Review article J Indian Rheumatol Assoc 2004 : 12 : 16 - 21

BIOLOGIC RESPONSE MODIFIERS

Firdaus Fatima, URK Rao
Consultant Rheumatologist Sri Deepti Rheumatology Centre, Hyderabad.

Rheumatoid Arthritis (RA) is a debilitating im- to it’s receptor on a target cell, it sets off a signaling
mune mediated disease affecting about 1% of the cascade and alteration of gene transcription in the tar-
world’s population. It is characterized by inflammation get cell. Cytokine synthesis and effect is controlled at
of synovial tissues, joint swelling, stiffness and pain that many levels (i) at the level of message induction, (ii) by
may progress to joint erosion. The traditional disease endogenous soluble receptor and (iii) by endogenous
modifying anti rheumatic drugs (DMARDs) are non- soluble receptor antagonist. Anticytokine therapy cuts
specific immunomodulators, each of which has substan- the communication links between the cells by inhibiting
tial drawbacks in terms of effectiveness or adverse ef- the action of cytokines.
fects. The development of biologic agents has provided In RA the balance between endogenous anti-
more effective therapeutic options. The terms biologic inflammatory mediators and pro inflammatory media-
therapies and biologics have emerged to describe agents tors is disturbed. The production of pro inflammatory
with biologic properties, including monoclonal antibod- cytokines –TNF ∝, IL –1 and others in RA is over-
ies and soluble cytokine receptors. However the term whelming. The anti inflammatory substances produced
biologics may better be replaced with biologic response endogenously in RA include soluble TNF receptors,
modifiers (BRMs). IL-1 receptor antagonist and inhibitory cytokines like
The human immune system comprises both IL-10.
soluble and cellular elements that are designed to de- New therapeutic strategies for blocking the bio-
fend against and eliminate pathogenic intrusion. When logical effects of inflammatory cytokines include anti-
a foreign antigen enters the body, complement and bodies directed against TNF ∝ (e.g., Infliximab),
antibody mediate phagocytosis by the macrophages1. soluble receptors (e.g., Etanercept) and IL-1receptor
Immune cells can interact either by cognate cell-to- antagonist (e.g., Anakinra). Clinical trails indicate that
cell interaction or through secreted mediators, these BRMs may be more effective than traditional
cytokines. . The effects of cytokines are primarily lo- agents because they can alter joint remodelling in addi-
cal; unless so much is made that systemic effects occur. tion to attenuating symptoms.
Many cells of the body, predominantly macrophages
secrete tumor necrosis factor –alpha (TNF-∝), is the Anti TNF therapy:
most important cytokine in the pathogenesis of RA. Two types of agents can supress circulating
Almost all cells of the body have TNF receptors. The TNF: recombinant soluble receptors and monoclonal
receptors for cytokines are present on cell surface and antibodies to TNF.
are proteins. Once a cytokine which is a protein, binds
Address for correspondence Etanercept (Enbrel):
U R K Rao Etanercept is a fusion protein combining soluble
President, Indian Rheumatology Association 6-2-45/8,
A.C.Guards, Hyderabad – 500 004, India. Ph : 91-40-23395684,
TNF type 2 receptorsp75 and the Fc constant region
Fax 91- 40-23390694 e-mail: urkrao@yahoo.com of human immunoglobulin. The fusion protein binds to
 Biologic response modifier

circulating TNF and reduces the amount of inflamma- to reduce antigenicity. Infliximab binds to soluble TNF
tory cytokines available for membrane receptor bind- and also to the membrane bound cytokines with high
ing. The Fc portion of the immunoglobulin increases affinity and specificity to human TNF.
the proteins half-life. Etanercept is given as a 25 mg Infliximab is given in a dose of 3mg/kg. as an
subcutaneous (sc) injection twice a week .It has a half IV infusion at ‘0’, ‘2’, ‘6’weeks repeated every two
life of 4-5 days. Several clinical studies support the ef- months thereafter. It has a half-life of 8-12 days.
ficacy of etanercept in RA. Moreland LW et al2 did a Lipsky PE9 et al studied 428 patients with ac-
randomized study of 158 patients comparing etanercept tive RA. Infliximab plus methotrexate was associated
with placebo. In a double blind study Weinblatt et al3 with an ACR 20 response in 50-60% of patients ver-
randomly assigned 89 patients with active disease on sus 20% of patients receiving methotrexate plus pla-
stable dose of Methotrexate to placebo or etanercept cebo. An infliximab dosage of 3 mg/kg every 8 weeks
25mg sc twice a week. All patients in the etanercept was as efficacious as 10mg/kg in some studies10. In-
group met the American college of Rheumatology fection was more likely when higher dose of infliximab
(ACR) -20 response criteria. were used.
Etanercept has also demonstrated efficacy in Drug induced lupus erythematosus11 occurred
the treatment of RA, Psoriatic arthritis (PsA), Juvenile in less than 0.5% of patients treated with infliximab.
rheumatoid arthritis (JRA) and ankylosing spondylitis Thirteen percent patients treated with infliximab devel-
(AS)4. In TEMPO trial (Trial of Etanercept and Meth- oped human anti chimeric antibodies thereby increas-
otrexate with radiographic Patient Outcomes)5 combi- ing the potential for future infusion reactions12.
nation therapy of etanercept with methotrexate signifi- It is useful in the treatment of RA, Seronega-
cantly slowed progression of structural damage as as- tive Spondylarthropathy (SSA), Crohn’s disease, sys-
sessed by radiography. TNF blockade has been pos- temic inflammatory diseases including various vascu-
tulated as a possible treatment for various forms of vas- litides and AOSD. Infliximab is effective in controlling
culitides. An ongoing multicenter, randomized, placebo- ocular and mucocutaneous inflammation in Behçet syn-
controlled trial is testing the efficacy of etanercept given drome. Case reports suggest a possible role of infliximab
with usual cytotoxic therapy for patients with active in refractory Wegeners Granulomatosis13, microscopic
Wegners Granulomatosis (WGET trial)6. Etanercept polyangitis and refractory giant cell arteritis.
also has a role in the treatment of Behcet’s disease and
Psoriasis7. Etanercept has been found to reduce dis- Adalimumab (Humira):
ease activity in patients with refractory adult onset Still’s Adalimumab is a humanized IgG1 anti TNF ∝
disease (AOSD)8. monoclonal antibody developed to treat RA. Rau 14 has
reviewed the results of five clinical trials of Adalimumab
Infliximab (Remicade): in RA. In the Anti TNF Research Study Programme of
Infliximab is a chimeric monoclonal antibody the Monoclonal Antibody Adalimumab in RA (AR-
consisting of 75% human and 25% mouse protein se- MADA)15 trial 271 patients with active RA on concur-
quences. The mouse portion consists of antigen bind- rent methotrexate were randomized to Adalimumab (in
ing fragment or Fab region, the human portion is used doses of 20,40, or 80 mg subcutaneously every other

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 Firdaus Fatima et al

week) or placebo. At 24 weeks more patients in the introducing a 5 methionine codon. This modified DNA
Adalimumab group met ACR 20 response criteria than is inserted into an Escherichia coli expression vector,
in placebo group (47.8%, 65.7%, 65.8% Vs 14.5%; the expressed protein sequence is identical to that of
P<0.001for each comparison). In an open label study naturally occurring IL-1 RA with the addition of an
of Adalimumab in RA, the patients continuing therapy amino- terminal methionine. As the protein is expressed
maintain stability in radiographic scores of joint dam- in E coli the recombinant product is unglycosylated,
age, while patients who switched to other treatments but the biological activity is identical to natural IL-1
were more likely to progress. RA17.
IL- 1 is a pro inflammatory cytokine that shares
Alternative ways of inhibiting TNF: many properties with TNF α and is strongly associ-
The available TNF blocking agents have effec- ated with inflammatory joint destruction of RA.
tive control of RA. However, approximately one third Anakinra is a recombinant form of IL- 1 receptor an-
of patients treated with etanercept or infliximab in clini- tagonist that competes with IL-1 for binding to cell sur-
cal trials failed to meet ACR 20 response criteria. face bound IL-1 receptor without inducing intracellular
Thus other means of reducing TNF activity are signaling.
currently being evaluated. In the adjuvant arthiritis Anakinra is given subcutaneously in a dose of
model, administration of PEG- ylated soluble TNF re- 1-2 mg/kg /day. Cohen et al18 studied 419 patients on
ceptor type 1 reduces synovitis and expression of long-term methotrexate who were given placebo or IL-
proinflammatory cytokines TNF α, gamma interferon 1 RA in a dose ranging from 0.4-2 mg/kg. At 24 weeks
(γIFN), IL-2 and IL-1716. Early phase studies are un- an ACR 20 response was observed in 42% patients
derway in human subjects. on a combination of IL-1 RA plus methotrexate com-
TNF α converting enzyme is a transemembrane pared to 23% of those treated with methotrexate plus
protein that cleaves cell surface bound TNF α to re- placebo. Anakinra was safe when added to traditional
lease soluble cytokine. Inhibition of this DMARD therapy in patients with active RA (OMEGA
metalloproteinase reduces lipopolysaccharide stimu- trial)19.
lated TNF production in whole blood by 95%. Sev- Bresnihan B et al20 studied 468 patients (119
eral orally bioavailable TNF α converting enzyme in- placebo and 119, 115, 115 on 30 mg 75 mg and 150
hibitors are currently in preclinical trials. mg of Anakinra respectively) in a monotherapy of
Anakinra; at 24 weeks 27% of placebo recipients met
Interleukin –1 blocking agents: the ACR 20 criteria compared with 43% of those given
IL-1 is a proinflammatory cytokine that shares Anakinra 150 mg/d (p=0.014).
many properties with TNF α and is strongly associ- Indications-The use of anakinra may not be lim-
ated with the characteristic inflammatory joint destruc- ited to RA; anakinra is a possible option for any disor-
tion of RA. der in which IL-1 may be implicated. Trials evaluating
anakinra in patients with graft versus host disease and
Anakinra (Kinaret): multiple sclerosis are underway. Anakinra is useful in
Anakinra is produced by cloning human IL-1RA the prevention of acute graft rejection, sarcoidosis, lu-
(receptor antagonist) complementary DNA and then pus erythematosus, giant-cell arteritis, and inflamma-
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 Biologic response modifier

tory bowel disease. Anakinra could also be used to tracellular signaling cascades such as the mitogen acti-
treat malignancies that require IL-1 as a mitogen; ex- vated protein kinase signal transduction pathways which
amples include solid tumors and leukemia. include the P38 mitogen activated protein kinase (P38
MAP γ) and the C-Jun N terminal kinase pathways.
Side effects of Biologic Response Modifiers: These two cascades are subject to investigational ef-
Side effects of BRMs include infusion reactions, forts to develop pathway specific inhibitors. These stud-
infections, hematological, cardiovascular, demyelinat- ies have been reviewed extensively 25. Several orally
ing, autoimmune and malignancies. Infections account bioavailable small molecule inhibitors of P39 MAPK
for 2% of all adverse events reported. are under study in clinical trials. Suppressors of the
cytokine signaling are also currently under study26.
Interferons: Chemokine and chemokine receptors control
The Interferons (IFN) are immunomodulatory the recruitment of leukocytes to sites of inflammation.
proteins classed as type 1 (IFN α, IFN β) and type 2 Pre clinical studies in arthritis models suggest that in-
(IFNγ). Type 2 IFNs at high concentration can down hibiting IL-18 activity via neutralizing monoclonal anti-
regulate expression of IL –12 and hence inhibit inflam- bodies or recombinant human IL-18 binding protein
matory T-cell responses. IFN β is an effective treat- can effectively reduce inflammation27. Several
ment for multiple sclerosis and is also used in the treat- chemokine antagonist including a humanized CXCL 8
ment of rheumatic diseases as reviewed by Van Holten / IL - 8 antibody and an oral CCR 1 antagonist are
et al21. The report summarized open label trials in RA under development.
and juvenile onset chronic arthritis. IFN α has potent T cell costimulatory molecules are cell surface
antiviral activity and antiangiogenic effects. Open label proteins that play important roles in activation of T cells.
studies of IFN α for the treatment of Behcets syndrome Clinical efforts to treat various inflammatory and im-
suggested efficacy22, which was confirmed by random- mune diseases by inhibiting costimulatory signals with
ized placebo controlled trial. Low dose IFN α can sig- monoclonal antibodies (anti CD 40 ligand) and re-
nificantly increase unstimulated whole saliva flow in combinant naturally occurring molecules (CTLA 4) are
patients with primary sjogren’s syndrome without caus- ongoing.
ing significant adverse events 23. T cell surface complex CD 11a / CD18 (also
called LFA-1) interacts with its ligand intercellular ad-
Other targeted therapies: hesion molecule -1 (ICAM-1) as part of a costimulatory
IL –6 plays an important role in RA. Pre clini- pathway for T cell activation. A humanized, monoclonal
cal work suggests that autoantibody production, T-cell antibody against CD11a (called efalizumab) has been
activation, acute phase protein production and osteo- developed. Efalizumab treatment of psoriasis has re-
clast activation can be explained by the effects of IL - sulted in consistent clinical and histological improve-
624. Currently clinical trials are underway to evaluate ment in several clinical trials28. A phase II, randomized,
the safety and efficacy of two IL -6 directed biologics, controlled trial of efalizumab for the treatment of pa-
a neutralizing monoclonal antibody against IL -6 and a tients with RA on concurrent methotrexate is under-
soluble IL -6 receptor. way.
Inflammatory mediators activate numerous in-
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 Firdaus Fatima et al

B Cell directed therapy lymphocyte stimulator (BLyS) is currently being stud-

Rituximab: ied in a phase I trial in SLE.
Rituximab (anti-CD20 antibody) is a mono-
clonal antibody that selectively depletes B cells bearing LJP 394:
the CD20 surface marker. Plasma cells do not express LJP 394 is an immunogen that binds anti-DNA
CD20; therefore, immunoglobulin levels are not signifi- autoantibodies in patients with SLE. Depletion of anti-
cantly affected by anti-CD20 treatment. Phase I, dose DNA antibodies and efficacy in controlling disease ac-
finding trial of rituximab in SLE is currently underway. tivity appears to be limited to those patients who pro-
Rituximab has also been shown to be effective for the duce antibodies with high affinity for LJP 39431. A phase
treatment of RA. In a phase II, placebo controlled, ran- III clinical trial of LJP 394 is currently underway.
domized trial of rituximab in RA, subjects with active
RA despite methotrexate were randomized to one of Summary:
four treatment groups: methotrexate and placebo, RA is a complex autoimmune disorder involv-
rituximab alone, rituximab and cyclophosphamide, and ing the joint and synovium. Biological response modifi-
rituximab and methotrexate. The rituximab dose was ers are effective in attenuating symptoms associated
the same in all groups: two 1-g infusions. All subjects with RA. The disease activity in RA may not be fully
received a course of corticosteroids (a total of 960 mg suppressed by inhibiting only one of the inflammatory
over 17 days). Interim results found that ACR20 crite- mediators. Thus a combination therapy may be more
ria were met by 58% treated with rituximab alone, 80% appropriate.
receiving rituximab and continuing methotrexate, and As BRMs are available in the country, the
84% treated with rituximab and cyclophosphamide, but management of RA may evolve to use these agents in
only 33% of those treated with methotrexate and pla- monotherapy or in combination with other biological
cebo. The primary outcome, ACR20 response, was and conventional agents. More studies are necessary
measured at 24 weeks 29. to establish the relevant uses, optimal dosage and du-
rations of therapy and long-term safety of BRMs.
Tumor Necrosis Factor Family Proteins:
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