Ch Rheumatoid Arthritis

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					                                                            CHAPTER 5

                                RHEUMATOID ARTHRITIS

                                                                Peter E. Lipsky

                                     Epidemiology and Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . 82
                                     Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
                                     Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 83
                                     Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
                                     Laboratory Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
                                     Radiographic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
                                     Clinical Course and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . 90
                                     Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
                                   ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Rheumatoid arthritis (RA) is a chronic multisystem dis-                                  compared to 18- to 29-year-old women. Recent data
ease of unknown cause. Although there are a variety of                                   indicate that the incidence of RA may be diminishing.
systemic manifestations, the characteristic feature of estab-                            Moreover, disease severity appears to be declining,
lished RA is persistent inflammatory synovitis, usually                                   although it is uncertain whether this reflects more aggres-
involving peripheral joints in a symmetric distribution.                                 sive therapeutic interventions.
The potential of the synovial inflammation to cause car-                                     Family studies indicate a genetic predisposition. For
tilage damage and bone erosions and subsequent changes                                   example, severe RA is found at approximately four times
in joint integrity is the hallmark of the disease. Despite                               the expected rate in first-degree relatives of individuals
its destructive potential, the course of RA can be quite                                 with disease associated with the presence of the autoanti-
variable. Some patients may experience only a mild oligoar-                              body, rheumatoid factor; ~10% of patients with RA will
ticular illness of brief duration with minimal joint damage,                             have an affected first-degree relative. Moreover, monozy-
but most will have a relentless progressive polyarthritis with                           gotic twins are at least four times more likely to be con-
marked functional impairment.                                                            cordant for RA than dizygotic twins, who have a similar
                                                                                         risk of developing RA as nontwin siblings. Only
                                                                                         15–20% of monozygotic twins are concordant for RA,
                                                                                         however, implying that factors other than genetics play
The prevalence of RA is ~0.8% of the population (range                                   an important etiopathogenic role. Despite this, genetic
0.3–2.1%); women are affected approximately three times                                  factors are thought to explain ~60% of the disease suscep-
more often than men.The prevalence increases with age,                                   tibility of RA. Of note, the highest risk for concordance
and sex differences diminish in the older age group. RA                                  of RA is noted in twins who have two HLA-DRB1
is seen throughout the world and affects all races. How-                                 alleles known to be associated with RA. The class II
ever, the incidence and severity seem to be less in rural                                major histocompatibility complex allele HLA-DR4
sub-Saharan Africa and in Caribbean blacks.The onset is                                  (DRβ1∗0401) and related alleles are known to be major
most frequent during the fourth and fifth decades of                                      genetic risk factors for RA. Early studies showed that as
life, with 80% of all patients developing the disease                                    many as 70% of patients with RA express HLA-DR4
between the ages of 35 and 50. The incidence of RA is                                    compared with 28% of control individuals. This associa-
more than six times greater in 60- to 64-year-old women                                  tion is particularly strong for individuals who develop

RA associated with antibodies to cyclic citrullinated           indicated that climate and urbanization have a major 83
polypeptides (CCP). An association with HLA-DR4 has             impact on the incidence and severity of RA in groups
been noted in many populations, but not all. In some            of similar genetic background. Smoking has clearly been
populations, including Israeli Jews, Asian Indians, and         identified as a risk for RA in persons expressing an HLA-
Yakima Indians of North America, however, there is no           β1 susceptibility allele. Such persons have an increased risk
association between the development of RA and HLA-              to develop severe RA associated with antibodies to CCP.
DR4. In these individuals, there is an association between
RA and the closely related HLA-DR1 (DRβ1∗0101).
The term shared epitope has been used to denote the

                                                                                                                                 CHAPTER 5
HLA-β1 alleles that appear to convey increased risk for         The cause of RA remains unknown. It has been sug-
RA because they have similar amino acids in the third           gested that RA might be a manifestation of the response
hypervariable region of the peptide binding cleft of the        to an infectious agent in a genetically susceptible host.
molecule. It has been estimated that the risk of develop-       Because of the worldwide distribution of RA, it has
ing RA in a person with DRβ1∗0401 or the closely                been hypothesized that if an infectious agent is involved,
related DRβ1∗0404 is 1 in 35 and 1 in 20, respectively,         the organism must be ubiquitous. A number of possible
whereas the presence of both alleles puts persons at an         causative agents have been suggested, including Mycoplasma,

                                                                                                                                 Rheumatoid Arthritis
even greater risk. In certain groups of patients, there         Epstein-Barr virus (EBV), cytomegalovirus, parvovirus,
does not appear to be a clear association between HLA-          and rubella virus, but convincing evidence that these or
DR4–related epitopes and RA. Thus, nearly 75% of                other infectious agents cause RA has not emerged. The
African-American RA patients do not have this genetic           process by which an infectious agent might cause chronic
element. Moreover, there is an association with HLA-            inflammatory arthritis with a characteristic distribution
DR10 (DRβ1∗1001) in Spanish and Italian patients,               also remains unknown.
with HLA-DR9 (DRβ1∗0901) in Chileans, and with
HLA-DR3 (DRβ1∗0301) in Arab populations.
                                                                PATHOLOGY AND PATHOGENESIS
   Additional genes in the HLA-D complex may also
convey altered susceptibility to RA. These include por-         Microvascular injury and an increase in the number of
tions of the HLA region outside of the coding regions of        synovial lining cells appear to be the earliest lesions in
HLA-DR molecules that increase risk. In addition, certain       rheumatoid synovitis.The nature of the insult causing this
HLA-DR alleles, including HLA-DR5 (DRβ1∗1101),                  response is not known. Subsequently, an increased number
HLA-DR2 (DRβ1∗1501), HLA-DR3 (DRβ1∗0301),                       of synovial lining cells is seen along with perivascular infil-
and HLA-DR7 (DRβ1∗0701), may protect against the                tration with mononuclear cells. Before the onset of clinical
development of RA in that they tend to be found at              symptoms, the perivascular infiltrate is predominantly com-
lower frequency in RA patients than in controls. A              posed of myeloid cells, whereas in symptomatic arthritis,
recent classification of HLA-β1 alleles based on the             T cells can also be found, although their number does not
sequence of the third hypervariable region, encoding a          appear to correlate with symptoms.As the process continues,
portion of the peptide binding cleft, has established a         the synovium becomes edematous and protrudes into the
hierarchy of disease susceptibility. Alleles of a group that    joint cavity as villous projections.
contained a lysine at position 71 conveyed the highest              Light-microscopic examination discloses a character-
risk, whereas alleles of a group that contained an argi-        istic constellation of features, which include hyperplasia
nine at position 71 also conveyed increased risk com-           and hypertrophy of the synovial lining cells; focal or seg-
pared to all other HLF-β1 alleles. It has been estimated        mental vascular changes, including microvascular injury,
that HLA genes contribute about one-third of the                thrombosis, and neovascularization; edema; and infiltration
genetic susceptibility to RA. Thus, genes outside the           with mononuclear cells, often collected into aggregates
HLA complex also contribute. Recent analyses have               around small blood vessels (Fig. 5-1). The endothelial
identified PTPN22, a phosphatase involved in antigen             cells of the rheumatoid synovium have the appearance
receptor signaling in lymphocytes, FcRL3, a molecule            of high endothelial venules of lymphoid organs that
involved in regulating B cell activation, PADI4, an enzyme      have been altered by cytokine exposure to facilitate entry
involved in conversion of citrulline to arginine in proteins,   of cells into tissue. Rheumatoid synovial endothelial
and CTLA4, a molecule involved in regulation of T cell          cells express increased amounts of various adhesion mol-
activation, as susceptibility genes for RA, in at least some    ecules involved in this process. Although this pathologic
populations. Except for PADI4, these genes also appear          picture is typical of RA, it can also be seen in a variety of
to convey risk for other autoimmune diseases.                   other chronic inflammatory arthritides.The mononuclear
   Genetic risk factors do not fully account for the            cell collections are variable in composition and size.The
incidence of RA, suggesting that environmental factors          predominant infiltrating cell is the T lymphocyte. CD4+
also play a role in the etiology of the disease. This is        T cells predominate over CD8+ T cells and are frequently
emphasized by epidemiologic studies in Africa that have         found in close proximity to HLA-DR+ macrophages
                      84                                                                               Osteoclasts are also prominent at sites of bone erosion.
                                                                                                       Activated mesenchymal stromal cells, similar to those
                                                                                                       found in normal bone marrow, can also be found in the
                                                                                                       rheumatoid synovium.
                                                                                                           The rheumatoid synovium is characterized by the
                                                                                                       presence of a number of secreted products of activated
                                                                                                       lymphocytes, macrophages, and fibroblasts. The local
                                                                                                       production of these cytokines and chemokines appears
                                                                                                       to account for many of the pathologic and clinical man-
                                                                                                       ifestations of RA. These effector molecules include

                                                                                                       those that are derived from T lymphocytes, those origi-
                                                                                                       nating from activated myeloid cells, and those secreted
                                                                                                       by other cell types in the synovium, such as fibroblasts
                                                                                                       and endothelial cells.The activity of these chemokines and
                                      A                              B                                 cytokines appears to account for many of the features of
                                                                                                       rheumatoid synovitis, including the synovial tissue
Disorders of Immune-Mediated Injury

                                      FIGURE 5-1
                                      Histology of rheumatoid synovitis. A. The characteristic         inflammation, synovial fluid inflammation, synovial pro-
                                      features of rheumatoid inflammation with hyperplasia of the       liferation, and cartilage and bone damage, as well as the
                                      lining layer (arrow) and mononuclear infiltrates in the sublin-   systemic manifestations of RA. In addition to the pro-
                                      ing layer (double arrow). B. A higher magnification of the        duction of effector molecules that propagate the inflam-
                                      largely CD4+ T cell infiltrate around postcapillary venules       matory process, local factors are produced that tend to
                                      (arrow).                                                         slow the inflammation, including specific inhibitors of
                                                                                                       cytokine action and additional cytokines, such as trans-
                                                                                                       forming growth factor β(TGF-β), which inhibits many
                                      and dendritic cells. Increased numbers of a separate             of the features of rheumatoid synovitis including T cell
                                      population of T cells expressing the γδ form of the              activation and proliferation, B cell differentiation, and
                                      T cell receptor have also been found in the synovium,            migration of cells into the inflammatory site, and may be
                                      although they remain a minor population there and                involved in generating a population of regulatory T cells,
                                      their role in RA has not been delineated. The major              as a means to control inflammation.
                                      population of T cells in the rheumatoid synovium is                  These findings have suggested that the propagation of
                                      composed of CD4+ memory T cells that form the                    RA is an immunologically mediated event, although the
                                      majority of cells aggregated around postcapillary                original initiating stimulus has not been characterized.
                                      venules. Scattered throughout the tissue are CD8+ T              One view is that the inflammatory process in the tissue
                                      cells. Both populations express the early activation anti-       is driven by the CD4+ T cells infiltrating the synovium.
                                      gen, CD69. Besides the accumulation of T cells,                  Evidence for this includes (1) the predominance of
                                      rheumatoid synovitis is also characterized by the infiltra-       CD4+ T cells in the synovium; (2) the increase in solu-
                                      tion of variable numbers of B cells and antibody-producing       ble interleukin (IL)-2 receptors, a product of activated
                                      plasma cells. In advanced disease, structures similar to         T cells, in blood and synovial fluid of patients with active
                                      germinal centers of secondary lymphoid organs may be             RA; and (3) amelioration of the disease by removal of
                                      observed in the synovium, but these are observed only in         T cells by thoracic duct drainage or peripheral lympha-
                                      a small fraction of patients. Both polyclonal immunoglob-        pheresis or suppression of their proliferation or function
                                      ulin and the autoantibody rheumatoid factor are pro-             by drugs, such as cyclosporine, leflunomide, or nonde-
                                      duced within the synovial tissue, which leads to the local       pleting monoclonal antibodies to CD4, or inhibitors of
                                      formation of immune complexes. Antibodies to synovial            T cell activation, such as the T cell co-stimulation com-
                                      tissue components may also contribute to inflammation.            petitor, CTLA-4·Ig (abatacept). In addition, the associa-
                                      Recent evidence suggests that antibodies to CCP, which           tion of RA with certain HLA-DR alleles, whose only
                                      are generated within the synovium, may contribute to             known functions are to shape the repertoire of CD4+ T
                                      RA synovitis. Increased numbers of activated mast cells          cells during ontogeny in the thymus and bind and present
                                      are also found in the rheumatoid synovium. Local                 antigenic peptides to CD4+ T cells in the periphery,
                                      release of the contents of their granules may contribute         strongly implies a role for CD4+ T cells in the patho-
                                      to inflammation. Finally, the synovial fibroblasts in RA           genesis of the disease.Within the rheumatoid synovium,
                                      manifest evidence of activation in that they produce a           the CD4+ T cells differentiate predominantly into TH1-
                                      number of enzymes such as collagenase and cathepsins             like effector cells producing the proinflammatory
                                      that can degrade components of the articular matrix.These        cytokine interferon (IFN)-γ and appear to be deficient
                                      activated fibroblasts are particularly prominent in the           in differentiation into TH2-like effector cells capable of
                                      lining layer and at the interface with bone and cartilage.       producing the anti-inflammatory cytokine IL-4.As a result
of the ongoing secretion of IFN-γ without the regula-          mediators such as leukotriene B4 and products of com- 85
tory influences of IL-4, macrophages are activated to           plement activation can attract neutrophils. Moreover,
produce the proinflammatory cytokines IL-1 and tumor            many of these same agents can also stimulate the
necrosis factor (TNF) and also increase expression of          endothelial cells of postcapillary venules to become more
HLA molecules. Direct contact between activated T cells        efficient at binding circulating cells. The net result is the
and myeloid cells may also lead to the production of           enhanced migration of PMNLs into the synovial site. In
proinflammatory cytokines by the latter. Moreover, T            addition, vasoactive mediators such as histamine pro-
lymphocytes express surface molecules such as CD154            duced by the mast cells that infiltrate the rheumatoid
(CD40 ligand) and also produce a variety of cytokines          synovium may also facilitate the exudation of inflamma-

                                                                                                                         CHAPTER 5
that promote B cell proliferation and differentiation into     tory cells into the synovial fluid. Finally, the vasodilatory
antibody-forming cells and therefore may also promote          effects of locally produced prostaglandin E2 may also
local B cell stimulation. The resultant production of          facilitate entry of inflammatory cells into the inflamma-
immunoglobulin and rheumatoid factor can lead to               tory site. Once in the synovial fluid, the PMNLs can
immune-complex formation with consequent comple-               ingest immune complexes, with the resultant production
ment activation and exacerbation of the inflammatory            of reactive oxygen metabolites and other inflammatory
process by the production of the anaphylatoxins, C3a           mediators, further adding to the inflammatory milieu.

                                                                                                                         Rheumatoid Arthritis
and C5a, and the chemotactic factor C5a. In addition,          Locally produced cytokines and chemokines can addi-
antibodies may be produced to other self-antigens, such        tionally stimulate PMNLs. The production of large
as CCP, that can contribute to disease pathogenesis. The       amounts of cyclooxygenase and lipoxygenase pathway
tissue inflammation is reminiscent of chronic inflamma-          products of arachidonic acid metabolism by cells in the
tory responses to persistent microorganisms, although it       synovial fluid and tissue further accentuates the signs and
has become clear that the number of T cells producing          symptoms of inflammation.
cytokines such as IFN-γ is less than is found in typical           The precise mechanism by which bone and cartilage
delayed-type hypersensitivity reactions, perhaps owing         destruction occurs has not been completely resolved.
to the large amount of reactive oxygen species produced        Although the synovial fluid contains a number of enzymes
locally in the synovium that can dampen T cell function        potentially able to degrade cartilage, the majority of
or the action of local regulatory cells. It remains unclear    destruction occurs in juxtaposition to the inflamed syn-
whether the persistent T cell activity represents a response   ovium, or pannus, that spreads to cover the articular car-
to a persistent exogenous antigen or to altered autoanti-      tilage. This vascular granulation tissue is composed of
gens such as collagen, immunoglobulin, one of the heat         proliferating fibroblasts, small blood vessels, and a vari-
shock proteins, or CCP. Alternatively, it could represent      able number of mononuclear cells and produces a large
persistent responsiveness to activated autologous cells        amount of degradative enzymes, including collagenase
such as might occur as a result of EBV infection or per-       and stromelysin, that may facilitate tissue damage. The
sistent response to a foreign antigen or superantigen in       cytokines IL-1 and TNF play an important role by stim-
the synovial tissue. Finally, rheumatoid inflammation           ulating the cells of the pannus to produce collagenase
could reflect persistent stimulation of T cells by syn-         and other neutral proteases. These same two cytokines
ovial-derived antigens that cross-react with determinants      also activate chondrocytes in situ, stimulating them to
introduced during antecedent exposure to foreign anti-         produce proteolytic enzymes that can degrade cartilage
gens or infectious microorganisms. The important con-          locally and also inhibiting synthesis of new matrix mol-
tribution of B lymphocytes to the chronic inflammatory          ecules. Finally, these two cytokines, along with IL-6, may
process has been emphasized by the observation that            contribute to the local demineralization of bone by
treatment with a monoclonal antibody to the B cell             contributing to the activation of osteoclasts that accu-
marker, CD20 (rituximab), caused prompt depletion of           mulate at the site of local bone resorption. Prostaglandin
B lymphocytes, a decline in serum rheumatoid factor            E2 produced by fibroblasts and macrophages may also
titers, and a partial amelioration of signs and symptoms       contribute to bone demineralization.The common final
of inflammation.                                                pathway of bone erosion is likely to involve the activation
    Overriding the chronic inflammation in the synovial         of osteoclasts that are present in large numbers at these
tissue is an acute inflammatory process in the synovial         sites. Systemic manifestations of RA can be accounted
fluid. The exudative synovial fluid contains more poly-          for by release of inflammatory effector molecules from
morphonuclear leukocytes (PMNLs) than mononuclear              the synovium.These include IL-1,TNF, and IL-6, which
cells. A number of mechanisms play a role in stimulating       account for many of the manifestations of active RA,
the exudation of synovial fluid. Locally produced anti-         including malaise, fatigue, and elevated levels of serum
bodies to tissue components and immune complexes can           acute-phase reactants. The importance of TNF in pro-
activate complement and generate anaphylatoxins and            ducing these manifestations is emphasized by the
chemotactic factors. Local production of chemokines and        prompt amelioration of symptoms following administra-
cytokines with chemotactic activity as well as inflammatory     tion of a monoclonal antibody to TNF or a soluble TNF
                      86 receptor Ig construct to patients with RA.This is associ-                               produce effector molecules that can cause tissue damage
                                      ated with a decrease in production of other proinflam-                      characteristic of chronic inflammation. It is important to
                                      matory cytokines, including IL-1 and IL-6. Other cytokines                 emphasize that there is no current way to predict the
                                      may also contribute to the inflammatory milieu, includ-                     progress from one stage of inflammation to the next,
                                      ing IL-17. In addition, immune complexes produced                          and once established, each can influence the other.
                                      within the synovium and entering the circulation may                       Important features of this model include the following:
                                      account for other features of the disease, such as systemic                (1) the major pathologic events vary with time in this
                                      vasculitis.                                                                chronic disease; (2) the time required to progress from
                                         As shown in Fig. 5-2, the pathology of RA evolves                       one step to the next may vary in different patients, and
                                      over the duration of this chronic disease. The earliest                    the events, once established, may persist simultaneously;

                                      event appears to be a nonspecific inflammatory response                      (3) once established, the major pathogenic events opera-
                                      initiated by an unknown stimulus and characterized by                      tive in an individual patient may vary at different times;
                                      accumulation of macrophages and other mononuclear                          (4) the process is chronic and reiterative, with successive
                                      cells within the sublining layer of the synovium. The                      events stimulating progressive amplification of inflamma-
                                      activity of these cells is demonstrated by the increased                   tion; and (5) once memory T cells and B cells have been
                                      appearance of macrophage-derived cytokines, including                      generated, anti-inflammatory and anti-cytokine therapy
Disorders of Immune-Mediated Injury

                                      TNF, IL-1β, and IL-6. Subsequently, activation and dif-                    may be capable of suppressing disease manifestations but not
                                      ferentiation of memory CD4+ T cells is induced, pre-                       preventing recrudescence of disease activity once therapy
                                      sumably in response to antigenic peptides displayed by a                   is discontinued.These considerations have important impli-
                                      variety of antigen-presenting cells in the synovial tissue.                cations with regard to appropriate treatment.
                                      The activated memory T cells are capable of producing
                                      cytokines, especially IFN-γ, which amplify and perpetu-
                                      ate the inflammation. The presence of activated T cells                     CLINICAL MANIFESTATIONS
                                      expressing CD154 (CD40 ligand) can induce polyclonal
                                      B cell stimulation and differentiation of memory B cells
                                      and plasma cells that produce autoantibodies locally.The                   Characteristically, RA is a chronic polyarthritis. In approxi-
                                      cascade of cytokines produced in the synovium activates                    mately two-thirds of patients, it begins insidiously
                                      a variety of cells in the synovium, bone, and cartilage to                 with fatigue, anorexia, generalized weakness, and vague

                                                             Nonspecific Inflammation             T Cell Activation                     Tissue Injury
                                                                    Initiation                      Amplification                   Chronic inflammation


                                                                                                                          B cell

                                                               Non-                                                 Chemokines/cytokines
                                                               specific                                              adhesion molecules
                                                               insult                                                CD40 ligand/CD154
                                                                                                Memory                             Macrophage
                                                                                                 T Cell

                                                                                          Macro- B Dendritic Cytokine-                            proteases
                                                                                          phage cell cell    activated
                                                                                                                                                  Acid phosphates
                                                                                              Antigen-presenting cells                            Acid hydrolases

                                      FIGURE 5-2
                                      The progression of rheumatoid synovitis. This figure                        of nonspecific inflammation, which may last for a protracted
                                      depicts the evolution of the pathogenic mechanisms and ulti-               period of time with no or moderate symptoms. When activa-
                                      mate pathologic changes involved in the development of                     tion of memory T cells in response to a variety of peptides
                                      rheumatoid synovitis. The stages of rheumatoid arthritis are               presented by antigen-presenting cells occurs in genetically
                                      proposed to be an initiation phase of nonspecific inflamma-                  susceptible individuals, amplification of inflammation occurs
                                      tion, followed by an amplification phase resulting from T cell              with the promotion of local rheumatoid factor and other
                                      activation, and finally a stage of chronic inflammation with                 autoantibody production and enhanced capacity to mediate
                                      tissue injury. A variety of stimuli may initiate the initial phase         tissue damage.
musculoskeletal symptoms until the appearance of syn-            deformity, and median nerve entrapment (carpal tunnel 87
ovitis becomes apparent. This prodrome may persist for           syndrome). Synovitis of the elbow joint often leads to
weeks or months and defy diagnosis. Specific symptoms             flexion contractures that may develop early in the dis-
usually appear gradually as several joints, especially those     ease.The knee joint is commonly involved with synovial
of the hands, wrists, knees, and feet, become affected in a      hypertrophy, chronic effusion, and frequently ligamen-
symmetric fashion. In ~10% of individuals, the onset is          tous laxity. Pain and swelling behind the knee may be
more acute, with a rapid development of polyarthritis,           caused by extension of inflamed synovium into the
often accompanied by constitutional symptoms, including          popliteal space (Baker’s cyst). Arthritis in the forefoot,
fever, lymphadenopathy, and splenomegaly. In approxi-            ankles, and subtalar joints can produce severe pain with

                                                                                                                             CHAPTER 5
mately one-third of patients, symptoms may initially be          ambulation as well as a number of deformities. Axial
confined to one or a few joints. Although the pattern of          involvement is usually limited to the upper cervical
joint involvement may remain asymmetric in some                  spine. Involvement of the lumbar spine is not seen, and
patients, a symmetric pattern is more typical.                   lower back pain cannot be ascribed to rheumatoid
                                                                 inflammation. On occasion, inflammation from the syn-
Signs and Symptoms of Articular Disease                          ovial joints and bursae of the upper cervical spine leads
                                                                 to atlantoaxial subluxation. This usually presents as pain

                                                                                                                             Rheumatoid Arthritis
Pain, swelling, and tenderness may initially be poorly           in the occiput but on rare occasions may lead to com-
localized to the joints. Pain in affected joints, aggravated     pression of the spinal cord.
by movement, is the most common manifestation of                     With persistent inflammation, a variety of character-
established RA. It corresponds in pattern to the joint           istic joint changes develop. These can be attributed to a
involvement but does not always correlate with the               number of pathologic events, including laxity of supporting
degree of apparent inflammation. Generalized stiffness is         soft tissue structures; damage or weakening of ligaments,
frequent and is usually greatest after periods of inactivity.    tendons, and the joint capsule; cartilage degradation;
Morning stiffness of >1-h duration is an almost invariable       muscle imbalance; and unopposed physical forces associ-
feature of inflammatory arthritis. Notably, however, the          ated with the use of affected joints. Characteristic
presence of morning stiffness may not reliably distinguish       changes of the hand include (1) radial deviation at the
between chronic inflammatory and noninflammatory                   wrist with ulnar deviation of the digits, often with palmar
arthritides, as it is also found frequently in the latter. The   subluxation of the proximal phalanges (“Z” deformity);
majority of patients will experience constitutional symp-        (2) hyperextension of the proximal interphalangeal
toms such as weakness, easy fatigability, anorexia, and          joints, with compensatory flexion of the distal interpha-
weight loss. Although fever to 40°C occurs on occasion,          langeal joints (swan-neck deformity); (3) flexion contrac-
temperature elevation of >38°C is unusual and suggests           ture of the proximal interphalangeal joints and extension
the presence of an intercurrent problem such as infection.       of the distal interphalangeal joints (boutonnière defor-
   Clinically, synovial inflammation causes swelling, ten-        mity); and (4) hyperextension of the first interphalangeal
derness, and limitation of motion. Initially, impairment         joint and flexion of the first metacarpophalangeal joint
in physical function is caused by pain and inflammation,          with a consequent loss of thumb mobility and pinch.
and disability owing to this is a frequent early feature of      Typical joint changes may also develop in the feet,
aggressive RA. Warmth is usually evident on examina-             including eversion at the hindfoot (subtalar joint), plan-
tion, especially of large joints such as the knee, but ery-      tar subluxation of the metatarsal heads, widening of the
thema is infrequent. Pain originates predominantly from          forefoot, hallux valgus, and lateral deviation and dorsal
the joint capsule, which is abundantly supplied with             subluxation of the toes. Later in the disease, disability is
pain fibers and is markedly sensitive to stretching or dis-       more related to structural damage to articular structures.
tention. Joint swelling results from accumulation of syn-
ovial fluid, hypertrophy of the synovium, and thickening
                                                                 Extraarticular Manifestations
of the joint capsule. Initially, motion is limited by pain.
The inflamed joint is usually held in flexion to maximize          RA is a systemic disease with a variety of extraarticular
joint volume and minimize distention of the capsule. Later,      manifestations. It is estimated that as many as 40% of
fibrous or bony ankylosis or soft tissue contractures lead to     patients may have extraarticular manifestations, and in
fixed deformities.                                                ~15% these are severe. On occasion, extraarticular mani-
   Although inflammation can affect any diarthrodial              festations may be the major evidence of disease activity
joint, RA most often causes symmetric arthritis with             and source of morbidity and require management per
characteristic involvement of certain specific joints such        se. As a rule, these manifestations occur in individuals
as the proximal interphalangeal and metacarpopha-                with high titers of autoantibodies to the Fc compo-
langeal joints. The distal interphalangeal joints are rarely     nent of immunoglobulin G (rheumatoid factors) or with
involved. Synovitis of the wrist joints is a nearly uniform      antibodies to CCP. Although the frequency of patients
feature of RA and may lead to limitation of motion,              with severe extraarticular manifestations appears to be
                      88 declining, these patients have an increased mortality                        when these are related to the total protein concentration.
                                      compared to other persons with RA or age-matched                Pulmonary fibrosis can produce impairment of the dif-
                                      normal controls.                                                fusing capacity of the lung. Pulmonary nodules may
                                          Rheumatoid nodules may develop in 20–30% of persons         appear singly or in clusters.When they appear in individ-
                                      with RA. They are usually found on periarticular struc-         uals with pneumoconiosis, a diffuse nodular fibrotic
                                      tures, extensor surfaces, or other areas subjected to           process (Caplan’s syndrome) may develop. On occasion,
                                      mechanical pressure, but they can develop elsewhere,            pulmonary nodules may cavitate and produce a pneu-
                                      including the pleura and meninges. Common locations             mothorax or bronchopleural fistula. Rarely, pulmonary
                                      include the olecranon bursa, the proximal ulna, the             hypertension secondary to obliteration of the pulmonary
                                      Achilles tendon, and the occiput. Nodules vary in size and      vasculature occurs. In addition to pleuropulmonary dis-

                                      consistency and are rarely symptomatic, but on occasion         ease, upper airway obstruction from cricoarytenoid
                                      they break down as a result of trauma or become infected.       arthritis or laryngeal nodules may develop.
                                      They are found almost invariably in individuals with cir-           Clinically apparent heart disease attributed to the
                                      culating rheumatoid factor. Histologically, rheumatoid          rheumatoid process was thought previously to be rare,
                                      nodules consist of a central zone of necrotic material          but evidence of asymptomatic pericarditis is found at
                                      including collagen fibrils, noncollagenous filaments, and         autopsy in 50% of cases. Pericardial fluid has a low glucose
Disorders of Immune-Mediated Injury

                                      cellular debris; a midzone of palisading macrophages that       level and is frequently associated with the occurrence of
                                      express HLA-DR antigens; and an outer zone of granula-          pleural effusion. Although pericarditis is usually asympto-
                                      tion tissue. Examination of early nodules has suggested         matic, on rare occasions death has occurred from tam-
                                      that the initial event may be a focal vasculitis. In some       ponade. Chronic constrictive pericarditis may also occur.
                                      patients, treatment with methotrexate can increase the          More recently, an increased incidence of congestive heart
                                      number of nodules dramatically.                                 failure and death from cardiovascular disease has been
                                          Clinical weakness and atrophy of skeletal muscle are        associated with RA. This relates to the level of disease
                                      common. Muscle atrophy may be evident within weeks              activity and can be mitigated with appropriate anti-
                                      of the onset of RA and is usually most apparent in mus-         inflammatory therapy.
                                      culature approximating affected joints. Muscle biopsy               RA tends to spare the central nervous system directly,
                                      may show type II fiber atrophy and muscle fiber necrosis          although vasculitis can cause peripheral neuropathy.
                                      with or without a mononuclear cell infiltrate.                   Neurologic manifestations may also result from atlantoaxial
                                          Rheumatoid vasculitis (Chap. 10), which can affect nearly   or midcervical spine subluxations. Nerve entrapment
                                      any organ system, is seen in patients with severe RA and        secondary to proliferative synovitis or joint deformities
                                      high titers of circulating rheumatoid factor. Rheumatoid        may produce neuropathies of median, ulnar, radial
                                      vasculitis is very uncommon in African Americans. In its        (interosseous branch), or anterior tibial nerves.
                                      most aggressive form, rheumatoid vasculitis can cause               The rheumatoid process involves the eye in 1% of
                                      polyneuropathy and mononeuritis multiplex, cutaneous            patients. Affected individuals usually have long-standing
                                      ulceration and dermal necrosis, digital gangrene, and vis-      disease and nodules. The two principal manifestations
                                      ceral infarction. While such widespread vasculitis is very      are episcleritis, which is usually mild and transient, and
                                      rare, more limited forms are not uncommon, especially           scleritis, which involves the deeper layers of the eye and
                                      in white patients with high titers of rheumatoid factor.        is a more serious inflammatory condition. Histologically,
                                      Neurovascular disease presenting either as a mild distal        the lesion is similar to a rheumatoid nodule and may
                                      sensory neuropathy or as mononeuritis multiplex may be          result in thinning and perforation of the globe (sclero-
                                      the only sign of vasculitis. Cutaneous vasculitis usually       malacia perforans). From 15–20% of persons with RA
                                      presents as crops of small brown spots in the nail beds,        may develop Sjögren’s syndrome with attendant kerato-
                                      nail folds, and digital pulp. Larger ischemic ulcers, espe-     conjunctivitis sicca.
                                      cially in the lower extremity, may also develop. Myocar-            Felty’s syndrome consists of chronic RA, splenomegaly,
                                      dial infarction secondary to rheumatoid vasculitis has          neutropenia, and, on occasion, anemia and thrombocytope-
                                      been reported, as has vasculitic involvement of lungs,          nia. It is most common in individuals with long-standing
                                      bowel, liver, spleen, pancreas, lymph nodes, and testes.        disease. These patients frequently have high titers of
                                      Renal vasculitis is rare.                                       rheumatoid factor, subcutaneous nodules, and other mani-
                                          Pleuropulmonary manifestations, which are more com-         festations of systemic rheumatoid disease. Felty’s syndrome
                                      monly observed in men, include pleural disease, intersti-       is very uncommon in African Americans. It may develop
                                      tial fibrosis, pleuropulmonary nodules, pneumonitis, and         after joint inflammation has regressed. Circulating immune
                                      arteritis. Evidence of pleuritis is found commonly at           complexes are often present, and evidence of complement
                                      autopsy, but symptomatic disease during life is infre-          consumption may be seen. The leukopenia is a selective
                                      quent.Typically, the pleural fluid contains very low levels      neutropenia with polymorphonuclear leukocyte counts of
                                      of glucose in the absence of infection. Pleural fluid            <1500 cells/μL and sometimes <1000 cell/μL. Bone mar-
                                      complement is also low compared with the serum level            row examination usually reveals moderate hypercellularity
with a paucity of mature neutrophils. However, the bone        RA are associated with the presence of rheumatoid factor. 89
marrow may be normal, hyperactive, or hypoactive; matu-        These include systemic lupus erythematosus, Sjögren’s
ration arrest may be seen. Hypersplenism has been pro-         syndrome, chronic liver disease, sarcoidosis, interstitial
posed as one of the causes of leukopenia, but splenomegaly     pulmonary fibrosis, infectious mononucleosis, hepatitis B,
is not invariably found and splenectomy does not always        tuberculosis, leprosy, syphilis, subacute bacterial endo-
correct the abnormality. Excessive margination of granulo-     carditis, visceral leishmaniasis, schistosomiasis, and malaria.
cytes caused by antibodies to these cells, complement acti-    In addition, rheumatoid factor may appear transiently in
vation, or binding of immune complexes may contribute          normal individuals after vaccination or transfusion and
to granulocytopenia. Patients with Felty’s syndrome have       may also be found in relatives of individuals with RA.

                                                                                                                            CHAPTER 5
increased frequency of infections usually associated with         The presence of rheumatoid factor does not establish
neutropenia. The cause of the increased susceptibility to      the diagnosis of RA, as the predictive value of the pres-
infection is related to the defective function of PMNLs as     ence of rheumatoid factor in determining a diagnosis of
well as the decreased number of cells.                         RA is poor. Thus less than one-third of unselected
   Osteoporosis secondary to rheumatoid involvement is         patients with a positive test for rheumatoid factor will
common and may be aggravated by glucocorticoid therapy.        be found to have RA. Therefore, the rheumatoid factor
Glucocorticoid treatment may cause significant loss of          test is not useful as a screening procedure. However, the

                                                                                                                            Rheumatoid Arthritis
bone mass, especially early in the course of therapy, even     presence of rheumatoid factor can be of prognostic sig-
when low doses are employed. Osteopenia in RA involves         nificance because patients with high titers tend to have
both juxtaarticular bone and long bones distant from           more severe and progressive disease with extraarticular
involved joints. RA is associated with a modest decrease       manifestations. Rheumatoid factor is uniformly found in
in mean bone mass and a moderate increase in the risk of       patients with nodules or vasculitis. In summary, a test for
fracture. Bone mass appears to be adversely affected by        the presence of rheumatoid factor can be employed to
functional impairment and active inflammation, especially       confirm a diagnosis in individuals with a suggestive clin-
early in the course of the disease.                            ical presentation and, if present in high titer, to designate
   RA is associated with an increased incidence of lym-        patients at risk for severe systemic disease.
phoma, especially large B cell lymphoma. Notably, this is         Antibodies to CCP (designated anti-CCP) can also be
particularly observed in those with persistent inflamma-        used to evaluate patients with RA. Although these anti-
tory disease.                                                  bodies are most commonly found in rheumatoid factor–
                                                               positive patients, on occasion they can be detected in the
RA in the Elderly                                              absence of rheumatoid factor. In addition, the anti-CCP
                                                               test has a similar sensitivity and a better specificity for
The incidence of RA continues to increase past age 60.         RA than does rheumatoid factor, and, therefore, some
It has been suggested that elderly-onset RA might have         have advocated its use to evaluate RA patients instead of
a poorer prognosis, as manifested by more persistent dis-      rheumatoid factor.This is particularly the case in individ-
ease activity, more frequent radiographically evident dete-    uals with early RA, in whom assessment of anti-CCP
rioration, more frequent systemic involvement, and more        may be the most useful to confirm the diagnosis and
rapid functional decline. Aggressive disease is largely        establish a likely prognosis. The presence of anti-CCP is
restricted to those patients with high titers of rheuma-       most common in persons with aggressive disease, with a
toid factor. By contrast, elderly patients who develop RA      tendency for developing bone erosions.The development
without elevated titers of rheumatoid factor (seronega-        of anti-CCP is most frequent in individuals with an RA
tive disease) generally have less severe, often self-limited   associated HLA-β1 allele and in those who smoke ciga-
disease.                                                       rettes, and may occur before the development of clinical
                                                               manifestations of RA. However, as with rheumatoid fac-
                                                               tor, the presence of anti-CCP is not useful to predict the
                                                               future development of RA because it can be found in
No tests are specific for diagnosing RA. However,               ~1.5% of normal individuals, most of whom will not
rheumatoid factors, which are autoantibodies reactive          develop RA, and occasionally in persons with other
with the Fc portion of IgG, are found in more than two-        rheumatic diseases. However, it is a useful test to confirm
thirds of adults with the disease and have classically been    a diagnosis of RA and to estimate prognosis.
used to evaluate patients with RA. Widely utilized tests          Normochromic, normocytic anemia is frequently
largely detect IgM rheumatoid factors. The presence of         present in active RA. It is thought to reflect ineffective
rheumatoid factor is not specific for RA, as rheumatoid         erythropoiesis; large stores of iron are found in the bone
factor is found in 5% of healthy persons.The frequency of      marrow. In general, anemia and thrombocytosis correlate
rheumatoid factor in the general population increases          with disease activity. The white blood cell count is
with age, and 10–20% of individuals >65 years have a           usually normal, but a mild leukocytosis may be present.
positive test. In addition, a number of conditions besides     Leukopenia may also exist without the full-blown picture
                      90 of Felty’s syndrome. Eosinophilia, when present, usually                       but fluctuating disease activity, accompanied by a variable
                                      reflects severe systemic disease.                                  degree of joint abnormalities and functional impairment.
                                         The erythrocyte sedimentation rate (ESR) is increased          After 10–12 years, <20% of patients had no evidence of
                                      in nearly all patients with active RA.The levels of a variety     disability or joint abnormalities. Moreover, within 10 years,
                                      of other acute-phase reactants including ceruloplasmin and        ~50% of patients had work disability. All of these out-
                                      C-reactive protein are also elevated, and generally such          comes are thought to be positively influenced by early
                                      elevations correlate with disease activity and the likelihood     aggressive intervention. A number of features are corre-
                                      of progressive joint damage.                                      lated with a greater likelihood of developing joint abnor-
                                         Synovial fluid analysis confirms the presence of inflam-          malities or disabilities.These include the presence of >20
                                      matory arthritis, although none of the findings are spe-           inflamed joints, a markedly elevated ESR, radiographic

                                      cific. The fluid is usually turbid, with reduced viscosity,         evidence of bone erosions, the presence of rheumatoid
                                      increased protein content, and a slightly decreased or nor-       nodules, high titers of serum rheumatoid factor or anti-
                                      mal glucose concentration. The white cell count varies            CCP antibodies, the presence of functional disability, per-
                                      between 5 and 50,000/μL; PMNLs predominate. A syn-                sistent inflammation, advanced age at onset, the presence
                                      ovial fluid white blood cell count >2000/μL with >75%              of comorbid conditions, low socioeconomic status or
                                      polymorphonuclear leukocytes is highly characteristic of          educational level, or the presence of HLA-DR‚1∗0401
Disorders of Immune-Mediated Injury

                                      inflammatory arthritis, although not diagnostic of RA.             or -DR‚∗0404. The presence of one or more of these
                                      Total hemolytic complement, C3, and C4 are markedly               implies the presence of more aggressive disease with a
                                      diminished in synovial fluid relative to total protein con-        greater likelihood of developing progressive joint abnor-
                                      centration as a result of activation of the classic comple-       malities and disability. Persistent elevation of the ESR,
                                      ment pathway by locally produced immune complexes.                disability, and pain on longitudinal follow-up are good
                                                                                                        predictors of work disability, whereas persistent synovitis
                                      RADIOGRAPHIC EVALUATION                                           of >12 weeks is associated with an increased likelihood
                                                                                                        of developing bone erosions. Patients who lack these fea-
                                      Early in the disease, radiographic evaluations of the             tures have more indolent disease with a slower progres-
                                      affected joints are usually not helpful in establishing a diag-   sion to joint abnormalities and disability. The pattern of
                                      nosis.They reveal only that which is apparent from physi-         disease onset does not appear to predict the development
                                      cal examination, namely, evidence of soft tissue swelling         of disabilities. Approximately 15% of patients with RA
                                      and joint effusion. As the disease progresses, abnormalities      will have a short-lived inflammatory process that remits
                                      become more pronounced, but none of the radiographic              without major disability. These individuals tend to lack
                                      findings is diagnostic of RA. The diagnosis, however, is           the aforementioned features associated with more aggres-
                                      supported by a characteristic pattern of abnormalities,           sive disease.
                                      including the tendency toward symmetric involvement.                  Several features of patients with RA appear to have
                                      Juxtaarticular osteopenia may become apparent within              prognostic significance. Remissions of disease activity are
                                      weeks of onset. Loss of articular cartilage and bone ero-         most likely to occur during the first year. White females
                                      sions develop after months of sustained activity. The pri-        tend to have more persistent synovitis and more progres-
                                      mary value of radiography is to determine the extent of           sively erosive disease than males. Persons who present with
                                      cartilage destruction and bone erosion produced by the            high titers of rheumatoid factor, anti-CCP antibodies,
                                      disease, particularly when one is attempting to estimate the      C-reactive protein, and haptoglobin also have a worse
                                      aggressive nature of the disease, monitoring the impact of        prognosis, as do individuals with subcutaneous nodules or
                                      therapy with disease-modifying drugs, or determining the          radiographic evidence of erosions at the time of initial
                                      need for surgical intervention. Other means of imaging            evaluation. Sustained disease activity of >1 year’s duration
                                      bones and joints, including 99mTc bisphosphonate bone             portends a poor outcome, and persistent elevation of
                                      scanning and MRI, may be capable of detecting early               acute-phase reactants appears to correlate strongly with
                                      inflammatory changes that are not apparent from standard           radiographic progression. Before the use of early aggres-
                                      radiography but are rarely necessary in the routine evalua-       sive therapy, a large proportion of inflamed joints mani-
                                      tion of patients with RA.                                         fested erosions within 2 years, whereas the subsequent
                                                                                                        course of erosions was highly variable; however, in gen-
                                                                                                        eral, radiographic damage appears to progress at a constant
                                      CLINICAL COURSE AND PROGNOSIS
                                                                                                        rate in patients with RA. Foot joints are affected more
                                      The course of RA is quite variable and difficult to pre-           frequently than hand joints. Despite the decrease in the
                                      dict in an individual patient. The current therapeutic            rate of progressive joint damage with time, functional dis-
                                      approach of early aggressive intervention appears to have         ability, which develops early in the course of the disease,
                                      mitigated the clinical course of RA, resulting in less per-       continues to worsen at the same rate, although the most
                                      sistent inflammation, disability, joint damage, and mortal-        rapid rate of functional loss occurs within the first 2 years
                                      ity. Classically, most patients had experienced persistent        of disease. Early in the course of RA, disability is more
associated with pain and inflammation, whereas later in           TABLE 5-1                                                               91
the course of the disease, damage to articular structures            THE 1987 REVISED CRITERIA FOR THE
makes a greater contribution.                                        CLASSIFICATION OF RA
    The median life expectancy of persons with RA is                 1. Guidelines for classification
shortened by 3–7 years. Of the 2.5-fold increase in mor-                a. Four of seven criteria are required to classify a
tality rate, RA itself is a contributing feature in 15–30%.                patient as having rheumatoid arthritis (RA).
The increased mortality rate seems to be limited to patients            b. Patients with two or more clinical diagnoses are not
with more severe articular disease and can be attributed                   excluded.
largely to infection and gastrointestinal bleeding and an            2. Criteriaa
                                                                        a. Morning stiffness: Stiffness in and around the joints

                                                                                                                                         CHAPTER 5
increased risk of cardiovascular disease. Recent evidence
                                                                           lasting 1 h before maximal improvement.
has emphasized the important role of cardiovascular dis-                b. Arthritis of three or more joint areas: At least three
ease in the increased mortality of RA patients, and this                   joint areas, observed by a physician simultaneously,
appears to diminish with effective anti-inflammatory ther-                  have soft tissue swelling or joint effusions, not just
apy. Drug therapy may also play a role in the increased                    bony overgrowth. The 14 possible joint areas
mortality rate seen in individuals with RA. Factors corre-                 involved are right or left proximal interphalangeal,
lated with early death include disability, disease duration or             metacarpophalangeal, wrist, elbow, knee, ankle, and

                                                                                                                                         Rheumatoid Arthritis
severity, persistent inflammation, glucocorticoid use, age at               metatarsophalangeal joints.
                                                                        c. Arthritis of hand joints: Arthritis of wrist, metacar-
onset, and low socioeconomic or educational status.
                                                                           pophalangeal joint, or proximal interphalangeal joint.
                                                                        d. Symmetric arthritis: Simultaneous involvement of
DIAGNOSIS                                                                  the same joint areas on both sides of the body.
                                                                        e. Rheumatoid nodules: Subcutaneous nodules over
The diagnosis of RA can be delayed because of the                          bony prominences, extensor surfaces, or juxtaartic-
nonspecific nature of initial symptoms. The diagnosis of                    ular regions observed by a physician.
RA is easily made in persons with typical established dis-              f. Serum rheumatoid factor: Demonstration of abnor-
                                                                           mal amounts of serum rheumatoid factor by any
ease.The typical picture of bilateral symmetric inflamma-
                                                                           method for which the result has been positive in less
tory polyarthritis involving small and large joints in both                than 5% of normal control subjects.
the upper and lower extremities with sparing of the axial               g. Radiographic changes: Typical changes of RA on
skeleton except the cervical spine suggests the diagnosis.                 posteroanterior hand and wrist radiographs that
Constitutional features indicative of the inflammatory                      must include erosions or unequivocal bony decalci-
nature of the disease, such as morning stiffness, support                  fication localized in or most marked adjacent to the
the diagnosis. Demonstration of subcutaneous nodules is                    involved joints.
a helpful diagnostic feature. Additionally, the presence of
rheumatoid factor, anti-CCP antibodies, inflammatory               Criteria a–d must be present for at least 6 weeks. Criteria b–e must
                                                                 be observed by a physician.
synovial fluid with increased numbers of PMNLs, and               Source: From Arnett et al.
radiographic findings of juxtaarticular bone demineral-
ization and erosions of the affected joints substantiate
the diagnosis.                                                   investigational purposes, they can be useful as guidelines
   The diagnosis is somewhat more difficult early in the          for establishing the diagnosis. Failure to meet these criteria,
course when only constitutional symptoms or intermit-            however, especially during the early stages of the disease,
tent arthralgias or arthritis in an asymmetric distribution      does not exclude the diagnosis. Indeed, these criteria do
may be present. A period of observation may be neces-            not effectively differentiate patients with new-onset RA
sary before the diagnosis can be established. A definitive        from those with a variety of other forms of early inflam-
diagnosis of RA depends predominantly on characteris-            matory arthritis. Moreover, in patients with early arthritis,
tic clinical features and the exclusion of other inflamma-        the criteria do not discriminate effectively between patients
tory processes. The isolated finding of a positive test for       who subsequently develop persistent, disabling, or erosive
rheumatoid factor, anti-CCP antibody, or an elevated             disease and those who do not.
ESR or C-reactive protein (CRP), especially in an older
person with joint pains, should not itself be used as
evidence of RA.
   In 1987, the American College of Rheumatology                         Treatment:
developed revised criteria for the classification of RA                   RHEUMATOID ARTHRITIS
(Table 5-1). These criteria demonstrate a sensitivity of
                                                                     GENERAL PRINCIPLES The goals of therapy for
91–94% and a specificity of 89% when used to classify
                                                                     RA are (1) relief of pain, (2) reduction of inflammation,
patients with RA compared with control subjects with
                                                                     (3) protection of articular structures, (4) maintenance of
rheumatic diseases other than RA. Although these criteria
                                                                     function, and (5) control of systemic involvement. Since
were developed as a means of disease classification for
                      92 the etiology of RA is unknown, the pathogenesis is not                    effects of agents such as methotrexate as well as the
                                      completely delineated, and the mechanisms of action of       protective effect of these agents on bone damage. An
                                      some of the therapeutic agents employed are uncer-           initial course of low-dose glucocorticoids should be
                                      tain, therapy remains somewhat empirical. None of the        considered in patients either alone or when therapy
                                      therapeutic interventions is curative, and therefore all     with disease modifying anti-rheumatic drugs (DMARDs)
                                      must be viewed as palliative, aimed at relieving the         is considered. Intraarticular glucocorticoids can often
                                      signs and symptoms of the disease. The various thera-        provide transient symptomatic relief when systemic
                                      pies employed are directed at nonspecific suppression         medical therapy has failed to resolve inflammation. The
                                      of the inflammatory or immunologic process with the           third line of agents includes the DMARDs just men-

                                      expectation of ameliorating symptoms and preventing          tioned. These agents appear to have the capacity to
                                      progressive damage to articular structures.                  decrease elevated levels of acute-phase reactants in
                                          Management of patients with RA involves an inter-        treated patients and, therefore, are thought to modify
                                      disciplinary approach, which attempts to deal with the       the inflammatory component of RA and thus its
                                      various problems that these individuals encounter with       destructive capacity. These agents include methotrex-
                                      functional as well as psychosocial interactions. A variety   ate, sulfasalazine, hydroxychloroquine, gold salts, or
Disorders of Immune-Mediated Injury

                                      of physical therapy modalities may be useful in decreas-     D-penicillamine, although the latter two are now used
                                      ing the symptoms of RA. Rest ameliorates symptoms            infrequently. Combinations of DMARDs appear to be
                                      and can be an important component of the total               more effective than single agents in controlling the
                                      therapeutic program. In addition, splinting to reduce        signs and symptoms of RA. A fourth group of agents are
                                      unwanted motion of inflamed joints may be useful.             the biologics, which include TNF-neutralizing agents
                                      Exercise directed at maintaining muscle strength and         (infliximab, etanercept, and adalimumab), IL-1-neutraliz-
                                      joint mobility without exacerbating joint inflammation        ing agents (anakinra), those that deplete B cells (ritux-
                                      is also an important aspect of the therapeutic regimen.      imab), and those that interfere with T cell activation
                                      A variety of orthotic and assistive devices can be helpful   (abatacept). These agents have been shown to have a
                                      in supporting and aligning deformed joints to reduce         major impact on the signs and symptoms of RA and
                                      pain and improve function. Education of the patient and      also to slow progressive damage to articular structures.
                                      family is an important component of the therapeutic          A fifth group of agents are the immunosuppressive and
                                      plan to help those involved become aware of the              cytotoxic drugs, including leflunomide, cyclosporine,
                                      potential impact of the disease and make appropriate         azathioprine, and cyclophosphamide, that have been
                                      accommodations in lifestyle to maximize satisfaction         shown to ameliorate the disease process in some
                                      and minimize stress on joints.                               patients. Additional approaches have been employed in
                                          Medical management of RA involves five general            an attempt to control the signs and symptoms of RA.
                                      approaches. The first is the use of nonsteroidal anti-        Substituting omega-3 fatty acids, such as eicosapen-
                                      inflammatory drugs (NSAIDs) and simple analgesics to          taenoic acid found in certain fish oils, for dietary omega-
                                      control the symptoms and signs of the local inflamma-         6 essential fatty acids found in meat has also been
                                      tory process. These agents are rapidly effective at miti-    shown to provide symptomatic improvement in patients
                                      gating signs and symptoms, but they appear to exert          with RA. A variety of nontraditional approaches have
                                      minimal effect on the progression of the disease.            also been claimed to be effective in treating RA, includ-
                                      Recently, specific inhibitors of the isoform of cyclooxy-     ing diets, plant and animal extracts, vaccines, hormones,
                                      genase (COX) that is upregulated at inflammatory sites        and topical preparations of various sorts. Many of these
                                      (COX-2) have been developed. COX inhibitors (known as        are costly, and none has been shown to be effective.
                                      Coxibs), which selectively inhibit COX-2 and not COX-1,      However, belief in their efficacy ensures their continued
                                      have been shown to be as effective as classic NSAIDs,        use by some patients.
                                      which inhibit both isoforms of COX, but to cause signifi-
                                      cantly less gastroduodenal ulceration. However, these        DRUGS
                                      agents are associated with an increased risk of cardio-      Disease-Modifying Anti-Rheumatic Drugs
                                      vascular events, and therefore their use must be guided      Clinical experience has delineated a number of agents—
                                      by a careful assessment of risk/benefit ratio. An impor-      the DMARDs—that appear to have the capacity to alter
                                      tant additional second line of therapy involves the use      the course of RA. Despite having no chemical or phar-
                                      of low-dose oral glucocorticoids. Although low-dose          macologic similarities, in practice these agents share a
                                      glucocorticoids have been widely used to suppress            number of characteristics. They exert minimal direct
                                      signs and symptoms of inflammation, recent evidence           nonspecific anti-inflammatory or analgesic effects, and
                                      indicates that they may also retard the development          therefore NSAIDs must be continued during their
                                      and progression of bone erosions. In addition, the use of    administration, except in a few cases when true remis-
                                      low-dose glucocorticoids increases the anti-inflammatory      sions are induced with them. The appearance of benefit
from DMARD therapy is usually delayed for weeks or             each of the DMARDs is associated with toxicity, and           93
months. As many as two-thirds of patients develop              therefore careful patient monitoring is necessary. Toxic-
some clinical improvement as a result of therapy with          ity of the various agents also becomes important in
any of these agents, although the induction of true            determining the drug of first choice. Of note, failure to
remissions is unusual. In addition to clinical improve-        respond or development of toxicity to one DMARD does
ment, there is frequently an improvement in serologic          not preclude responsiveness to another. Thus, a similar
evidence of disease activity, and titers of rheumatoid         percentage of RA patients who have failed to respond
factor and C-reactive protein and the ESR frequently           to one DMARD will respond to another when it is given
decline. Moreover, DMARD therapy, especially early in          as the second disease-modifying drug.

                                                                                                                             CHAPTER 5
the disease course, retards the development of bone
                                                               GLUCOCORTICOID THERAPY Systemic gluco-
                                                               corticoid therapy can provide effective symptomatic
    No characteristic features of patients have emerged
                                                               therapy in patients with RA. Low-dose (<7.5 mg/d)
that predict responsiveness to a DMARD. Moreover, the
                                                               prednisone is a useful additive therapy to control symp-
indications for the initiation of therapy with one of
                                                               toms. Moreover, recent evidence suggests that low-dose
these agents are not well defined. Recently, evidence
                                                               glucocorticoid therapy may retard the progression of

                                                                                                                             Rheumatoid Arthritis
has emerged that the initiation of DMARD therapy early
                                                               bone erosions and that an initial course of low-dose
in the course of RA clearly has a major impact on the
                                                               glucocorticoids may have a long-term protective effect
development of bone erosions and the progression to
                                                               against bone damage. Monthly pulses with high-dose
disability. It is now felt that DMARD therapy should be
                                                               glucocorticoids may be useful in some patients and may
begun as soon as the diagnosis of RA is established,
                                                               hasten the response when therapy with a DMARD is ini-
especially in those with any evidence of aggressive dis-
                                                               tiated. Finally, a course of low-dose oral glucocorticoids
ease with a poor prognosis.
                                                               combined with DMARD therapy can be beneficial in
    Which DMARD should be the drug of first choice
                                                               controlling signs and symptoms rapidly and affording
remains controversial, and trials have failed to demon-
                                                               long-term retardation of bone erosion.
strate a consistent advantage of one over the other.
Despite this, methotrexate has emerged as the DMARD            BIOLOGICS A range of biologic agents that bind
of choice especially in individuals with risk factors for      and neutralize TNF are available. One of these is a TNF
development of bone erosions or persistent synovitis of        type II receptor fused to IgG1 (etanercept), the second is
>3 months’ duration, because of its relatively rapid           a chimeric mouse/human monoclonal antibody to TNF
onset of action, its capacity to effect sustained improve-     (infliximab), a third is a fully human antibody to TNF
ment with ongoing therapy, and the higher level of             (adalimumab), and a fourth is a humanized monoclonal
patient retention on therapy. Methotrexate is usually          antibody that neutralizes TNF (golimumab). Clinical trials
employed on a weekly schedule of 7.5–25 mg given               have shown that parenteral administration of any of
either orally in divided doses or, if necessary, SC or IM to   these TNF-neutralizing agents is remarkably effective at
avoid gastrointestinal toxicity. Recent trials have docu-      controlling signs and symptoms of RA in patients who
mented the efficacy of methotrexate and have indi-              have failed DMARD therapy, as well as in DMARD-naïve
cated that its onset of action is more rapid than other        patients. Repetitive therapy with these agents is effective
DMARDs, and patients tend to remain on therapy with            with or without concomitant methotrexate, although
methotrexate longer than they remain on other DMARDs           combination therapy with methotrexate or another
because of better clinical responses and less toxicity.        DMARD appears to provide the greatest benefit. These
Long-term trials have indicated that methotrexate does         agents not only are effective in persistently controlling
not induce remission but rather suppresses symptoms            signs and symptoms of RA in a majority of patients, but
while it is being administered. Maximal improvement is         they have also been shown to slow the rate of progres-
observed after 6 months of therapy, with little addi-          sion of joint damage assessed radiographically and to
tional improvement thereafter. Major toxicity includes         improve disability. Side effects include the potential for
gastrointestinal upset, oral ulceration, and liver function    an increased risk of serious infections. Particularly
abnormalities that appear to be dose related and               notable is the capacity of TNF blockade to increase the
reversible and hepatic fibrosis that can be quite insidious,    risk of developing reactivation of dormant tuberculosis.
requiring liver biopsy for detection in its early stages.      It is prudent to carry out tuberculin skin testing and, if
Drug-induced pneumonitis has also been reported.               necessary, further evaluation with chest radiographs
Liver biopsy is recommended for individuals with per-          before beginning therapy with an anti-TNF agent to limit
sistent or repetitive liver function abnormalities. Con-       the chance of inciting reactivation of tuberculosis. Anti-
current administration of folic acid or folinic acid may       TNF therapy also has the potential to increase the risk of
diminish the frequency of some side effects, although          lymphoma and possibly other malignancies in treated
efficacy may be diminished somewhat. In this regard,            patients. TNF-neutralizing therapy can also induce the
                      94 development of anti-DNA antibodies, but rarely is there                      therapeutic effects similar to those of the DMARDs.
                                      associated evidence of signs and symptoms of systemic           However, these agents appear to be no more effective
                                      lupus erythematosus. Other side effects include infusion        than the DMARDs. Moreover, they cause a variety of
                                      or injection site reactions and rarely the development of       toxic side effects, and cyclophosphamide appears to
                                      demyelinating central nervous system disease. Although          predispose patients to the development of malignant
                                      these side effects are uncommon, their occurrence man-          neoplasms. Therefore, these drugs have been reserved
                                      dates that TNF-neutralizing therapy be supervised by            for patients who have clearly failed therapy with
                                      physicians with experience in their use.                        DMARDs and biologics. On occasion, extraarticular dis-
                                          Anakinra is a recombinant IL-1 receptor antagonist          ease such as rheumatoid vasculitis may require cyto-

                                      that competitively blocks the binding of IL-1β and IL-1α        toxic immunosuppressive therapy.
                                      to the IL-1 receptor and thereby inhibits the activity of          Leflunomide is metabolized to an active metabolite
                                      these two related proinflammatory cytokines. Anakinra            that acts to inhibit dihydroorotate dehydrogenase, an
                                      has been shown to improve the signs and symptoms of             essential enzyme in the pyrimidine biosynthetic path-
                                      RA, to decrease disability, and to slow progression of artic-   way. Its predominant action is to inhibit the proliferation
                                      ular damage assessed radiographically. It can be given as       of T lymphocytes. Leflunomide has been shown to con-
Disorders of Immune-Mediated Injury

                                      monotherapy or in combination with methotrexate. The            trol the signs and symptoms of RA and to slow the pro-
                                      major side effects are injection site reactions. In general,    gression of joint damage as effectively as methotrexate.
                                      the clinical impact of anakinra appears to be less than that    Leflunomide can be given alone or with methotrexate
                                      of TNF-neutralizing therapy, but it may be used in those in     and is the most frequently employed immunosuppres-
                                      whom TNF-neutralizing therapy is precluded. It is rarely        sive agent used to treat patients with RA. It is used as
                                      effective in those who have failed TNF-neutralizing therapy.    monotherapy in patients who have had adverse reac-
                                      Combining anakinra with a TNF-blocking agent does not           tions to methotrexate or inadequate responses to it. The
                                      increase efficacy and is associated with an increased fre-       major side effect is the associated increase in liver func-
                                      quency of infection and, therefore, is not recommended.         tion enzymes that occurs in 5% of patients receiving
                                          Rituximab, a chimeric antibody directed to CD20 that        leflunomide alone and in >50% of individuals taking
                                      depletes mature B cells, has been approved for treatment        leflunomide with methotrexate.
                                      of RA patients who have failed anti-TNF therapy. In com-
                                                                                                      SURGERY          Surgery plays a role in the management
                                      bination with methotrexate, this therapy can improve
                                                                                                      of patients with severely damaged joints. Although
                                      signs and symptoms in these patients and also retard the
                                                                                                      arthroplasties and total joint replacements can be done
                                      progress of bone damage. The major adverse events
                                                                                                      on a number of joints, the most successful procedures
                                      relate to transfusion reactions that can be controlled with
                                                                                                      are carried out on hips, knees, and shoulders. Realistic
                                      glucocorticoids. Although the optimal regimen has not
                                                                                                      goals of these procedures are relief of pain and reduc-
                                      been established, therapy can be repeated usually at
                                                                                                      tion of disability. Reconstructive hand surgery may lead
                                      6-month intervals when circulating B cells return.
                                                                                                      to cosmetic improvement and some functional benefit.
                                          Abatacept is a fusion protein consisting of CTLA4
                                                                                                      Open or arthroscopic synovectomy may be useful in
                                      and the Fc portion of IgG1. It inhibits T cell activation by
                                                                                                      some patients with persistent monarthritis, especially of
                                      competitively inhibiting the co-stimulation of T cells
                                                                                                      the knee. Although synovectomy may offer short-term
                                      that results from interaction of T cell–expressed CD28
                                                                                                      relief of symptoms, it does not appear to retard bone
                                      and CD80/86 expressed by antigen-presenting cells. It
                                                                                                      destruction or alter the natural history of the disease. In
                                      can be used with or without methotrexate, although its
                                                                                                      addition, early tenosynovectomy of the wrist may pre-
                                      efficacy is greater as co-therapy with methotrexate. It
                                                                                                      vent tendon rupture.
                                      has a positive effect on signs and symptoms of RA and
                                      also retards progressive bone damage. It is usually
                                      reserved for patients who have failed TNF-neutralizing
                                      therapy or in those who have contraindications to               Approach to the Patient:
                                      TNF blockade. Abatacept is tolerated quite well. Com-           RHEUMATOID ARTHRITIS
                                      bining abatacept with a TNF-blocking agent does not
                                                                                                      An approach to the medical management of patients
                                      increase efficacy, and is associated with more adverse
                                                                                                      with RA is depicted in Fig. 5-3. The principles
                                      events, including serious infections, and, therefore, is not
                                                                                                      underlying care of these patients reflect the value of
                                                                                                      early appropriately aggressive intervention, the vari-
                                      IMMUNOSUPPRESSIVE THERAPY The im-                               ability of the disease, the frequent persistent nature of
                                      munosuppressive drugs azathioprine, leflunomide,                 the inflammation and its potential to cause disability,
                                      cyclosporine, and cyclophosphamide have been shown              the relationship between sustained inflammation and
                                      to be effective in the treatment of RA and to exert             bone erosions and mortality, and the need to reevaluate
                                                     DIAGNOSIS OF RHEUMATOID ARTHRITIS                                                    95
                     Risk factors for disability/erosions?
                              Rheumatoid factor
                              Anti-CCP antibody                            Coxib or               Responders
                             Multiple swollen joints                       hydroxychloroquine
                        Elevated acute-phase reactants                     w/wo low-dose
                            DR4+ (Shared epitope)                          glucocorticoids
                               Erosions on x-ray


                                                                                                                                          CHAPTER 5
                                 Early aggressive
                                     therapy                                          Persistent synovitis
                                                                                      for >12 weeks

                    MTX or Combination DMARD therapy
                    Methotrexate w/wo HCQ w/wo SSA with

                                                                                                                                          Rheumatoid Arthritis
                    low-dose glucocorticoids

                     Responders         Partial responders          Toxicity           Nonresponders

                                         Add                 Switch                 Add                 Switch
                                           Leflunomide         Leflunomide                Leflunomide
                                           TNF blocker         TNF blocker                TNF blocker

                                                         Responder         Nonresponder or toxicity

                                                         Continue         Consider abatacept, rituximab, cyclosporine

Algorithm for the medical management of rheumatoid                        MTX, methotrexate; SSA, sulfasalazine; TNF, tumor necrosis
arthritis. Coxib, COX-2 inhibitors; DMARD, disease-modifying              factor.
anti-rheumatic drug; CCP, cyclic citrullinated polypeptide;

 the patient frequently for symptomatic response to                            major impact on subsequent damage to articular
 therapy, progression of disability and joint damage,                          structures and disability.
 and side effects of treatment. At the onset of disease it                        At some time during the course for most patients,
 is difficult to predict the natural history of an indi-                        the possibility of initiating DMARD therapy is enter-
 vidual patient’s illness. Therefore, the classic approach                     tained. The presence of risk factors for bone damage
 was to attempt to alleviate the patient’s symptoms                            or disability or persistent synovitis of >3 months’
 with NSAIDs or Coxibs. Some patients may have                                 duration are the usual indications to initiate DMARD
 mild disease that requires no additional therapy.                             therapy.The decision to begin use of a DMARD and/
 However, most patients will require additional ther-                          or low-dose oral glucocorticoids requires experience
 apy, and the treating physician must be vigilant and                          and clinical judgment as well as the ability to assess
 prepared to institute appropriate therapy as soon as                          joint swelling and functional activity and the patient’s
 indicated. Nearly all patients will benefit from a                             pain tolerance and expectation of therapy accurately.
 course of low-dose glucocorticoids, and this should                           In this setting, the fully informed patient must play
 be considered routinely. If the patient has any evi-                          an active role in the decision to begin DMARD
 dence of aggressive disease, as described above, or                           and/or low-dose oral glucocorticoid therapy, after
 persistent synovitis for >3 months, initiation of                             careful review of the therapeutic and toxic potential
 DMARD therapy should be considered as early as                                of the various drugs. If DMARD therapy, usually
 feasible. In RA patients there appears to be a window                         methotrexate, fails to control signs and symptoms of
 of opportunity early in the course of the disease, dur-                       RA, a decision to add or switch to a biologic agent is
 ing which initiation of aggressive therapy can have a                         considered.These are quite potent at controlling signs
                      96               and symptoms of RA, slowing damage to articular
                                                                                                               BREEDVELD FC et al:The PREMIER study: A multicenter, random-
                                                                                                                  ized, double-blind clinical trial of combination therapy with
                                       structures, and limiting disability, but are very expen-                   adalimumab plus methotrexate versus methotrexate alone or
                                       sive and associated with serious adverse events. The                       adalimumab alone in patients with early, aggressive rheumatoid
                                       decision to employ these agents requires considerable                      arthritis who had not had previous methotrexate treatment.
                                       experience, judgment, and the agreement of a fully                         Arthritis Rheum 54(1):26, 2006
                                       informed patient.                                                       BRESNIHAN B et al:Treatment of rheumatoid arthritis with recombi-
                                          If a patient responds to a DMARD, therapy is con-                       nant human interleukin-1 receptor antagonist. Arthritis Rheum
                                                                                                                  41:2196, 1998
                                       tinued with careful monitoring to avoid toxicity. All
                                                                                                               BROWN SL et al: Tumor necrosis factor antagonist therapy and lym-
                                       DMARDs provide a suppressive effect and therefore                          phoma development: Twenty-six cases reported to the Food and

                                       require prolong administration. Even with successful                       Drug Administration.Arthritis Rheum 46(12):3151, 2002
                                       therapy, local injection of glucocorticoids may be nec-                 BUCH MH et al: Lack of response to anakinra in rheumatoid arthritis
                                       essary to diminish inflammation that may persist in a                       following failure of tumor necrosis factor alpha blockade.Arthritis
                                       limited number of joints. In addition, NSAIDs or                           Rheum 50(3):725, 2004
                                       Coxibs may be necessary to mitigate symptoms. Even                      BUKHARI M et al: Rheumatoid factor is the major predictor of
                                                                                                                  increasing severity of radiographic erosions in rheumatoid
                                       after inflammation has totally resolved, symptoms from
                                                                                                                  arthritis: Results from the Norfolk Arthritis Register Study, a
Disorders of Immune-Mediated Injury

                                       loss of cartilage and supervening degenerative joint                       large inception cohort.Arthritis Rheum 46(4):906, 2002
                                       disease or altered joint function may require additional                CARREIRA PE et al: Polymorphism of the interleukin-1 receptor
                                       treatment. Surgery may also be necessary to relieve                        antagonist gene: A factor in susceptibility to rheumatoid arthritis
                                       pain or diminish the functional impairment secondary                       in a Spanish population. Arthritis Rheum 52(10):3015, 2005
                                       to alterations in joint function.                                       CHOY EH et al: Therapeutic benefit of blocking interleukin-6
                                                                                                                  activity with an anti-interleukin-6 receptor monoclonal anti-
                                                                                                                  body in rheumatoid arthritis:A randomized, double-blind, placebo-
                                                                                                                  controlled, dose-escalation trial. Arthritis Rheum 46(12):53, 2002
                                                                                                               COHEN SB et al: A multicentre, double-blind, randomised, placebo-
                                      FURTHER READINGS
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                                          rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in                 and hydroxychloroquine, methotrexate and sulfasalazine, or a
                                          Rheumatoid Arthritis with Concomitant Therapy Study Group.                combination of the three medications: Results of a two-year,
                                          N Engl J Med 343(22):1594, 2000                                           randomized, double-blind, placebo-controlled trial. Arthritis
                                      ——— et al: Why does rheumatoid arthritis involve the joints? N                Rheum 46:1164, 2002
                                          Engl J Med 356:2419, 2007                                             ——— et al: Etanercept in combination with sulfasalazine, hydroxy-
                                      LISTING J et al: Infections in patients with rheumatoid arthritis             chloroquine, or gold in the treatment of rheumatoid arthritis.
                                          treated with biologic agents. Arthritis Rheum 52(11):3403, 2005           J Rheumatol 33(2):213, 2006
                                      MADDISON P et al: Leflunomide in rheumatoid arthritis: Recom-              OLSEN NJ, STEIN CM: New drugs for rheumatoid arthritis. N Engl
                                          mendations through a process of consensus. Rheumatology                   J Med 350(21):2167, 2004
                                          (Oxford) 44(3):280, 2005                                              OZMINKOWSKI RJ et al:The impact of rheumatoid arthritis on med-
                                      MAINI RN et al: Sustained improvement over two years in physical              ical expenditures, absenteeism, and short-term disability benefits.
                                          function, structural damage, and signs and symptoms among                 J Occup Environ Med 48(2):135, 2006
                                          patients with rheumatoid arthritis treated with infliximab and         PARK YB et al: Atherosclerosis in rheumatoid arthritis: Morphologic
                                          methotrexate.Arthritis Rheum 50(4):1051, 2004                             evidence obtained by carotid ultrasound. Arthritis Rheum
                                      ——— et al: Double-blind, randomized, controlled clinical trial of             46(7):1714, 2002
                                          the interleukin-6 receptor antagonist, tocilizumab, in European       PINCUS T et al: Patients seen for standard rheumatoid arthritis care have
                                          patients with rheumatoid arthritis who had an incomplete                  significantly better articular, radiographic, laboratory, and functional
                                          response to methotrexate.Arthritis Rheum 54:2817, 2006                    status in 2000 than in 1985.Arthritis Rheum 52(4):1009, 2005
                                      MARADIT-KREMERS H et al: Cardiovascular death in rheumatoid               PINHEIRO GC et al: Anti-cyclic citrullinated peptide antibodies in
                                          arthritis: A population-based study. Arthritis Rheum 52(3):722,           advanced rheumatoid arthritis. Ann Intern Med 139(3):234, 2003
                                          2005                                                                  PLENGE RM et al: Replication of putative candidate-gene associations
                                      ——— et al: Increased unrecognized coronary heart disease and sud-             with rheumatoid arthritis in >4,000 samples from North Amer-
                                          den deaths in rheumatoid arthritis: A population-based cohort             ica and Sweden: Association of susceptibility with PTPN22,
                                          study.Arthritis Rheum 52(2):402, 2005                                     CTLA4, and PADI4.Am J Hum Genet 77(6):1044, 2005
                                      MESSORI A et al: New drugs for rheumatoid arthritis. N Engl J Med         POOR G et al: Efficacy and safety of leflunomide 10 mg versus 20 mg
                                          351(9):937, 2004                                                          once daily in patients with active rheumatoid arthritis: Multinational
   double-blind, randomized trial. Rheumatology (Oxford) 43(6):           SVENSSON B et al: Low-dose prednisolone in addition to the initial         99
   744, 2004                                                                 disease-modifying antirheumatic drug in patients with early active
PROKUNINA L et al: Association of the PD-1.3A allele of the                  rheumatoid arthritis reduces joint destruction and increases the
   PDCD1 gene in patients with rheumatoid arthritis negative for             remission rate: A two-year randomized trial. Arthritis Rheum
   rheumatoid factor and the shared epitope. Arthritis Rheum                 52(11): 3360, 2005
   50(6):1770, 2004                                                       TURESSON C, MATTESON EL: Genetics of rheumatoid arthritis. Mayo
PROTS I et al: Association of the IL4R single-nucleotide polymor-            Clin Proc 81(1):94, 2006
   phism I50V with rapidly erosive rheumatoid arthritis. Arthritis        UHLIG T, KVIEN TK: Is rheumatoid arthritis disappearing? Ann
   Rheum 54(5):1491, 2006                                                    Rheum Dis 64(1):7, 2005
PUOLAKKA K et al: Impact of initial aggressive drug treatment with a      VAN DE PUTTE LB et al: Efficacy and safety of adalimumab as
   combination of disease-modifying antirheumatic drugs on the               monotherapy in patients with rheumatoid arthritis for whom

                                                                                                                                                     CHAPTER 5
   development of work disability in early rheumatoid arthritis: A           previous disease modifying antirheumatic drug treatment has
   five-year randomized followup trial. Arthritis Rheum 50(1):55,             failed.Ann Rheum Dis 63(5):508, 2004
   2004                                                                   VAN DER BIJL AE et al: Infliximab and methotrexate as induction
QUINN MA et al: Prognostic factors in a large cohort of patients             therapy in patients with early rheumatoid arthritis. Arthritis
   with early undifferentiated inflammatory arthritis after applica-          Rheum 56:2129, 2007
   tion of a structured management protocol. Arthritis Rheum              VAN DER HEIJDE D et al: Presentation and analysis of data on radi-
   48(11):3039, 2003                                                         ographic outcome in clinical trials: Experience from the TEMPO

                                                                                                                                                     Rheumatoid Arthritis
——— et al: Very early treatment with infliximab in addition to                study.Arthritis Rheum 52(1):49, 2005
   methotrexate in early, poor-prognosis rheumatoid arthritis reduces     VAN DER HELM-VAN MIL AH et al: Antibodies to citrullinated pro-
   magnetic resonance imaging evidence of synovitis and damage,              teins and differences in clinical progression of rheumatoid arthri-
   with sustained benefit after infliximab withdrawal: Results from            tis.Arthritis Res Ther 7(5):R949, 2005
   a twelve-month randomized, double-blind, placebo-controlled trial.     VAN EVERDINGEN AA et al: Low-dose prednisone therapy for patients
   Arthritis Rheum 52(1):27, 2005                                            with early active rheumatoid arthritis: Clinical efficacy, disease-
RADSTAKE TR et al: Correlation of rheumatoid arthritis severity with         modifying properties, and side effects: A randomized, double-blind,
   the genetic functional variants and circulating levels of macrophage      placebo-controlled clinical trial.Ann Intern Med 136(1):1, 2002
   migration inhibitory factor.Arthritis Rheum 52(10):3020, 2005          VAN GAALEN FA et al: Autoantibodies to cyclic citrullinated peptides
RANTAPAA-DAHLQVIST S et al: Antibodies against cyclic citrullinated          predict progression to rheumatoid arthritis in patients with
   peptide and IgA rheumatoid factor predict the development of              undifferentiated arthritis: A prospective cohort study. Arthritis
   rheumatoid arthritis.Arthritis Rheum 48(10):2741, 2003                    Rheum 50(3):709, 2004
RASCH EK et al: Prevalence of rheumatoid arthritis in persons 60 years    VERSTAPPEN SM et al: Five-year followup of rheumatoid arthritis
   of age and older in the United States: Effect of different methods        patients after early treatment with disease-modifying antirheumatic
   of case classification.Arthritis Rheum 48(4):917, 2003                     drugs versus treatment according to the pyramid approach in the
RAZA K et al: Early rheumatoid arthritis is characterized by a distinct      first year.Arthritis Rheum 48(7):1797, 2003
   and transient synovial fluid cytokine profile of T cell and stromal      WARRINGTON KJ et al: Rheumatoid arthritis is an independent risk
   cell origin.Arthritis Res Ther 7(4):R784, 2005                            factor for multi-vessel coronary artery disease: A case control
SCHIFF MH et al: The safety of anakinra in high-risk patients with           study.Arthritis Res Ther 7(5):R984, 2005
   active rheumatoid arthritis: Six-month observations of patients        WASSENBERG S et al: Very low-dose prednisolone in early rheuma-
   with comorbid conditions.Arthritis Rheum 50(6):1752, 2004                 toid arthritis retards radiographic progression over two years:
SHARP JT et al: Treatment with leflunomide slows radiographic pro-            A multicenter, double-blind, placebo-controlled trial. Arthritis
   gression of rheumatoid arthritis: Results from three randomized           Rheum 52(11):3371, 2005
   controlled trials of leflunomide in patients with active rheuma-        WEINBLATT ME et al: A trial of etanercept, a recombinant tumor
   toid arthritis.Arthritis Rheum 43:495, 2000                               necrosis factor receptor: Fc fusion protein, in patients with rheuma-
SMOLEN JS et al: Evidence of radiographic benefit of treatment with           toid arthritis receiving methotrexate. N Engl J Med 340:253, 1999
   infliximab plus methotrexate in rheumatoid arthritis patients who       ——— et al: Adalimumab, a fully human anti-tumor necrosis factor
   had no clinical improvement: A detailed subanalysis of data from          alpha monoclonal antibody, for the treatment of rheumatoid
   the anti-tumor necrosis factor trial in rheumatoid arthritis with         arthritis in patients taking concomitant methotrexate: The
   concomitant therapy study.Arthritis Rheum 52(4):1020, 2005                ARMADA trial.Arthritis Rheum 48(1):35, 2003
——— et al: Predictors of joint damage in patients with early              ——— et al: Selective co-stimulation modulation using abatacept in
   rheumatoid arthritis treated with high-dose methotrexate with             patients with active rheumatoid arthritis while receiving etaner-
   or without concomitant infliximab: Results from the ASPIRE                 cept:A randomized trial.Ann Rheum Dis 66:228, 2007
   trial.Arthritis Rheum 54(3):702, 2006                                  WELSING PM et al: Is the disease course of rheumatoid arthritis
SOKKA T et al: Radiographic progression is getting milder in patients        becoming milder? Time trends since 1985 in an inception cohort
   with early rheumatoid arthritis. Results of 3 cohorts over 5 years.       of early rheumatoid arthritis. Arthritis Rheum 52(9):2616, 2005
   J Rheumatol 31(6):1073, 2004                                           WOLFE F et al: Predicting mortality in patients with rheumatoid
ST CLAIR EW et al: Combination of infliximab and methotrexate                 arthritis.Arthritis Rheum 48(6):1530, 2003
   therapy for early rheumatoid arthritis: A randomized, controlled       ——— et al: Lymphoma in rheumatoid arthritis: The effect of
   trial.Arthritis Rheum 50(11):3432, 2004                                   methotrexate and anti-tumor necrosis factor therapy in 18,572
SUZUKI A et al: Functional haplotypes of PADI4, encoding citrulli-           patients.Arthritis Rheum 50(6):1740, 2004
   nating enzyme peptidylarginine deiminase 4, are associated with        ——— et al: Household income and earnings losses among 6,396
   rheumatoid arthritis. Nat Genet 34(4):395, 2003                           persons with rheumatoid arthritis. J Rheumatol 32(10):1875, 2005

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