Current Advances in Rheumatoid Arthritis Therapy-A Review
By - 12/22/2006
Shashikant V.Bhandari
Exciting advances in the understanding of rheumatoid arthritis (RA)
and its pathogenesis are providing new hope for those suffering from this
debilitating disease.
A currently incurable autoimmune disorder, RA is one of
the most common forms of inflammatory arthritis, causing suffering, disability
(90% within 20 years will become clinically disabled), and even premature
death.
Many of the past and current therapies offer little more than
symptomatic relief.
1
Even the so-called disease modifying
anti-rheumatic drugs (DMARDs) do not halt the progression of this disease, but
rather decrease the onset of disability by 30%.
2
Recent research
into the complex and varied components of this disease is leading to the
development of more effective targets for pharmacological approach than ever
before.
NonSteroidal Anti-Inflammatory Drugs
(NSAIDs)
Current treatment of RA frequently includes the use of
nonsteroidal
anti-inflammatory drugs
(NSAIDs), such as ibuprofen and diclofenac. As
first line drugs, these offer little protection against tissue degeneration.
They do, however, reduce the levels of prostaglandins, bradykinins, and oxygen
radicals; thereby contributing to pain relief.
3
NSAIDs work by
inhibiting cyclooxygenase (COX), decreasing prostanoid production. Two types of
this enzyme exist in the body. Type I is “constitutive” and helps maintain
mucosal blood flow and platelet function. Type II is “inducible” and is
generated at sites of inflammation. Most available NSAIDs inhibit both COX-I
and COX-II, reducing pain and inflammation, but also leading to side effects
such as peptic ulceration, impairment of renal blood flow, renal papillary
necrosis, nephrotic syndrome, and hepatic injury.
4
Despite these
complications, NSAIDs remain a first-line treatment for pain and inflammation,
although not all patients respond favorably to treatment with these agents.
12
An encouraging new development is the discovery of agents that selectively
target COX-II, such as
rofecoxib
and
celecoxib
. COX-II inhibitors
have proven to reverse oedema and cellular infiltrate, reduce joint
inflammation, and return PGE
2
levels to normal. They also decrease
COX-II mRNA levels to normal without affecting COX-I, and they modulate local
and systemic cytokine production (including IL-6), thereby reducing
inflammation in affected joints and diminishing subsequent erosion of bone and
cartilage.
11
It is hoped that COX-II selective inhibitors will allow
for the same therapeutic benefits of non-selective COX inhibitors, without the
typical NSAID side effects.
Corticosteroids
For many years,
corticosteroids
have been used extensively as
another modality for treatment of RA. These drugs have been shown to decrease
circulating monocytes and reduce macrophage phagocytosis and IL-1 secretion,
resulting in inhibition of collagenase and lysosomal enzyme release (as well as
reducing prostaglandin and leukotriene synthesis).
7
Their
anti-inflammatory and immunosuppressive effects provide relief for many
patients and are especially useful for those patients refractory to treatment
with NSAIDs. Unfortunately, corticosteroid therapy is often accompanied by
numerous side effects, including bone loss, increased susceptibility to
infection, osteoporosis, and peptic ulcers. Additionally, weaning patients from
corticosteroids can be difficult and relapses of articular degeneration are frequent
once the steroid is discontinued.
13
Intra-articular application of
these drugs has been implemented (in order to diminish the complications of
oral administration) and has proven effective in reducing symptomatic joint
inflammation.
5
Disease-Modifying Anti-Rheumatic Drugs
(DMARDs)
In addition to the drugs mentioned previously, current therapy also
involves the
DMARDs
, which are often given simultaneously with NSAIDs.
DMARDs include gold, hydroxychloroquine, methotrexate, auranofin,
sulfasalazine, d-penicillamine, cyclosporin, azathioprine, and
cyclophosphamide. There is little evidence to suggest that DMARDs affect the
underlying disease in the long run. They do improve physical function and
retard radiographically apparent joint degeneration, and improvements in
clinical condition are observed in as many as two-thirds of the patients.
6
Like corticosteroids, DMARDS act to decrease inflammation. Sulphasalazine, for
example, inhibits translocation of NF-kappa B into the nucleus by inhibiting
I-kappa-B-alpha kinase.
17
This in turn inhibits transcription of
various inflammatory cytokines, adhesion molecules, and chemokines.
Methotrexate (an immunosuppressive agent) has become the dominant second line
agent for treatment of RA.
16
One study has shown that it induces
apoptosis and clonal deletion of activated T-cells (which play a pivotal role
in initiating and modulating humoral and cellular immune responses in RA).
14
A comparison study using a combination of prednisone, sulphasalazine, and
methotrexate versus sulphasalazine alone found that combination therapy induced
immediate and highly significant improvement (including remission) of disease
activity in patients with severe, early RA. Furthermore, withdrawal rates and
lack of efficacy were also lower with this combined therapy.
15
A newer drug, which acts at the level of T-cells, is
leflunamide
(LFM). LFM is an anti-inflammatory and immunomodulatory drug that has been used
to treat RA and to prevent organ rejection following transplant. In addition to
suppressing the effects of IL-2 (and other cytokines) and inhibiting adhesion
and migration of inflammatory cells, LFM also retards the proliferation of
activated T-cells, which are known to play a significant role in RA. The
mechanism of LFM has been disputed for some time, but recent findings suggest
that LFM exerts its anti-proliferative effects on activated T-cells by blocking
biosynthesis of pyrimidines at the level of dihydroorotic acid dehydrogenase.
Pyrimidine ribonucleotide availability is crucial for DNA synthesis and
lymphoblast transformation. Pyrimidine availability is also important for
regulating the magnitude and duration of the T-cell response and for modulating
the nucleotide-related cascade following T-cell activation. LFM clearly has a
unique role to play in current RA treatment and has been documented to bring
about clinical improvement in RA patients.
32
Traditional therapies no doubt reduce the discomfort and improve the
functionality of many patients who suffer from RA, but they do not offer a cure
for the underlying disease processes. RA is currently being addressed earlier
and with more aggressive treatment than ever before. This approach may further
improve the outcome of the long-term disease process.
8
Unfortunately, this aggressive approach cannot yet be unreservedly advocated
due to lack of long-term studies. Some researchers suggest that early treatment
of this nature is only appropriate in specific cases and may otherwise pose
extra problems for the RA patient, including unnecessary drug-induced toxicity.
10
Paving the road for newer intervention strategies is increased understanding of
the roles of cells, mediator molecules, and cytokines involved in the
initiation and perpetuation of joint disease in RA. These new approaches,
directed at removing or impairing the function of lymphocytes, or by blocking
the pro-inflammatory cytokines, may further improve the outcome of RA treatment
(if not offer long-term remission or cure).
9
Immunomodulation
T-lymphocytes play an important initiating and modulating role in humoral and
cellular immune responses in RA. In fact, RA is characterized by accumulation
of T-cells in the synovial compartment. For this reason, targets for
therapeutic research in RA are beginning to include vaccinations, immunizations,
monoclonal antibodies targeting surface receptors of T-cells, and induction of
apoptosis in specific T-cells. T-cell receptors (TCR) are thought to share a
limited number of variable region determinants, which are important in inciting
auto-antigens. Most T-cells express the á and â forms of TCR on their surfaces.
TCR peptide vaccination (with IR501) has been shown to promote improvement in
the disease after only a short period of time.
18
TCR vaccination is
presumed to induce inactivation, tolerance, suppression, or deletion of the
autoreactive TCR.
19
In animal models, immunization with TCR Vâ chain
peptides has proven to block the development of inflammation, synovial
hyperplasia, and erosion of cartilage and bone. This is thought to result from
development of antibodies that recognize self-reactive TCR; the exact mechanism
remains elusive.
20
Future human studies may prove this to be
effective in providing protective immunity against RA by blocking joint
infiltration by inflammatory cells and subsequent joint destruction.
Another approach to slow the autoimmune process may be through genetically
engineered monoclonal antibodies. Antibodies that target the CD4 surface
receptors of helper T-cells may help to dampen T-cell activity without
affecting the normal immune functions of the patient.
22
The
accumulation of T-cells may be due in part to an anti-apoptotic environment as
well as recruitment of these cells to the area. Apoptosis of T-cells in
rheumatoid synovia may be inhibited due to the micro-environment that exists in
RA. Fibroblasts allow for prolonged T-cell survival in the synovium and may be
important therapeutic targets for the resolution of inflammation at the joint
site rather than (or in addition to) inhibiting T-cells themselves.
21
Angiogenesis Inhibitors
Another important feature in the development and maintenance of the
disease state of RA includes neovascularization. Angiogenesis aids in the
delivery of inflammatory cells to the synovium and delivers blood borne
elements to the pannus (interdigitating folds of tissue resulting from synovial
proliferation over articular surfaces). Pannus blood vessels demonstrate
increased expression of the integrin v3. A cyclic peptide antagonist of v3,
which can be administered intra-articularly, has targeted this in animal
models. Upon introduction to the joint capsule, the cyclic peptide induces
vascular apoptosis and decreased pannus formation, synovial infiltrate, and
joint swelling. This agent also appears to serve as a protector against the
erosive damage characteristic of RA.
23
With further development and
clinical trials on human subjects, this discovery may provide for another novel
approach to the treatment of RA.
Gene Therapy
Recent animal studies have also suggested that gene therapy
attenuation of hyperactive synovial cells (characteristic of RA) may present a
possible route for treating RA. When hyperactive synovial cells and arthrogenic
lymphocytes are eliminated, cytokines and degradation enzymes are no longer
introduced into the joint and inflammation ceases. Through adenovirus-mediated
gene transfer, the death factor Fas/Apo-1 and its ligand (FasL) confer high
levels of FasL expression (Fas is normally up-regulated at sites of
inflammation). FasL induces apoptosis of synovial cells (normally playing a
role in self-tolerance) and effectively reduces inflammation and prevents the
progression of the disease in mice.
24
Another approach (also through
adenovirus-mediated gene transfer) is to induce expression of anti-inflammatory
molecules such as IL-1Ra (a natural inhibitor of TNF-alpha and IL-1), found in
synovial tissue.
25
In the future, transgenic expression of specific
proteins in arthritic joints may prove to be yet another valuable therapy for
RA.
Cytokines
Because of the emerging acceptance of RA as an autoimmune disorder,
much of the current therapeutic research has naturally focused on the immune
mediators associated with the development and persistence of RA. One such
mediator is tumor necrosis factor (TNF), a cytokine produced by many cell types
(especially macrophages) which is known to be one of the pivotal factors
initiating and maintaining the inflammatory cascade. TNF-alpha is thought to
stimulate production (by RA synovial cells) of IL-1, IL-6, and
granulocyte-macrophage colony stimulating factor. TNF-alpha is also known to
induce release of tissue degradative enzymes (such as matrix
metalloproteinases) from neutrophils and various synoviocytes.
29
TNF-alpha exerts its effects through binding with two types of membrane-bound
receptors (TNFRs), type I (p55 and p60) and type II (p75 and p80). The
extracellular portions of these receptors can be cleaved to become soluble
TNFRs (sTNFRs) in sera and synovial fluid and have been shown to suppress the
pro-inflammatory actions of TNF-alpha.
26
Based on these findings, it
was thought that RA treatment might involve infusion of sTNFRs into RA affected
joints to suppress the actions of TNF-alpha. To increase the half-life and
affinity of the sTNFRs for TNF-alpha, researchers developed recombinant sTNFR
fusion proteins (rsTNFR:Fc), composed of monomeric sTNFR and the Fc portion of
IgG
1
. These compounds are currently undergoing clinical trials.
19
One such agent, rhu sTNFR:Fc (p75), or
etanercept
, has already shown
significant efficacy in decreasing joint pain and reducing clinical signs of
inflammation and joint destruction. It is currently being evaluated in selected
patients. A related strategy for diminishing the actions of TNF-alpha involves
treatment of patients with anti-TNF-alpha monoclonal antibodies derived from
murine anti-TNF-alpha mAb and human IgG
1
(
infliximab
). This
complex (which binds TNF-alpha and appears to reduce its activity) has been
shown to significantly reduce joint pain and swelling.
27
Both sTNFRs
and anti-TNF-alpha mAbs are currently receiving a great deal of attention and
present much promise as therapies for RA.
As potent mediators of immune response, the interleukins are also being
considered as potential targets in RA treatment. In particular, IL-6 (a
cytokine with both pro- and anti-inflammatory activities) is released in large
amounts by rheumatoid fibroblast-like synoviocytes (FLSs), and is involved in
T-cell and B-cell growth among many other activities. Recent clinical studies
have shown that anti-IL-6 mAbs are very effective at reducing many of the
clinical and biochemical markers of disease activity. Additionally, recent
research has shown that transcription of IL-6 genes (specifically in FLSs) may
be regulated by IL-1,
30
a finding which shows some potential for
very specific local regulation IL-6 production in the RA patient. Other
interleukins are also under investigation as therapies for RA. IL-4 and IL-10
appear to be natural anti-inflammatory cytokines that suppress the release and
actions of TNF-alpha, IL-1, and IL-6, and increase the release of cytokine
inhibitors such as sTNFRs. IL-4 and IL-10 also limit the production of certain
compounds, such as matrix metalloproteinases (MMPs), which are collagenases
responsible for breakdown of joint tissues. Recombinant IL-10 and IL-4 are
currently undergoing clinical trials in RA treatment.
19
IL-11 is
also gaining some attention as an anti-inflammatory agent for RA. IL-11 has
recently been shown to indirectly decrease production of TNF-alpha, as well as
directly reduce the activity of MMP-1 and MMP-3 (thereby reducing destruction
of joint tissue). IL-11 also shows other indirect anti-inflammatory effects by
enhancing the activity of IL-10.
28
Based on these findings,
interleukins clearly present another promising pathway in the fight against RA.
Physical Treatments for RA
While this paper concentrates mainly on the pharmacological
treatment of rheumatoid arthritis, physical therapy must also be acknowledged
as an important adjunctive treatment in managing RA. The main goals of physical
therapy are to maintain or increase muscle strength around affected joints and
to maintain joint range of motion while taking steps to limit or relieve pain.
Physical therapy programs will necessarily be tailored to each individual
patient and will involve various physical agents and exercises based upon the
desired outcome. Heat, for example, is applied in various forms in order to
provide pain relief, increase blood flow, and decrease stiffness in the
affected joints. Cryotherapy is also used in RA patients to mitigate acute
swelling and to directly elevate the pain threshold by reducing the temperature
of neural receptors. Joint mobilization exercises are also crucial and serve to
overcome joint hypomobility, restore proprioception, and separate adhesions
between articular surfaces. Joint mobilization can be passive or active and can
involve massage, which is indicated to relieve pain and stiffness and increase
blood flow to the area. Physical therapy also plays an important recovery role
for those patients undergoing total joint replacement operations. The two most
common joint replacements are total hip arthroplasty (THA) and total knee
arthroplasty (TKA). The suggested recovery time and recommended physical
therapy regimes for TKA or THA will vary based upon the surgeon, the technique
employed, the surgical approach, and the condition of the patient. Generally,
post-operative rehabilitation routines will involve therapeutic exercise, gait
training, and instruction in safe and proper execution of daily living
activities. Whether preventative or post-operative, proper adherence to
physical therapy guidelines is very important in complete management of the RA
patient.
31
Conclusion
Even based on the superficial overview of rheumatoid arthritis therapy
put forth in this paper, it is clear that RA is immensely complex and very
likely caused by more than one type of inciting factor in each individual
patient. Modern biochemical techniques are allowing researchers to delve deeper
into the workings of RA, and each new experimental finding potentially
represents another unique avenue of treatment (and perhaps cure) for this
disease. Developing ways in which to tailor the various available therapies to
the unique circumstances and disease processes of each individual patient will
prove very challenging. Fortunately for patients and clinicians, the sheer
amount of scientific interest and research in RA guarantee that innovative
therapeutic advances will continue to trickle into mainstream medical practice
for many years to come. The new immunological treatments currently on trial,
promise to go far beyond the symptomatic relief of the NSAIDS and
corticosteroids to a refined treatment of the disease mechanisms that drive
rheumatoid arthritis.
References
1. Buckley CD. Science, medicine, and the future: treatment of
rheumatoid arthritis.
BMJ
1997; 315: 236-238.
2. Brooks P. Recent advances: rheumatology.
BMJ
1998; 316: 1810-1812.
3. Seibert K, Zhang Y, Leahy, et al. Pharmacological and biochemical
demonstration of the role of cyclooxygenase 2 in inflammation and pain.
Proc
Natl Acad Sci
1994; 91: 12013.
4. Jain R, Lipsky PE. Advances in rheumatology: treatment of rheumatoid
arthritis.
Med Clin N Amer
1997; 81: 58-84.
5. Weiss MM. Corticosteroids in rheumatoid arthritis.
Semin Arthritis
Rheum
1989; 19: 9.
6. Schiff M. Emerging treatments for rheumatoid arthritis.
Am J Med
1997; 102 Suppl(1S): 11S-15S.
7. Boyce E. Pharmacology of antiarthritic drugs.
Clin Podiatric Med Surg
1992; 9: 327-348.
8. Mottonen T, Paimela L, Ahonon J, Helve T, Hannonen P, Leirisalo-Repo M.
Outcome in patients with early rheumatoid arthritis treatment according to the
“saw tooth” strategy.
Arthritis Rheum
1996; 39: 996-1005.
9. Panush R, Arend W. Emerging role of biologic therapies for treatment of
rheumatic disease.
JAMA
1997; 277: 1899-1900.
10. Wollheim F. Disease modifying drugs in rheumatoid arthritis: encouraging
signs but effects not proved.
Brit Med J
1997; 314: 766-767.
11. Anderson G, Hauser S, McGarity K, Bremer M, Isakson P, Gregory S.
Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and
expression of COX-2 and interleukin 6 in rat adjuvant arthritis.
J Clin
Invest
1996; 97: 2672-2679.
12. Walker J, Sheather-Reid R, Carmody J, Vial J, Day R. Nonsteroidal
antiinflammatory drugs in rheumatoid arthritis and osteoarthritis.
Arthritis
Rheum
1997; 40: 1944-1954.
13. Dennison E, Cooper C. Corticosteroids in rheumatoid arthritis: effective
anti-inflammatory agents but doubts about safety remain.
BMJ
1998; 316:
789-790.
14. Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P, Revillard JP.
Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of
activated peripheral T cells.
J Clin Invest
1998; 102: 322-328.
15. Boers M, Verhoeven A, Markusse H, et al. Randomised comparison of
combined step-down prednisolone, methotrexate and sulphasalazine with
sulphasalazine alone in early rheumatoid arthritis.
Lancet
1997; 350:
309-318.
16. Kremer J. Methotrexate and emerging therapies.
Rheum Dis Clin Nth Am
1998; 24: 651-658.
17. Wahl C, Liptay S, Adler G, Schmid R. Sulfasalazine: a potent and
specific inhibitor of nuclear factor kappa B.
J Clin Invest
1998; 101:
1163-1174.
18. Moreland L, Morgan E, Adamson T, Fronek Z, Calabrese L, et al. T cell
receptor peptide vaccination in rheumatoid arthritis.
Arthritis Rheum
1998;
41: 1919-1929.
19. Moreland L, Heck L, Koopman W. Biologic agents for treating rheumatoid
arthritis.
Arthritis Rheum
1997; 40: 397-409.
20. Haqqi T, Qu XM, Anthony D, Ma J, Sy MS. Immunization with T cell
receptor V? chain peptides deletes pathogenic T cells and prevents the
induction of collagen-induced arthritis in mice.
J Clin Invest
1996; 97:
2849-2858.
21. Salmon M, Scheel-Toellner D, Huisson A, Pilling D, Shamsadeen N, et al.
Inhibition of T cell apoptosis in the rheumatoid synovium.
J Clin Invest
1997; 99: 439-446.
22. Skolnick A. Biological response modifiers may yield a new class of drugs
to treat arthritis.
JAMA
1997; 277: 276-278.
23. Storgard C, Stupack D, Jonczykl A, Goodman S, Fox R, Cheresh D.
Decreased angiogenesis and arthritic disease in rabbits treated with an ?v?3
antagonist.
J Clin Invest
1999; 103: 47-54.
24. Zhang H, Yang Y, Horton J, Samoilova E, Judge T, et al. Amelioration of
collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer.
J Clin
Invest
1997; 100: 1951-1957.
25. Roessler FJ, Allen ED, Wilson JM, Hartman JW, Davidson BL.
Adenoviral-mediated gene transfer to rabbit synovium in vivo.
J Clin Invest
1993; 92: 1085-1092.
26. Moreland L. Soluble tumor necrosis factor receptor (p75) fusion protein
(ENBREL) as a therapy for rheumatoid arthritis.
Rheum Dis Clin Nth Am
1998; 24: 579-591.
27. Kavanaugh A. Anti-tumor necrosis factor-alpha monoclonal antibody
therapy for rheumatoid arthritis.
Rheum Dis Clin Nth Am
1998; 24:
593-614.
28. Hermann J, Hall M, Maini R, Feldmann M, Brennan F. Important
immunoregulatory role of interleukin-11 in the inflammatory process in
rheumatoid arthritis.
Arthritis Rheum
1998; 41: 1388-1397.
29. Hanemaaijer R, Sorsa T, Konttinen Y, Ding Y, Sutinen M, et al. Matrix
metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and
endothelial cells.
J Biol Chem
1997; 272: 31504-31509.
30. Miyazawa K, Mori A, Yamamoto K, Okudaira H. Transcriptional roles of
CCAAT/enhancer binding protein-?, nuclear factor-?B, and C-promoter binding
factor 1 in interleukin (IL)-1?-induced IL-6 synthesis by human rheumatoid
fibroblast-like synoviocytes.
J Biol Chem
1998; 273: 7620-7627.
31. Ganz S, Harris L. Trends in orthopedic surgery for rheumatoid arthritis:
general overview of rehabilitation in the rheumatoid patient.
Rheum Dis Clin
Nth Am
1998; 24: 181-201.
32. Rückemann K, Fairbanks L, Carrey E, Hawrylowicz C, Richards D, et al.
Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated
T-lymphocytes from healthy humans.
J Biol Chem
1998; 273: 21682-2169
About
Authors
Shashikant V.Bhandari ,Mayuresh K.Raut
A.I.S.S.M.S College of Pharmacy Pune
Mr
Mayuresh K. Raut
,2nd year M.Pharm student(Pharm.Chem)A.I.S.S.M.S College of
Pharmacy,Pune,Maharashtra,India
sought
admission to M Pharm through national level qualifying exam(GATE) under UGC
scholarship .has 1 international publication to his credit.Stood 1st in Pune University at M Pharm 1st year
Email-mayuresh_raut2005@yahoo.co.in
Mr S.V.Bhandari M Pharm(Pharm.chemistry),Asst.Professor at A.I.S.S.M.S College of Pharmacy,Pune,Maharashtra, India
Teaching experience-7 years,teaches students at under graduate and post graduate level.Involved in design synthesis of novel antiinflammatory molecules as new chemical enctities using COMPUTER AIDED DRUG DESIGN APPROACH.Currently working as dessertation guide for M.Pharm students.,has guided 2 students so far.presented 12 papers at various national and international level conferences.Has 3 international publication to his credit.