| Cytokines in Rheumatoid
Arthritis William P. Arend, MD
Division of Rheumatology
University of Colorado School of Medicine
Denver, CO
Summary Points
- Levels of IL-1 and TNF-a are increased in RA and allow migration of
WBCs into inflammatory sites and the release of MMPs, which increase the inflammation and
tissue damage.
- Etanercept and infliximab -- agents that
block TNF-a -- result in clinical improvement in RA and limit bony damage.
- Anakinra, an IL-1 receptor antagonist, also
results in clinical improvement of RA and limits bony damage.
Introduction
Cytokines are small molecular weight
proteins that mediate communication between cells (1,2). The generic term
“cytokines” includes colony-stimulating factors, growth factors, interleukins,
and interferons.
Cytokines carry out their functions
primarily in the immediate cell environment in tissues, although some cytokines may act at
a distance by traveling through the bloodstream. Cytokines work by binding to specific
receptors on target cell surfaces, stimulating responses in cells that result in the
increased or decreased production of proteins.
Cytokines are involved as mediator
molecules in normal biologic processes. These physiologic functions include growth and
differentiation of hematopoietic, lymphoid, and mesenchymal cells, as well as
orchestration of host defense mechanisms.
Cytokines act in a self-regulatory network
that is intended to maintain homeostasis of the internal environment. However, the
unregulated or inappropriate production of particular cytokines may lead to pathological
consequences in autoimmune and inflammatory diseases (3,4).
The inhibition of production or effects of
specific cytokines has reached the therapeutic marketplace. The objective of this brief
review is to present the background on tumor necrosis factor alpha (TNF-a) and
interleukin-1 (IL-1) in rheumatoid arthritis (RA) and to summarize the results of clinical
trials on new therapeutic approaches to block these cytokines.
IL-1 and TNF-a
IL-1 and TNF-a have been implicated in
pro-inflammatory mechanisms in many human diseases including inflammatory arthritis,
inflammatory bowel disease, sepsis syndrome, and both acute and chronic inflammation of
many organs (5,6). These cytokines are important in host defense against microorganisms
that reside within cells, such as mycobacteria or listeria, as well as in other host
defense responses and physiological processes.
IL-1 and TNF-a bind to different receptors
but share many properties in mechanisms of disease. For purposes of this review, these
cytokines will be considered together, but it should be noted that one cytokine or the
other may predominate in a particular disease.
IL-1 and TNF-a are produced primarily by
monocytes and tissue macrophages, and are major cytokines in the initial line of defense
against pathogens as part of the innate immune system (7). The major effects of these
cytokines in diseases include stimulation of adhesion molecule expression on endothelial
cells and induction of the production and release of matrix metalloproteinases (MMPs) from
fibroblasts, chondrocytes, osteoblasts, and other cells.
The end result of these unregulated effects
of IL-1 and TNF-a include the migration of leukocytes and lymphocytes from the blood into
inflammatory tissues and the degradation of connective tissues and cartilage. This
produces inflammation and tissue destruction.
The reasons why IL-1 and TNF-a are produced
in excess in RA and other diseases are not clear but may involve activation of macrophages
by T lymphocytes and fibroblasts, as well as by soluble factors produced as part of the
inflammatory response. Natural anti-inflammatory mechanisms exist to limit or dampen the
effects of IL-1 and TNF-a. These mechanisms include the release of soluble cytokine
receptors and the production of IL-1 receptor antagonist (IL-1Ra), a structural variant of
IL-1 that binds to target cells but fails to stimulate intracellular responses (8).
Based on new knowledge on the importance of
IL-1 and TNF-a in inflammation and tissue destruction in many human diseases, new
therapeutic approaches have been developed to block the production or effects of these
cytokines (9). Existing therapeutic agents such as corticosteroids, gold injections, and
methotrexate may all work at least in part by blocking the production of IL-1 and TNF-a.
However, the recent development of more potent anti-cytokine biologic agents has lead to
dramatic clinical responses, particularly in RA.
TNF-a Blockade in the Treatment of RA
The two available TNF-a blockers are
etanercept, a form of soluble TNF receptors, and infliximab, a monoclonal antibody to TNF.
Etanercept is delivered by subcutaneous (SC) injections of 25 mg twice weekly each whereas
infliximab is given by intravenous infusion at 0, 2, and 6 weeks and every 8 weeks
thereafter. The indications for use of these biologic agents in the treatment of RA are
unresponsiveness to the usual disease-modifying drugs, including methotrexate in high dose
and in combination with other drugs, or intolerable side effects to these agents.
Etanercept is approved for use with or without methotrexate whereas infliximab is approved
for use only with methotrexate.
A series of publications over the past five
years have described the results of clinical trials with etanercept in RA. The initial
clinical trials are summarized in Table 1 (10-12). Either used alone or in combination
with methotrexate, etanercept led to significant clinical improvement as measured by the
ACR 20, 50, and 70. It was observed that stopping etanercept after 3 months led to a
return of active synovitis. The major side effects to etanercept were injection site
reactions and mild upper respiratory tract symptoms. In addition, 5% of treated patients
developed anti-double-stranded DNA antibodies at 6 months.
In the most recent trial in RA, 632
patients with early RA (< 3 years) were treated either with etanercept at 10 or 25 mg
SC twice weekly or with methotrexate (mean dose 19 mg/week) (13). Although the percentages
of patients achieving ACR 20, 50, and 70 levels of improvement were no different at 12
months, the patients treated with 25 mg injections of etanercept exhibited slightly more
rapid responses over the first 4 months. In addition, 72% of the patients who received the
higher dose of etanercept exhibited no increase in radiographic erosions at 1 year in
comparison to 60% of the patients who received methotrexate. Etanercept also has been
shown to be effective in the treatment of polyarticular juvenile rheumatoid arthritis
(14).
A monoclonal antibody to TNF-a, infliximab,
also has been shown to be effective in the treatment of RA (15). In the original
controlled trial, patients receiving a single or multiple infusions of infliximab
demonstrated early efficacy (16,17). However, human antibodies to the murine IgG developed
in over half of these patients and possibly were associated with reduced clinical
responses.
Infliximab was next evaluated in
combination therapy with methotrexate (18). A trial carried out over 4 months described a
Paulus 20 or 50 response in 50% to 60% of patients treated with 5 infusions of infliximab
at 1, 3, or 10 mg/kg combined with methotrexate, compared to up to 10% of patients treated
with methotrexate alone. Patients receiving infliximab alone at the higher 2 doses
exhibited lower percentages of Paulus 50 responses. However, the development of human
antibodies to murine IgG was greatly reduced by the concomitant treatment with
methotrexate.
The results of more recent clinical trials
of infliximab given in combination with methotrexate are summarized in Table 2 (19,20). In
studies carried out over 7 to 12 months, significantly higher ACR 20, 50, and 70 responses
were observed in patients receiving infliximab 3 or 10 mg/kg every 4 to 8 weeks, along
with methotrexate at a median dose of 15 mg/wk, in comparison to methotrexate alone. In
addition, patients treated with the combination of infliximab and methotrexate over 12
months demonstrated an absence of radiographic evidence of progressive joint damage
whether or not they exhibited a clinical response.
Side effects to treatment with infliximab
included the development of antinuclear antibodies in up to 68% of patients and of
anti-DNA antibodies in 10% (21). A few patients treated with infliximab developed clinical
symptoms of systemic lupus erthematosus (SLE), with these manifestations responding to
discontinuation of the agent. Other adverse events observed in patients treated with the
combination of infliximab and methotrexate, compared with methotrexate alone, included
upper respiratory infections, sinusitis, pharyngitis, and headache. Infusion reactions
have also occurred with infliximab.
Recent publications have described the
appearance of additional serious side effects to treatment with TNF-blocking agents.
Whether these therapeutic agents
predispose to the development of malignancy will require longer-term follow-up studies.
Voluntary reporting to the FDA described
the reactivation of latent tuberculosis in 70 patents treated with infliximab (22).
Tuberculosis also has developed after treatment with etanercept, but whether this
complication occurs equally with both forms of anti-TNF therapy is not known. Both
anti-TNF agents may predispose to other infectious complications, primarily with
intracellular pathogens such as listeria and fungi.
In addition, demyelination has been
described in 19 patients after TNF blockade, 17 following etanercept and 2 after
infliximab (23). Thus, anti-TNF therapy should not be used in patients with known
infections, or should be stopped should infections develop, and these therapies should be
avoided in patients with SLE, multiple sclerosis, or poorly defined neurological
syndromes.
IL-1 Inhibition in the Treatment of RA
An inhibitor of IL-1, anakinra, has
recently been approved by the FDA for the treatment of RA. This therapeutic agent is the
interleukin-1 receptor antagonist (IL-1Ra) molecule (8). As opposed to the anti-TNF
therapies that bind TNF around cells, preventing their interaction with cell surface
receptors, anakinra competitively inhibits IL-1 binding to cells at the receptor level.
An initial clinical trial in 175 patients
with active RA examined the use of daily SC injections of 3 doses of anakinra or placebo
over 2 months (24). This therapeutic agent was shown to be safe with injection site
reactions the major side effect, although the trial was too small to establish efficacy.
A subsequent clinical trial examined
treatment of 472 patients with active RA with daily SC injections of anakinra or placebo
over 6 months (25). An ACR 20 response was observed in 39%, 34%, and 43%, respectively, of
patients treated with 30, 75, or 150 mg of anakinra in comparison to 27% who received
placebo. An injection site reaction again was the main adverse reaction, leading to a 5%
withdrawal rate in the highest dose group. The radiological progression of disease was
significantly reduced in all 3 treatment groups in comparison to the control patients
(26).
The results of a recently reported trial of
anakinra used in combination with methotrexate are summarized in Table 3 (27). At the most
optimal dose examined, 1.0 mg/kg/day SC injection, 42%, 24%, and 10%, respectively, of
patients treated with anakinra demonstrated ACR 20, 50, and 70 responses at 6 months,
compared to 23%, 4%, and 0% in the placebo group.
Injection site reactions led to withdrawal
of 7% of the patients in this group, and 1.2% of patients developed leukopenia (WBC <
3,000) that reversed after discontinuation of treatment. No increased incidence of
significant infections was observed. However, longer-term follow-up studies are necessary
to assess the possible risk of developing infections or malignancies with anakinra
treatment.
Treatments Under Development
In addition to the 3 therapeutic agents
discussed above, other anti-cytokine agents are under development. Several alternative
approaches to blocking TNF are already undergoing clinical study.
Additional approaches to inhibition of IL-1
include the use of soluble type II IL-1 receptors or an agent called the “IL-1
Trap,” consisting of the extracellular regions of the IL-1 receptor and IL-1 receptor
accessory protein molecules. Initial reports of studies looking at IL-15 and IL-17
blockade in RA also are potentially promising.
Conclusions
Numerous cytokines are involved in
pathophysiologic mechanisms in RA. Both TNF-a and IL-1 mediate events of inflammation and
tissue destruction in this disease. Biologic agents that specifically inhibit the effects
of TNF-a or IL-1 are effective in
the treatment of RA patients who respond poorly to methotrexate.
However, the use of these agents needs to
be monitored carefully for possible side effects, including the development of infections.
Additional anti-cytokine agents for the treatment of rheumatoid arthritis are under
further development.
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