OTHER AUTOIMMUNE DISORDERS

Overview of biologictherapies in autoimmunerheumatic diseasesMaria Mouyis

David Isenberg

AbstractFirst-line treatment of autoimmune rheumatic diseases (ARD) ranging

from systemic lupus erythematosus (SLE), through small and large vessel

vasculitides to Behc‚et’s syndrome, is still based upon the use of tradi-

tional immunosuppressive drugs. Increasingly, the newly developed bio-

logic agents are used as second-line treatments of these diseases. This

summary article highlights the biologic agents that are used in clinical

practice as well as their indications, contraindications and adverse effect

profiles. Efficacy of these biologic agents is tabulated in accordance with

current evidence of open-label studies and trials, and new advances in

the biologic treatment of several ARDs are also discussed. Overall, this

paper highlights the contribution that the biologic therapies have made

to progressive advancements in the treatment of ARD.

Keywords Anti-TNF; autoimmune rheumatic diseases; biologic agents;

efficacy

Background information

Advances in molecular biology have led to a number of new

treatment approaches for autoimmune rheumatic diseases. These

agents, termed biologic therapies, are engineered recombinant

proteins. Most commonly, they are either monoclonal antibodies

or engineered receptor-blocking proteins. Some of themonoclonal

antibodies in clinical use contain sequences of mouse protein

(termed chimeric), whereas others are fully human antibodies.

The theoretical advantage of these agents is that they target

specific cytokines, receptors or cell types thought to be involved in

the pathogenesis of the diseases in question. The major biologic

approaches in clinical use include blocking cytokines (e.g. inflix-

imab) and cytokine receptors (e.g. etanercept), interfering with

T cell co-stimulation (e.g. abetacept), or depleting cell types (e.g.

rituximab) (Table 1).

The place of biologic agents in the management of autoim-

mune rheumatic diseases, such as systemic lupus erythematosus

(SLE) has not yet been fully defined. In this era of cost con-

straints there is a need to demonstrate improved efficacy and/or

a favourable adverse event profile compared with the use of

traditional immunosuppressive agents such as corticosteroids,

cyclophosphamide, azathioprine, mycophenolate mofetil,

Maria Mouyis MBBCh MRCP Centre of Rheumatology, University College

Hospital, London, UK. Conflicts of interest: none.

David Isenberg MD FRCP FAMS is Academic Director of Rheumatology at

University College London, London, UK. Competing interests: none

declared. Conflicts of interest: none.

MEDICINE 42:3 184

methotrexate and others. In many cases, biologic agents are used

alongside traditional immunosuppression, or in cases where

conventional therapy has failed. However, there is no doubt that

these agents provide additional treatment options for our pa-

tients. Table 2 lists the current evidence base for the use of

common biologic agents in autoimmune rheumatic diseases.

The management strategies for individual diseases are dis-

cussed in more detail in the individual disease chapters. Here we

discuss the general advantages and disadvantages of biologic

agents, and we discuss some of the major pathways targeted.

Advantages and disadvantages of biologic agents

Advantages of biologic therapy include effectiveness both in

terms of disease control and financial cost in the long term. They

also do not have to be withdrawn in the pre-pregnancy phase,

unlike methotrexate, or require a washout period, as does

leflunomide. This said, there is inconclusive evidence regarding

the safety of these drugs in pregnancy.

Despite the advantages of anti-tumour necrosis factor (TNF)

therapy, there are some disadvantages including allergic/trans-

fusion reaction, infection, particularly with Mycobacterium tuber-

culosis (which will occur within first 6 months), lymphoma, drug-

induced SLE, new-onset or exacerbation of heart failure, and

demyelination. It is also important to screen patients for hepatitis B

and C infections as reactivation of disease may occur when the

patient is immunosuppressed. This screening is particularly

important as a prelude to anti-TNF therapy because TNF is

important for viral clearance.3 Rituximab has a very similar

adverse effect profile to anti-TNF therapy but the risk of infections

is lower; it may also be used in patients who have had previous

malignancy,whereas anti-TNF therapy is not recommendedunless

the patient has been cancer free for 10 years. A rare but significant

risk of rituximab is the development of JC virus infection, which

causes progressive multifocal leucoencephalopathy.4 An ongoing

problem in both drug classes is the formation of antibodies to the

drugs, such as human anti-chimeric antibodies (HACA; incidence

10%)5 or human antimouse antibodies (HAMA; seen with

etanercept/adalimumab; incidence 5%).6 Concomitant treatment

with methotrexate decreases the appearance of antibodies.7

Targets of biologic agents

Examples of anti-cytokine approaches

TNFa: TNFa is a cytokine that is released by macrophages, mast

cells and T-helper 1 cells. TNFa stimulates macrophages to further

release cytokines and increase phagocytosis. Anti-TNF agents

therefore bind to TNF, neutralizing the pro-inflammatory cytokine

effect.

Interleukin (IL)-1 blockade: The IL-1 family is a group of 11

cytokines that induces a complex network of pro-inflammatory

cytokines and, by means of an expression of integrins on leuko-

cytes and endothelial cells, regulates and initiates inflammatory

responses, notably during the early phases of an immune response.

Blocking IL-1 has clear potential in autoimmune rheumatic

diseases, but in reality hopes that such blockade would provide

a major breakthrough in the treatment of RA have not been sus-

tained. This approach has been more successful in the inherited

‘fever syndromes’, also known as auto-inflammatory conditions.

� 2014 Published by Elsevier Ltd.

An overview of the biologic therapies approved for clinical use, in autoimmune rheumatic diseases1,2

Biologic Target Clinical indication NICE

approved

Contraindications Adverse effects

Etanercept Anti-TNFa human

receptor fusion protein

RA, AS, PSA PSA

AS

Congestive cardiac failure

Demyelinating disease (rare)

Septic arthritis

Pregnancy

Breast feeding

Infection e TB, hepatitis

Malignancy

Live vaccines

Blood dyscrasia

Injection site reaction

Allergic reaction

Infection

Adalimumab Anti-TNFa recombinant

human IgG1 monoclonal

antibody.

RA, AS, PSA PSA

RA

Crohn’s

As above As above

Infliximab Anti-TNFa Chimeric

monoclonal antibody.

RA, PSA, AS,

IBD

PSA

AS

RA

UC/Crohn’s

As above As above

Golimumab Anti-TNFa Human

monoclonal receptor

RA, PSA, AS,

chronic sarcoid,

UC

RA As above Infection

Hypertension

Hypersensitivity reaction

Skin exfoliation

Malignancies

Dizziness

Certolizumab Pegylated TNFa RA

Crohn’s

RA As above URTI

Nausea

Lupus-like syndromes

Malignancy

Hypersensitivity

Skin reactions

Severe infections

Rituximab Anti-CD20 cells RA

SLE

NHL

ANCA vasculitis

RA

Vasculitis

Pregnancy

Breast feeding

Live vaccines

Infusion reaction

Infection

Belimumab Inhibits B-lymphocyte

stimulator (BLyS)

SLE Severe depression

Pregnancy

Infections

Infusion reaction

Hypersensitivity reaction

Pyrexia

Diarrhoea

Infection

Depression

Nausea

Headaches

Abatacept Chimeric protein that

inhibits T lymphocyte

activation

RA RA Active infections

Live vaccines

Anti-TNFa

?Severe COPD

Infection

Hypertension

URTI

Dyspepsia

Lymphoma

Back pain

Anakinra IL-1 receptor antagonist RA

CAPS

Autoimmune

inflammatory

conditions

Gout

RA Thalidomide/lenalidomide

Hypersensitivity to anakinra,

E. coli-derived proteins

Active infection

Concomitant live vaccines

Concomitant TNFa blockers

Infusion reaction

Injection site reaction

Nausea

Diarrhoea

Pyrexia

(continued on next page)

OTHER AUTOIMMUNE DISORDERS

MEDICINE 42:3 185 � 2014 Published by Elsevier Ltd.

Table 1 (continued )

Biologic Target Clinical indication NICE

approved

Contraindications Adverse effects

Tocilizumab Monoclonal

antibody

against IL-6.

RA RA

JIA

Active infections

Live vaccines

Hypersensitivity

Infusion reaction

Infections

Abnormal LFT

Increased triglycerides

Mouth ulcers

Gastritis

Hypertension

Abbreviations: AS, ankylosing spondylitis; CAPS, cryopyrin-associated periodic syndromes; COPD, chronic obstructive pulmonary disease; IBD, inflammatory bowel

disease; JIA, juvenile inflammatory arthritis; LFT, liver function test; NHL, non-Hodgkin’s lymphoma; PSA, psoriatic arthritis; RA, rheumatoid arthritis; SLE, systemic

lupus erythematosus; TB, tuberculosis; UC, ulcerative colitis; URTI, upper respiratory tract infection.

Table 1

OTHER AUTOIMMUNE DISORDERS

IL-6 blockade: IL-6 has many pleotropic effects. First it promotes

B cells to mature into immunoglobulin producing cells, induces

cytotoxic T cells and inhibits TGF-b, which promotes T regula-

tory cells. Second, it stimulates hepatocytes to produce C-reactive

protein and hepcidin, while reducing albumin and transferrin.

Third, it has an effect upon bone, stimulating NF-kB ligand

(RANKL), which is important for the activation of osteoclasts.

The agent responsible for IL-6 blockade is a humanized anti-IL-

6R monoclonal antibody called tocilizumab. By binding to the

IL-6 receptor it prevents the pleotropic effects of IL-6.

Co-stimulation blockade

T cell and B cell communication relies on co-stimulatory mole-

cules, such as CTLA4-Ig and CD40 ligand.

CD 40 ligand is a glycoprotein expressed on stimulated T cells,

mast cells and platelets. It communicates with CD40, which is

found on B cells. CD40L is highly expressed in autoimmune

conditions. Trials have been undertaken to assess anti-CD40L

antibody effects.8 CTLA4 is a co-stimulatory molecule

expressed on activated T cells and binds to receptors of B7

antigen-presenting cells (APC), down-regulating the immune

response. CD 28 molecules are expressed on resting T cells and

bind to B7 APC also, but this interaction results in apoptosis.

CTLA4-Ig (abatacept) blocks the interaction of CD28 on the B cell

receptor, therefore promoting down-regulation of the immune

response.

Efficacy of biologics in various rheumatic conditions

Clinical condition Etanercept Adalimumab Infliximab Ritu

RA þþþ þþþ þþþ þþþAS þþþ þþþ þþ þPSA þþþ þþþ þþþ þþSLE þ þ þ þþANCA vasculitis þþ þþþ

Key: þ case reports; þþ strong open-labelled study; þþþ trial confirmed.

Table 2

MEDICINE 42:3 186

Cell depletion strategies

The most common cell depletion strategy used in autoimmune

rheumatic disease (ARD) is B cell depletion. B cells are precursors

of autoantibody-producing plasma cells in ARD, andmay promote

autoimmunity in other less well-defined ways, including cytokine

production and antigen presentation. CD20 is a protein expressed

on B cells, which are healthy andmalignant. It is involved in B cell

activation and regulation. Rituximab is an anti-CD20 monoclonal,

chimeric antibody, which binds to CD20 of B cells and causes cell

lysis. The mechanism of this process is not entirely clear but may

be due to self apoptosis of the cell, activation of complement

proteins that cause damage to cell membrane, or recognition of

the cell as foreign by macrophages causing cell lysis. Adverse

effects of cell depletion include lymphopenia, reactivation of

hepatitis B, serious infections and infusion reactions.

Experimental therapeutic agents

The future is almost here, as some key advances in the past 2

years suggest. Further novel approaches against biologic targets

include production of fusion proteins as well as Janus kinase

(JAK) and other cytokine inhibitors.

Fusion proteins: atacicept

Atacicept is a TACI-Ig fusion protein that inhibits BLyS and a

proliferation-inducing ligand (APRIL), thereby reducing B cell

ximab Abatacept Tocilizumab Belimumab Golimumab

þþþ þþþ þþþþ

þþ þþþþ þþþ

� 2014 Published by Elsevier Ltd.

OTHER AUTOIMMUNE DISORDERS

proliferation, interferon gamma and immunoglobulin produc-

tion.8 It is a novel agent as it affects both BLyS and APRIL

simultaneously. In a recent study, atacicept 150 mg once weekly

was shown to reduce the rate of flares, over a 1-year period, in

patients with SLE compared to placebo ( p ¼ 0.002).9

Small molecule-signalling inhibitor

Tofacitinib has been developed as a second-line agent for severe

rheumatoid arthritis. It may used as monotherapy or with meth-

otrexate, provided this is tolerated.10 It is a JAK protein inhibitor.

JAK proteins are tyrosine kinases that have an intracellular effect.

They allow an inflammatory response by transmitting signals from

cellular cytokines to the intracellular cell, by promoting signal

transducers and activators of transcription (STATs) that modulate

intracellular activity. Inhibition of JAK therefore decreases signal

transduction and inflammatory response. The adverse effect pro-

file includes infection, lymphopenia, malignancy, and derange-

ment in liver function tests and the serum lipid profile.11

Cytokines: IL-17 inhibitors

Interleukin-23 induces IL-17, which is produced by the gdT-helper

cells. This pro-inflammatory cytokine binds to the IL-17 cell sur-

face receptor, ofwhich there are three types (A, B, and C), and then

promotes chemokine production to promote neutrophils and

monocytes to the area of inflammation. IL-17 inhibitors such a

vidofludimus are being trialled in the treatment of psoriasis and

rheumatoid arthritis and these results may then be extrapolated to

treatment of psoriatic arthritis.12 Ustekinumab is an anti-IL-23

antibody and is being trialled in the treatment of psoriasis.13

Conclusion

The future of biologic drugs in rheumatology is exciting and

rapidly expanding, but what is needed ultimately is an attempt to

pre-define which of these drugs will be beneficial for individual

patients, perhaps using biomarkers to assess susceptibility to

treatment. This is an area that will need further exploration. A

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