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REVIEW
Immune-mediated inflammatory diseases (IMIDs) and biologic
therapy: a medical revolution
Annabel Kuek, Brian L Hazleman, Andrew J K O
¨
sto¨r
...................................................................................................................................
Postgrad Med J 2007;83:251–260. doi: 10.1136/pgmj.2006.052688
Targeted biologic therapies have revolutionised treatment of
immune-mediated inflammatory diseases (IMIDs) due to their
efficacy, speed of onset and tolerability. The discovery that
clinically unrelated conditions, such as rheumatoid arthritis and
Crohn’s disease, share similar immune dysregulation has led to
a shift in the management of IMIDs from one of organ-based
symptom relief to mechanism-based treatment. The fact that
anticytokine therapy has been effective in treating multiple
orphan inflammatory conditions confirms the IMID paradigm. In
this review we examine the biologic agents currently licensed
for use in the US and Europe: infliximab, etanercept,
adalimumab, rituximab, abatacept, anakinra, alefacept and
efalizumab. We also discuss the rationale behind the
management of IMIDs using rheumatoid arthritis, Crohn’s
disease, psoriasis and psoriatic arthritis as examples. For the
medical profession, IMID represents a breakthrough in the way
pathology is classified. In this burgeoning era of biologic
therapy the prospect of complete disease remission is
conceivable.
.............................................................................
See end of article for
authors’ affiliations
........................
Correspondence to:
Dr A J K O
¨
sto¨r,
Rheumatology Research
Unit, Box 194, E6,
Addenbrooke’s Hospital,
Hills Road, Cambridge CB2
2QQ, UK; andrew.ostor@
addenbrookes.nhs.uk
Received 24 August 2006
Accepted
29 November 2006
........................
I
mmune-mediated inflammatory disease (IMID)
is a concept used to collectively describe a group
of ostensibly unrelated conditions that share
common inflammatory pathways. Encompassing
disorders as diverse as ankylosing spondylitis (AS),
type 1 diabetes and multiple sclerosis, the immune
dysregulation may afflict any organ system and
result in significant morbidity, reduced quality of
life (QoL) and premature death. Although the
aetiology of these conditions is unknown,
advances in molecular research have revealed that
an imbalance in inflammatory cytokines is central
to their pathogenesis.
1
The incidence of IMIDs in Western society
approximates 5–7%. Genetic factors are crucial
determinants of susceptibility and animal models
have led to the identification of several genes that
contribute to an autoimmune diathesis when
deleted or overexpressed.
2
Many of these diseases
also share similar environmental precipitants such
as infection and trauma. Frequently, multiple
IMIDs co-exist within the same patient, for
example a large study of AS found that 39% of
patients also developed iritis, 16% psoriasis and 8%
inflammatory bowel disease.
3
Various IMIDs may
also co-exist within the same family.
The most convincing evidence linking the
pathophysiology and treatment of autoimmune
diseases has been demonstrated with the tumour
necrosis factor-a (TNFa) inhibitors. Infliximab, the
first anti-TNFa agent licensed, has shown clinical
benefit in a number of seemingly unrelated
conditions including rheumatoid arthritis (RA),
Crohn’s disease (CD) and psoriasis. In addition,
there have been anecdotal suggestions of efficacy
with anti-TNFa agents in a multitude of orphan
inflammatory diseases. This, together with the
observation that treatment of one condition is
capable of improving multiple organ systems,
further validates the IMID paradigm and has
inspired additional research for common treat-
ment strategies. IMID therapy truly epitomises the
triumph of translational research (bench to bed-
side).
The therapeutic aims for IMIDs are identical: to
gain rapid control of inflammation, prevent tissue
damage, improve QoL and, if possible, achieve
long-term disease remission. As these goals are
rarely met in each patient with traditional treat-
ments, presumably due to failure to address the
underlying immunopathology, targeted biologic
therapy has been revolutionary. In this review we
describe the molecular basis for the IMID concept,
examine the immune dysregulation that many
IMIDs share, and briefly focus on the evidence for
biologic therapies that are currently licensed for
use in immune-mediated conditions.
IMID PATHOGENESIS
Over a decade ago, investigators discovered that
cytokine dysregulation was pivotal to the patho-
physiology of IMIDs. While these molecules are
known to be indispensable mediators of normal
immune function, an imbalance in their produc-
tion can lead to chronic inflammatory conditions.
Commonly, IMIDs are associated with a relative
over-expression of cytokines, such as TNFa in RA,
yet a relative under-expression of cytokines may be
equally important in disease pathogenesis, for
example interleukin 10 (IL10) deficiency in CD.
45
Interestingly, cytokines may have different effects,
Abbreviations: ACR, American College of Rheumatology;
ANA, antinuclear antibodies; AS, ankylosing spondylitis;
CD, Crohn’s disease; CTLA4, cytotoxic T lymphocyte
antigen-4; DMARDs, disease modifying anti-rheumatic
drugs; EMEA, European Medicines Agency; FDA, US Food
and Drug Administration; IL1, interleukin 1; IL6, interleukin
6; IL10, interleukin 10; IMID, immune-mediated
inflammatory disease; JIA, juvenile idiopathic arthritis; MTX,
methotrexate; NICE, National Institute for Health and
Clinical Excellence; PEG, polyethylene glycol; PsA, psoriatic
arthritis; QoL, quality of life; RA, rheumatoid arthritis; RCT,
randomised controlled trial; TB, tuberculosis; TNFa, tumour
necrosis factor-a; UC, ulcerative colitis
251
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either pro- or anti-inflammatory, depending on the stage of
disease.
2
Although immunoregulatory cytokines are produced by
many different cell types, CD4+ T lymphocytes are thought to
be the main orchestrators of the immune response. These T
helper cells are typically divided into two functionally hetero-
geneous subsets, Th 1 and Th 2, on the basis of the cytokines
they produce (fig 1). Th 1 cells have predominantly pro-
inflammatory effects and have been implicated in the immu-
nopathogenesis of IMIDs. Th 2 cells are thought to have anti-
inflammatory or protective functions in this context.
6
Because
of this central role in IMIDs, modulation of T cell function has
became an attractive target for intervention.
Another area arousing considerable interest is the role of B
lymphocytes in IMIDs. Early concepts focused on the ability of
B cells to produce antibodies, however it is now known that B
cells have much broader functions within the immune system,
including T cell activation, cytokine synthesis, regulation of
lymphoid architecture and maintenance of tolerance.
7
Emerging evidence indicates that disruption of these tightly
regulated B cell processes can potentially lead to autoimmune
disease. Certainly in RA loss of B cell tolerance and inappropri-
ate autoantibody production is a key pathological process, and
this has motivated investigators to attempt B cell depletion as a
novel therapeutic strategy.
8
Preliminary studies with the anti-
CD20 monoclonal antibody, rituximab, have now been com-
pleted for a number of IMIDs with clear evidence of efficacy
(table 1).
An appraisal of the specific pathogenic mechanisms involved
in every IMID is beyond the scope of this article, however this
review will focus on four common IMIDs in which biologic
agents have had a major impact, namely RA, CD, and psoriasis
and psoriatic arthritis (PsA).
RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a systemic inflammatory condi-
tion that primarily affects the synovial membrane of affected
joints. Extra-articular manifestations are common and may
involve any organ system. RA affects approximately 1% of the
adult population and is associated with chronic pain, disability
and increased mortality.
9
The long-term prognosis is generally
poor with approximately 80% of patients experiencing sig-
nificant functional disability within 20 years of diagnosis.
10
Although the aetiology of RA remains unknown, it is
postulated that an antigen, either exogenous or endogenous,
triggers an abnormal immune response in a genetically
susceptible individual.
11
Th 1 cells, activated by antigen
presenting cells and co-stimulatory pathways, infiltrate the
synovium and stimulate the production of pro-inflammatory
cytokines and destructive proteinases. While many cell types
and mediators are involved in the pathogenesis of RA, the key
drivers of inflammation are thought to be TNFa, interleukin 1
(IL1) and interleukin 6 (IL6).
12
There is clear evidence from
clinical trials that antibodies directed against TNFa and IL1 are
capable of ameliorating disease activity. In contrast, the anti-
inflammatory cytokines IL4 and IL10 may play a protective role
in RA.
13
IL4, for example, is produced by Th 2 cells and has been
shown, in vitro, to inhibit the activation of Th 1 cells and
therefore decrease the production of IL1 and TNFa (fig 1).
14
The exact role of B lymphocytes in the pathogenesis of RA
requires elucidation, however several possible mechanisms
have been proposed. Perhaps the most well described process
is loss of B cell tolerance and the production of pathogenic
autoantibodies, such as rheumatoid factor.
15
Additional experi-
ments in mice have demonstrated that T cell activation within
the rheumatoid synovium is critically dependent on the
presence of B cells.
16
Biologics have significantly expanded the therapeutic options
available for RA patients who remain refractory to traditional
disease modifying anti-rheumatic drugs (DMARDs). Agents
currently licensed for use are the three TNFa inhibitors
(infliximab, etanercept and adalimumab) and the two newer
agents, rituximab (anti-CD20) and abatacept (T cell co-
stimulation blocker). Anakinra, a recombinant IL1 receptor
antagonist is also licensed, however its efficacy in clinical trials
has been less impressive than with the TNFa blockers and thus
the National Institute for Health and Clinical Excellence (NICE)
does not recommend its use in the United Kingdom. The anti-
IL6 receptor antibody tocilizumab is however showing promise
in clinical trials and a US Food and Drug Administration (FDA)
licence application is anticipated for 2007.
CROHN’S DISEASE
Crohn’s disease (CD) is a T cell mediated disorder characterised
by a relapsing inflammatory process in the gut with extra-
intestinal manifestations typically involving the skin, eyes and
joints.
17
Although the cause of CD is unknown, the most
prominent theory implicates a dysfunctional mucosal immune
response to an otherwise innocuous luminal antigen in a
genetically susceptible host.
18
Complications such as perianal
fistulae occur in up to 43% of patients, many of which require
surgery.
19
With a prevalence of around 0.1% in the developed
world,
20
CD places a major burden on health care resources.
Similar to RA, an imbalance in the cytokine milieu is central
to its pathogenesis. Gut inflammation typically begins with
mucosal infiltration of neutrophils and macrophages, which in
turn activate T cells.
18
By stimulating the production of pro-
inflammatory cytokines, Th 1 cells amplify the immune
response and promote tissue destruction.
21
Equally, a relative
underproduction of regulatory cytokines (IL4 and IL10) has
been observed in Crohn’s affected mucosa.
5
This finding has led
to targeted drug therapies focusing on either inhibiting or
augmenting cytokine action. IL10, for example, is thought to be
a potent downregulator of the Th 1 response, and although
Figure 1 Th 1 and Th 2 cell responses. APC, antigen presenting cell; IL,
interleukin; MHC, major histocompatibility complex; Th, T helper cell; TNF,
tumour necrosis factor.
252 Kuek, Hazleman, O
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animal models have shown a strong link between IL10
deficiency and gut inflammation, the use of IL10 therapy in
clinical trials has been disappointing.
22
Great success however,
has been achieved with certain anti-TNFa agents.
Infliximab is currently the only biologic agent approved for
the treatment of moderate-severe and/or fistulising CD.
Certolizumab (Cimzia, Nektar), a subcutaneous anti-TNFa
agent, has also demonstrated efficacy in CD and an application
has been submitted to the FDA for appraisal.
23
Interestingly, the
TNF receptor fusion protein etanercept has failed to show
significant benefit in clinical trials, presumably due to its
different mechanism of action.
24
Etanercept only binds soluble
TNF, yet it is the transmembrane binding of TNF that is crucial
for inducing apoptosis of T cells in CD.
25
PSORIASIS AND PSORIATIC ARTHRITIS
Psoriasis is a chronic inflammatory disease of uncertain
aetiology that affects approximately 2% of the population.
26
Characterised by scaly erythematous plaques, the disease can
lead to significant physical and psychological distress, and in up
to 30% of patients a debilitating arthropathy may develop.
27
A
genetic predisposition for psoriasis is clear, with concordance of
approximately 70% in monozygotic twins, however a complex
interplay with environmental factors is likely.
28
Akin to RA and CD, psoriasis and PsA are T cell-mediated.
Histologically, skin plaques and inflamed synovial tissue
demonstrate an abundance of T cells and increased vascularity.
The inflammatory cascade is thought to be triggered by the
local activation of CD4+ T cells which generate a series of pro-
inflammatory cytokines such as TNFa that subsequently
activate CD8+ T cells, the main effector cells.
29
High concentra-
tions of TNFa have been detected in psoriatic skin lesions and
in the synovium of affected joints and it is believed that this
cytokine plays a pivotal role in perpetuating inflammation in
addition to stimulating the angiogenesis and keratinocyte
proliferation.
30
In many cases, conventional systemic therapies for both
psoriasis and PsA are either ineffective, are poorly tolerated or
are unable to maintain long-lasting remission.
31
Recently,
however, enormous growth in our understanding of the disease
pathogenesis has led to an expansion in therapeutic options.
Biologic agents that are currently licensed for plaque
psoriasis include the TNFa inhibitors, etanercept and inflix-
imab, as well as the T cell-targeted therapies, efalizumab and
alefacept (FDA only). NICE guidance has recently been issued
for the use of etanercept in severe plaque psoriasis in patients
who have failed conventional therapies, and for efalizumab as a
second line agent to etanercept. For PsA, three anti-TNFa
agents (infliximab, etanercept and adalimumab) are licensed,
however only infliximab and etanercept are NICE approved.
Benefit in psoriasis trials has also been seen with the T cell
costimulation blocker, abatacept.
32
BIOLOGICS CURRENTLY LICENSED FOR IMID
TREATMENT
Infliximab
Infliximab (Remicade, Schering-Plough/Centocor), a mouse-
human chimeric monoclonal antibody directed against TNFa,is
licensed for use in RA, AS, PsA, CD, ulcerative colitis (UC) and
psoriasis (tables 2 and 3). To date, the only NICE-approved
indications for infliximab are RA, CD and PsA, although an
appraisal is in development for AS. The drug is given as a 2 h
intravenous infusion with a dose of 3–5 mg/kg at weeks 0, 2
and 6, and then every 8 weeks thereafter. In the event of
waning efficacy, the dose may be increased up to 10 mg/kg, or
the infusion frequency increased to four to six weekly.
Infliximab is currently approved for active RA in those who
have failed DMARDs, and for severe progressive RA in those not
previously treated with DMARDs. The efficacy of infliximab has
been well documented in randomised controlled trials (RCTs).
In the ATTRACT trial, infliximab was compared with placebo in
428 RA patients taking methotrexate (MTX).
33
The actively
Table 1 IMIDs in which biologic therapy appears promising
Infliximab Etanercept Adalimumab Rituximab
Sjogren’s Sjogren’s Crohn’s disease Polymyositis/dermatomyositis
Polymyositis/dermatomyositis Polymyositis/dermatomyositis UC Wegener’s granulomatosis
Wegener’s vasculitis Wegener’s vasculitis Psoriasis GCA/PMR
Behcet’s Behcet’s JIA Polyarteritis nodosa
GCA/PMR GCA Behcet’s JIA
Takayasu’s arteritis Takayasu’s arteritis Takayasu’s arteritis Graft versus host disease
Polyarteritis nodosa Polyarteritis nodosa Sarcoidosis Cryoglobulinaemic vasculitis
Sarcoidosis Sarcoidosis Adult onset Still’s disease ITP
Adult onset Still’s disease Adult onset Still’s disease Hydradenitis supprativa TTP
JIA Cryoglobulinaemic vasculitis Pyoderma gangrenosum AIHA
Kawasaki disease Relapsing polychondritis Pemphigus Anti-phospholipid syndrome
Cryoglobulinaemic vasculitis Hydradenitis supprativa Idiopathic membranous GN
Relapsing polychondritis Pyoderma gangrenosum Hep C associated GN
Hydradenitis supprativa Graft versus host disease Multiple sclerosis
Coeliac disease Chronic hepatitis C Myasthenia gravis
Myelodysplastic syndrome ITP Pemphigus
Pyoderma gangrenosum Refractory asthma Grave’s disease
Erythema nodosum Amyloidosis CIDP
SAPHO syndrome Multicentric reticulohistiocytosis
Graft versus host disease Pemphigus
Chronic hepatitis B/C Grave’s disease
TTP CIDP
Refractory asthma
SLE
Amyloidosis
Multicentric reticulohistiocytosis
Pemphigus
This list is not exhaustive. AIHA, autoimmune haemolytic anaemia; CIDP, chronic inflammatory demyelinating polyneuropathy; GCA, giant cell arteritis; GN,
glomerulonephritis; JIA, juvenile idiopathic arthritis; PMR, polymyalgia rheumatica; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis; SLE, systemic lupus
erythematosus; TTP/ITP, thrombotic/idiopathic thrombocytopaenic purpura; UC, ulcerative colitis.
IMIDs and biologic therapy 253
www.postgradmedj.com
treated subjects showed significant improvements in all
American College of Rheumatology (ACR) responder indices
(box 1). Radiological progression was inhibited and QoL was
improved in the infliximab-MTX groups for up to 2 years.
34
Interestingly, sub-analysis showed reduced radiological pro-
gression even in the absence of clinical response.
The ASPIRE trial examined MTX naive patients with early
active RA.
35
In the group taking MTX alone, radiographic
progression was associated with high inflammatory markers
and persistent disease activity.
36
Infliximab plus MTX, on the
other hand, virtually halted radiographic progression of disease
and improvement was seen in all ACR indices. These data
suggested that early aggressive treatment of RA may avert joint
destruction.
Approval for infliximab in psoriasis was based on two large
RCTs. In the SPIRIT study, 88% of patients treated with
infliximab met the primary end point of PASI 75 (75%
improvement in Psoriasis Area and Severity Index) at week
10 versus 6% receiving placebo.
37
Significant improvements
were also seen in health related QoL. Similarly, in the EXPRESS
study, 80% of patients on infliximab therapy achieved a PASI 75
response compared to 3% on placebo.
38
For PsA, the efficacy of infliximab plus MTX has been studied
in two RCTs.
39 40
At week 16 in the IMPACT trial, almost two
thirds of patients achieved an ACR20 response compared to
10% on MTX alone. Improvements in articular and dermato-
logic manifestations of PsA were sustained until study
completion and significant benefits in health related QoL and
physical function were noted.
41
In an early trial of 108 patients with moderate to severe CD,
81% responded to a single dose of infliximab 5 mg/kg compared
to 17% on placebo. Remarkably, clinical remission was achieved
in almost half of those on active treatment.
42
In the ACCENT I
trial, patients who demonstrated an initial response were found
to be more likely to sustain a clinical response with infliximab
maintenance therapy than those on placebo.
43
Clinical improve-
ment was associated with endoscopic evidence of mucosal
healing.
44
The approval for infliximab maintenance therapy in
fistulising CD was based on the results of the ACCENT II
study.
45
At the end of 1 year, maintenance therapy with
infliximab resulted in a more sustained clinical response, a
higher rate of complete fistula closures and improvement in
QoL. Importantly, infliximab maintenance therapy also reduced
the number of hospitalisations and need for surgery.
46
Table 2 Properties of approved biologics
Biologic agent Infliximab Etanercept Adalimumab Rituximab Abatacept Anakinra
Proprietary name Remicade Enbrel Humira Rituxan Orencia Kineret
Mabthera
Construct Chimeric mAb to TNFa receptor Fully humanised Chimeric mAb to CTLA4Ig IL1 receptor antagonist
TNFa fusion protein mAb to TNFa CD20
Mode of action Binds to soluble and Binds to soluble Binds to soluble Binds to CD20 Blocks T cell co- Binds to IL1 receptor
membrane bound TNFa and TNFb and membrane molecule on B cells stimulation via
TNFa bound TNFa CD28-CD80/86
Half-life 9 days 4 days 14 days Variable 13 days 6 h
Dose 3–5 mg/kg of body 25 mg twice 40 mg every second 1000 mg on day 1 10 mg/kg of body 100 mg daily
weight at 0, 2 and weekly week. For incomplete and day 15 weight at 0, 2 and
6 weeks, and then response, dose may 4 weeks, and then
8 weekly. Dose be given weekly monthly thereafter
can be increased Repeated every 6–
to 10 mg/kg or 9 months
frequency of
injection increased
Administration Intravenous Subcutaneous Subcutaneous Intravenous Intravenous Subcutaneous
CTLA4, cytotoxic T lymphocyte antigen-4; IL, interleukin; mAb, monoclonal antibody; TNF, tumour necrosis factor.
Table 3 Biologics approved for IMIDs: FDA, EMEA and NICE
Biologic agent Action FDA licence EMEA licence NICE approval
Infliximab Anti-TNFa RA RA RA
AS AS PsA
PsA PsA CD
CD CD AS (appraisal)
UC UC UC (submitted)
Paediatric CD Psoriasis Psoriasis
Paediatric CD (appraisal)
Etanercept Anti-TNFa RA RA RA
JIA JIA JIA
AS AS PsA
PsA PsA Psoriasis
Psoriasis Psoriasis AS (appraisal)
Adalimumab Anti-TNFa RA RA RA (appraisal)
PsA PsA PsA
AS AS AS
Rituximab Anti-CD20 RA RA RA (submitted)
Abatacept CTLA4Ig RA RA (submitted) RA (submitted)
Efalizumab Anti-CD11a Psoriasis Psoriasis Psoriasis
Alefacept LFA-3/IgG Fc construct Psoriasis None None
Anakinra Anti-IL1 RA RA None
AS, ankylosing spondylitis; CD, Crohn’s disease; CTLA4, cytotoxic T lymphocyte antigen-4; EMEA, European Medicines Agency; FDA, US Food and Drug
Administration; IL, interleukin; JIA, juvenile idiopathic arthritis; NICE, UK National Institute for Health and Clinical Excellence; PsA, psoriatic arthritis; RA, rheumatoid
arthritis; TNFa, tumour necrosis factor-a; UC, ulcerative colitis.
254 Kuek, Hazleman, O
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Based on success in RCTs, infliximab was the first biologic
approved for the treatment of UC and a licence has also been
granted for use in AS. Additional case reports have demonstrated
the therapeutic value of infliximab in many other IMIDs (table 1).
Etanercept
Etanercept (Enbrel, Wyeth-Ayerst/Amgen) is a soluble TNF
receptor fusion protein which comprises two TNFa receptors
linked to human IgG and binds soluble TNFa. It is given as a
25 mg subcutaneous injection twice weekly or 50 mg weekly.
Etanercept is licensed for use in RA, psoriasis, PsA, AS and
juvenile idiopathic arthritis (JIA) (tables 2 and 3). Unlike
infliximab, etanercept has not shown benefit in CD as
mentioned previously.
The efficacy of etanercept in RA was initially evaluated as
monotherapy. Significant improvements were found in all ACR
responder indices and QoL measures in the etanercept groups
compared with placebo.
47
The TEMPO study, combining
etanercept with MTX, however, indicated that the two drugs
are significantly more effective in retarding disease progression
than either agent alone.
48
In the ERA trial, etanercept was directly compared with MTX
in patients with RA diagnosed within the previous 3 years.
Although response rates were initially more rapid with
etanercept, responses converged at 12 months.
49
After 2 years,
however, significantly more etanercept-treated patients met the
ACR20 improvement criteria than those on MTX monotherapy,
and the rate of erosive change was also retarded.
50
In a 5 year
open-label extension study, sustained efficacy was observed
with etanercept and erosive change was clearly retarded.
Furthermore, many patients were able to discontinue MTX
and corticosteroid therapy.
51
These findings support prompt
treatment of early aggressive RA.
Approval for the use of etanercept in psoriasis was based on
data from two large phase III trials involving over 1200
patients. Similar results were obtained from both studies, with
almost half of the patients on etanercept achieving a PASI 75
response compared to 4% on placebo. With extended etanercept
therapy, clinical improvement was sustained and patient-
reported outcomes reflected a positive effect on QoL.
52 53
For
PsA, 59% of etanercept-treated patients achieved an ACR20
response compared to 15% on placebo at 12 weeks.
Improvement was sustained with maintenance therapy at
1 year and radiographic progression of disease was halted.
54
Approval for etanercept has also been given for JIA and AS
following positive results in RCTs. Pilot studies have also shown
benefit in many other IMIDs (table 1).
Adalimumab
Adalimumab (Humira, Abbott), a fully human anti-TNFa
monoclonal antibody, is licensed for clinical use in RA, PsA
and AS. NICE appraisals are in development for all these
indications. The drug is administered as a 40 mg subcutaneous
injection every other week.
Adalimumab has been assessed in over 2000 RA patients in
RCTs. In the ARMADA trial, patients taking adalimumab plus
MTX showed significant improvements in all ACR responder
indices at 6 months, with effects seen as early as the first
week.
55
In a similar 12 month study, clinical benefit was
accompanied by marked improvements in radiographic and
functional outcomes.
56
Evidence supporting the use of adali-
mumab as monotherapy has also been demonstrated.
57
Approval has also been granted for adalimumab as first-line
therapy for early progressive RA based on data from the
PREMIER study. Although clinical responses were comparable
when either adalimumab and MTX were used alone, impressive
results were seen when the two drugs were combined. Nearly
50% of patients achieved clinical remission, rates approximately
double those found among those receiving monotherapy.
Furthermore, three-quarters of the patients on combination
therapy showed no radiographic progression of disease for
2 years.
58
Again, these data support the notion that early
treatment of RA may prevent long-term disability.
In a 6 month study of PsA, patients treated with adalimumab
showed a dramatic improvement in all arthritis severity scores
in addition to a reduction in joint damage progression and an
improvement in QoL. Among the adalimumab-treated patients
with plaque psoriasis, 59% achieved a PASI 75 response,
compared with 1% on placebo.
59
Phase III trials for psoriasis are
in progress.
For CD, limited published data indicate that adalimumab is
safe and effective for inducing remission in up to 36% of
patients.
60
The efficacy of adalimumab has also been demon-
strated in AS and phase III clinical trials are underway in UC
and JIA (table 1).
Rituximab
Rituximab (Mabthera, Roche; Rituxan, Genentech/Biogen) is a
chimeric anti-CD20 monoclonal antibody of human and mouse
origin that was initially approved for treatment of non-
Hodgkin’s B cell lymphoma. The drug has since been
investigated in a variety of IMIDs in which B cells have been
suggested to play a role.
Convincing evidence of efficacy comes from trials in RA with
significant benefit being demonstrated when using rituximab
either alone or in combination with MTX or cyclophospha-
mide.
61
The subsequent DANCER trial, involving 645 patients,
confirmed the benefit of rituximab plus MTX and the effect was
independent of glucocorticoids.
62
In another phase III trial, the
REFLEX study, patients with an inadequate response to anti-
TNFa therapy also noted marked clinical improvement with
rituximab therapy.
63
The efficacy was similar to that of the
TNFa inhibitors.
In 2006, the FDA and European Medicines Agency (EMEA)
approved rituximab for the treatment of RA in patients who
have failed anti-TNFa therapy. The recommended dose is
1000 mg given intravenously 2 weeks apart with concomitant
MTX. Although the safest and most effective timing for repeat
treatment has yet to be determined, preliminary data suggest
that the interval will likely be 6–12 months.
The use of rituximab has not been limited to RA. Published
open-label studies have shown efficacy in the treatment of
more than 30 other IMIDs including SLE, dermatomyositis and
Wegener’s granulomatosis (table 1).
Abatacept
Abatacept (Orencia, Bristol Myers Squibb) is a recombinant
fusion protein consisting of the extracellular domain of human
cytotoxic T lymphocyte antigen-4 (CTLA-4) with the Fc domain
of IgG. Classed as a co-stimulation blocker, the drug is designed
to inhibit T cell activation by blocking the interaction between
antigen presenting cells and T cells. This interaction is mediated
Box 1 American College of Rheumatology
response criteria for 20% improvement (ACR20)
20% reduction in the number of tender and swollen joints, plus
20% improvement in 3 of the following 5 parameters:
Physician global assessment of disease
Patient global assessment of disease
Patient assessment of physical function
Patient assessment of pain
Erythrocyte sedimentation rate or C-reactive protein
IMIDs and biologic therapy 255
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via the CD28-CD80/86 pathway. In 2005, the FDA approved
abatacept for the treatment of moderate to severe RA in
patients who have had an inadequate response to one or more
DMARDs or TNFa antagonists. The recommended dose is
10 mg/kg by intravenous infusion at 0, 2 and 4 weeks initially,
and then monthly thereafter.
The observation that the CD28 and CD80/86 ligands are
highly expressed on cells within the rheumatoid synovium
suggests that co-stimulation may play a direct role in the
pathogenesis as well as progression of RA.
64
Endogenous CTLA4
is also expressed on T cells in the rheumatoid joint and is
thought to function as a regulator of T cell activation by
interrupting the CD28 pathway, in addition to stimulating the
release of immunoregulatory cytokines, such as TGFb.
65 66
CTLA4 can also mediate antigen-specific apoptosis of T cells.
67
In the clinical setting, two pivotal efficacy studies have now
been published for RA. In the first, 339 subjects with an
inadequate response to MTX were randomised to receive
abatacept plus MTX or MTX alone. At 1 year, marked clinical
improvements were observed with abatacept, with almost twice
as many patients achieving an ACR20 response compared to
placebo.
68
Striking radiographic improvements have since been
demonstrated in a subsequent phase III study.
69
Abatacept has
also been evaluated in patients with an inadequate response to
anti-TNFa therapy, and again, significant improvements in all
ACR indices were seen with active treatment compared to
placebo.
70
Success with abatacept has been noted in psoriasis, with
early studies showing a clear clinical and biochemical improve-
ment in addition to a quantitative reduction of T cells
infiltrating the skin.
32
Overall, these findings support the view
that T cell activation plays an essential role in the pathogenesis
of IMIDs, and therefore it is likely that abatacept will have great
utility in the treatment of T cell mediated diseases in the future.
Alefacept and efalizumab
Two additional agents have been approved for the treatment of
plaque psoriasis. Efalizumab (Raptiva, Genentech/Xoma), a
humanised monoclonal antibody, binds to the alpha subunit
(CD11a) of leukocyte-function-associated antigen type-1 (LFA-
1) and inhibits the activation of T cells. Alefacept (Amevive,
Biogen/Idec), a fully human LFA-3/IgG1 fusion protein, also
inhibits T cell activation and selectively reduces memory T cells.
These drugs have shown excellent responses in RCTs, with
approximately a quarter of patients achieving 75% improve-
ment in skin lesions within 3 months.
71 72
Alefacept has also
demonstrated efficacy in RA, in combination with MTX, and in
PsA.
73 74
Certolizumab pegol (CDP870)
A new anti-TNFa agent, certolizumab (Cimzia, Nektar),
previously known as CDP870, has recently been submitted to
the FDA and EMEA for appraisal for the treatment of CD.
Certolizumab consists of the Fab fragment of a humanised anti-
TNFa antibody, coupled to polyethylene glycol (PEG). This
produces a drug that can remain in circulation longer and can
be conveniently administered once a month via subcutaneous
injection.
Data from a 12 week phase II clinical trial demonstrated that
certolizumab produced a significant clinical benefit in CD over
placebo from weeks 2 to 10, but not at week 12.
23
In a more
recent trial, however, certolizumab convincingly induced
clinical remission for up to 6 months.
75
Overall, the drug is
well tolerated with a safety profile similar to other anti-TNFa
agents. Not surprisingly, certolizumab has also demonstrated
efficacy in RA with outcomes comparable to that of etanercept
and infliximab.
76
Studies have also begun in psoriasis.
Anakinra
Anakinra (Kineret, Amgen), a recombinant IL1 receptor
antagonist, was approved for use in RA in 2001. In the UK,
however, NICE did not approve its use in RA as it was deemed
to be cost ineffective. To date, RCTs involving nearly 3000
patients have demonstrated efficacy of anakinra in RA, either
as monotherapy or in combination with MTX.
77 78
Rapid
improvements in functional status reflected radiographic
evidence of reduced joint damage.
SAFETY
Few serious adverse events were documented in the clinical
trials of anti-TNFa agents, however post-marketing surveillance
revealed several important complications. Principle among
these was reactivation of latent mycobacterium tuberculosis
(TB) infection as TNFa plays a key role in the integrity of
granumolata.
79
Serious bacterial infections have also been
described, however a recent report from the British Society of
Rheumatology Biologics Register found that the overall risk of
serious infections in RA patients was not increased by anti-
TNFa therapy when compared to those on standard DMARD
therapy. There were however more opportunistic infections,
such as histoplasmosis, and more skin and soft tissue infections
in the cohort on biologic therapy.
80
Additional complications of TNFa blockade include possible
exacerbation of congestive cardiac failure, demyelinating
disease and lymphoproliferative disorders.
81
For RA patients,
the occurrence of lymphoma secondary to biologic therapy is
controversial as there is a two- to threefold increased incidence
of this disease with RA per se. The possible increased risk for
the development of solid malignancy is far from clear. A further
potential side effect of anti-TNFa therapy is the development of
antinuclear antibodies (ANA), although an SLE-like illness is
rare and ANA development alone does not necessitate stopping
therapy.
The tolerability of rituximab and abatacept in clinical trials
has been very favourable with integrated safety data indicating
that adverse events, such as malignancy and serious infections,
are rare. In relation to rituximab, the experience in lymphoma
patients has been vast (.750 000 patients treated) and no
increased risk of TB or opportunistic infection has been noted.
Infusion reactions are common with rituximab, although these
events may be minimised by the use of peri-infusional
corticosteroids.
62
The commonest side effect of anakinra is injection-site
reaction. Although neutropaenia has been noted in clinical
trials with the IL1 blocker, the rate of serious infection is
comparable to control patients. In an RA study comparing the
combined efficacy of anakinra and etanercept, however, no
added benefit was seen and there was an unacceptably high
incidence of serious infections.
82
Thus treatment with con-
current biologic agents is not advised and a warning has been
issued by the regulatory health bodies.
The precise relationship between several of these complica-
tions and biologic therapy is unknown, partly due to under-
reporting but also due to lack of comparison cohorts. It may be
that several of these comorbidities are associated with the
disease itself, or perhaps due to extended exposure to standard
DMARD therapy. Robust safety data will emerge from the
numerous biologic registries established across Europe and the
US.
83
COST
One of the drawbacks of biologic therapy is the expense; the
TNFa antagonists cost approximately US$15–18 000 per patient
per annum in the US and around J10 000 in Europe.
84 85
The
cost of B cell targeted therapy may be less, however further
256 Kuek, Hazleman, O
¨
sto¨r
www.postgradmedj.com
work on the appropriate dosing regimen is needed. Due to the
infrastructure required to manufacture these agents, the prices
are unlikely to plummet following patent expiry. This cost,
however, must be balanced against the significant economic
burden IMIDs can pose to the individual patient and to
society as a whole. Direct annual costs for IMIDs vary
widely from US$791 for psoriasis
86
to US$5822 for RA
87
and
US$12 417 for CD.
88
The indirect costs however, such loss of
productivity and income, may be several times greater as
many IMIDs affect young people subjecting them to chronic
disability.
1
In 1992, the total annual cost of RA to UK society
was over £1 billion, approximately half of which was attri-
buted to loss of productivity.
89
Clearly, those with severe,
debilitating disease consume greater resources than those
less afflicted. In CD for example, it has been estimated that
2% of the patient population accounts for 34% of the medical
costs.
90
CONCLUSIONS
Biologics have revolutionised the treatment of autoimmune
diseases due to their efficacy, speed of onset and tolerability.
The fact that anti-cytokine therapies, such as infliximab, have
been effective in treating multiple orphan inflammatory
conditions confirms that the IMID concept is valid. For the
medical profession, this represents an important breakthrough
in the way we classify pathology. Traditionally, IMIDs are
treated by doctors who specialise in the organ most affected,
however given that CD shares similar cytokine dysregulation to
both RA and psoriasis, these systemic disorders may in the
future be grouped as one disorder.
Although biologics provide a very useful addition to our
therapeutic armamentarium, evidence suggests that they
should not be considered a panacea. Serious adverse events
have been reported and long-term safety data are lacking.
Furthermore, a substantial number of patients demonstrate a
poor response to these agents, confirming that our under-
standing of IMID immunopathogenesis is far from complete.
The current challenge is to identify exactly when to introduce
biologics into the therapeutic algorithm. Traditionally they have
been used in those least likely to respond, that is, those who
have failed multiple DMARDs and still have active disease.
Certainly in rheumatology, the prevailing philosophy is to treat
as early as possible in order to avoid the potential sequelae of
joint destruction and functional loss.
While RCTs have demonstrated efficacy in early RA with the
combination of MTX and TNFa inhibitors, it may be argued
that evidence is lacking to promote this as initial therapy for all
patients. In up to one third of patients with RA, progressive
joint destruction does not develop and anti-TNFa therapy may
be not only costly but unnecessary.
91
Furthermore, combination
conventional DMARD therapy has shown to be very effective in
reducing disease activity in RA.
92–94
There is however evidence
from early RA trials that infliximab, etanercept and adalimu-
mab, when used in combination with MTX, are more effective
in rapidly suppressing disease activity than MTX alone in
patients with aggressive disease diagnosed within the preceding
3 years.
35 49 58
Clearly further studies are required to determine
exactly who and when to treat. If we could identify the patients
most likely to respond, it may be possible to save time and
expense and to avert potential toxic reactions. The field of
pharmacogenetics will address this.
Overall, biologic therapies represent an exciting advance in
the treatment of autoimmune diseases. For millions of patients,
treatment success may translate to rapid suppression of
inflammation, prevention of disability, improved quality of life,
and the goal of complete disease remission – something
unthinkable a decade ago.
MULTIPLE CHOICE QUESTIONS (TRUE (T)/FALSE (F),
ANSWERS AFTER THE REFERENCES)
Choose the best of the five options for each question.
1. Which of the following is true regarding anti-TNFa
therapy?
A. Anti-TNFa therapy can be administered both sub-
cutaneously and orally
B. Infliximab and etanercept are of comparable efficacy
in treating Crohn’s disease
C. Etanercept can be used as first line therapy in psoriasis
Summary box
N
Biologic agents are highly effective disease-modifying
medications.
N
Currently licensed biologics target TNFa, interleukin-1, T
cell activation and B cells.
N
Biologic agents improve the signs and symptoms and
quality of life of patients with rheumatoid arthritis,
Crohn’s disease, psoriasis and many orphan inflamma-
tory conditions.
N
Physicians should be vigilant for the potential side-effects
of biologic agents.
N
Treatment should commence early for optimal outcome.
N
IMIDs represent a breakthrough in the way pathology is
classified.
Key references
N
33 Maini R, St Clair EW, Breedveld F, et al. Infliximab
(chimeric anti-tumour necrosis factor alpha monoclonal
antibody) versus placebo in rheumatoid arthritis patients
receiving concomitant methotrexate: a randomised phase
III trial. ATTRACT Study Group. Lancet 1999;354:1932–
9.
N
49 Bathon JM, Martin RW, Fleischmann RM, et al.A
comparison of etanercept and methotrexate in patients
with early rheumatoid arthritis. N Engl J Med
2000;343:1586–93.
N
58 Breedveld FC, Weisman MH, Kavanaugh AF, et al.
The PREMIER study: a multicenter, randomized, double-
blind clinical trial of combination therapy with adalimu-
mab plus methotrexate versus methotrexate alone or
adalimumab alone in patients with early, aggressive
rheumatoid arthritis who had not had previous metho-
trexate treatment. Arthritis Rheum 2006;54:26–37.
N
62 Emery P, Fleischmann R, Filipowicz-Sosnowska A, et
al. DANCER Study Group. The efficacy and safety of
rituximab in patients with active rheumatoid arthritis
despite methotrexate treatment: results of a phase IIB
randomized, double-blind, placebo-controlled, dose-
ranging trial. Arthritis Rheum 2006;54:1390–400.
N
94 Goekoop-Ruiterman YP,deVries-BouwstraJK,
Allaart CF, et al. Clinical and radiographic outcomes of
four different treatment strategies in patients with early
rheumatoid arthritis (the BeSt study): a randomized,
controlled trial. Arthritis Rheum 2005;52:3381–90.
IMIDs and biologic therapy 257
www.postgradmedj.com
D. D. Adalimumab is administered subcutaneously every
other week
E. E. Only one anti-TNFa agent is licensed in the UK for
the treatment of rheumatoid arthritis
2. Which of the following is true regarding rituximab?
A. It decreases the number of circulating B cells
B. It is licensed for the treatment of rheumatoid arthritis
and juvenile idiopathic arthritis
C. It is licensed in Europe as a second line agent for
patients who have failed methotrexate
D. The efficacy of rituximab is far greater than inflix-
imab in the treatment of rheumatoid arthritis
E. The recommended dose is 1000 mg given intrave-
nously every month.
3. Which of the following are IMIDs?
A. Systemic lupus erythematosus
B. Type 1 diabetes
C. Osteoarthritis
D. Multiple sclerosis
E. Ankylosing spondylitis
4. In clinical trials which of the following have been shown
to be beneficial?
A. Abatacept for rheumatoid arthritis
B. Etanercept for Crohn’s disease
C. Alefacept for psoriasis
D. Anakinra for rheumatoid arthritis
E. Infliximab for ankylosing spondylitis
5. Which of the following is true regarding the safety of
biologics?
A. Infliximab is safer than adalimumab
B. Anti-TNFa treatment is associated with an increased
risk of lung cancer
C. Patients must be screened for tuberculosis before
commencing anti-TNFa therapy
D. Patients commonly have infusion reactions with
rituximab
E. The development of antinuclear antibodies necessi-
tates stopping therapy
Authors’ affiliations
.......................
Annabel Kuek, Brian L Hazleman, Andrew J K O
¨
sto¨r, Rheumatology
Research Unit, Addenbrooke’s Hospital, Cambridge, UK
Financial support was provided by CARE (Cambridge Arthritis Research
Endeavour) Charity.
Competing interests: Dr Annabel Kuek declares no conflicts of interest. Dr
Andrew O
¨
sto¨r and Dr Brian Hazleman receive sponsorship from Schering-
Plough, Wyeth, Abbott and Roche.
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ANSWERS
1. (A) F, (B) F, (C) F, (D) T, (E) F.
2. (A) T, (B) F, (C) F, (D) F, (E) F.
3. (A) T, (B) T, (C) F, (D) T, (E) T.
4. (A) T, (B) F, (C) T, (D) T, (E) T.
5. (A) F, (B) F, (C) T, (D) T, (E) F.
BMJ Clinical Evidence—Call for contributors
BMJ Clinical Evidence is a continuously updated evidence-based journal available worldwide on
the internet which publishes commissioned systematic reviews. BMJ Clinical Evidence needs to
recruit new contributors. Contributors are healthcare professionals or epidemiologists with
experience in evidence-based medicine, with the ability to write in a concise and structured way
and relevant clinical expertise.
Areas for which we are currently seeking contributors:
N
Secondary prevention of ischaemic cardiac events
N
Acute myocardial infarction
N
MRSA (treatment)
N
Bacterial conjunctivitis
However, we are always looking for contributors, so do not let this list discourage you.
Being a contributor involves:
N
Selecting from a validated, screened search (performed by in-house Information Specialists)
valid studies for inclusion.
N
Documenting your decisions about which studies to include on an inclusion and exclusion form,
which we will publish.
N
Writing the text to a highly structured template (about 1500–3000 words), using evidence from
the final studies chosen, within 8–10 weeks of receiving the literature search.
N
Working with BMJ Clinical Evidence editors to ensure that the final text meets quality and style
standards.
N
Updating the text every 12 months using any new, sound evidence that becomes available. The
BMJ Clinical Evidence in-house team will conduct the searches for contributors; your task is to
filter out high quality studies and incorporate them into the existing text.
N
To expand the review to include a new question about once every 12 months.
In return, contributors will see their work published in a highly-rewarded peer-reviewed
international medical journal. They also receive a small honorarium for their efforts.
If you would like to become a contributor for BMJ Clinical Evidence or require more information
about what this involves please send your contact details and a copy of your CV, clearly stating the
clinical area you are interested in, to CECommissioning@bmjgroup.com.
Call for peer reviewers
BMJ Clinical Evidence also needs to recruit new peer reviewers specifically with an interest in the
clinical areas stated above, and also others related to general practice. Peer reviewers are
healthcare professionals or epidemiologists with experience in evidence-based medicine. As a
peer reviewer you would be asked for your views on the clinical relevance, validity and
accessibility of specific reviews within the journal, and their usefulness to the intended audience
(international generalists and healthcare professionals, possibly with limited statistical knowledge).
Reviews are usually 1500–3000 words in length and we would ask you to review between 2–5
systematic reviews per year. The peer review process takes place throughout the year, and our
turnaround time for each review is 10–14 days. In return peer reviewers receive free access to
BMJ Clinical Evidence for 3 months for each review.
If you are interested in becoming a peer reviewer for BMJ Clinical Evidence, please complete the
peer review questionnaire at www.clinicalevidence.com/ceweb/contribute/peerreviewer.jsp
260 Kuek, Hazleman, O
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sto¨r
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