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Ritchlin: Editorial 1229

Editorial

Mechanisms of Erosion in Rheumatoid Arthritis

Irreversible joint destruction characterized by cartilagedegradation and bone resorption is the major longtermconsequence of inflammatory events initiated early in thecourse of rheumatoid synovitis. Although the relationshipbetween early symptoms and joint destruction is still notcompletely understood, a significant amount of osteolysisoccurs early in the disease and correlates with diseaseactivity1. This osteolysis manifests in several forms,including localized or juxtaarticular osteopenia and general-ized bone loss in the appendicular and axial skeleton1-3.Localized and generalized bone resorption is initiated andmaintained by complex pathways. Activation events initi-ated by cell–cell contact between infiltrating T lymphocytesand monocytes, along with resident synovial lining cells,trigger intercellular signaling cascades2. Elucidation of themolecules involved in these signaling processes has trans-lated into improved therapeutic modalities.

The purpose of this editorial is to describe the molecularand cellular features of rheumatoid cartilage and bone,provide an overview of the molecular basis of bone erosion,and review the clinical efficacy of the new biologic responsemodifiers (BRM) approved for the treatment of rheumatoidarthritis (RA).

INFLAMMATORY EVENTS IN RHEUMATOIDSYNOVIUMThe normal synovial membrane is one to 2 cell layers thickand composed of synoviocytes derived from monocytoid(type A) and mesenchymal (type B) lineages. In the rheuma-toid joint, this delicate tissue is transformed into a prolifer-ating cell mass that destroys surrounding tissue and bone4.This remarkable degree of synovial lining hyperplasia iscorrelated with the influx of infiltrating CD4+ lymphocytesand their subsequent binding to activated endothelial cells,although details of this interaction and the initiatingimmunologic stimuli are not well understood5. The forma-tion of pannus results from migration of these inflammatorycells into the synovium and neovascularization of synovialtissue. Hyperplasia of synovial cells also plays a critical rolein pannus formation6. Indeed, hyperplasia of type Bsynoviocytes is a major reason contributing to joint inflam-mation and matrix degradation, which results in the releaseof effector molecules that attract leukocytes into the jointand which enhances the production of matrix metallopro-

teinases (MMP)7. Additionally, fibroblasts isolated fromrheumatoid joints have been shown to release solublefactors known as cytokines that stimulate fibroblast prolif-eration, a property not observed in fibroblasts isolated fromosteoarthritic joints8.

Cytokines are small proteins that are involved in manyaspects of inflammation, including the initiation and ampli-fication of leukocyte recruitment into the joint space. Acomplex cascade of cytokine mediated events alters thephenotype of the type A and type B synoviocytes, resultingin widespread tissue destruction9. Two main cytokines at theapex of the cytokine network in the rheumatoid joint aretumor necrosis factor (TNF) and interleukin 1 (IL-1). TNF-α is a proinflammatory cytokine produced by monocytes, Tlymphocytes, macrophages, and fibroblasts that stimulatesprostaglandin E2 (PGE2) and collagenase release fromhuman synovial cells10 and potentiates osteoclast differenti-ation (osteoclastogenesis) and activation11. IL-1 is typicallysynthesized and released simultaneously with TNF, and the2 cytokines share similar biologic properties. Although theirfunctional roles are not entirely coupled, TNF and IL-1 dodisplay highly synergistic and overlapping biologicaleffects. The complex nature of this synergy is not wellunderstood. Moreover, IL-1 and TNF exert autocrine effectson macrophages, thereby leading to upregulated synthesis ofboth cytokines. IL-1 and TNF bind to distinct receptors andare regulated independently of one another12. However, IL-1 can induce the release of TNF in peripheral bloodmononuclear cells in vitro and TNF-like activity in the seraof rabbits13. Additional evidence suggests that TNF is theprimary inducer of IL-1 in human synovial cells14, under-scoring the pivotal role of TNF as the initiator of down-stream proinflammatory pathways15.

There is also evidence that TNF can induce the synthesisof IL-6 by monocytes, T lymphocytes, and fibroblasts. IL-6 shares many biologic properties with IL-1 and TNF;however, there are several important differences. First, IL-6does not stimulate production of PGE2 and collagenase fromhuman fibroblast and synovial cells12. Second, IL-6enhances rather than inhibits the production of tissueinhibitor of metalloproteinases (TIMP), the natural antago-nist of MMP16. Third, in contrast to the actions of IL-1 andTNF, intraarticular injection of IL-6 has been shown toenhance proteoglycan synthesis, suggesting a protective role

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for IL-6 in the joint17. The contribution of IL-6 to MMPactions is complex. For example, Ito, et al showed that IL-6stimulates the production of TIMP, while enhancing IL-1induced production of metalloproteinase proenzymes18.Thus, while IL-6 participates in the regulation of cartilagehomeostasis, the net effect of IL-6 on cartilage in theinflamed joint remains to be determined.

Elevated concentrations of proinflammatory cytokineshave been identified in the peripheral blood and joints ofpatients with RA6. Plasma levels of IL-1 correlated withdisease activity and were significantly higher in patientswith RA compared with age matched controls19. Similarly,synovial fluid concentrations of IL-6 were significantlygreater in RA than in patients with osteoarthritis20. Further,RA synovial fluid levels of TNF correlated with the amountof bone resorbed in joint tissues21. Animal data have shownthat the combined blockade of TNF and IL-1 reducessynovial inflammation and joint destruction and preservesbone density in arthritic rats22. A study using porcine carti-lage explants showed increased resorption and inhibition ofproteoglycan synthesis after treatment with TNF or IL-1.These effects were additive when the explants were treatedwith the 2 cytokines simultaneously23. Studies in murinemodels of arthritis have demonstrated suppression ofproteoglycan synthesis after intraarticular injection of IL-1α, IL-1ß, and high doses of TNF, further supporting apleiotropic role for cytokines in rheumatoid joint destruc-tion17.

Both IL-1 and TNF, as well as granulocyte/monocyte-colony stimulating factor (GM-CSF), stimulate fibroblastgrowth. In addition to its promotion of pannus formation viastimulation of fibroblast growth, GM-CSF also enhances thetranscription of TNF24. In turn, TNF and IL-1 stimulate GM-CSF secretion by synovial cells; such regulatory interdepen-dence may contribute to the accelerated rate of pannusformation in the advanced stages of RA6. In addition, TNFand IL-1 increase the expression of cellular adhesion mole-cules, such as intercellular adhesion molecule-1, endothelialleukocyte adhesion molecule, and vascular cell adhesionmolecule, which enhance leukocyte migration into thesynovium24.

In summary, animal and human studies indicate that bothIL-1 and TNF are dominant cytokines that promote thedegradation of articular cartilage in the inflamed joint.These 2 cytokines inhibit the osteogenic properties of bone-remodeling cells, accelerate matrix degradation via the acti-vation of proteolytic enzymes, stimulate osteoclastogenesis,and indirectly promote pannus formation and inflammationvia interactions with other cytokines.

A MOLECULAR BASIS FOR THE BREAKDOWNOF CARTILAGEBecause RA has devastating effects on cartilage as thedisease progresses, it is worth reviewing some of the char-

acteristics of cartilage. The basic function of cartilage in thejoint is to provide a tough, elastic shock absorber that limitsfriction and resists wear on the bones as the joints move25.Matrix is composed of chondroitin-rich proteoglycan andcollagen. Chondrocytes in lacunae synthesize and enzymat-ically digest matrix, and these are processes that fall out ofequilibrium in diseases that destroy articular cartilage.Activation of catabolic enzymes and decreased productionof enzyme inhibitors can lead to accelerated matrix break-down (Figure 1).

Two major processes contribute to the cartilage destruc-tion seen in arthritis: decreased synthetic activity of chon-drocytes and increased enzymatic degradation of thematrix26. Evidence suggests that cartilage breakdown ismediated by MMP synthesized by transformed fibroblastsand chondrocytes in the synovium and macrophages at theinterface of pannus and cartilage9. Additional evidenceimplicates cathepsins and mast cell proteinases in the degra-dation of matrix components and osteolysis of bone7,27. IL-1 stimulates metalloproteinase synthesis in synovial cellsand chondrocytes28. These MMP exhibit selectivity for thedifferent components of cartilage. For example, collagen isthe primary substrate of MMP-1, while gelatin is theprimary substrate of MMP-2. MMP-3 degrades proteogly-cans, laminin, and fibronectin. However, cells that produceMMP also produce TIMP, suggesting that the regulation ofcartilage turnover is dependent on the balance of matrixdegradation by MMP and inhibition of MMP by TIMP16. Anadditional level of regulation is suggested by studies thatshow that TIMP production is differentially regulated byvarious cytokines in a cell-specific manner. For example, inendothelial cells, synoviocytes, and chondrocytes, TNFinhibits while IL-6 stimulates the production of TIMP16.Calcitonin also opposes this degradative activity byinhibiting bone resorption29.

BONE LOSS IN RAThe destruction of diarthrodial joints is a prominent mani-festation of RA. A high proportion of RA patients developlesions detectable by magnetic resonance imaging (MRI) ofthe wrist early in the disease process (median symptomduration 4 months)30. Bone edema, manifested as increasedsignals on fat-suppressed T2-weighted MRI images, isalmost always associated with synovitis, suggesting thatsynovial inflammation may be a predecessor to bonedamage in RA patients31. Radiologic damage progresses at afairly constant rate over the first 6 years after onset of RA32.Compston, et al have reported that the reduced bone mass insteroid-naive RA patients results from a negative remod-eling balance associated with a reduced rate of bone forma-tion33. Other studies have demonstrated a relationshipbetween increased bone resorption and disease activity inRA patients2. Focal bone erosions are associated withincreased morbidity and may correlate with the severity of

The Journal of Rheumatology 2004; 31:71230



disease29. In one study, a majority of patients experiencedsevere morbidity, with lower grip strength and functionalcapacity in over 90% of patients, and an increase inmortality relative to expected rates for age and sex matchedindividuals34. Functional disability was evident at baselineand continued to worsen with time34. Further, the pain andfunctional impairment associated with RA have substantialeffects on quality of life and medical costs35,36, as well as onmorbidity and mortality.

OSTEOCLASTS AS MEDIATORS OF BONERESORPTIONNormal remodeling of bone depends on the coordinatedactivity of bone-forming and bone-resorbing cells.Osteoclasts, multinucleated cells derived from the mono-

cyte/macrophage line (Figure 2), are primarily responsiblefor bone resorption. Under normal physiologic conditions,mature osteoclasts are solely responsible for bone resorptionin matrix lacunae37. Osteoclastic resorption of bone requiresthe cells to adhere to the bone surface, an interactionenhanced by increased osteoclast number38. The shortlifespan (about 2 weeks) of osteoclasts suggests that factorsrelated to the formation and maturation of these cells repre-sent important mechanisms for regulating their activity39.

Histologic analyses suggest that, in addition to their roleas mediators of normal bone turnover, osteoclasts alsomediate focal bone resorption in RA3. Osteoclasts wereoriginally identified by acid phosphatase staining inrheumatoid joints showing erosion at the junction betweencartilage and pannus40. Osteoclasts have been identified


Figure 1. Activation of catabolic enzymes can lead to accelerated matrix breakdown. A.Rheumatoid bone stained with antibody to RANK (red). Osteoclasts are prominent inresorption pits at the bone-pannus junction. RANK-positive cells can be seen radiatingfrom vessels in the synovium. B. Hematoxylin and eosin staining of rheumatoid synovium.Mononuclear cells are infiltrating the subsynovium and the lining is hyperplastic.

A

B



more specifically by tartrate-resistant acid phosphatasestaining and expression of calcitonin receptor mRNA inrheumatoid lesions29,41. Further, osteoclast precursors havebeen identified in bone resorption lacunae adjacent toinvading pannus27,29. Together with data suggesting thatother cell types (e.g., macrophages) at the bone–pannusjunction have a limited ability to resorb mineralized bone29,these findings suggest that osteoclasts may be the cell typeprimarily responsible for bone loss in patients with RA.

The differentiation of osteoclast precursors into mature,bone-resorbing cells depends on a network of cytokines thatincludes TNF, IL-1, and IL-6. These cytokines have beenlocalized to rheumatoid synovium at the cartilage–pannusjunction16. Recently, an additional member of the TNFfamily of cytokines was discovered by 2 independent teams;the factor was named either osteoprotegerin ligand, osteo-clast differentiation factor, or receptor activator of nuclearfactor κB ligand (RANKL). RANKL is synthesized byosteoblasts and bone stromal cells, and in conjunction withmacrophage-colony stimulating factor (M-CSF), is anessential factor for osteoclast differentiation29,42,43. In ananimal model, RANKL has been shown to induce osteo-clastogenesis and bone loss44. RANKL binds to its cell-surface receptor (RANK) located on dendritic, Tlymphocytes, osteoclast precursors, and osteoclasts (Figure1). In addition, a soluble “decoy” receptor for RANKL hasbeen identified, termed osteoprotegerin45. This “decoy”receptor blocks the binding of RANKL, thereby preventingRANK activation and subsequent osteoclastogenesis (Table

1)29. Together with data showing that blockade of RANKLsignaling prevents destruction of bone and cartilage inarthritic rats44, the observation of RANKL transcription insynovial tissue derived from RA patients suggests that thisosteoclast differentiation factor may play a key role inpromoting bone loss in the rheumatoid joint27.

Additional cytokines such as IL-1α, IL-1ß, and IL-11may also contribute to the proinflammatory cascade bybinding to osteoblasts and stimulating the release of factorsthat, in turn, lead to the differentiation of osteoclasts29. Oneof these factors is M-CSF, which has been shown to beuniquely essential in osteoclastic differentiation46.

TRADITIONAL TREATMENT OF RAThe treatment of RA has centered on relieving the symp-toms of inflammation, improving overall function, andpreventing disease progression. However, there is littleevidence supporting the concept that therapies that improvepain and mobility significantly lessen joint destruction anddisease progression47. Enthusiasm for the step-up orpyramid approach to treating RA waned when observationaland MRI studies revealed that functional decline and jointerosions emerge early in the disease30. This realization led tothe use of standard disease-modifying antirheumatic drugs(DMARD) early in the disease48. The use of combinationDMARD regimens also became popular48,49. Despite thisaggressive strategy, only modest inhibition of joint destruc-tion has been obtained in trials with individual DMARD,such as sulfasalazine, hydroxychloroquine, and cyclo-


Figure 2. Osteoclast precursors originate from hematopoietic stem cells and myeloid progenitor cells residing inthe bone marrow. The osteoclast precursors arise directly from a subpopulation of circulating CD14+ monocytesthat increase in response to tumor necrosis factor (TNF). The CD14+ monocytes can differentiate into: tissuemacrophages in response to macrophage-colony stimulating factor (M-CSF), dendritic cells in response to granu-locyte/monocyte-colony stimulating factor, and IL-4, or osteoclast precursors in response to TNF and presumablyother factors. Upon entering the inflamed joint, osteoclast precursors encounter relatively high expression ofRANK ligand (RANKL) and low levels of the inhibitory decoy receptor osteoprotegerin (OPG). RANKL andmacrophage colony stimulating factor (M-CSF) promote differentiation of osteoclast precursors into mature osteo-clasts that resorb bone. Adapted with permission, from Athanasou. J Bone Joint Surg Am 1996;78:1096-112.



sporine50-53. Based on several comparative trials, aconsensus has emerged suggesting that treatment withmethotrexate (MTX) limits joint damage more effectivelythan treatment with the other traditional DMARD54.Initiation of treatment with MTX early in the course of RAcoupled with rapid escalation to a target dose of 17.5mg/week significantly reduced joint erosions and progres-sion of the disease55. Longterm treatment with MTX,however, has been associated with significant toxicity andtreatment discontinuation over a 5 year period of up to 75%of patients56,57.

Leflunomide inhibits dihydroorotate dehydrogenase, anenzyme involved in de novo pyrimidine synthesis58. Theactive metabolite of leflunomide, A77 1726, inhibits DNAsynthesis in lymphocytes by limiting the pool of availablepyrimidines, thus resulting in an antiproliferative effect.Decreases in T cell proliferation may have antiinflammatoryeffects via a decrease in proinflammatory cytokines such asIL-1 and TNF59. Leflunomide has been shown to be similarin efficacy to sulfasalazine and MTX in reducingswollen/tender joint counts, as well as in decreasing radio-graphic progression as assessed by erosions and joint spacenarrowing60,61. Concern has been mounting recently,however, on a possible association between leflunomide andliver toxicity62-65.

THE EMERGENCE OF BIOLOGIC AGENTS IN RAAdvances in the understanding of the pathophysiology ofRA have resulted in the development of 3 new agents withproven efficacy in halting radiographic progression of thedisease: etanercept, infliximab, and anakinra. These agentshave all been approved for the treatment of RA. Etanerceptand infliximab are TNF-neutralizing agents (Figure 3).Etanercept is a human fusion protein produced by recombi-nant DNA technology and consists of 2 copies of the solubleform of the p75 TNF receptor (p75 TNFR) fused to the Fcportion of human IgG166. Etanercept blocks the biologicactivity of TNF by competitively inhibiting the associationof TNF with its cell-surface receptors, thereby mimicking

the action of endogenous soluble TNFR that neutralize freeTNF67. Infliximab is a chimeric monoclonal antibody thatbinds with high affinity and selectivity to TNF68. Like etan-ercept, infliximab prevents the association of TNF with itscell-surface receptor, thereby blocking the signaling activityof TNF. Unlike etanercept, infliximab may cause comple-ment-mediated lysis of TNF-expressing cells69 and does notneutralize the activity of the related proinflammatorycytokine lymphotoxin-α, which also exerts biologic actionsvia TNFR70. The clinical significance of this finding is underinvestigation.

Anakinra is an IL-1 receptor antagonist (IL-1Ra) synthe-sized by recombinant DNA technology. Anakinra competi-tively inhibits binding of IL-1 to its cell-surface receptor,thus blocking the biologic activity of IL-171,72. Anakinraclosely resembles naturally occurring IL-1Ra with respect tostructure and prevents interactions between IL-1 and cellsinvolved in inflammation71,73,74.

Clinical trials have provided convincing evidence for theefficacy of the new biologic agents in retarding progressionof RA. Etanercept has been shown to improve the inflam-matory symptoms of RA and to attenuate radiographicprogression of the disease55,67. Further, patients whoreceived etanercept had more rapid improvement than thosereceiving MTX55. In a 2-year followup study of 512 patientsreceiving monotherapy of either etanercept or MTX, 72% ofetanercept patients achieved American College ofRheumatology 20% (ACR 20) improvement criteria versus59% of MTX patients (p = 0.005). Etanercept patients alsohad better outcomes as measured by Sharp scale total scoreand erosion score (mean change 1.3 and 0.66 units, respec-tively, vs 3.2 and 1.86 units; p = 0.001). More etanerceptpatients had improvement in Health AssessmentQuestionnaire disability index (55% vs 37%; p < 0.001)75. Maini, et al observed a rapid reduction indisease activity in patients who were treated with infliximaband who had failed to respond adequately to previous treat-ment with MTX. Although infliximab produced dramaticresults, one disadvantage of this agent is that it must be used


Table 1. Factors regulating osteoclast differentiation. Adapted with permission from Gravallese EM, GoldringSR. Arthritis Rheum 2000; 43:2143-51.

Factor Function Effect on Osteoclast Differentiation

RANKL (TRANCE, OPGL) Cell-surface ligand that induces osteoclast Stimulatesdifferentiation and activity

RANK (ODAR) Receptor for RANKL StimulatesOPG (OCIF) Soluble receptor that binds RANKL and prevents Inhibits

RANK activation

RANKL: receptor activator of nuclear factor-κB ligand/osteoclast differentiation factor; TRANCE: tumornecrosis factor-related activation-induced cytokine; OPGL: osteoprotegerin ligand; RANK: receptor activator ofnuclear factor-κB; ODAR: osteoclast differentiation and activation receptor; OPG: osteoprotegerin; OCIF: osteo-clastogenesis inhibitory factor.



concomitantly with MTX76. Further, many patients becometolerant to the medication, requiring either dose escalationor more frequent administration. Clinical trials withanakinra have also shown that this agent reduces the rate ofjoint destruction and improves measures of disease activity.Moreover, patients who received longterm (1 year) treat-ment with anakinra continued to show improvement throughthe study endpoint77.

Although overwhelming evidence suggests that thecytokine family represents a rational target for treating RA,the choice of which individual cytokine/receptor system totarget for optimal therapeutic effects remains a central issue.Studies to date suggest that TNF-neutralizing agentsproduce better symptomatic and functional relief than IL-1-neutralizing agents. In both human studies and animalmodels of arthritis, the effect of anakinra on measures ofinflammation was relatively modest77-79. Intermittent dosingwith subcutaneous administration coupled with a short half-life (4 to 6 h)71 may have contributed to the modest effects,insofar as maximal effects in animal studies necessitatedcontinuous infusion of anakinra77. In contrast, etanercept

has produced more impressive effects on pain, inflamma-tion, and radiographic progression in RA patients80.However, it is not possible to compare the efficacy ofanakinra with that of anti-TNF agents, owing to differencesin study design, patient population, and outcome measures81,82.Regrettably, combination of anakinra and etanercept in RApatients did not significantly improve clinical efficacy andwas associated with a high rate of infections. For example,neutralization of TNF inhibits production of IL-1, IL-6, andGM-CSF in synovial cells derived from RA patients;neutralization of IL-1, however, does not decrease theproduction of TNF83,84. These experiments suggest that TNFmay be the primary inducer of IL-1 and other proinflamma-tory cytokines, thus representing the crucial mediator in acascade that leads to diminished synthetic activity by artic-ular chondrocytes and enzymatic destruction of the matrix.

The clinical efficacy and potency of TNF and IL-1-neutralizing biologic reagents, in not only alleviating RAsymptoms, but also in retarding the progression of thedisease, may have profound implications for othercytokine/receptor systems that potentiate RA synovitis,


Figure 3. Neutralization of proinflammatory cytokines by etanercept, infliximab, and anakinra. Activation of tumor necrosis factorreceptors (TNFR) and interleukin receptors (IL-1R) initiates signaling events that lead to processes responsible for joint erosion.Etanercept is a human fusion protein consisting of 2 p75 TNFR linked to the Fc region of human IgG. Infliximab is a monoclonalantibody consisting of human constant and murine variable regions. Both etanercept and infliximab neutralize activation of TNFR,with the former mimicking endogenous soluble TNFR and the latter functioning as a high affinity antibody, to prevent binding ofTNF to its cell-surface receptor. Anakinra mimics the action of the endogenous IL-1R antagonist (IL-1Ra) by binding to the IL-1cell-surface receptor, thereby preventing its activation by IL-1. Anakinra differs from IL-1Ra by the addition of a single methionineresidue at its amino terminus. Target cells include synoviocytes, chondrocytes, osteoblasts, osteoclast precursors, and endothelialcells.



including interferon-α, interferon-ß, IL-6, and IL-1785.Current studies of RA-derived tissues and in arthritic mousemodels have identified other potential therapeutic targetssuch as IL-15, an IL-2-like cytokine, and IL-18, an IL-1-likecytokine, as important mediators in the proinflammatoryresponse underlying RA pathogenesis86. Evidence fromthese studies shows elevated concentrations of bothcytokines in RA synovial fluids, as well as a synergisticeffect of IL-15 and IL-18 to induce TNF expression in vitro.In converse experiments, however, it has been shown thatTNF can similarly upregulate IL-15 and IL-18 synthesis,illustrating the complexity in establishing cytokine hier-archy during RA inflammatory responses87. Although thedetails of this hierarchy remain incomplete, TNF is clearlycentral to the pathogenesis of inflammatory osteolysis andacts as the primary trigger in the early phases of synovitis.

CONCLUSIONSThe erosive processes leading to joint destruction in RAarise from a complex network of cytokines that mediatesignaling among lymphocytes, fibroblasts, chondrocytes,and synovial cells. Advances in understanding the role ofcytokines in the inflammatory process have led to newerDMARD that have the potential to dramatically improve thetreatment of this chronic disease. IL-1Ra primarily affectssecretion of metalloproteinases, degradation of proteogly-cans, and osteoclast activation, thereby reducing damage tocartilage and bone. Clinically, this manifests as a reductionin radiographic disease progression with only modestimprovements in inflammation. Etanercept and infliximabneutralize the effects of TNF, which may play more of apivotal role in blocking synovial inflammation than IL-1Ra.By virtue of blocking critical upstream activation events inthe cytokine cascade, these agents can produce dramaticimprovements in both inflammation and radiographicdamage.

Further, these agents improve quality-of-life assessmentsin patients with RA67,88. Additional studies comparingbiologic agents as monotherapy and in combination withconventional DMARD and other biologic response modi-fiers will be necessary to determine the most effective andsafe treatment regimen for longterm treatment of rheuma-toid synovitis.

CHRISTOPHER T. RITCHLIN, MD,

Associate Professor of Medicine,Clinical Director, Allergy, Immunology and Rheumatology Unit,University of Rochester School of Medicine and Dentistry,Rochester, New York, USA

Address reprint requests to Dr. C.T. Ritchlin, University of RochesterSchool of Medicine and Dentistry, 601 Elmwood Avenue, Room G-6427J, Rochester, NY 14642-0001. E-mail: [email protected]

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