect by binding to the IL-1 receptor and through cell signaling and production of these various molecules and cytokines. IL-1 receptor antagonist (IL-1Ra), is a naturally occurring, acute phase antiinflammatory protein, part of the IL-1 supergene family. Anakinra is a manufactured IL-1Ra.


IL-1Ra is the most important physiologic regulator of IL-1–induced activity. By binding to the IL-1 receptor on cell surfaces, it prevents the interaction of the receptor with IL-1 and subsequent cell signaling. An imbalance between IL-1 and IL-1Ra can lead to uncontrolled inflammation.


Anakinra is a human recombinant form of IL-1Ra. It has a short half-life of 4 to 6 hours (when given at a dose of 1 to 2 mg/kg in adults with RA ) and requires daily subcutaneous injection. Dramatic responses to anakinra in some cases of systemic JIA and cryopyrin-associated periodic syndrome (CAPS), and the deficiency of the IL-1 receptor antagonist (DIRA) provide the evidence for pediatric use ( Table 13-12 ). These responses also provide evidence that this group of disorders are IL-1 driven and autoinflammatory in nature (see below).


Jun 30, 2019 | Posted by in RHEUMATOLOGY | Comments Off on Pharmacology: Biologics

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