Current Advances in Rheumatoid Arthritis Therapy

Current Advances in Rheumatoid

Arthritis Therapy

Ann Pittier, 4th _{Year Medicine}

INTRODUCTION

Exciting advances in the understanding of rheumatoid arthritis (RA) and its pathogenesis are providing new hope for those suffering from this de-bilitating 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 progres-sion 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 phar-macological approach than ever before.

N

S

A

-I

D

(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 ulcera-tion, 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 dis-covery of agents that selectively target COX-II, such as rofecoxib and celecoxib. COX-II inhibitors have proven to reverse oedema and cellular infiltrate, re-duce joint inflammation, and return PGE₂ 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}

inhibi-tors 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 ex-tensively as another modality for treatment of RA. These drugs have been shown to decrease circulat-ing monocytes and reduce macrophage phagocyto-sis and IL-1 secretion, resulting in inhibition of colla-genase and lysosomal enzyme release (as well as re-ducing prostaglandin and leukotriene synthesis).7

Their anti-inflammatory and immunosuppressive ef-fects provide relief for many patients and are espe-cially useful for those patients refractory to treatment with NSAIDs. Unfortunately, corticosteroid therapy is often accompanied by numerous side effects, in-cluding bone loss, increased susceptibility to infec-tion, osteoporosis, and peptic ulcers. Additionally, weaning patients from corticosteroids can be diffi-cult and relapses of articular degeneration are fre-quent once the steroid is discontinued.13

Intra-ar-ticular application of these drugs has been imple-mented (in order to diminish the complications of oral administration) and has proven effective in reducing symptomatic joint inflammation.5

D

-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, meth-otrexate, auranofin, sulfasalazine, d-penicillamine, cyclosporin, azathioprine, and cyclophosphamide. There is little evidence to suggest that DMARDs af-fect 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 immunosuppres-sive 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 acti-vated T-cells (which play a pivotal role in initiating and modulating humoral and cellular immune re-sponses in RA).14 _{A comparison study using a}

com-bination of prednisone, sulphasalazine, and meth-otrexate versus sulphasalazine alone found that com-bination therapy induced immediate and highly sig-nificant improvement (including remission) of disease activity in patients with severe, early RA. Further-more, 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-inflam-matory and immunomodulatory drug that has been used to treat RA and to prevent organ rejection fol-lowing 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 ribo-nucleotide availability is crucial for DNA synthesis and lymphoblast transformation. Pyrimidine avail-ability is also important for regulating the magnitude and duration of the T-cell response and for modulat-ing the nucleotide-related cascade followmodulat-ing 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 dis-comfort and improve the functionality of many pa-tients 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 ag-gressive treatment than ever before. This approach may further improve the outcome of the long-term disease process.8 _{Unfortunately, this aggressive}

ap-proach 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 prob-lems for the RA patient, including unnecessary drug-induced toxicity.10 _{Paving the road for newer}

inter-vention strategies is increased understanding of the roles of cells, mediator molecules, and cytokines in-volved in the initiation and perpetuation of joint dis-ease in RA. These new approaches, directed at re-moving or impairing the function of lymphocytes, or by blocking the pro-inflammatory cytokines, may fur-ther improve the outcome of RA treatment (if not of-fer long-term remission or cure).9

IMMUNOMODULATION

T-lymphocytes play an important initiating and modulating role in humoral and cellular immune re-sponses in RA. In fact, RA is characterized by accu-mulation 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 ex-press 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, suppres-sion, or deletion of the autoreactive TCR.19 _{In animal}

models, immunization with TCR Vâ chain peptides has proven to block the development of inflamma-tion, synovial hyperplasia, and erosion of cartilage and bone. This is thought to result from develop-ment of antibodies that recognize self-reactive TCR; the exact mechanism remains elusive.20 _Future

hu-man studies may prove this to be effective in provid-ing protective immunity against RA by blockprovid-ing 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 thera-peutic 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 ery of inflammatory cells to the synovium and deliv-ers blood borne elements to the pannus (interdigitat-ing folds of tissue result(interdigitat-ing from synovial prolifera-tion over articular surfaces). Pannus blood vessels demonstrate increased expression of the integrin v3. A cyclic peptide antagonist of v3, which can be ad-ministered intra-articularly, has targeted this in ani-mal 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 syno-vial cells (characteristic of RA) may present a possi-ble route for treating RA. When hyperactive syno-vial 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 inflamma-tion 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 natu-ral inhibitor of TNF-á and IL-1), found in synovial tissue.25 _{In the future, transgenic expression of}

spe-cific proteins in arthritic joints may prove to be yet another valuable therapy for RA.

C

Because of the emerging acceptance of RA as an autoimmune disorder, much of the current thera-peutic research has naturally focused on the immune mediators associated with the development and per-sistence 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 stimu-late production (by RA synovial cells) of IL-1, IL-6, and granulocyte-macrophage colony stimulating fac-tor. 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-al-pha.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 IgG₁. 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 strat-egy 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 IgG₁ (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 re-leased in large amounts by rheumatoid fibroblast-like synoviocytes (FLSs), and is involved in T-cell and B-cell growth among many other activities. Recent clini-cal studies have shown that anti-IL-6 mAbs are very effective at reducing many of the clinical and bio-chemical 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 investiga-tion 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 treat-ment.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-inflam-matory 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 in-crease 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 el-evate 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 be-tween 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 under-going total joint replacement operations. The two most common joint replacements are total hip arthro-plasty (THA) and total knee arthroarthro-plasty (TKA). The suggested recovery time and recommended physical therapy regimes for TKA or THA will vary based upon the surgeon, the technique employed, the sur-gical approach, and the condition of the patient. Gen-erally, post-operative rehabilitation routines will in-volve therapeutic exercise, gait training, and instruc-tion in safe and proper execuinstruc-tion of daily living ac-tivities. 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 rheu-matoid 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 tech-niques are allowing researchers to delve deeper into the workings of RA, and each new experimental find-ing potentially represents another unique avenue of treatment (and perhaps cure) for this disease. Devel-oping 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 prac-tice for many years to come. The new immunological treatments currently on trial, promise to go far be-yond the symptomatic relief of the NSAIDS and corticosteroids to a refined treatment of the disease mechanisms that drive rheumatoid arthritis.

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