. . . REPORT . . .

Immune-Mediated
Inflammatory Disorders (I.M.I.D.s):
The Economic and Clinical Costs

John P. Williams, MD, MBA; Jonathan A. Meyers, FSA, MAAA

Abstract in these shared mechanisms. In the last 5

Immune-mediated inflammatory disorders years, anticytokine therapies have pro-
(I.M.I.D.s) are a group of diseases that involve an duced therapeutic breakthroughs in con-
immune response that is inappropriate or exces- ditions ranging from rheumatoid arthritis
sive, and is caused, signified, or accompanied by
(RA) to Crohn’s disease (CD). Nevertheless,
dysregulation of the body’s normal cytokine
despite shared pathophysiology and thera-
milieu. I.M.I.D.s cause acute or chronic inflamma-
tory injury, sometimes severe, in any organ sys- py, autoimmune conditions are not typical-
tem. Despite strong evidence linking the ly seen as interrelated by payers, providers,
pathophysiologies and treatments of the diseases employers, and benefits consultants (per-
that constitute the I.M.I.D. group, providers, pay- sonal communication, P. Lopatka, July
ers, employers, and benefits consultants have been 2002). For example, RA is usually consid-
slow to adopt the I.M.I.D. concept. As a result, ered a rheumatological disorder and CD a
these stakeholders risk underestimating the signifi- gastrointestinal condition, even though the
cant clinical and economic burdens of the I.M.I.D. cytokine dysregulation and treatment of
class. In this review we examine those burdens, each illness may be similar.3
specifically analyzing I.M.I.D. prevalence and cost
This review describes a new medical
data for a group of large employers. We also
paradigm—the immune-mediated inflam-
describe the scientific rationale for the I.M.I.D.
paradigm, examine the cytokine dysregulation that matory disorders (I.M.I.D.s)—that will
many I.M.I.D.s share, and focus in detail on the help healthcare stakeholders understand
pathophysiology of 3 I.M.I.D.s with high morbidi- the economic and clinical burden of a
ty: rheumatoid arthritis, Crohn’s disease, and type group of diseases that together may affect
1 diabetes mellitus. The review concludes with an as much as 5%-7% of the American popu-
evaluation of approved anticytokine I.M.I.D. ther- lation.1,4 I.M.I.D.s involve an immune
apies and those in development. response that is inappropriate or excessive
(Am J Manag Care. 2002;8:S664-S681) and is caused, signified, or accompanied
by a dysregulation of the normal cytokine
milieu. They also cause acute or chronic
he concept of autoimmune disease inflammatory injury, sometimes severe, in

T has existed for at least 100 years,

and there has been biochemical
evidence of these conditions’ shared
any organ system.
Many illnesses fulfill these criteria,
from the relatively obscure, such as giant
mechanisms for at least 15 years.1,2 cell arteritis, to public health crises, such
Dysregulation of cytokines, a group of as type 1 diabetes mellitus (T1DM). For
small proteins produced ubiquitously in payers, it is helpful to focus on the condi-
the body, has proven to be a key element tions that have the highest per-member-

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 Immune-Mediated Inflammatory Disorders (I.M.I.D.s): The Economic and Clinical Costs

per-year (PMPY) cost, which takes into oping helper T cells down the Th1 or Th2
account prevalence of the disease and paths, and cytokines produced by the Th1
claims per patient. Before discussing subset tend to be proinflammatory, with
I.M.I.D.s, however, it makes sense to Th2 cytokines typically being anti-inflam-
briefly consider what exactly cytokines are matory.16 It should be noted, however,
and how their dysregulation can lead to that recent investigations have shown that
pathophysiology. the Th1/Th2 paradigm may be incom-
plete. First, just as typically proinflamma-
What Are Cytokines and tory cytokines may sometimes be
Why Do They Matter? anti-inflammatory and anti-inflammatory
Cytokines are a family of proteins and cytokines may be proinflammatory, Th1
polypeptides that are secreted by many cells may sometimes have an anti-inflam-
different cell types and that are required matory effect, and Th2 cells a proinflam-
for physiological immune function, matory effect.5 Second, a new class of
inflammation, cell growth, and tissue helper T cells known as Th3 has recently
repair.3 Cytokine dysregulation, however, been identified, and there may be other
can lead to I.M.I.D.s.5 In some cases undescribed classes.17
cytokine overproduction may be associat- Although the molecular biology of T cell
ed with I.M.I.D. pathophysiology, as in differentiation is complex, it is worth
rheumatoid arthritis and Crohn’s dis- examining, as many of the involved
ease.4,5 Underproduction of cytokines cytokines have offered and will offer
may also be seen in certain I.M.I.D.s, as in important therapeutic targets. Simplified,
systemic lupus erythematosus.4 To make the process works as follows: IL-12 causes
matters even more complicated, over- or differentiation of helper T cells into the
underproduction of certain cytokines Th1 proinflammatory subtype.18 The Th1
may have different effects, depending on cells then produce IL-2, which activates
where, when, and in what tissue microen- other T cells, and IFN-γ, which causes
vironments the dysregulation occurs.5 additional IL-12 production, which in turn
Additionally, blocking or augmenting leads to more Th1 differentiation.14
cytokine action through pharmacothera- Although not produced by T cells, IL-1
py may reduce inflammation—or may causes the production of IL-2 by T cells
have an unintended proinflammatory and the synthesis of TNF-α by many dif-
effect.6 ferent cell types.19,20 TNF-α causes the
As a general rule, it is helpful to think of production of more IL-1 and the activa-
cytokines as having proinflammatory or tion of more T cells, creating an inflam-
anti-inflammatory characteristics. The matory feedback loop.20 As will be shown
cytokines interleukin 1 (IL-1), interleukin shortly, overproduction of these cytokines
2 (IL-2), interleukin 12 (IL-12), interferon has been associated with a number of
γ (IFN-γ), and tumor necrosis factor α I.M.I.D.s.4 In contrast, IL-4 and IL-10 lead
(TNF-α) are typically proinflammatory, to the differentiation of helper T cells into
whereas the cytokines interleukin 4 (IL- the Th2 anti-inflammatory subtype and to
4), interleukin 10 (IL-10), and transform- the suppression of Th1 proinflammatory
ing growth factor β (TGF-β) are often development.21 TGF-β, produced by a
anti-inflammatory.3,5,7-14 These cytokines variety of cells, causes the production of
generate many of their pro- and anti- IL-10, which further steers T cells into
inflammatory effects through their actions Th2 differentiation.21
on a group of immune cells known as
helper or CD4+ T lymphocytes. Cytokines and I.M.I.D.s:
These helper T cells comprise 2 sub- What’s the Connection?
sets: Th1 and Th2.15 The Th1 cells have As stated above, dysregulation of
been associated with the development of cytokines can lead to the tissue damage
I.M.I.D.s, and the Th2 cells may suppress associated with I.M.I.D.s. But how exactly
their development. Cytokines steer devel- does it happen? This review will examine

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REPORT

the process in 3 I.M.I.D.s with significant induce other cells to produce IL-1 and
clinical and economic burdens: rheuma- TNF-α, as well as an additional proin-
toid arthritis, Crohn’s disease, and type 1 flammatory cytokine, interleukin-6 (IL-
diabetes mellitus. 6).36,37 Further, IL-1 and TNF-α further
activate the T cell response, as well as lead
RA: The Arche-typal I.M.I.D. RA is a to the secretion of destructive enzymes
chronic, destructive arthropathy that dis- that erode the joint space.22,38
ables as many as 80% of its sufferers.22 A number of cytokines, such as IL-4,
Small joint destruction proceeds at 2%-3% IL-10, and TGF-β, may play an anti-
per year, and after 20 years of disease, inflammatory role in RA.21 IL-10, for
23% of patients have near-total joint example, is one of the key cytokines that
destruction in their hands and feet.23 The steers T cells toward the anti-inflammato-
degenerative process, however, extends ry Th2 pathway, and it can be detected in
beyond the small joints, and RA may the joint fluid of RA patients.39 IL-4 and
involve the cervical spine in approximate- IL-10 lead to the formation of a naturally
ly half of patients.24 occurring IL-1 receptor antagonist that
Most important, RA is a systemic dis- acts as a kind of molecular sponge for
ease that causes substantially increased IL-1.40 In addition, when IL-10 activity is
mortality, especially due to cardiac dis- blocked in patients with RA, secretion of
ease.25,26 Specifically, it has been postulat- proinflammatory cytokines TNF-α and
ed that the inflammatory milieu of RA IL-1 increases.41
leads to increased atherosclerosis.27 These findings demonstrate that RA fits
RA’s social costs are dramatic. As many the I.M.I.D. paradigm. As defined in the
as 10% of patients quit their jobs within 3 beginning of the review, an I.M.I.D.
years of disease onset, and those patients involves an immune response that is inap-
with the most severe disease can expect propriate or excessive. Although the trig-
a 60% decline in earnings during the first ger for this immune response remains
6 years of illness.28,29 In addition, the unknown, there can be no doubt that
divorce rate of those with RA is said to severe autoimmunity does occur in RA
be 70% higher than that of the general and involves the widespread activation of
population.29 immune cells. In addition, with RA there
The pathogenesis of RA is not com- are significant alterations in the physio-
pletely understood. For example, it is like- logical cytokine profile of the joint space
ly that RA’s inflammatory process is that correlate with and may sometimes
initiated by an arthritogenic antigen, pos- cause the immune response. Most impor-
sibly of bacterial origin, but the antigen’s tantly, this cytokine-driven immune
identity is currently unknown.30,31 That response causes devastating injury to
antigen activates helper T cells of the Th1 the host.
subtype, which subsequently secrete or
cause to be secreted an array of cytokines CD: Is It RA of the Gut? Crohn’s dis-
that indirectly leads to joint inflammation ease (CD) is a chronic condition that
and destruction.22,32 involves severe, asymmetric inflamma-
It was observed more than a decade ago tion throughout the gastrointestinal tract,
that significant amounts of IL-1 and TNF- as well as extragastrointestinal manifes-
α are found in the joint spaces of RA tations in the skin, eyes, and joints.42
patients, but not in those of normal con- Like RA, CD is a systemic disease. One
trols.33,34 In addition, an early transgenic epidemiological study showed that after
mouse study showed that mice constitu- 20 years of disease, 26% of CD patients
tively expressing TNF-α developed a developed perianal fistulae, and 23% of
chronic arthritis and that this arthritis those fistulae required bowel resection.43
could be stopped by treatment with anti- The incidence rates of liver/biliary tract
bodies against TNF-α.35 It is now thought and small bowel carcinoma in CD
that T cells, once activated in RA, patients are, respectively, 5.2 and 17.4

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 Immune-Mediated Inflammatory Disorders (I.M.I.D.s): The Economic and Clinical Costs

times greater than the incidence rates of T1DM: The Most Morbid I.M.I.D. Just
those cancers in the general popula- as RA has been considered a rheumato-
tion.44 Not surprisingly, depression and logical condition and CD a gastrointesti-
anxiety are significantly more common nal one, T1DM is typically viewed as an
in CD patients after diagnosis than endocrine disease. The reason is obvious:
before.45 destruction of the pancreas β cells in
Neither the cause nor the complete T1DM produces a hypoinsulinemia that,
pathogenesis of CD is known, although a if untreated, invariably leads to death.
gene mutation on chromosome 16 is more The condition’s only therapy to date has
than twice as likely to occur in CD patients been insulin replacement, but even with
as in controls.46 Like RA, CD appears to be insulin therapy, the risk of morbidity is
set in motion by an inappropriate or high. One study showed that after 10
excessive immune response, potentially to years of routine care, patients with T1DM
intestinal bacteria. For example, mice have a 16% chance of developing sight-
deficient in the anti-inflammatory threatening retinopathy.51 The risks of
cytokine IL-10 develop a CD-like condi- renal failure and lower extremity ampu-
tion—unless they are maintained in a tations are also greatly increased in
germ-free environment.47 T1DM.52-54
In normal individuals, subpopulations Findings of the last decade have estab-
of T cells, supported by IL-10, prevent an lished that almost all cases of T1DM have
immune response against gut bacteria, I.M.I.D. pathophysiology.55-57 It is now
but this regulation appears to be disrupt- thought that Th1 cells mediate the diabet-
ed in CD.48 In addition, the balance of ic immune response, and in a T1DM
proinflammatory and anti-inflammatory mouse model, suppression of T cell activi-
cytokines is disturbed, and as in RA, ty prevents development of the dis-
the production of IL-1 and TNF-α is ease.56,58,59 As in the case of RA, the
increased.49,50 This overproduction is sig- Th1-driven immune response in T1DM
nificant because both of these cytokines generates a series of proinflammatory
cause the release of other inflammatory cytokines, including IL-1, IL-2, IFN-γ, and
cytokines and proteolytic enzymes. TNF-α.59 Certain cytokines such as IL-1
Clinical findings alone show little con- are indirectly cytotoxic to the β cells,
nection between RA and CD. The causing free radicals to be generated that
immunological and molecular evidence, kill the insulin-producing cells.60 In addi-
however, suggest that CD and RA are tion, these proinflammatory cytokines
both I.M.I.D.s. To review, I.M.I.D.s suppress β cell insulin secretion and also
involve an immune response that is inap- stimulate so-called cytotoxic T cells,
propriate or excessive and is caused, sig- which then attack and kill the β cells.59,60
nified, or accompanied by a dysregulation In contrast, the Th2 response and the
of the normal cytokine milieu. They also cytokines that it elaborates have been
cause acute or chronic inflammatory shown to suppress the development of
injury, sometimes severe, in any organ T1DM, potentially by inhibiting the
system. pathogenic Th1 response, as in the case
CD likely involves an immune of IL-4.57,61
response to a currently unknown gut anti- These findings strongly suggest that,
gen, which is normally suppressed by like RA and CD, T1DM is an I.M.I.D. First,
appropriate cytokine regulation. Once it involves an immune response that is
in place, that aberrant immune response excessive and inappropriate: total
leads to a cytokine-driven inflammatory destruction of the pancreas’s insulin-
cascade that eventually causes major producing β cells. Second, it is caused or
tissue damage throughout the gastroin- signified by a disruption in the normal
testinal tract and elsewhere in the body. cytokine milieu, specifically the over-
In summary, CD has cytokine dysregula- production of Th1 cytokines.57 Third,
tion similar to that found in RA. the result of the immune-mediated

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REPORT

Table 1. Selected Immune-Mediated Inflammatory Disorders

Relative Relative
Overexpression Underexpression
Condition of Cytokines of Cytokines Reference

Autoimmune hepatitis TNF-α IL-2, IL-4 62

Crohn’s disease TNF-α, IL-1, IL-2, IL-6, IL-8, IL-12, IL-3 4, 49, 50
and IFN-γ
Giant cell arteritis IFN-γ, IL-1, IL-2, TNF-γ 63, 64
Type 1 diabetes mellitus TNF-α, IL-1, IL-2, IL-12, IFN-γ 59, 65
Multiple sclerosis IL-6, IL-12, TNF-α IL-10 66, 67
Sarcoidosis TNF-α, IL-1, IL-6, TGF-β 68, 69
Psoriatic arthritis TNF-α, IL-1, IL-6, IL-8, IFN-γ 70
Psoriasis TNF-α 71
Ankylosing spondylitis TNF-α, IL-10 IFN-γ, IL-2 72
Rheumatoid arthritis TNF-α, IL-1, IL-6 22
Systemic lupus erythematosus IFN-γ TNF-α 4
Systemic sclerosis IL-4, TGF-β 73, 74
Ulcerative colitis IL-1, IL-5, IL-6, IL-8, TNF-α IL-3 49, 50, 65

IFN indicates interferon; IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor.

inflammatory destruction of β cells is sarcoidosis is a systemic inflammatory

catastrophic. disorder whose clinical manifestations can
range from asymptomatic chest X-ray
The Other I.M.I.D.s. Many other abnormalities to multiorgan failure.69
autoimmune diseases fit the I.M.I.D. pro- Despite their clinical dissimilarities, the
file, and Table 1 offers an extensive but by 2 conditions’ cytokine pathophysiology is
no means complete list. It should be noted similar. In sarcoidosis, a condition in
that similar cytokine dysregulation can which granulomas are formed inappropri-
cause different pathologies in different ately and in absence of an infectious
organ systems, depending on when, threat, high expression of IL-1 and TNF-α
where, why, and how the dysregulation correlates with granuloma formation.68,75
occurs. This is critical because the most With giant cell arteritis, there are similar
efficacious treatment for apparently unre- reports of cytokine elevation, specifically
lated conditions may turn out to be a sin- of IL-1 and TNF-α.64,76
gle drug or group of drugs, as in the case of Twenty years from now, a complete list
anti-TNF-α therapy in RA and CD. of I.M.I.D.s may encompass not only the
Giant cell (or temporal) arteritis and relatively rare diseases that we today con-
sarcoidosis present interesting examples sider to be of autoimmune origin but
of similar cytokine dysregulation in differ- other, more prevalent conditions, includ-
ent tissue microenvironments causing dif- ing chronic obstructive pulmonary dis-
ferent clinical findings. The former is an ease, asthma, and even atherosclerosis.
inflammatory condition involving upper Not all of these conditions will necessarily
extremity and particularly facial arteries, be treated or cured with pro- or anticy-
and results in headache, jaw pain, and tokine therapy. Cytokine dysregulation
even blindness, if untreated.63 In contrast, and immune-mediated inflammation,

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 Immune-Mediated Inflammatory Disorders (I.M.I.D.s): The Economic and Clinical Costs

however, may prove to be key drivers of employers, and benefits consultants. To

these conditions’ pathophysiologies. understand the effect of I.M.I.D.s on the
lives most pertinent to these groups, we
The Clinical and Economic Burden will also examine I.M.I.D. claim preva-
of I.M.I.D.s for Large Employers and lence and cost in a random sample of cor-
Managed Care Organizations porate workers and their dependents. To
Although I.M.I.D.s may affect as much do so we will use the Medstat Group’s
as 5% to 7% of the overall population and MarketScan claims database.
can cause severe morbidity and mortali-
ty, employers, managed care organiza- I.M.I.D. Epidemiology and Cost in the
tions (MCOs), and benefits consultants Overall US Population. If autoimmune
have not typically thought of I.M.I.D.s as disease affects 5%-7% of Western popula-
a specific class of disease1,4 (personal tions, the prevalence of I.M.I.D.s at this
communication, P. Lopatka, July 2002). time may be less, as cytokine dysregula-
Major diagnostic categories (MDCs) tion has not been convincingly impli-
group related diseases according to their cated in all autoimmune conditions.
International Classification of Diseases, Nevertheless, because autoimmune dis-
Ninth Revision (ICD-9) codes, and there eases involve immune-mediated inflam-
is an MDC called Endocrine, Metabolic, mation—which almost by definition
and Immunity Disorders.77 The immuni- involves cytokine dysregulation—it can be
ty disorders included in that MDC, how- argued that many additional autoimmune
ever, typically involve reduction, not diseases will be classified as I.M.I.D.s once
dysregulation, of immune function (eg, their molecular mechanisms are fully
hypogammaglobulinemia). understood.
Rather than being included in that Table 2 lists the prevalence numbers
MDC, most I.M.I.D.s fall into MDCs specif- for various I.M.I.D.s as cited in the litera-
ic to the organs they affect. For example, ture. The prevalence rates vary dramati-
RA falls into Diseases of the Musculo- cally, from a low of 16.9 per 100 000 for
skeletal System and Connective Tissue, autoimmune hepatitis to 860 per 100 000
and multiple sclerosis is grouped with for RA. Although some I.M.I.D.s, such as
Diseases of the Nervous System and Sense CD, ulcerative colitis, and T1DM, have
Organs.77 This type of organ-based classifi- similar prevalence among men and
cation somewhat mirrors the allocation of women, many I.M.I.D.s, including RA,
I.M.I.D.s to medical specialists. Although multiple sclerosis, and systemic lupus ery-
it is true that rheumatologists treat sever- thematosus, are much more prevalent
al kinds of I.M.I.D.s, including RA, sys- among women.78 There are at least 2 the-
temic lupus erythematosus, and systemic ories for the differential prevalence. First,
sclerosis, many other I.M.I.D.s are treated female sex hormones may drive immune-
by clinicians who specialize in the organs mediated inflammation, and second, fetal
the I.M.I.D.s afflict. cells may lodge within the organs of preg-
Discussing the reasons why organ- nant women during gestation (a phenom-
based classification of the I.M.I.D.s still enon called microchimerism) and later
exists is beyond the scope of this review. It cause I.M.I.D. pathophysiology.79-81
should be emphasized, however, that The I.M.I.D. costs reported in the liter-
because I.M.I.D.s are usually not seen as a ature similarly vary, both between differ-
distinct disease class, their aggregate clin- ent I.M.I.D.s and within the range of
ical and economic tolls are easily over- values for individual I.M.I.D.s. The latter
looked. Within the epidemiological variance results in part from conflicting
literature, there are some estimates of the methodologies used in the different stud-
I.M.I.D.s’ burden on the overall popula- ies to calculate cost.
tion, and the article will review those data. Before considering these numbers, we
Yet for reasons described below, those will review the different types of costs.
data may not be relevant to MCOs, large Direct costs are those generated in the

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REPORT

provision of care, and indirect costs are Of all I.M.I.D.s, RA offers the most
those nonmedical losses, such as lost extensive direct cost information. Inflated
productivity, that result from illness. by the Medical Care consumer price index
Intangible costs are those losses, (eg, pain to year 2000 dollars, annual direct costs
and suffering) that can be measured only for the disease range from $2607 to
subjectively. Direct costs can be divided $9644 96,97 (Table 3). For the other
into those that are medical (eg, surgeon’s I.M.I.D.s, annual direct cost estimates
fees) and nonmedical (eg, parking at the range widely, from $791 for psoriasis to
hospital).95 $15 733 for systemic lupus erythematosus.
Direct medical costs are the expenses Most I.M.I.D.s, especially those that are
most frequently considered in health eco- debilitating, exhibit substantial cost skew-
nomic studies, and those are the costs pre- ness (ie, their costs are not evenly distrib-
sented here, both from the literature and uted among the patients suffering from the
from MarketScan.95 When only direct disease). With RA, for example, less than
costs are considered, however, the true 25% of the patient population is responsi-
financial burden of a disease on patients, ble for between 43% and 75% of the dis-
payers, employers, and society will likely ease’s annual direct cost.96 With CD and
be underestimated. This is especially true ulcerative colitis, the skewness is even
with the I.M.I.D.s because so many of more dramatic, with 2% of the patient pop-
them strike young people at the prime of ulation accounting for 34% and 39% of
their productivity and subject them to medical costs paid, respectively.83 If the
chronic disability. disease burden of these mostly severely
afflicted individuals could be reduced,
substantial cost savings might result.

I.M.I.D. Epidemiology and Cost in

Table 2. Prevalence of Immune-Mediated Inflammatory Disorders
the Medstat MarketScan Population.
as Reported in the Literature
There are 2 main reasons why the above
Prevalence
data may not be relevant for MCOs, large
employers, and benefits consultants.
Condition Per 100 000 % Female Reference
First, many of these cost and prevalence
Autoimmune hepatitis 16.9 N/A 82
values are taken from the American pop-
ulation as a whole rather than from the
Crohn’s disease 1.2-106 ~50 83, 84, 85
population of workers/dependents to
Giant cell arteritis 27.9 N/A 86
which large employers provide health
Type 1 diabetes mellitus 192 47.8 78
insurance, and these 2 populations may
Multiple sclerosis 120.5 64.2 87 not be comparable. For example, the
Sarcoidosis 0.2-64 57.3 88 overall population might include the sick-
Psoriasis 537 N/A 89 est I.M.I.D. patients who have become so
Psoriatic arthritis* 101 N/A 90 disabled that they are unable to work,
Ankylosing spondylitis 100-200 ~30 91, 92 causing the overall population’s I.M.I.D.
Rheumatoid arthritis 860 74.8 78 cost-severity mix to be higher than that of
Systemic lupus erythematosus 50.8 88.2 78, 93 the large employer population. In con-
Systemic sclerosis 37.5 92.2 78, 94 trast, I.M.I.D. prevalence might be higher
Ulcerative colitis 39-117 ~50 83,84,85
in the large employer population than
generally if I.M.I.D. patients or caregivers
All Prevalence-Listed I.M.I.D.s† 2258 per 100 000
strive to work for large employers, know-
ing that health insurance and disability
*Psoriatic arthritis prevalence is assumed to be captured within psoriasis
benefits are likely to be generous at those
prevalence. corporations.
†Range midpoints were used for total prevalence calculations. Second, there is no consensus on how
I.M.I.D. indicates immune-mediated inflammatory disorder; NA, not available. direct cost is calculated in the literature.

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 Immune-Mediated Inflammatory Disorders (I.M.I.D.s): The Economic and Clinical Costs

Are copayments included or not? Do med-

ical costs reflect what providers charge or Table 3. Immune-Mediated Inflammatory Disorder Costs in
what they actually collect? The claims the United States as Reported in the Literature
that providers make to payers (ie,
Direct Cost
charges) represent the price of the Disease (Year 2000 $) Reference
providers’ services, but not necessarily the
actual economic inputs required to offer
Ankylosing spondylitis 1838 91
those services. Alternatively, the amount
actually paid to providers for care may be Autoimmune hepatitis N/A
less than its true economic cost. Even if Crohn’s disease 14 647 98
payment equals cost, it may be difficult to 14 302 83, 99
define what has been paid where. To make 5082 100
the data even more problematic, most of Type 1 diabetes mellitus 8800 101
the literature cost studies were completed Giant cell arteritis N/A
before the advent of anticytokine therapy.
Multiple sclerosis 10 732 102
Because of these potentially insoluble
problems, large employers, MCOs, and Psoriasis 791 89
benefits consultants need a different Rheumatoid arthritis 9644 103
approach to understand the prevalence 9134 103
and cost of I.M.I.D.s in the corporate pop- 7904 103
ulations they represent. To that end, we 7539 103
calculate prevalence and cost using a 6807 104
method based on what employers desig- 6547 96
6189 105
nate as “eligible” (to be paid) claims for all
5383 106
inpatient and outpatient I.M.I.D. care.
4765 103
Rather than use a single employer or 2971 107
MCO, we use a group of employers, specif- 2882 103
ically those that are represented in the 2621 103
Medstat MarketScan database. 2607 103
Sarcoidosis N/A
Methods of Analysis
Systemic lupus erythematosus 15 733 108
The Medstat Group, a subsidiary of the
8002 109
Thomson Corporation, is a health informa-
tion company that maintains a multi- Systemic sclerosis 5856 94
source database of privately insured claim Ulcerative colitis 9609 83, 99
and encounter data known as MarketScan.
The database includes 4 years of data
(1997-2000), approximately 45 companies NA indicates not available.
for each year of data, and approximately
2.5 million covered lives in each year.
Individuals can be tracked via a unique summed in each plan year. Patient identi-
identifier through all years for which fication numbers were checked between
MarketScan has data, and claims data cap- the inpatient and outpatient claims lists to
ture inpatient admissions and services, ensure there was no duplication.
outpatient services, and drug information. (Although it is possible that those patients
Patients are grouped by age, gender, suffering from milder I.M.I.D. cases might
employee classification, industry of not make a single I.M.I.D.-related claim
employer, region, and insurance plan type. during a plan year, this was deemed to be
Data runs were performed for 1999 and unlikely. Nevertheless, it should be noted
2000. To calculate the prevalence num- that for this reason, our methodology of
bers, the number of unique lives with at prevalence calculation may slightly
least 1 inpatient or outpatient claim underestimate true I.M.I.D. prevalence.)
indexed to 1 of the ICD-9 codes listed was The numbers of claimants for each

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REPORT

cost for those patients with each I.M.I.D.

Table 4. Immune-Mediated Inflammatory Disorder In this way we removed what we estimat-
Prevalence According to Medstat MarketScan, 1999-2000 ed to be the medical cost for I.M.I.D.
patients not associated with or secondary
Prevalence Per to I.M.I.D.s. In essence, the remaining
Condition 100 000 % Female
value is the best possible valuation of med-
ical claims directly or indirectly due to
Autoimmune hepatitis 15.2 48.2
I.M.I.D. pathophysiology.
Crohn’s disease 118.6 54.9
To generate the PMPY figure for each
Type 1 diabetes mellitus 700.3 49.5
I.M.I.D., we multiplied the prevalence
Giant cell arteritis 9.5 72.2 numbers per 100 000 lives by the average
Multiple sclerosis 130.4 74.3 I.M.I.D. eligible claims cost (net of the
Sarcoidosis 61.0 62.5 baseline claims cost, as described above)
Psoriasis 329.5 50.8 and divided by 100 000. A query estab-
Psoriatic arthritis 23.6* 48.1 lished that no claimant fell into multiple
Ankylosing spondylitis 24.2 36.1 claims categories (eg, no patient with
Rheumatoid arthritis 335.8 73.7 T1DM claims also had claims for CD). As a
Systemic lupus erythematosus 97.0 89.4 result, the PMPY figures generated are
Systemic sclerosis 18.9 85.3
additive.
I.M.I.D. prevalence and gender distribu-
Ulcerative colitis 156.0 52.9
tion for the MarketScan population, aver-
Sum prevalence of listed I.M.I.D.s 2020 per 100 000
aged for the years 1999 and 2000, are
listed in Table 4. The percentage-female
*Psoriatic arthritis prevalence is assumed to be captured within psoriasis values from MarketScan are similar to
prevalence those found in the literature. For example,
I.M.I.D. indicates immune-mediated inflammatory disorder. 49.5% of T1DM claimants in MarketScan
are female, as compared to 47.8% in the
literature. Likewise, the gender distribu-
I.M.I.D. ICD-9 codes were then divided tion for CD and ulcerative colitis is evenly
by the total number of database partici- split both in the literature and in
pants to obtain prevalence rates per 100 MarketScan. For I.M.I.D.s that are typical-
000 lives. In addition, male and female ly more prevalent in the female popula-
distributions were determined. These tion, there is also concurrence between
operations were performed for both MarketScan and the literature. The litera-
1999 and 2000. ture cites female percentages of 74.8% for
To generate I.M.I.D. cost data, we used RA and 88.2% for systemic lupus erythe-
the MarketScan’s eligible claims field. For matosus, and from MarketScan the
those male and female claimants for each respective numbers are 73.7% and 89.4%.
ICD-9 codes, we summed all of their eligi- There are, however, significant differ-
ble claims. This calculation provided the ences in the I.M.I.D. prevalence rates
total eligible healthcare claims for those between the literature and MarketScan. In
people with I.M.I.D.s. For the people with several cases, MarketScan I.M.I.D. preva-
each I.M.I.D., we then divided their total lences are higher than those cited in the
costs by the number of claimants to gen- literature. For example, the MarketScan
erate an average eligible claim cost for prevalences for CD, T1DM, and systemic
each I.M.I.D. patient; this operation was lupus erythematosus are greater than the
performed separately for both the male literature values by approximately 200%
and female populations. Next, average eli- or more. In contrast, the MarketScan
gible claim cost was generated for the prevalence for RA is considerably less
overall MarketScan male and female popu- than that cited in the literature. Given
lations, excluding those people with the evidence that RA incidence has been
I.M.I.D. claims. Next, that value was sub- progressively decreasing for at least 50
tracted from the average eligible claim years, from 61.2 per 100 000 in 1955-

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 Immune-Mediated Inflammatory Disorders (I.M.I.D.s): The Economic and Clinical Costs

1964 to 32.7 per 100 000 in 1985-1994,

the MarketScan figure may be more reflec- Table 5. Immune-Mediated Inflammatory
tive of actual RA prevalence.110,111 Disorder Eligible Claim Cost According to
Medstat MarketScan, 1999-2000
As stated above, one might expect that
I.M.I.D. prevalence would be lower in the Eligible Claim
MarketScan population than in the general Condition Cost ($)
population, as most of the I.M.I.D.s are
chronic and many can be debilitating. For Autoimmune hepatitis 5151
that reason, people with severe cases might Crohn’s disease 7420
be expected to quit their jobs and apply
Type 1 diabetes mellitus 9476
for Medicare/Social Security Insurance dis-
Giant cell arteritis 8642
ability payments, thus exiting the
MarketScan population. Large employers, Multiple sclerosis 9382
however, typically provide benefits for Sarcoidosis 5388
employees and dependents with chronic Psoriasis 2126
illnesses that are better than those offered Psoriatic arthritis 3638
by Medicare.112 The generosity of these
Ankylosing spondylitis 4571
benefits, combined with the disability cov-
Rheumatoid arthritis 6204
erage provided by large employers, might
induce employees diagnosed with I.M.I.D.s Systemic lupus erythematosus 8141
to stay with their companies for as long as Systemic sclerosis 9075
possible. Similarly, healthy workers with Ulcerative colitis 5775
I.M.I.D.-afflicted dependents might be
compelled to remain with their employers.
Moreover, job seekers either suffering from
I.M.I.D.s or with dependents who have the and dependents in the insured population.
diseases might opt for employment at large Importantly, PMPY eligible claims reflect
corporations, especially given the limita- the average liability that employers can
tions on pre-existing condition exclusions expect from I.M.I.D.s for claimants who
in effect since adoption of the Health have no other insurance policy primary to
Insurance Portability and Accountability their employer-sponsored plan.
Act. For these same reasons, it could be Although some PMPY values listed seem
argued that I.M.I.D. patients in MarketScan small and potentially insignificant (eg,
might be more severely afflicted and thus those for autoimmune hepatitis and giant
more costly than those in the general pop- cell arteritis), the sum PMPY expenses for
ulation. the I.M.I.D.s listed total $139.84. To put
In fact, I.M.I.D. cost estimates are rel- this in perspective, the average per capita
atively similar in MarketScan and in non-I.M.I.D. eligible claims cost—which
the literature (Table 5). For example, represents the sum of all claims for those
MarketScan’s average, annual, per patient people without an I.M.I.D. diagnosis—aver-
eligible claims for RA are approximately aged $2098.62 in 1999-2000. The per-capi-
$6204, as compared to literature citations ta eligible claim costs for the I.M.I.D.s
of $2607 to $9694. For CD, the per patient listed are therefore 6.7% of the total per
eligible claims are $7420, as compared to capita claim costs for non-I.M.I.D. patients
literature reports of $5082 to $14 647. in MarketScan.
Combining the prevalence and cost data It should be emphasized that many clas-
from MarketScan offers perhaps the most sical autoimmune diseases, such thyroidi-
important I.M.I.D. cost statistic for large tis, autoimmune anemia, and myasthenia
employers, MCOs, and benefits consult- gravis, have not been included in the
ants: PMPY eligible claims (Table 6). For review because the role of cytokines in
each I.M.I.D., the PMPY cost represents the these conditions has yet to be elucidated.
potential amount of disease-related cost As the frontiers of molecular medicine
divided by the total number of all workers expand, many of these autoimmune condi-

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REPORT

disease often seemed to progress, despite

Table 6. Immune-Mediated Inflammatory the extremely high doses that were used in
Disorder Per Member Per Year Costs in the early years of treatment.114
Medstat MarketScan, 1999-2000 For other I.M.I.D.s, glucocorticoid ther-
apy has achieved a much less controversial
PMPY Eligible record and is often the standard of care. In
Condition Claim Cost ($) CD, for example, prednisone is widely used
for flares, and methylprednisone is stan-
Type 1 diabetes mellitus 66.35 dard therapy for multiple sclerosis relaps-
Rheumatoid arthritis 20.84 es.115,116 Nevertheless, even with the
Multiple sclerosis 12.23
much lower doses used now than in
Hench’s time and careful tapers, pro-
Ulcerative colitis 9.01
longed glucocorticoid therapy remains
Crohn’s disease 8.80 fraught with side effects, including but
Systemic lupus erythematosus 7.90 not limited to osteoporosis, hypertension,
Psoriasis 7.00
hyperglycemia, and weight gain.117
Cognizant of these side effects, clinicians
Sarcoidosis 3.29
have long wanted a new type of I.M.I.D.
Systemic sclerosis 1.71 therapy with the same wide-reaching
Ankylosing spondylitis 1.11 applicability and efficacy as glucocorti-
Giant cell arteritis 0.82
coids but with much greater safety.
Over the years, a wide range of immuno-
Autoimmune hepatitis 0.78
suppressant therapies, including azathio-
Total 139.84 prine, cyclophosphamide, cyclosporine,
leflunomide, methotrexate, and tacrolimus,
PMPY indicates per member per year. have been used to treat I.M.I.D.s, often
with great success.118 Yet because many of
these therapies involve serious systemic
toxicity, the search continued for an effec-
tions may be determined to be cytokine tive I.M.I.D. therapy with moderate side
driven, potentially allowing their inclusion effects.
in the I.M.I.D. group. For that reason, The concept that proinflammatory
future studies could show that I.M.I.D.s cytokines might play a key role in the
represent a far greater share of large pathogenesis of not one but many I.M.I.D.s
employers’ total healthcare liability. led investigators to theorize that blocking
those cytokines might have therapeutic
benefit. The hypothesis was correct, and
What Can Be Done—I.M.I.D. Therapy currently, at least 5 anticytokine therapies
in the 21st Century have significantly advanced the treatment
Before the 1940s, little could be done of several I.M.I.D.s, including RA and CD.
to treat most I.M.I.D.s. That changed in In this section the review will examine the
1948 when American rheumatologist anticytokine therapies currently in use
Phillip Hench administered a newly iso- and those in development. It is important
lated compound called cortisone to to emphasize that anticytokine therapy is
patients with RA.113 In many patients the not appropriate for all patients with all
results of treatment were dramatic, and I.M.I.D.s. Nevertheless, the data presented
word spread globally of a new miracle below demonstrate the potential for signif-
cure, with Hench and his colleagues win- icant therapeutic benefit in certain clini-
ning the Nobel Prize for Medicine in cal situations.
1950.114 Unfortunately, the severe side
effects of cortisone and other glucocorti- TNF-α Blockade—The First Anticyto-
coid compounds quickly became appar- kine Therapy. As mentioned above, sev-
ent. In addition, even with therapy, the eral mouse studies suggested that TNF-α

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 Immune-Mediated Inflammatory Disorders (I.M.I.D.s): The Economic and Clinical Costs

blockade could be therapeutic in reducing patients to attain remission and that

the joint inflammation of RA.35,119 These repeated infliximab infusions could help
findings, as well as an overall appreciation recipients maintain it.124
of the inflammatory capabilities of TNF-α, Infliximab’s use has not been limited
presaged the development of several dif- to RA and CD. Open-label studies have
ferent TNF-α–blocking molecules, 2 of shown it to be effective in the treatment of
which are now available commercially. psoriasis and ankylosing spondylitis, and
Anti-TNF-α therapy is not appropriate for case reports have demonstrated its thera-
all I.M.I.D. patients, but for certain peutic value in sarcoidosis and giant cell
patients there is substantial evidence of arteritis.71,125-127
clinical benefit.
Etanercept. A fusion protein contain-
Infliximab. Infliximab, a mouse- ing domains from the TNF-α receptor,
human chimeric antibody against TNF-α, etanercept is the other commercially
showed promise in early human clinical available anti-TNF-α therapy.3 A blinded
trials for RA. It significantly reduced a trial of 180 RA patients showed those
host of inflammatory signs, including joint receiving etanercept had a 61% reduction
swelling.120 A larger trial tested infliximab in their number of swollen joints, as com-
with and without methotrexate, a stan- pared to a 25% reduction with placebo.128
dard therapy for RA. This trial of 101 In a subsequent study in which RA
patients showed that infliximab infusions patients received etanercept and
of 10 mg/kg combined with methotrexate methotrexate or methotrexate alone, 39%
caused a 70%-90% reduction in the of the etanercept patients met ACR 50 cri-
number of swollen joints and C-reactive teria, as compared to 3% of those patients
protein, a marker for inflammation.121 receiving methotrexate alone.129 (The
The efficacy of infliximab, however, American College of Rheumatology [ACR]
was most convincingly demonstrated definition of improvement in clinical trials
in the randomized, controlled Anti-TNF involves a) improvement in joint counts
Trial in Rheumatoid Arthritis with and b) improvement in at least 3 of the
Concomitant Therapy (ATTRACT). Four following: patient assessment, physician
hundred and twenty-eight patients assessment, erythrocyte sedimentation
receiving methotrexate were given inflix- rate, pain scale, and functional ques-
imab, 3 mg/kg or 10 mg/kg, or placebo for tionnaire. The ACR 20, ACR 50, and
2 years. Infliximab and methotrexate were ACR 70 criteria reflect an improvement of
shown to be significantly better than 20%, 50%, or 70% in these metrics).130
methotrexate alone in reducing the signs Etanercept has also been shown to be
and symptoms of RA. Most important, effective in reducing the signs and symp-
infliximab and methotrexate—but not toms of juvenile RA.131
methotrexate alone—were shown to halt Like infliximab, etanercept has demon-
the progression of joint damage.122 strated efficacy in treating other I.M.I.D.s
Infliximab’s therapeutic value is not besides RA. A randomized, controlled trial
limited to RA—not surprising given the of 60 patients with psoriasis and psoriatic
common cytokine-driven pathophysiology arthritis showed that etanercept-treated
of many I.M.I.D.s. Infliximab, for example, patients achieved a 46% improvement in
has proven both safe and efficacious in the their psoriasis symptoms, as compared to
treatment of CD. An initial clinical trial of a 9% improvement for placebo-treated
108 patients showed that a single infusion patients.132 In addition, 87% of etanercept-
of infliximab was an effective short-term treated patients had significant improve-
treatment in patients with moderate-to- ment of their arthritic symptoms, as
severe disease, with 33% of infliximab compared to 23% of patients treated with
patients but only 4% of placebo controls placebo.132 A trial of 40 patients has
achieving remission.123 A subsequent demonstrated etanercept to be effective in
study showed that infliximab enabled the treatment of ankylosing spondylitis,

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REPORT

with 80% of patients in the treatment that effect.138 Both infliximab and etan-
group achieving a clinical response as ercept have been associated anecdotally
compared to 30% of patients in the place- with systemic lupus erythematosus and
bo group.133 more broadly with the induction of anti-
nuclear antibodies in as many as 10% of
IL-1 and IL-2 Blockade—Another treated patients.139,140
Anti-inflammatory Strategy. The above- There is also evidence that inhibition of
mentioned studies confirmed what has TNF-α may suppress normal immunity.
long been suspected about TNF-α: it plays For example, a retrospective study of
a proinflammatory role in several 147 000 patients treated with infliximab
I.M.I.D.s. Similarly, a recently approved suggests the rate of active tuberculosis
anti-IL-1 therapy, anakinra, and 2 recent- infection is higher in those patients than
ly approved anti-IL-2 therapies, daclizum- in controls.141 Similarly, a series of ran-
ab and basiliximab, highlight the domized, controlled trials with 771
importance of these 2 cytokines in the patients showed those receiving inflix-
generation of I.M.I.D. pathophysiology. imab had a 26% risk of any infection dur-
Approved in 2001, anakinra is the ing 27 weeks of follow-up as compared to
recombinant version of a naturally occur- a 16% risk at 20 weeks for those receiv-
ring molecule known as the IL-1 recep- ing placebo. Despite this increased risk
tor antagonist.134 IL-1 plays a critical role of infections in the infliximab popula-
in the inflammatory cascade of RA, and tion, there was no increased risk of seri-
by blocking IL-1, anakinra has demon- ous infection.142 In summary, none of the
strated clinical efficacy in the treat- anticytokine therapies are without side
ment of the disease.135 In a randomized, effects, but these adverse events appear
controlled trial of 472 patients, 43% of to be relatively rare.142,143
those receiving anakinra at 150mg/day
achieved the ACR 20 response, as com- Anticytokine Therapy—The Next
pared to 27% of patients receiving Generation. With the success of inflix-
placebo.134 imab and etanercept, many new anticy-
Like IL-1, IL-2 plays a key part in T cell tokine therapies are in development, and
activation, an important event in the several are in phase III trials. Like inflix-
inflammatory process that leads to rejec- imab, many of these products are mon-
tion of organ transplants in the absence of oclonal antibodies. Because monoclonal
immunosuppressive therapy. By blocking antibodies in phase III trials have a 30%
IL-2, both daclizumab and basiliximab or higher chance of receiving final Food
have been shown to reduce the rejection and Drug Administration approval, large
of kidney transplants at 6 months as com- employers, MCOs, and benefit consult-
pared to placebo, by 37% and 32%, respec- ants should consider these molecules in
tively.136,137 Given the widespread role of advance of their potential launches.144
IL-2 in the inflammatory process, IL-2 Adalimumab, a human anti-TNF mono-
blockade may prove to have wide-reaching clonal antibody; CDP571, a “humanized”
therapeutic utility. anti-TNF monoclonal antibody; and
CDP870, a high affinity anti-TNF-α anti-
Anticytokine Therapy—Is it a body fragment are each in phase III
Panacea? The new anticytokine thera- clinical trials.145-147 Preliminary results
pies have dramatically improved the from the Safety Trial of Adalimumab in
prognoses for several I.M.I.D.s, includ- Rheumatoid Arthritis (STAR) indicate a
ing RA and CD. The success of these 30% achievement of ACR 50 criteria with
therapies, however, raises the question adalimumab treatment, as compared to
of whether blocking cytokine activity 11% with placebo.148 With the success of
might interfere with normal physiology. anti-TNF-α therapy in the treatment of
Unfor-tunately, anticytokine therapies CD, trials of adalimumab for that condi-
may, in relatively rare instances, have tion are also scheduled.149

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 Immune-Mediated Inflammatory Disorders (I.M.I.D.s): The Economic and Clinical Costs

A phase III trial of CDP571 for CD has

recently yielded preliminary results, Table 7. Other Anticytokine Therapies in Development
which showed treated patients did not
meet the study’s primary end point.147 Development
Phase of
The drug has, however, shown promise
Condition Product Cytokine Targeted Product
as a potential therapy for RA.150 CDP870
is also undergoing phase III testing for
Crohn’s disease J-695 IL-12 Phase II
RA and CD.145 CDP870 is different from SMART IFN-γ Phase II
adalimumab and CDP571, however, in
Multiple sclerosis J-695 IL-12 Phase II
that it is PEGylated (ie, the drug formu-
lation contains a polyethylene glycol Rheumatoid arthritis J-695 IL-12 Phase II
[PEG] moiety that improves the drug’s HuMax-IL15 IL-15 Phase II
pharmacokinetics and allows it to stay Psoriasis ABX-IL-8 IL-8 Phase II
in the circulation longer). 151,152 The Systemic sclerosis CAT-192 TGF-β Phase II
PEGylation strategy is also being used
with a new soluble version of the TNF-α
receptor, currently in phase II trials.153 IFN indicates interferon; IL, interleukin; TGF, transforming growth factor.
In addition to these anti-TNF-α thera-
pies, several molecules targeting other
cytokines are also in development
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