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InternalMed_Harrison. 2140 effect on risk; they also contribute to the risk for developing other autoimmune diseases, such as type 1 diabetes mellitus, systemic lupus erythematosus, and multiple sclerosis. Second, although most of the non-HLA associations are described in patients with anti-CCP antibody-positive disease, there are several risk loci that are unique to anti-CCP antibody-negative disease. Third, risk alleles vary among ethnic groups. And fourth, the risk loci mostly reside in genes encoding proteins involved in the regulation of the immune response. However, the risk alleles identified by GWAS only account at present for approximately 5% of the genetic risk, suggesting that rare variants or other classes of DNA variants, such as variants in copy number, maybeyetfoundthatsignificantlycontributetotheoverallriskmodel. Recently, imputation of SNP data from a GWAS meta-analysis shows amino acid substitutions in the MHC locus independently associated with the risk forRAareatposition11,


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InternalMed_Harrison. Recently, imputation of SNP data from a GWAS meta-analysis shows amino acid substitutions in the MHC locus independently associated with the risk forRAareatposition11, 71,and74inHLA-DRβ1, position 9 of HLA-B, andposition 9of HLA-DPβ1.Theamino acidsat position 11, 71, and 74 are located in the antigen-binding grove of the HLA-DRβ1 molecule, highlighting positions 71 and 74 that form part of the original shared epitope. Among the best examples of the non-MHC genes contributing to the risk of RA is the gene encoding protein tyrosine phosphatase non-receptor 22 (PTPN22). This gene varies in frequency among patients from different parts of Europe (e.g., 3–10%), but is absent in patients of East Asian ancestry. PTPN22 encodes lymphoid tyrosine phosphatase, a protein that regulates T and B cell function. Inheritance of the risk allele for PTPN22 produces a gain-of-function in the protein that is hypothesized to result in the abnormal thymic selection of auto-reactive T and B cells and


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InternalMed_Harrison. cell function. Inheritance of the risk allele for PTPN22 produces a gain-of-function in the protein that is hypothesized to result in the abnormal thymic selection of auto-reactive T and B cells and appears to be associated exclusively with anti-CCP-positive disease. The peptidyl arginine deiminase type IV (PADI4) gene is another risk allele that encodes an enzyme involved in the conversion of arginine to citrulline and is postulated to play a role in the development of antibodies to citrullinated antigens. A polymorphism in PADI4 has been associated with RA only in Asian populations. Epigeneticsis the study of heritabletraits thataffect gene expression but do not modify DNA sequence. It may provide a link between environmental exposure and predisposition to disease. The best-studied mechanismsinclude posttranslational histone modifications and DNA methylation. Although studies of epigenetic phenomena are limited, DNA methylation patterns have been shown to differ between RA patients


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InternalMed_Harrison. posttranslational histone modifications and DNA methylation. Although studies of epigenetic phenomena are limited, DNA methylation patterns have been shown to differ between RA patients and healthy controls, as well as patients with osteoarthritis.


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InternalMed_Harrison. In addition to genetic predisposition, a host of environmental factors have been implicated in the pathogenesis of RA. The most reproducible of these environmental links is cigarette smoking. Numerous cohort and case control studies have demonstrated that smoking confers a relative risk for developing RA of 1.5–3.5. In particular, women who smoke cigarettes have a nearly 2.5 times greater risk of RA, a risk that persistseven 15years after smoking cessation.A twin whosmokes willhavea significantlyhigher risk forRAthanhisor hermonozygotic co-twin, theoretically with the same genetic risk, who does not smoke. Interestingly, the risk from smoking is almost exclusively related to RF and anti-CCP antibody-positive disease. However, it has not been shown that smoking cessation, while having many health benefits, improves disease activity.


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InternalMed_Harrison. Researchers began to aggressively seek an infectious etiology for RA after the discovery in 1931 that sera from patients with this disease could agglutinate strains of streptococci. Certain viruses such as Epstein-Barr virus (EBV) have garnered the most interestover the past 30 years given their ubiquity, ability to persist for many years in the host, and frequent association with arthritic complaints. For example, titers of IgG antibodies against EBV antigens in the peripheral blood and saliva are significantly higher in patients with RA than the general population. EBV DNA has also been found in synovial fluid and synovial cells of RA patients. Because the evidence for these links is largely circumstantial, it has not been possible to directly implicate infection as a causative factor in RA.


InternalMed_Harrison

InternalMed_Harrison. RA affects the synovial tissue and underlying cartilage and bone. The synovial membrane, which covers most articular surfaces, tendon sheaths, and bursae, normally is a thin layer of connective tissue. In joints, it faces the bone and cartilage, bridging the opposing bony surfaces and inserting at periosteal regions close to the articular cartilage. It consists primarily of two cell types—type A synoviocytes (macrophage-derived) and type B synoviocytes (fibroblast-derived). The synovial fibroblasts are the most abundant and produce the structural components of joints, including collagen, fibronectin, and laminin, as well as other extracellular constituents of the synovial matrix. The sublining layer consists of blood vessels and a sparse population of mononuclear cells within a loose networkof connective tissue. Synovial fluid, an ultrafiltrate of blood, diffuses through the subsynovial lining tissue across the synovial membrane and into the joint cavity. Its main constituents are


InternalMed_Harrison

InternalMed_Harrison. connective tissue. Synovial fluid, an ultrafiltrate of blood, diffuses through the subsynovial lining tissue across the synovial membrane and into the joint cavity. Its main constituents are hyaluronan and lubricin. Hyaluronan is a glycosaminoglycan that contributes to the viscous nature of synovial fluid, which along with lubricin, lubricates the surface of the articular cartilage.


InternalMed_Harrison

InternalMed_Harrison. The pathologic hallmarks of RA are synovial inflammation and proliferation, focal bone erosions, and thinning of articular cartilage. Chronic inflammation leads to synovial lining hyperplasia and the formation of pannus, a thickened cellular membrane containing fibroblast-like synoviocytes and granulation-reactive fibrovascular tissue that invades the underlying cartilage and bone. The inflammatory infiltrateismadeupofnolessthansixcelltypes:Tcells,Bcells,plasma cells, dendritic cells, mast cells, and, to a lesser extent, granulocytes. The T cells comprise 30–50% of the infiltrate, with the other cells accounting for the remainder. The topographical organization of these cells is complex and may vary among individuals with RA. Most often, the lymphocytes are diffusely organized among the tissue resident cells; however, in some cases, the B cells, T cells, and dendritic cells may form higher levels of organization, such as lymphoid follicles and germinal center–like structures. Growth


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InternalMed_Harrison. tissue resident cells; however, in some cases, the B cells, T cells, and dendritic cells may form higher levels of organization, such as lymphoid follicles and germinal center–like structures. Growth factors secreted by synovial fibroblasts and macrophages promote the formation of new blood vessels in the synovial sublining that supply the increasing demands for oxygenation and nutrition required by the infiltrating leukocytes and expanding synovial tissue.


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InternalMed_Harrison. The structural damage to the mineralized cartilage and subchondral bone is mediated by the osteoclast. Osteoclasts are multinucleated giant cells that can be identified by their expression of CD68, tartrateresistant acid phosphatase, cathepsin K, and the calcitonin receptor. They appear at the pannus-bone interface where they eventually form resorption lacunae. These lesions typically localize where the synovial membraneinsertsintotheperiostealsurfaceattheedgesofbonesclose to the rim of articular cartilage and at the attachment sitesof ligaments and tendon sheaths. This process most likely explains why bone erosions usually develop at the radial sites of the MCP joints juxtaposed to the insertion sites of the tendons, collateral ligaments, and synovial membrane. Another form of bone loss is periarticular osteopenia that occursin jointswithactive inflammation. It is associatedwithsubstantial thinning of the bony trabeculae along the metaphyses of bones, and likely results from


InternalMed_Harrison

InternalMed_Harrison. loss is periarticular osteopenia that occursin jointswithactive inflammation. It is associatedwithsubstantial thinning of the bony trabeculae along the metaphyses of bones, and likely results from inflammation of the bone marrow cavity. These lesions can be visualized on MRI scans, where they appear as signal alterations in the bone marrow adjacent to inflamed joints. Their signal characteristics show they are water-rich with a low fat content and are consistent with highly vascularized inflammatory tissue. These bone marrow lesions are often the forerunner of bone erosions.


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InternalMed_Harrison. The cortical bone layer that separates the bone marrow from the invading pannus is relatively thin and susceptible to penetration by the inflamed synovium. The bone marrow lesions seen on MRI scans are associated with an endosteal bone response characterized by the accumulation of osteoblasts and deposition of osteoid. Thus, in recent years, the concept of joint pathology in RA has been extended to include the bone marrow cavity. Finally, generalized osteoporosis, which results in the thinning of trabecular bone throughout the body, is a third form of bone loss found in patients with RA.


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InternalMed_Harrison. Articular cartilage is an avascular tissue comprised of a specialized matrix of collagens, proteoglycans, and other proteins. It is organized in four distinct regions (superficial, middle, deep, and calcified cartilage zones)—chondrocytes constitute the unique cellular component in these layers. Originally, cartilage was considered to be an inert tissue, but it is now known to be a highly responsive tissue that reacts to inflammatory mediators and mechanical factors, which in turn, alter the balance between cartilage anabolism and catabolism. In RA, the initial areas of cartilage degradation are juxtaposed to the synovial pannus. The cartilage matrix is characterized by a generalized loss of proteoglycan, most evident in the superficial zones adjacent to the synovial fluid. Degradation of cartilage may also take place in the perichondrocytic zone and in regions adjacent to the subchondral bone.


InternalMed_Harrison

InternalMed_Harrison. The pathogenic mechanisms of synovial inflammation are likely to result from a complex interplay of genetic, environmental, and immunologic factors that produces dysregulation of the immune system and a breakdown in self-tolerance (Fig. 380-4). Precisely what triggers these initiating events and what genetic and environmental factors disrupt the immune system remains a mystery. However, a detailed molecular picture is emerging of the mechanisms underlying the chronic inflammatory response and the destruction of the articular cartilage and bone.


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InternalMed_Harrison. In RA, the preclinical stage appears to be characterized by a breakdown in self-tolerance. This idea is supported by the finding that autoantibodies, such as RF and anti-CCP antibodies, may be found in sera from patients many years before clinical disease can be detected. However, the antigenic targets of anti-CCP antibodies and RF are not restricted to the joint, and their role in disease pathogenesis remains speculative.Anti-CCPantibodiesaredirectedagainstdeaminatedpeptides, which result from posttranslational modification by the enzyme PADI4. They recognize citrulline-containing regions of several different matrix proteins, including filaggrin, keratin, fibrinogen, and vimentin, and are present at higher levels in the joint fluid compared to the serum. Other autoantibodies have been found in a minority of patients with RA, but they also occur in the setting of other types of arthritis.They bind toadiversearrayofautoantigens,includingtypeII collagen, human cartilage gp-39, aggrecan,


InternalMed_Harrison

InternalMed_Harrison. in a minority of patients with RA, but they also occur in the setting of other types of arthritis.They bind toadiversearrayofautoantigens,includingtypeII collagen, human cartilage gp-39, aggrecan, calpastatin, BiP (immunoglobulin binding protein), and glucose-6-phosphate isomerase.


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InternalMed_Harrison. In theory, environmental stimulants may synergize with other factors to bring about inflammation in RA. People who smoke display higher citrullination of proteins in bronchoalveolar fluid than those who do not smoke. Thus, it has been speculated that long-term exposure to tobacco smoke might induce citrullination of cellular proteins in the lung and stimulate the expression of a neoepitope capable of inducing self-reactivity, which in turns, leads to formation of immune complexes and joint inflammation. Exposure to silicone dust and mineraloil,whichhasadjuvanteffects,hasalso beenlinkedtoanincreased risk for anti-CCP antibody-positive RA.


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InternalMed_Harrison. How might microbes or their products be involved in the initiating events of RA? The immune system is alerted to the presence of microbial infections through Toll-like receptors (TLRs). There are 10 TLRsinhumansthatrecognizeavarietyofmicrobialproducts,including bacterial cell-surface lipopolysaccharides and heat-shock proteins (TLR4), lipoproteins (TLR2), double-strand RNA viruses (TLR3), and unmethylated CpG DNA from bacteria (TLR9). TLR2, -3, and -4 are abundantly expressed by synovial fibroblasts in early RA and, when bound by their ligands, upregulate production of proinflammatory cytokines. Although such events could amplify inflammatory pathways in RA, a specific role for TLRs in disease pathogenesis has not been elucidated.


InternalMed_Harrison

InternalMed_Harrison. The pathogenesis of RA is built upon the concept that self-reactive T cells drive the chronic inflammatory response. In theory, self-reactive T cells might arise in RA from abnormal central (thymic) selection due to defects in DNA repair leading to an imbalance of T cell death and life, or defects in the cell signaling apparatus lowering the threshold for T cell activation. Similarly, abnormal selection of the T cell repertoire in the periphery might lead to a breakdown in T cell tolerance. The support for these theories comes mainly from studies of arthritis in mouse models. It has not been shown that patients with RA have 2141 abnormal thymic selection of T cells or defective apoptotic pathways regulating cell death. At least some antigen stimulation inside the joint seems likely, owing to the fact that T cells in the synovium express a cell-surface phenotype indicating prior antigen exposure and show evidence of clonal expansion. Of interest, peripheral blood T cells from patients


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InternalMed_Harrison. to the fact that T cells in the synovium express a cell-surface phenotype indicating prior antigen exposure and show evidence of clonal expansion. Of interest, peripheral blood T cells from patients with RA have been shown to display a fingerprint of premature aging that mostly affects inexperienced naïve T cells. In these studies, the most glaring findings have been the loss of telomeric sequencesandadecreaseinthethymicoutputofnewTcells.Although intriguing, it is not clear how generalized T cell abnormalities might provoke a systemic disease dominated by synovitis.


InternalMed_Harrison

InternalMed_Harrison. There is substantial evidence supporting a role for CD4+ T cells in the pathogenesis of RA. First, the co-receptor CD4 on the surface of T cells binds to invariant sites on MHC class II molecules, stabilizing the MHC-peptide–T cell receptor complex during T cell activation. Because the SE on MHCclass IImolecules is arisk factor for RA, itfollows that CD4+ T cell activation may play a role in the pathogenesis of thisdisease.Second,CD4+memoryTcellsareenrichedinthesynovial tissue from patients with RA and can be implicated through “guilt by association.” Third, CD4+ T cells have been shown to be important in the initiation of arthritis in animal models. Fourth, some, but not all, T cell–directed therapies have shown clinical efficacy in this disease. Taken together, these lines of evidence suggest that CD4+ T cells play an important role in orchestrating the chronic inflammatory response in RA. However, other cell types, such as CD8+ T cells, natural killer (NK)cells, andBcellsarepresent


InternalMed_Harrison

InternalMed_Harrison. that CD4+ T cells play an important role in orchestrating the chronic inflammatory response in RA. However, other cell types, such as CD8+ T cells, natural killer (NK)cells, andBcellsarepresent insynovialtissueandmayalsoinflu ence pathogenic responses.


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InternalMed_Harrison. In the rheumatoid joint, by mechanisms of cell-cell contact and release of soluble mediators, activated T cells stimulate macrophages and fibroblast-like synoviocytes to generate proinflammatory mediators and proteases that drive the synovial inflammatory response and destroy the cartilage and bone. CD4+ T cell activation is dependent on two signals: (1) T cell receptor binding to peptide-MHC on antigen-presenting cells; and (2) CD28 binding to CD80/86 on antigen-presenting cells. CD4+ T cells also provide help to B cells, which in turn, produce antibodies that may promote further inflammation in the joint. The previous T cell–centric model for the pathogenesis of RA was based on a TH1-driven paradigm, which came from studies indicating that CD4+ T helper (TH) cells differentiated into TH1 and TH2 subsets, each with their distinctive cytokine profiles. TH1 cells were found to mainly produce interferon γ (IFN-γ), lymphotoxin β, and TNF-α, whereas TH2 cells predominately secreted


InternalMed_Harrison

InternalMed_Harrison. TH1 and TH2 subsets, each with their distinctive cytokine profiles. TH1 cells were found to mainly produce interferon γ (IFN-γ), lymphotoxin β, and TNF-α, whereas TH2 cells predominately secreted interleukin (IL)-4, IL-5, IL-6, IL-10, and IL-13. The recent discovery of another subset of TH cells, namely the TH17 lineage, has revolutionized our concepts concerning the pathogenesis of RA. In humans, naïve T cells are induced to differentiate into TH17 cells by exposure to transforming growth factor β (TGF-β), IL-1, IL-6, and IL-23. Upon activation, TH17 cells secrete a variety of proinflammatory mediators such as IL-17, IL-21, IL-22, TNF-α, IL-26, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Substantial evidence now exists from both animal models and humans that IL-17 plays an important role not only in promoting joint inflammation, but also in destroying cartilage and subchondral bone


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InternalMed_Harrison. The immune system has evolved mechanisms to counterbalance the potential harmful immune-mediated inflammatory responses provoked by infectious agents and other triggers. Among these negative regulators are regulatory T (Treg) cells, which are produced in the thymus and induced in the periphery to suppress immune-mediated inflammation. They are characterized by the surface expression of CD25 and the transcription factor forkhead box P3 (FOXP3) and orchestrate dominant tolerance through contact with other immune cells and secretion of inhibitory cytokines, such as TGF-β, IL-10, and IL-35. T reg cells appear to be heterogeneous and capable of suppressing distinct classes (TH1, TH2, TH17) of the immune response. In RA, the data that Treg numbers are deficient compared to normal healthy controls are contradictory and inconclusive. Although some experimental evidence suggests that Treg suppressive activity is lost due to dysfunctional expression of cytotoxic T lymphocyte antigen 4


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InternalMed_Harrison. IFN-˜, TNF-° IL-17A, IL-17F, lymphotoxin-˛ TNF-°, IL-6, GM-CSF +++St CD40 Pre-OB Wnt Dkk-1 IFN-˜, IL17 IL15, GM-CSF, TNF-°RF, Anti-CCP Ab IL-6, IL-8 IL-1, IL-6, IL-18 MMP OPG RANK-L RANK FGF, TGF-˛TH OC OB B M SF Teff


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InternalMed_Harrison. FIGUrE 380-4 Pathophysiologic mechanisms of inflammation and joint destruction. Genetic predisposition along with environmental factors may trigger the development of rheumatoid arthritis (RA), with subsequent synovial T cell activation. CD4+ T cells become activated by antigen-presenting cells (APCs) through interactions between the T cell receptor and class II major histocompatibility complex (MHC)-peptide antigen (signal 1) with co-stimulation through the CD28-CD80/86 pathway, as well as other pathways (signal 2). In theory, ligands binding Toll-like receptors (TLRs) may further stimulate activation of APCs inside the joint. Synovial CD4+ T cells differentiate into TH1 and TH17 cells, each with their distinctive cytokine profile. CD4+ TH cells in turn activate B cells, some of which are destined to differentiate into autoantibody-producing plasma cells. Immune complexes, possibly comprised of rheumatoid factors (RFs) and anti–cyclic citrullinated peptides (CCP) antibodies, may form


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InternalMed_Harrison. destined to differentiate into autoantibody-producing plasma cells. Immune complexes, possibly comprised of rheumatoid factors (RFs) and anti–cyclic citrullinated peptides (CCP) antibodies, may form inside the joint, activating the complement pathway and amplifying inflammation. T effector cells stimulate synovial macrophages (M) and fibroblasts (SF) to secrete proinflammatory mediators, among which is tumor necrosis factor α (TNF-α). TNF-α upregulates adhesion molecules on endothelial cells, promoting leukocyte influx into the joint. It also stimulates the production of other inflammatory mediators, such as interleukin 1 (IL-1), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). TNF-α has a critically important function in regulating the balance between bone destruction and formation. It upregulates the expression of dickkopf-1 (DKK-1), which can then internalize Wnt receptors on osteoblast precursors. Wnt is a soluble mediator that promotes osteoblastogenesis and


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InternalMed_Harrison. and formation. It upregulates the expression of dickkopf-1 (DKK-1), which can then internalize Wnt receptors on osteoblast precursors. Wnt is a soluble mediator that promotes osteoblastogenesis and bone formation. In RA, bone formation is inhibited through the Wnt pathway, presumably due to the action of elevated levels of DKK-1. In addition to inhibiting bone formation, TNF-α stimulates osteoclastogenesis. However, it is not sufficient by itself to induce the differentiation of osteoclast precursors (Pre-OC) into activated osteoclasts capable of eroding bone. Osteoclast differentiation requires the presence of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB (RANK) ligand (RANKL), which binds to RANK on the surface of Pre-OC. Inside the joint, RANKL is mainly derived from stromal cells, synovial fibroblasts, and T cells. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL, thereby inhibiting osteoclastogenesis and bone loss. FGF,


InternalMed_Harrison

InternalMed_Harrison. RANKL is mainly derived from stromal cells, synovial fibroblasts, and T cells. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL, thereby inhibiting osteoclastogenesis and bone loss. FGF, fibroblast growth factor; IFN, interferon; TGF, transforming growth factor.


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InternalMed_Harrison. (CTLA-4), the nature of Treg defects in RA, if they exist, remains unclear. Cytokines, chemokines, antibodies, and endogenous danger signals bind to receptors on the surface of immune cells and stimulate a cascade of intracellular signaling events that can amplify the inflammatory response. Signaling molecules and their binding partners in these pathways are the target of small-molecule drugs designed to interfere with signal transduction and block these reinforcing inflammatory loops. Examples of signal molecules in these critical inflammatory pathways include Janus kinase (JAK)/signal transducers and activators of transcription (STAT), spleen tyrosine kinase (Syk), mitogen-activated protein kinases (MAPKs), and nuclear factor-κB (NF-κB). These pathways exhibit significant cross-talk and are found in many cell types. Some signal transducers, such as JAK3, are primarily expressed in hematopoieticcellsandplayanimportantroleintheinflammatoryresponseinRA.


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InternalMed_Harrison. Activated B cells are also important players in the chronic inflammatory response. B cells give rise to plasma cells, which in turn, produce antibodies, including RF and anti-CCP antibodies. RFs may form large immune complexes inside the joint that contribute to the pathogenic process by fixing complement and promoting the release of proinflammatory chemokines and chemoattractants. In mouse models of arthritis, RF-containing immune complexes and anti-CCPcontaining immune complexes synergize with other mechanisms to exacerbate the synovial inflammatory response.


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InternalMed_Harrison. RA is often considered to be a macrophage-driven disease because this cell type is the predominant source of proinflammatory cytokines inside the joint. Key proinflammatory cytokines released by synovial macrophagesincludeTNF-α,IL-1,IL-6,IL-12,IL-15,IL-18,andIL-23. Synovial fibroblasts, the other major cell type in this microenvironment, produce the cytokines IL-1 and IL-6 as well as TNF-α. TNF-α is a pivotal cytokine in the pathobiology of synovial inflammation. It upregulates adhesion molecules on endothelial cells, promoting the influx of leukocytes into the synovial microenvironment; activates synovial fibroblasts; stimulates angiogenesis; promotes pain receptor sensitizing pathways; and drives osteoclastogenesis. Fibroblasts secrete matrix metalloproteinases (MMPs) as well as other proteases that are chiefly responsible for the breakdown of articular cartilage.


InternalMed_Harrison

InternalMed_Harrison. Osteoclast activation at the site of the pannus is closely tied to the presence of focal bone erosion. Receptor activator of nuclear factor-κB ligand (RANKL) is expressed by stromal cells, synovial fibroblasts, and T cells. Upon binding to its receptor RANK on osteoclast progenitors, RANKL stimulates osteoclast differentiation and bone resorption. RANKL activity is regulated by osteoprotegerin (OPG), a decoy receptor of RANKL that blocks osteoclast formation. Monocytic cells in the synovium serve as the precursors of osteoclasts and, when exposed to macrophage colony-stimulating factor (M-CSF) and RANKL, fuse to formpolykaryonstermed preosteoclasts.Theseprecursorcells undergo further differentiation into osteoclasts with the characteristic ruffled membrane. Cytokines such as TNF-α, IL-1, IL-6, and IL-17 increase the expression of RANKL in the joint and thus promote osteoclastogenesis. Osteoclasts also secrete cathepsin K, which is a cysteine protease that degrades the bone matrix by


InternalMed_Harrison

InternalMed_Harrison. IL-6, and IL-17 increase the expression of RANKL in the joint and thus promote osteoclastogenesis. Osteoclasts also secrete cathepsin K, which is a cysteine protease that degrades the bone matrix by cleaving collagen. Stimulation of osteoclasts also contributes to generalized bone loss and osteoporosis.


InternalMed_Harrison

InternalMed_Harrison. Increased bone loss is only part of the story in RA, as decreased bone formation plays a crucial role in bone remodeling at sites of inflammation. Recent evidence shows that inflammation suppresses boneformation.TheproinflammatorycytokineTNF-αplaysakeyrole in actively suppressing bone formation by enhancing the expression of dickkopf-1 (DKK-1). DKK-1 is an important inhibitor of the Wnt pathway, which acts to promote osteoblast differentiation and bone formation. The Wnt system is a family of soluble glycoproteins that bind to cell-surface receptors known as frizzled (fz) and low-density lipoprotein (LDL) receptor–related proteins (LRPs) and promote cell growth. In animal models, increased levels of DKK-1 are associated with decreased bone formation, whereas inhibition of DKK-1 protects against structural damage in the joint. Wnt proteins also induce the formation of OPG and thereby shut down bone resorption, emphasizing their key role in tightly regulating the balance between bone


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InternalMed_Harrison. against structural damage in the joint. Wnt proteins also induce the formation of OPG and thereby shut down bone resorption, emphasizing their key role in tightly regulating the balance between bone resorption and formation.


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InternalMed_Harrison. The clinical diagnosis of RA is largely based on signs and symptoms of a chronic inflammatory arthritis, with laboratory and radiographic results providing important supplemental information. In 2010, a collaborative effort between the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised the 1987 ACR classification criteria for RA in an effort to improve early diagnosis with the goal of identifying patients who would benefit from early introduction of disease-modifying therapy (Table 380-1). Application of the newly revised criteria yields a score of 0–10, with a score of ≥ 6 fulfilling the requirements for definite RA. The new classification criteria differ in severalwaysfromtheoldercriteriaset.Thenewcriteriaincludeapositive testforserumanti-CCPantibodies(alsotermedACPA,anti-citrullinated peptide antibodies) as an item, which carries greater specificity for the diagnosis of RA than a positive test for RF. The newer classification criteria


InternalMed_Harrison

InternalMed_Harrison. peptide antibodies) as an item, which carries greater specificity for the diagnosis of RA than a positive test for RF. The newer classification criteria also do not take into account whether the patient has rheumatoid nodules orradiographic jointdamagebecause these findingsoccurrarely inearlyRA.Itisimportanttoemphasizethatthenew2010ACR-EULAR criteria are “classification criteria” as opposed to “diagnostic criteria” and serve todistinguishpatientsatthe onsetof disease who haveahigh likelihood of evolution to chronic disease with persistent synovitis and joint damage. The presence of radiographic joint erosions or subcutaneous nodules may inform the diagnosis in the later stages of the disease.


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InternalMed_Harrison. Patients with systemic inflammatory diseases such as RA will often present with elevated nonspecific inflammatory markers such as an ESRorCRP.DetectionofserumRFandanti-CCPantibodiesisimportant in differentiating RA from other polyarticular diseases, although RF lacks diagnostic specificity and may be found in association with other chronic inflammatory diseases in which arthritis figures in the clinical manifestations.


InternalMed_Harrison

InternalMed_Harrison. IgM, IgG, and IgA isotypes of RF occur in sera from patients with RA, although the IgM isotype is the one most frequently measured by commercial laboratories. Serum IgM RF has been found in 75–80% of patientswithRA;therefore,anegativeresultdoesnotexcludethepresence of this disease. It is also found in other connective tissue diseases, such as primary Sjögren’s syndrome, systemic lupus erythematosus, and type II mixed essential cryoglobulinemia, as well as chronic infections such as subacute bacterial endocarditis and hepatitis B and C. Serum RF may also be detected in 1–5% of the healthy population. Note: These criteria are aimed at classification of newly presenting patients who have at least one joint with definite clinical synovitis that is not better explained by another disease. A score of ≥6 fulfills requirements for definite RA.


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InternalMed_Harrison. Abbreviations: ACPA, anti-citrullinated peptide antibodies; CCP, cyclic citrullinated peptides; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IP, interphalangeal joint; MCP, metacarpophalangeal joint; MTP, metatarsophalangeal joint; PIP, proximal interphalangeal joint; RF, rheumatoid factor; ULN, upper limit of normal. Source: D Aletaha et al: Arthritis Rheum 62:2569, 2010.


InternalMed_Harrison

InternalMed_Harrison. Source: D Aletaha et al: Arthritis Rheum 62:2569, 2010. 2144 The presence of serum anti-CCP antibodies has about the same sensitivityasserumRFforthediagnosisofRA.However,itsdiagnostic specificity approaches 95%, so a positive test for anti-CCP antibodies in the setting of an early inflammatory arthritis is useful for distinguishing RA from other forms of arthritis. There is some incremental value in testing for the presence of both RF and anti-CCP, as some patientswithRAarepositiveforRF butnegativefor anti-CCP and visa versa. The presence of RF or anti-CCP antibodies also has prognostic significance, with anti-CCP antibodies showing the most value for predicting worse outcomes.


InternalMed_Harrison

InternalMed_Harrison. Typically,synovialfluidfrompatientswithRAreflectsaninflammatory state. Synovialfluidwhitebloodcell (WBC)countscanvarywidely, but generally range between 5000 and 50,000 WBC/μL compared to <2000 WBC/μL for a noninflammatory condition such as osteoarthritis. In contrast to the synovial tissue, the overwhelming cell type in the synovial fluid is the neutrophil. Clinically, the analysis of synovial fluid is most useful for confirming an inflammatory arthritis (as opposed to osteoarthritis), while at the same time excluding infection or a crystal-induced arthritis such as gout or pseudogout (Chap. 395).


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InternalMed_Harrison. Joint imaging is a valuable tool not only for diagnosing RA, but also for tracking progression of any joint damage. Plain x-ray is the most common imaging modality, but it is limited to visualization of the bony structures and inferences about the state of the articular cartilage based on the amount of narrowing of the joint space. MRI and ultrasound techniques offer the added value of detecting changes in the soft tissues such as synovitis, tenosynovitis, and effusions as well as greater sensitivity for identifying bony abnormalities. Plain radio-graphs are usually relied upon in clinical practice for the purpose of diagnosis and monitoring of affected joints. However, in selected cases, MRI and ultrasound can provide additional diagnostic information that may guide clinical decision making. Musculoskeletal ultrasound with power Doppler is increasingly used in rheumatology clinical practice for detecting synovitis and bone erosion.


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InternalMed_Harrison. Plain radiography Classically in RA, the initial radiographic finding is periarticular osteopenia. Practically speaking, however, this finding is difficult to appreciate on plain films and, in particular, on the newer digitalized x-rays. Other findings on plain radiographs include soft tissue swelling, symmetric joint space loss, and subchondral erosions, most frequently in the wrists and hands (MCPs and PIPs) and the feet (MTPs). In the feet, the lateral aspect of the fifth MTP is often targeted first, but other MTP joints may be involved at the same time. X-ray imaging of advanced RA may reveal signs of severe destruction, including joint subluxation and collapse (Fig. 380-5). FIGUrE 380-5 X-ray demonstrating progression of erosions ontheproximalinterphalangealjoint.(Courtesy of the American College of Rheumatology.)


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InternalMed_Harrison. FIGUrE 380-5 X-ray demonstrating progression of erosions ontheproximalinterphalangealjoint.(Courtesy of the American College of Rheumatology.) MrI MRI offers the greatest sensitivity for detecting synovitis and joint effusions, as well as early bone and bone marrow changes. These soft tissue abnormalities often occur before osseous changes are noted on x-ray. Presence of bone marrow edemahasbeen recognizedto be an early sign of inflammatory joint disease and can predict the subsequent development of erosions on plain radiographs as well as MRI scans. Cost and availability of MRI are the main factors limiting its routine clinical use.


InternalMed_Harrison

InternalMed_Harrison. Ultrasound Ultrasound, including power color Doppler, has the ability to detect more erosions than plain radiography, especially in easily accessible joints. It can also reliably detect synovitis, including increased joint vascularity indicative of inflammation. The usefulness of ultrasound is dependent on the experience of the sonographer; however, it does offer the advantages of portability, lack of radiation, and low expense relative to MRI, factors that make it attractive as a clinical tool.


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InternalMed_Harrison. The natural history of RA is complex and affected by a number of factors including age of onset, gender, genotype, phenotype (i.e., extraarticular manifestations or variants of RA), and comorbid conditions, which make for a truly heterogeneous disease. There is no simple way to predict the clinical course. It is important to realize that as many as 10% of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will undergo a spontaneous remission within 6 months (particularly seronegative patients). However, the vast majority of patients will exhibit a pattern of persistent and progressive disease activity that waxes and wanes in intensity over time. A minority of patients will show intermittent and recurrent explosive attacks of inflammatory arthritis interspersed with periods of disease quiescence. Finally, an aggressive form of RA may occur in an unfortunate few with inexorable progression of severe erosive joint disease, although this highly destructive


InternalMed_Harrison

InternalMed_Harrison. with periods of disease quiescence. Finally, an aggressive form of RA may occur in an unfortunate few with inexorable progression of severe erosive joint disease, although this highly destructive course is less common in the modern treatment era of biologics.


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InternalMed_Harrison. Disability, as measured by the Health Assessment Questionnaire (HAQ), shows gradual worsening of disability over time in the face of poorly controlled disease activity and disease progression. Disability may result from both a disease activity–related component that is potentially reversible with therapy and a joint damage–related component owing to the cumulative and largely irreversible effects of cartilage and bone breakdown. Early in the course of disease, the extent of joint inflammation is the primary determinant of disability, while in the later stages of disease, the amount of joint damage is the dominant contributing factor. Previous studies have shown that more than one-half of patients with RA are unable to work 10 years after the onset of their disease; however, increased employability and less work absenteeismhasbeen reported recently with the useofnewer therapies and earlier treatment intervention.


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InternalMed_Harrison. The overall mortality rate in RA is two times greater than the general population, with ischemic heart disease being the most common cause of death followed by infection. Median life expectancy is shortened by an average of 7 years for men and 3 years for women compared to control populations. Patients at higher risk for shortened survival are those with systemic extraarticular involvement, low functional capacity, low socioeconomic status, low education, and chronic prednisone use.


InternalMed_Harrison

InternalMed_Harrison. The amount of clinical disease activity in patients with RA reflects the overall burden of inflammation and is the variable most influencing treatment decisions. Joint inflammation is the main driver of joint damage and is the most important cause of functional disability in the early stages of disease. Several composite indices have been developed to assess clinical disease activity. The ACR 20, 50, and 70 improvement criteria (which corresponds to a 20%, 50%, and 70% improvement, respectively, in joint counts, physician/patient assessment of disease severity, pain scale, serum levels of acute-phase reactants [ESR or CRP], and a functional assessment of disability using a self-administered patient questionnaire) are a composite index with a dichotomous response variable. The ACR improvement criteria are commonly used in clinical trials as an endpoint for comparing the proportion of responders between treatment groups. In contrast, the Disease Activity Score (DAS), Simplified Disease


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InternalMed_Harrison. criteria are commonly used in clinical trials as an endpoint for comparing the proportion of responders between treatment groups. In contrast, the Disease Activity Score (DAS), Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI) are continuous measures of disease activity. These scales are increasingly used in clinical practice for tracking disease status and, in particular, for documenting treatment response.


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InternalMed_Harrison. Several developments during the past two decades have changed the therapeutic landscape in RA. They include (1) the emergence of methotrexate as the disease-modifying antirheumatic drug (DMARD) of first choice for the treatment of early RA; (2) the development of novel highly efficacious biologicals that can be used alone or in combination with methotrexate; and (3) the proven superiority of combination DMARD regimens over methotrexate alone. The medications used for the treatment of RA may be divided into broad categories: nonsteroidal anti-inflammatory drugs (NSAIDs); glucocorticoids, such as prednisone and methylprednisolone; conventional DMARDs; and biologic DMARDs (Table 380-2). Although disease for some patients with RA is managed adequately with a single DMARD, such as methotrexate, the situation in most cases demands the use of a combination DMARD regimen that may vary in its components over the treatment course depending on fluctuations in disease activity and emergence of


InternalMed_Harrison

InternalMed_Harrison. the situation in most cases demands the use of a combination DMARD regimen that may vary in its components over the treatment course depending on fluctuations in disease activity and emergence of drug-related toxicities and comorbidities.


InternalMed_Harrison

InternalMed_Harrison. NSAIDs were formerly viewed as the core of all other RA therapy, but they are now considered to be adjunctive therapy for management of symptoms uncontrolled by other measures. NSAIDs exhibit both analgesic and anti-inflammatory properties. The anti-inflammatory effects of NSAIDs derive from their ability to nonselectively inhibit cyclooxygenase (COX)-1 and COX-2. Although the results of clinical trials suggest NSAIDs are roughly equivalent in their efficacy, experience suggests that some individuals may preferentially respond to a particular NSAID. Chronic use should be minimized due to the possibility of side effects, including gastritis and peptic ulcer disease as well as impairment of renal function.


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InternalMed_Harrison. Glucocorticoids may serve in several ways to control disease activity in RA. First, they may be administered in low to moderate doses to achieve rapid disease control before the onset of fully effective DMARD therapy, which often takes several weeks or even months. Second, a 1to 2-week burst of glucocorticoids may be prescribed for the management of acute disease flares, with dose and duration guided by the severity of the exacerbation. Chronic administration of low doses (5–10 mg/d) of prednisone (or its equivalent) may also be warranted to control disease activity in patients with an inadequate response to DMARD therapy. Low-dose prednisone therapy has been shown in prospective studies to retard radiographic progression of joint disease; however, the benefits of this approach must be carefully weighed against the risks. Best practices minimize chronic use of low-dose prednisone therapy owing to the risk of osteoporosis and other long-term complications; however, the use of chronic


InternalMed_Harrison

InternalMed_Harrison. weighed against the risks. Best practices minimize chronic use of low-dose prednisone therapy owing to the risk of osteoporosis and other long-term complications; however, the use of chronic prednisone therapy is unavoidable in many cases. High-dose glucocorticoids may be necessary for treatment of severe extraarticular manifestations of RA, such as ILD. Finally, if a patient exhibits one or a few actively inflamed joints, the clinician may consider intraarticular injection of an intermediate-acting glucocorticoid such as triamcinolone acetonide. This approach may allow for rapid control of inflammation in the setting of a limited number of affected joints. Caution must be exercised to appropriately exclude joint infection, as it often mimics an RA flare.


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InternalMed_Harrison. Osteoporosis ranks as an important long-term complication of chronic prednisone use. The ACR recommends primary prevention of glucocorticoid-induced osteoporosis with a bisphosphonate in any patient receiving 5 mg/d or more of prednisone for greater than 2145 3 months. Although prednisone use is known to increase the risk of peptic ulcer disease, especially with concomitant NSAID use, no evidence-based guidelines have been published regarding the use of gastrointestinal ulcer prophylaxis in this situation.


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InternalMed_Harrison. DMARDs are so named because of their ability to slow or prevent structural progression of RA. The conventional DMARDs include hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide; they exhibit a delayed onset of action of approximately 6–12 weeks. Methotrexate is the DMARD of choice for the treatment of RA and is the anchor drug for most combination therapies. It was approved for the treatment of RA in 1986 and remains the benchmark for the efficacy and safety of new disease-modifying therapies. At the dosages used for the treatment of RA, methotrexate has been shown to stimulate adenosine release from cells, producing an anti-inflammatory effect. The clinical efficacy of leflunomide, an inhibitor of pyrimidine synthesis, appears similar to that of methotrexate; it has been shown in well-designed trials to be effective for the treatment of RA as monotherapy or in combination with methotrexate and other DMARDs.


InternalMed_Harrison

InternalMed_Harrison. Although similar to the other DMARDs in its slow onset of action, hydroxychloroquine has not been shown to delay radiographic progression of disease and thus is not considered to be a true DMARD. In clinical practice, hydroxychloroquine is generally used for treatment of early, mild disease or as adjunctive therapy in combination with other DMARDs. Sulfasalazine is used in a similar manner and has been shown in randomized, controlled trials to reduce radiographic progression of disease. Minocycline, gold salts, penicillamine, azathioprine, and cyclosporine have all been used for the treatment of RA with varying degrees of success; however, they are used sparingly now due to their inconsistent clinical efficacy or unfavorable toxicity profile.


InternalMed_Harrison

InternalMed_Harrison. Biologic DMARDs have revolutionized the treatment of RA over the past decade (Table 380-2). They are protein therapeutics designed mostly to target cytokines and cell-surface molecules. The TNF inhibitors were the first biologicals approved for the treatment of RA. Anakinra, an IL-1 receptor antagonist, was approved shortly thereafter; however, its benefits have proved to be relatively modest compared with the other biologicals and is rarely used for the treatment of RA with the availability of other more effective agents. Abatacept, rituximab, and tocilizumab are the newest members of this class.


InternalMed_Harrison

InternalMed_Harrison. anti-TNF agents The development of TNF inhibitors was originally spurred by the experimental finding that TNF is a critical upstream mediator of joint inflammation. Currently, five agents that inhibit TNF-α are approved for the treatment of RA. There are three different anti-TNF monoclonal antibodies. Infliximab is a chimeric (part mouse and human) monoclonal antibody, whereas adalimumab and golimumab are humanized monoclonal antibodies. Certolizumab pegol is a pegylated Fc-free fragment of a humanized monoclonal antibody with binding specificity for TNF-α. Lastly, etanercept is a soluble fusion protein comprising the TNF receptor 2 in covalent linkage with the Fc portion of IgG1. All of the TNF inhibitors have been shown in randomized controlled clinical trials to reduce the signs and symptoms of RA, slow radiographic progression of joint damage, and improve physical function and quality of life. Anti-TNF drugs are typically used in combination with background methotrexate therapy.


InternalMed_Harrison

InternalMed_Harrison. of RA, slow radiographic progression of joint damage, and improve physical function and quality of life. Anti-TNF drugs are typically used in combination with background methotrexate therapy. This combination regimen, which affords maximal benefit in many cases, is often the next step for treatment of patients with an inadequate response to methotrexate therapy. Etanercept, adalimumab, certolizumab pegol, and golimumab have also been approved for use as monotherapy.


InternalMed_Harrison

InternalMed_Harrison. Anti-TNF agents should be avoided in patients with active infection or a history of hypersensitivity to these agents and are contraindicated in patients with chronic hepatitis B infection or class III/IV congestive Rituximab 200–400 mg/d orally (≤6.5 mg/kg) Initial: 500 mg orally twice daily Maintenance: 1000–1500 mg twice daily Folic acid 1 mg/d to reduce toxicities Infliximab: 3 mg/kg IV at weeks 0, 2, 6, then every 8 weeks. May increase dose up to 10 mg/kg every 4 weeks Etanercept: 50 mg SQ weekly, or 25 mg SQ biweekly Adalimumab: 40 mg SQ every other week Golimumab: 50 mg SQ monthly Certolizumab: 400 mg SQ weeks 0, 2, 4, then 200 mg every other week Weight based: <60 kg: 500 mg 60–100 kg: 750 mg >100 kg: 1000 mg IV dose at weeks 0, 2, and 4, and then every 4 weeks 1000 mg IV × 2, days 0 and 14 Premedicate with methylprednisolone 100 mg to decrease infusion reaction Risk bacterial, fungal infections Reactivation of latent TB Risk bacterial, viral infections


InternalMed_Harrison

InternalMed_Harrison. Premedicate with methylprednisolone 100 mg to decrease infusion reaction Risk bacterial, fungal infections Reactivation of latent TB Risk bacterial, viral infections Risk bacterial, viral infections Reactivation of latent TB Neutropenia Risk bacterial, viral infections Infusion reaction CBC, LFTs G6PD level CBC, LFTs CBC, LFTs Viral hepatitis panela CBC every 2–4 weeks for first 3 months, then every 3 months CBC, creatinine, CBC, creatinine, LFTs every 2–3 months CBC every month for 3 months, then every 4 months for 1 year Risk of infection Risk of infection Upper respiratory PPD skin test CBC, LFTs, and lipids at tract infections aViral hepatitis panel: hepatitis B surface antigen, hepatitis C viral antibody. Abbreviations: CBC, complete blood count; DMARDs, disease-modifying antirheumatic drugs; G6PD, glucose-6-phosphate dehydrogenase; IV, intravenous; LFTs, liver function tests; PPD, purified protein derivative; SQ, subcutaneous; TB, tuberculosis.


InternalMed_Harrison

InternalMed_Harrison. heart failure. The major concern is the increased risk for infection, including serious bacterial infections, opportunistic fungal infection, and reactivation of latent tuberculosis. For this reason, all patients are screened for latent tuberculosis according to national guidelines prior to starting anti-TNF therapy (Chap. 202). In the United States, patients are skin tested using an intradermal injection of purified protein derivative (PPD); individuals with skin reactions of more than 5 mm are presumed to have had previous exposure to tuberculosis and are evaluated for active disease and treated accordingly. The QuantiFERON IFN-γ release assay may also be used in selected circumstances to screen for previous exposure to tuberculosis.


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InternalMed_Harrison. anakinra Anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist. Although anakinra has seen limited use for the treatment of RA, it has enjoyed a resurgence of late as an effective therapy of some rare inherited syndromes dependent on IL-1 production, including neonatal-onset inflammatory disease, Muckle-Wells syndrome, and familial cold urticaria, as well as systemic juvenile-onset inflammatory arthritis and adult-onset Still’s disease. Anakinra should not be combined with an anti-TNF drug due to the high rate of serious infections as observed with this regimen in a clinical trial.


InternalMed_Harrison

InternalMed_Harrison. abatacept Abatacept is a soluble fusion protein consisting of the extracellular domain of human CTLA-4 linked to the modified portion of human IgG. It inhibits the co-stimulation of T cells by blocking CD28-CD80/86 interactions and may also inhibit the function of antigen-presenting cells by reverse signaling through CD80 and CD86. Abatacept has been shown in clinical trials to reduce disease activity, slow radiographic progression of damage, and improve functional disability. Many patients receive abatacept in combination with methotrexate or another DMARD such as leflunomide. Abatacept therapy has been associated with an increased risk of infection.


InternalMed_Harrison

InternalMed_Harrison. rituximab Rituximab is a chimeric monoclonal antibody directed against CD20, a cell-surface molecule expressed by most mature B lymphocytes. It works by depleting B cells, which in turn, leads to a reduction in the inflammatory response by unknown mechanisms. These mechanisms may include a reduction in autoantibodies, inhibition of T cell activation, and alteration of cytokine production. Rituximab has been approved for the treatment of refractory RA in combination with methotrexate and has been shown to be more effective for patients with seropositive than seronegative disease. Rituximab therapy has been associated with mild to moderate infusion reactions as well as an increased risk of infection. Notably, there have been isolated reports of a potentially lethal brain disorder, progressive multifocal leukoencephalopathy (PML), in association with rituximab therapy, although the absolute risk of this complication appears to be very low in patients with RA. Most of these cases have


InternalMed_Harrison

InternalMed_Harrison. multifocal leukoencephalopathy (PML), in association with rituximab therapy, although the absolute risk of this complication appears to be very low in patients with RA. Most of these cases have occurred on a background of previous or current exposure to other potent immunosuppressive drugs.


InternalMed_Harrison

InternalMed_Harrison. Tocilizumab Tocilizumab is a humanized monoclonal antibody directed against the membrane and soluble forms of the IL-6 receptor. IL-6 is a proinflammatory cytokine implicated in the pathogenesis of RA, with detrimental effects on both joint inflammation and damage. IL-6 binding to its receptor activates intracellular signaling pathways that affect the acute-phase response, cytokine production, and osteoclast activation. Clinical trials attest to the clinical efficacy of tocilizumab therapy for RA, both as monotherapy and in combination with methotrexate and other DMARDs. Tocilizumab has been associated with an increased risk of infection, neutropenia, and thrombocytopenia; however, the hematologic abnormalities appear to be reversible upon stopping the drug. In addition, this agent has been shown to increase LDL cholesterol; however, it is not known as yet if this effect on lipid levels increases the risk for development of atherosclerotic disease.


InternalMed_Harrison

InternalMed_Harrison. Because some patients do not adequately respond to conventional DMARDS or biologic therapy, other therapeutic targets have been investigated to fill this gap. Recently, drug development in RA has focused attention on the intracellular signaling pathways that transduce the positive signals of cytokines and other inflammatory mediators that create the positive feedback loops in the immune response. These synthetic DMARDs aim to provide the same efficacy as biological therapies in an oral formulation.


InternalMed_Harrison

InternalMed_Harrison. Tofacitinib Tofacitinib is a small-molecule inhibitor that primarily inhibits JAK1 and JAK3, which mediate signaling of the receptors for the common γ-chain-related cytokines IL-2, -4, -7, -9, -15, and -21 as well as IFN-γ and IL-6. These cytokines all play roles in promoting T and B cell activation as well as inflammation. Tofacitinib, an oral agent, has been shown in randomized, placebo-controlled clinical trials to improve the signs and symptoms of RA significantly over placebo. Major adverse events include elevated serum transaminases indicative of liver injury, neutropenia, increased cholesterol levels, and elevation in serum creatinine. Its use is also associated with an increased risk of infections. Tofacitinib can be used as mono-therapy or in combination with methotrexate. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: The original treatment pyramid for RA is now considered to be obsolete and has evolved into a new strategy that focuses on several goals: (1) early, aggressive therapy to prevent jointdamageanddisability;(2) frequent modification of therapy withutilization of combination therapy where appropriate; (3) individualization of therapy in an attempt to maximize response and minimize side effects; and (4) achieving, whenever possible, remission of clinical disease activity. A considerable amount of evidence supports this intensive treatment approach.


InternalMed_Harrison

InternalMed_Harrison. As mentioned earlier, methotrexate is the DMARD of first choice for initial treatment of moderate to severe RA. Failure to achieve adequate improvement with methotrexate therapy calls for a change in DMARD therapy, usually transition to an effective combination regimen. Effective combinations include: methotrexate, sulfasalazine, and hydroxychloroquine (oral triple therapy); methotrexate and leflunomide; and methotrexate plus a biological. The combination of methotrexate and an anti-TNF agent, for example, has been shown in randomized, controlled trials to be superior to methotrexate alone not only for reducing signs and symptoms of disease, but also for retarding the progression of structural joint damage. Predicting which patients will ultimately show radiologic joint damage is imprecise at best, although some factors such as an elevated serum level of acute-phase reactants, high burden of joint inflammation, and the presence of erosive disease are associated with increased


InternalMed_Harrison

InternalMed_Harrison. imprecise at best, although some factors such as an elevated serum level of acute-phase reactants, high burden of joint inflammation, and the presence of erosive disease are associated with increased likelihood of developing structural injury.


InternalMed_Harrison

InternalMed_Harrison. In 2012 a joint task force of the ACR and EULAR updated the treatment guidelines for RA. They do make a distinction between patients with early RA (<6 months of disease duration) and patients with established RA. These guidelines highlight the need to switch or add DMARD therapy after 3 months of worsening or persistent moderate/high disease activity. If disease still persists after 3 months of intense DMARD therapy, addition of a biologic agent is warranted. Treatment with a biologic agent or aggressive combination DMARD therapy was also recommended as initial therapy in certain patients with high disease activity and poor prognosis. However, it has not been clearly established that this more intensive initial approach is superior to starting with methotrexate alone and, in the absence of an inadequate therapeutic response, moving rapidly to combination therapy.


InternalMed_Harrison

InternalMed_Harrison. Some patients may not respond to an anti-TNF drug or may be intolerant of its side effects. Initial responders to an anti-TNF agent that later worsen may benefit from switching to another anti-TNF agent. The 2012 guidelines recommend that with loss or lack of effectiveness of anti-TNF after 3 months, one should switch to another anti-TNF or non-TNF biologic agent. In patients with high diseaseactivityandaserious adverseeventfromananti-TNFagent, a non-TNF drug should be used. Studies have also shown that oral triple therapy (hydroxychloroquine, methotrexate, and sulfasalazine) is a reasonable first step for the treatment of early RA, including its use as a step-up strategy where treatment is initiated with methotrexate alone and then combined at 6 months with hydroxychloroquine and sulfasalazine if the disease is not adequately controlled.


InternalMed_Harrison

InternalMed_Harrison. A clinical state defined as low disease activity or remission is the optimal goal of therapy, although most patients never achieve remission despite every effort to achieve it. Composite indices, such as the Disease Activity Score-28 (DAS-28), are useful for classifying states of low disease activity and remission; however, they are imperfect tools due to the limitations of the clinical joint examination in which low-grade synovitis may escape detection. Complete remission has been stringently defined as the total absence of all articular and extraarticular inflammation and immunologic activity related to RA. However, evidence for this state can be difficult to demonstrate in clinical practice. In an effort to standardize and simplify the definition of remission for clinical trials, the ACR and EULARdevelopedtwoprovisionaloperationaldefinitionsofremissioninRA (Table 380-3).A patientmaybe consideredinremission if he or she (1) meets all of the clinical and laboratory criteria listed in


InternalMed_Harrison

InternalMed_Harrison. and EULARdevelopedtwoprovisionaloperationaldefinitionsofremissioninRA (Table 380-3).A patientmaybe consideredinremission if he or she (1) meets all of the clinical and laboratory criteria listed in Table 380-3 or (2) has a composite SDAI score of <3.3. The SDAI is calculated by taking the sum of a tender joint and swollen joint count (using 28 joints), patient global assessment (0–10 scale), physicianglobalassessment (0–10scale), and CRP (inmg/dL). This definition of remission does not take into account the possibility of subclinical synovitis or that damage alone may produce a tender or swollen joint. Ignoring the semantics of these definitions, the aforementioned remission criteria are nonetheless useful for setting


InternalMed_Harrison

InternalMed_Harrison. At any time point, patient must satisfy all of the following: At any time point, patient must have a Simplified Disease Activity Index score of ≤3.3 Source: Adapted from DT Felson et al: Arthritis Rheum 63:573, 2011. a level of disease control that will likely result in minimal or no progression of structural damage and disability. All patients should receive a prescription for exercise and physical activity. Dynamic strength training, community-based comprehensive physical therapy, and physical-activity coaching (emphasizing 30 min of moderately intensive activity most days a week) have all been shown to improve muscle strength and perceived health status. Foot orthotics for painful valgus deformity decrease foot pain and resulting disability and functional limitations. Judicious use of wrist splints can also decrease pain; however, their benefits may be offset by decreased dexterity and a variable effect on grip strength.


InternalMed_Harrison

InternalMed_Harrison. Surgical procedures may improve pain and disability in RA—most notably the hands, wrists, and feet, typically after the failure of medical therapy with varying degrees of reported long-term success. For large joints, such as the knee, hip, shoulder, or elbow, total joint arthroplasty is an option for advanced joint disease. A few surgical options exist for dealing with the smaller hand joints. Silicone implants are the most common prosthetic for MCP arthroplasty and are generally implanted in patients with severe decreased arc of motion, marked flexion contractures, MCP joint pain with radiographic abnormalities, and severe ulnar drift. Arthrodesis and total wrist arthroplasty are reserved for patients with severe disease who have substantial pain and functional impairment. These two procedures appear to have equal efficacy in terms of pain control and patient satisfaction. Numerous surgical options exist for correction of hallux valgus in the forefoot, including arthrodesis and


InternalMed_Harrison

InternalMed_Harrison. procedures appear to have equal efficacy in terms of pain control and patient satisfaction. Numerous surgical options exist for correction of hallux valgus in the forefoot, including arthrodesis and arthroplasty, as well as primarily arthrodesis for refractory hindfoot pain.


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InternalMed_Harrison. OTHEr MaNaGEMENT CONSIDEraTIONS Pregnancy Up to 75% of female RA patients will note overall improvement in symptoms during pregnancy, but often will flare after delivery. Flares during pregnancy are generally treated with low doses of prednisone; hydroxychloroquine and sulfasalazine are probably the safest DMARDs to use during pregnancy. Methotrexate and leflunomide therapy are contraindicated during pregnancy due to their teratogenicity in animals and humans. The experience with biologic agents has been insufficient to make specific recommendations for their use during pregnancy. Most rheumatologists avoid their use in this setting; however, exceptions are considered depending on the circumstances.


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InternalMed_Harrison. Elderly Patients RA presents in up to one-third of patients after the ageof60;however,olderindividualsmayreceivelessaggressivetreatment due to concerns about increased risks of drug toxicity. Studies suggest that conventional DMARDs and biologic agents are equally effective and safe in younger and older patients. Due to comorbidities, many elderly patients have an increased risk of infection. Aging alsoleadstoagradualdeclineinrenalfunctionthatmayraisetherisk for side effects from NSAIDs and some DMARDS, such as methotrexate. Renal function must be taken into consideration before prescribing methotrexate, which is mostly cleared by the kidneys. To reduce the risks of side effects, methotrexate doses may need to be adjusted downward for the drop in renal function that usually comes with the seventh and eighth decades of life. Methotrexate is usually not prescribed for patients with a serum creatinine greater Jonathan R. Carapetis than 2 mg/dL.


InternalMed_Harrison

InternalMed_Harrison. Developing countries are finding an increase in the incidence of noncommunicable, chronic diseases such as diabetes, car diovascular disease, and RA in the face of ongoing poverty, rampant infectious disease, and poor access to modern health care facilities. In theseareas,patientstend tohavea greater delay indiagnosis and limited access to specialists, and thus greater disease activity and disability at presentation. In addition, infection risk remains a significant issue for the treatment of RA in developing countries because of the immunosuppression associated with the use of glucocorticoids and most DMARDs. For example, in some developing countries, patients undergoing treatment for RA have a substantial increase in the incidence of tuberculosis, which demands the implementation of far more comprehensive screening practices and liberal useofisoniazidprophylaxisthanindevelopedcountries.Theincreased prevalence of hepatitis B and C, as well as human immunodeficiency virus (HIV), in


InternalMed_Harrison

InternalMed_Harrison. more comprehensive screening practices and liberal useofisoniazidprophylaxisthanindevelopedcountries.Theincreased prevalence of hepatitis B and C, as well as human immunodeficiency virus (HIV), in these developing countries also poses challenges. Reactivation of viral hepatitis has been observed in association with some of the DMARDs, such as rituximab. Also, reduced access to antiretroviral therapy may limit the control of HIV infection and therefore the choice of DMARD therapies.


InternalMed_Harrison

InternalMed_Harrison. Despite these challenges, one should attempt to initiate early treatment of RA in the developing countries with the resources at hand. Sulfasalazine and methotrexate are all reasonably accessible throughout the world where they can be used as both monotherapy and in combination with other drugs. The use of biologic agents is increasing in the developedcountriesaswellasinotherareasaroundtheworld,although theiruseislimitedbyhighcost;nationalprotocolsrestricttheiruse,and concerns remain about the risk for opportunistic infections.


InternalMed_Harrison

InternalMed_Harrison. Improved understanding of the pathogenesis of RA and its treatment has dramatically revolutionized the management of this disease. The outcomes of patients with RA are vastly superior to those of the prebiologic modifier era; more patients than in years past are able to avoid significant disability and continue working, albeit with some job modifications in many cases. The need for early and aggressive treatment of RA as well as frequent follow-up visits for monitoring of drug therapy has implications for our health care system. Primary care physicians and rheumatologists must be prepared to work together as a team to reach the ambitious goals of best practice. In many settings, rheumatologists have reengineered their practice in a way that places high priority on consultations for any new patient with early inflammatory arthritis.


InternalMed_Harrison

InternalMed_Harrison. The therapeutic regimens for RA are becoming increasingly complex with the rapidly expanding therapeutic armamentarium. Patients receiving these therapies must be carefully monitored by both the primary care physician and the rheumatologist to minimize the risk of side effects and identify quickly any complications of chronic immunosuppression. Also, prevention and treatment of RA-associated conditionssuchasischemicheartdiseaseandosteoporosiswilllikelybenefit from a team approach owing to the value of multidisciplinary care.


InternalMed_Harrison

InternalMed_Harrison. Research will continue to search for new therapies with superior efficacyandsafetyprofiles and investigatetreatmentstrategiesthatcan bring the disease under control more rapidly and nearer to remission. However, prevention and cure of RA will likely require new breakthroughs in our understanding of disease pathogenesis. These insights may come from genetic studies illuminating critical pathways in the mechanisms of joint inflammation. Equally ambitious is the lofty goal of biomarker discovery that will open the door to personalized medicine for the care of patients with RA. Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A streptococcus. Although many parts of the body may be affected, almost all of the manifestations resolve completely. The major exception is cardiac valvular damage (rheumatic heart disease [RHD]), which may persist after the other features have disappeared.


InternalMed_Harrison

InternalMed_Harrison. ARF and RHD are diseases of poverty. They were common in all countries until the early twentieth century, when their inci dence began to decline in industrialized nations. This decline was largely attributable to improved living conditions—particularly less crowded housing and better hygiene—which resulted in reduced transmission of group A streptococci. The introduction of antibiotics and improved systems of medical care had a supplemental effect.


InternalMed_Harrison

InternalMed_Harrison. The virtual disappearance of ARF and reduction in the incidence of RHDin industrialized countries during thetwentieth centuryunfortunately was not replicated in developing countries, where these diseases continue unabated. RHD is the mostcommon cause of heartdisease in children in developing countries and is a major cause of mortality and morbidity in adults as well. It has been estimated that between 15 and 19 million people worldwide are affected by RHD, with approximately one-quarter of a million deaths occurring each year. Some 95% of ARF cases and RHD deaths now occur in developing countries, with particularly high rates in sub-Saharan Africa, Pacific nations, Australasia, and South and Central Asia. The pathogenetic pathway from exposure to group A streptococcus followed by pharyngeal infection and subsequent development of ARF, ARF recurrences, and development of RHD and its complications is associated with a range of risk factors and, therefore, potential interventions at each


InternalMed_Harrison

InternalMed_Harrison. infection and subsequent development of ARF, ARF recurrences, and development of RHD and its complications is associated with a range of risk factors and, therefore, potential interventions at each point (Fig. 381-1). In affluent countries, many of these risk factors are well controlled, and where needed, interventions are in place. Unfortunately, the greatest burden of disease is found in developing countries, most of which do not have the resources, capacity, and/or interestto tacklethis multifaceted disease. In particular, almost none of the developing countries has a coordinated, register-based RHD control program, which is proven to be cost effective in reducing the burden of RHD. Enhancing awareness of RHD and mobilizing resources for its control in developing countries are issues requiring international attention.


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InternalMed_Harrison. ARF is mainly a disease of children age 5–14 years. Initial episodes become less common in older adolescents and young adults and are rare in persons age >30 years. By contrast, recurrent episodes of ARF remain relatively common in adolescents and young adults. This pattern contrasts with the prevalence of RHD, which peaks between 25 and40years.ThereisnocleargenderassociationforARF,butRHD more commonly affects females, sometimes up to twice as frequently as males. Based on currently available evidence, ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci (Chap. 173). Although classically, certain M-serotypes (particularly types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29) were associated with ARF, in high-incidence regions, it is now thought that any strain of group A streptococcus has the potential to cause ARF. The potential role of skin infection and of groups C and G streptococci is currently being investigated.


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InternalMed_Harrison. Exposure to Group A streptococcal *Role of streptococcal skin infection unclear FIGUrE 381-1 Pathogenetic pathway for acute rheumatic fever and rheumatic heart disease, with associated risk factors and opportunities for intervention at each step. Interventions in parentheses are either unproven or currently unavailable.


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InternalMed_Harrison. Approximately 3–6% of any population may be susceptible to ARF, and this proportion does not vary dramatically between populations. Findings of familial clustering of cases and concordance in mono-zygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic, with 44% concordance in mono-zygotic twins compared to 12% in dizygotic twins, and heritability more recently estimated at 60%. Most evidence for host factors focuses on immunologic determinants. Some human leukocyte antigen (HLA) class II alleles, particularly HLA-DR7 and HLA-DR4, appear to be associated with susceptibility, whereas other class II alleles have been associated with protection (HLA-DR5, HLA-DR6, HLA-DR51, HLA-DR52, and HLA-DQ). Associations have also been described with polymorphisms at the tumor necrosis factor α locus (TNF-α-308 and TNF-α-238), high levels of circulating mannose-binding lectin, and Toll-like receptors.


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InternalMed_Harrison. The most widely accepted theory of rheumatic fever pathogenesis is based on the concept of molecular mimicry, whereby an immune response targeted at streptococcal antigens (mainly thought to be on the M protein and the N-acetylglucosamine of group A streptococcal carbohydrate) also recognizes human tissues. In this model, cross-reactive antibodies bind to endothelial cells on the heart valve, leading to activation of the adhesion molecule VCAM-1, with resulting recruitment of activated lymphocytes and lysis of endothelial cells in the presence of complement. The latter leads to release of peptides including laminin, keratin, and tropomyosin, which, in turn, activates cross-reactive T cells that invade the heart, amplifying the damage and causing epitope spreading. An alternative hypothesis proposes that the initial damage is due to streptococcal invasion of epithelial surfaces, with binding of M protein to type IV collagen RHD allowing it to become immunogenic, but not through the


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InternalMed_Harrison. proposes that the initial damage is due to streptococcal invasion of epithelial surfaces, with binding of M protein to type IV collagen RHD allowing it to become immunogenic, but not through the mechanism of molecular mimicry.


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InternalMed_Harrison. There is a latent period of ~3 weeks (1–5 weeks) between the precipitating group A streptococcal infection and the appearance of the clinical features of ARF. The exceptions are chorea and indolent carditis, which may follow prolonged latent periods lasting up to 6 months. Although many patients report a prior sore throat, the preceding group A streptococcal infection is commonly subclinical; in these cases, it can only be confirmed using streptococcal antibody testing. The most common clinical features are polyarthritis (present in 60–75% of cases) and carditis (50–60%). The prevalence of chorea in ARF varies substantially between populations, ranging from <2 to 30%. Erythema marginatum and subcutaneous nodules are now rare, being found in <5% of cases. Up to 60% of patients with ARF progress to RHD. The endocardium, pericardium, or myocardium may be affected. Valvular damage is the hallmark of rheumatic carditis. The mitral valve is almost always


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InternalMed_Harrison. FIGUrE 381-2 Transthoracic echocardiographic image from a 5-year-old boy with chronic rheumatic heart disease. This diastolic image demonstrates leaflet thickening, restriction of the anterior mitral valve leaflet tip and doming of the body of the leaflet toward the inter-ventricular septum. This appearance (marked by the arrowhead) is commonly described as a “hockey stick” or an “elbow” deformity. AV, aortic valve; LA, left atrium; LV, left ventricle; MV, mitral valve; RV, right ventricle. (Courtesy of Dr. Bo Remenyi, Department of Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Auckland, New Zealand.) affected, sometimes together with the aortic valve; isolated aortic valve involvement is rare. Damage to the pulmonary or tricuspid valves is usually secondary to increased pulmonary pressures resulting from left-sided valvular disease. Early valvular damage leads to regurgitation. Over ensuing years, usually as a result of recurrent episodes, leaflet


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InternalMed_Harrison. to increased pulmonary pressures resulting from left-sided valvular disease. Early valvular damage leads to regurgitation. Over ensuing years, usually as a result of recurrent episodes, leaflet thickening, scarring, calcification, and valvular stenosis may develop (Fig. 381-2). See Videos 381-1 and 381-2 on the DVD. Therefore, the characteristic manifestation of carditis in previously unaffected individuals is mitral regurgitation, sometimes accompanied by aortic regurgitation. Myocardial inflammation may affect electrical conduction pathways, leading to P-R interval prolongation (first-degree atrioventricular block or rarely higher level block) and softening of the first heart sound.


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InternalMed_Harrison. People with RHD are often asymptomatic for many years before their valvular disease progresses to cause cardiac failure. Moreover, particularly in resource-poor settings, the diagnosis of ARF is often not made, so children, adolescents, and young adults may have RHD but not know it. These cases can be diagnosed using echocardiography; auscultation is poorly sensitive and specific for RHD diagnosis in asymptomatic patients. Echocardiographic screening of school-aged children in populations with high rates of RHD is becoming more widespread and has been facilitated by improving technologies in portable echocardiography and the availability of consensus guidelines for the diagnosis of RHD on echocardiography (Table 381-1). Although a diagnosis of definite RHD on screening echocardiography should lead to commencement of secondary prophylaxis, the clinical significance of borderline RHD has yet to be determined.


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InternalMed_Harrison. The most common form of joint involvement in ARF is arthritis, i.e., objective evidence of inflammation, with hot, swollen, red, and/or tender joints, and involvement of more than one joint (i.e., polyarthritis). Polyarthritis is typically migratory, moving from one joint to another over a period of hours. ARF almost always affects the large joints— most commonly the knees, ankles, hips, and elbows—and is asymmetric. The pain is severe and usually disabling until anti-inflammatory medication is commenced. Definite RHD (either A, B, C, or D): Pathologic MR and at least two morphologic features of RHD of the mitral valve MS mean gradient ≥4 mmHg (note: congenital MV anomalies must be excluded) Pathologic AR and at least two morphologic features of RHD of the AV (note: bicuspid AV and dilated aortic root must be excluded) Borderline disease of both the MV and AV Borderline RHD (either A, B, or C): At least two morphologic features of RHD of the MV without pathologic MR or MS


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InternalMed_Harrison. Borderline disease of both the MV and AV Borderline RHD (either A, B, or C): At least two morphologic features of RHD of the MV without pathologic MR or MS Normal Echocardiographic Findings (all of A, B, C, and D): An isolated morphologic feature of RHD of the MV (e.g., valvular thickening), without any associated pathologic stenosis or regurgitation Morphologic feature of RHD of the AV (e.g., valvular thickening), without any associated pathologic stenosis or regurgitation Definitions of Pathologic Regurgitation and Morphologic Features of RHD: Pathologic MR: All of the following: seen in two views; in at least one view, jet length 2 cm; peak velocity ≥3 m/s; pansystolic jet in at least one envelope Pathologic AR: All of the following: seen in two views; in at least one view, jet length ≥1 cm; peak velocity ≥3 m/s; pandiastolic jet in at least one envelope


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InternalMed_Harrison. Pathologic AR: All of the following: seen in two views; in at least one view, jet length ≥1 cm; peak velocity ≥3 m/s; pandiastolic jet in at least one envelope Morphologic features of RHD in MV: anterior MV leaflet thickening ≥3 mm (age specific); chordal thickening; restricted leaflet motion; excessive leaflet tip motion during systole Morphologic features of RHD in AV: irregular or focal thickening; coaptation defect; restricted leaflet motion; prolapse aFor criteria in individuals >20 years of age, see source document. Abbreviations: AR, aortic regurgitation; AV, aortic valve; MR, mitral regurgitation; MS, mitral stenosis; MV, mitral valve. Source: Adapted from Remenyi B et al: World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease-an evidence-based guideline. Nat Rev Cardiol 9:297–309, 2012.


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InternalMed_Harrison. Source: Adapted from Remenyi B et al: World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease-an evidence-based guideline. Nat Rev Cardiol 9:297–309, 2012. Less severe joint involvement is also relatively common and has been recognized as a potential major manifestation in high-risk populations in diagnostic guidelines from Australia, but at the time of writing, this was not reflected in the Jones criteria. Arthralgia without objective joint inflammation usually affects large joints in the same migratory pattern as polyarthritis. In some populations, aseptic monoarthritis may be a presenting feature of ARF, which may, in turn, result from early commencement of anti-inflammatory medication before the typical migratory pattern is established.


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InternalMed_Harrison. The joint manifestations of ARF are highly responsive to salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs). Indeed, joint involvement that persists for more than 1 or 2 days after starting salicylates is unlikely to be due to ARF.


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InternalMed_Harrison. Sydenham’s chorea commonly occurs in the absence of other manifestations, follows a prolonged latent period after group A streptococcal infection, and is found mainly in females. The choreiform movements affect particularly the head (causing characteristic darting movements of the tongue) and the upper limbs (Chap. 448). They may be generalized or restrictedtoonesideofthebody(hemi-chorea).Inmildcases,choreamay be evident only on careful examination, whereas in the most severe cases, the affected individuals are unable to perform activities of daily living. Thereisoftenassociatedemotionallabilityorobsessive-compulsivetraits, 2152 which may last longer than the choreiform movements (which usually resolve within 6 weeks but sometimes may take up to 6 months).


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InternalMed_Harrison. The classic rash of ARF is erythema marginatum (Chap. 24), which begins as pink macules that clear centrally, leaving a serpiginous, spreading edge. The rash is evanescent, appearing and disappearing before the examiner’s eyes. It occurs usually on the trunk, sometimes on the limbs, but almost never on the face. Subcutaneous nodules occur as painless, small (0.5–2 cm), mobile lumps beneath the skin overlying bony prominences, particularly of the hands, feet, elbows, occiput, and occasionally the vertebrae. They are a delayed manifestation, appearing 2–3 weeks after the onset of disease, last for just a few days up to 3 weeks, and are commonly associated with carditis. Fever occurs in most cases of ARF, although rarely in cases of pure chorea. Although high-grade fever (≥39°C) is the rule, lower grade temperature elevations are not uncommon. Elevated acute-phase reactants are also present in most cases.


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InternalMed_Harrison. With the exception of chorea and low-grade carditis, both of which may become manifest many months later, evidence of a preceding group A streptococcal infection is essential in making the diagnosis of ARF. Because most cases do not have a positive throat swab culture or rapidantigen test,serologicevidenceisusuallyneeded. Themost common serologic tests are the anti-streptolysin O (ASO) and anti-DNase B (ADB) titers. Where possible, age-specific reference ranges should be determined in a local population of healthy people without a recent group A streptococcal infection.


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InternalMed_Harrison. Because there is no definitive test, the diagnosis of ARF relies on the presence of a combination of typical clinical features together with evidence of the precipitating group A streptococcal infection, and the exclusion of otherdiagnoses. ThisuncertaintyledDr. T. DuckettJones in 1944 to develop a set of criteria (subsequently known as the Jones criteria)toaidinthediagnosis.Atthetimeofwriting,theJonescriteria were undergoing revision but had not yet been released. The existing diagnostic guideline is a World Health Organization update of the 1992JonesCriteria (Table 381-2),thoughitshouldbenotedthatother guidelines, including those from Australia and New Zealand, suggest more sensitive criteria for making the diagnosis in patients from settings or populations at high risk of ARF.


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InternalMed_Harrison. Patients with possible ARF should be followed closely to ensure that the diagnosis is confirmed, treatment of heart failure and other symptoms is undertaken, and preventive measures including commencement of secondary prophylaxis, inclusion on an ARF registry, and health education are commenced. Echocardiography should be performed on all possible cases to aid in making the diagnosis and to determine the severity at baseline of any carditis. Other tests that should be performed are listed in Table 381-3. There is no treatment for ARF that has been proven to alter the likelihood of developing, or the severity of, RHD. With the exception of treatment of heart failure, which may be life-saving in cases of severe carditis, the treatment of ARF is symptomatic.


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InternalMed_Harrison. All patients with ARF should receive antibiotics sufficient to treat the precipitating group A streptococcal infection (Chap. 173). Penicillin is the drug of choice and can be given orally (as phenoxymethyl penicillin, 500 mg [250 mg for children ≤27 kg] PO twice daily, or amoxicillin, 50 mg/kg [maximum, 1 g] daily, for 10 days) or as a 2002–2003 WOrlD health OrganIzatIOn CrIterIa fOr the DIagnOSIS Of rheuMatIC feVer anD rheuMatIC heart DISeaSe (BaSeD On the 1992 reVISeD jOneS CrIterIa) Primary episode of rheumatic fevera Two major or one major and two Recurrent attack of rheumatic fever in Two major or one major and two matic heart disease of preceding group A streptococcal Recurrent attack of rheumatic fever in Two minor manifestations plus evia patient with established rheumatic dence of preceding group A streptoheart diseaseb coccal infectionc Rheumatic chorea Other major manifestations or evidence of group A streptococcal


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InternalMed_Harrison. Rheumatic chorea Other major manifestations or evidence of group A streptococcal Chronic valve lesions of rheumatic Do not require any other criteria to heart disease (patients presenting for be diagnosed as having rheumatic the first time with pure mitral steno-heart disease sis or mixed mitral valve disease and/ or aortic valve disease)d Minor manifestations Clinical: fever, polyarthralgia Laboratory: elevated erythrocyte sedimentation rate or leukocyte counte Electrocardiogram: prolonged P-R interval Supporting evidence of a preceding Elevated or rising anti-streptolysin streptococcal infection within the last O or other streptococcal antibody, or 45 days A positive throat culture, or


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InternalMed_Harrison. Rapid antigen test for group A streptococcus, or aPatients may present with polyarthritis (or with only polyarthralgia or monoarthritis) and with several (three or more) other minor manifestations, together with evidence of recent group A streptococcal infection. Some of these cases may later turn out to be rheumatic fever. It is prudent to consider them as cases of “probable rheumatic fever” (once other diagnoses are excluded) and advise regular secondary prophylaxis. Such patients require close follow-up and regular examination of the heart. This cautious approach is particularly suitable for patients in vulnerable age groups in high-incidence settings. bInfective endocarditis should be excluded. cSome patients with recurrent attacks may not fulfill these criteria. dCongenital heart disease should be excluded. e1992 Revised Jones criteria do not include elevated leukocyte count as a laboratory minor manifestation (but do include elevated C-reactive protein), and do not include


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InternalMed_Harrison. disease should be excluded. e1992 Revised Jones criteria do not include elevated leukocyte count as a laboratory minor manifestation (but do include elevated C-reactive protein), and do not include recent scarlet fever as supporting evidence of a recent streptococcal infection.


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InternalMed_Harrison. Source: Reprinted with permission from WHO Expert Consultation on Rheumatic Fever and Rheumatic Heart Disease (2001: Geneva, Switzerland): Rheumatic Fever and Rheumatic Heart Disease: Report of a WHO Expert Consultation (WHO Tech Rep Ser, 923). Geneva, World Health Organization, 2004. single dose of 1.2 million units (600,000 units for children ≤27 kg) IM benzathine penicillin G. These may be used for the treatment of arthritis, arthralgia, and fever, once the diagnosis is confirmed. They are of no proven value in the treatment of carditis or chorea. Aspirin is the drug of choice, delivered at a dose of 50–60 mg/kg per day, up to a maximum of 80–100 mg/kg per day (4–8 g/d in adults) in four to five divided doses. At higher doses, the patient should be monitored for symptoms of salicylate toxicity such as nausea, vomiting, or tinnitus; if symptoms appear, lower doses should be used. When the acute


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InternalMed_Harrison. White blood cell count Erythrocyte sedimentation rate C-reactive protein Blood cultures if febrile Electrocardiogram (if prolonged P-R interval or other rhythm abnormality, repeat in 2 weeks and again at 2 months if still abnormal) Chest x-ray if clinical or echocardiographic evidence of carditis Echocardiogram (consider repeating after 1 month if negative) Throat swab (preferably before giving antibiotics)—culture for group A streptococcus Antistreptococcal serology: both anti-streptolysin O and anti-DNase B titers, if available (repeat 10–14 days later if first test not confirmatory) Tests for Alternative Diagnoses, Depending on Clinical Features Copper, ceruloplasmin, antinuclear antibody, drug screen for choreiform movements Serology and autoimmune markers for arboviral, autoimmune, or reactive arthritis Source: Reprinted with permission from Menzies School of Health Research.


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InternalMed_Harrison. Serology and autoimmune markers for arboviral, autoimmune, or reactive arthritis Source: Reprinted with permission from Menzies School of Health Research. symptoms are substantially resolved, usually within the first 2 weeks, patients on higher doses can have the dose reduced to 50–60 mg/kg per day for a further 2–4 weeks. Fever, joint manifestations, and elevated acute-phase reactants sometimes recur up to 3 weeks after the medication is discontinued. This does not indicate a recurrence and can be managed by recommencing salicylates for a brief period. Naproxen at a dose of 10–20 mg/kg per day is a suitable alternative to aspirin and has the advantage of twice-daily dosing.


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InternalMed_Harrison. CONGESTIVE HEarT FaILUrE Glucocorticoids The use of glucocorticoids in ARF remains controversial. Two meta-analyses have failed to demonstrate a benefit of glucocorticoids compared to placebo or salicylates in improving the shortor longer term outcome of carditis. However, the studies included in these meta-analyses all took place >40 years ago and did not use medications in common usage today. Many clinicians treat cases of severe carditis (causing heart failure) with glucocorticoids in the belief that they may reduce the acute inflammation and result in more rapid resolution of failure. However, the potential benefits of this treatment should be balanced against the possible adverse effects. If used, prednisone or prednisolone is recommended at a dose of 1–2 mg/kg per day (maximum, 80 mg), usually for a few days or up to a maximum of 3 weeks. See Chap. 280.


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InternalMed_Harrison. See Chap. 280. Traditional recommendations for long-term bed rest, once the cornerstone of management, are no longer widely practiced. Instead, bed rest should be prescribed as needed while arthritis and arthralgia are present and for patients with heart failure. Once symptoms are well controlled, gradual mobilization can commence as tolerated.


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InternalMed_Harrison. Medications to control the abnormal movements do not alter the duration or outcome of chorea. Milder cases can usually be managed by providing a calm environment. In patients with severe chorea, carbamazepine or sodium valproate is preferred to haloperidol. A response may not be seen for 1–2 weeks, and medication should be continued for 1–2 weeks after symptoms subside. There is recent evidence that corticosteroids are effective and lead to more rapid 2153 symptom reduction in chorea. They should be considered in severe or refractory cases. Prednisone or prednisolone may be commenced at 0.5 mg/kg daily, with weaning as early as possible, preferably after 1 week if symptoms are reduced, although slower weaning or temporary dose escalation may be required if symptoms worsen.


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InternalMed_Harrison. Small studies have suggested that IVIg may lead to more rapid resolution of chorea but have shown no benefit on the shortor long-term outcome of carditis in ARF without chorea. In the absence of better data, IVIg is not recommended except in cases of severe chorea refractory to other treatments. Untreated, ARF lasts on average 12 weeks. With treatment, patients are usually discharged from hospital within 1–2 weeks. Inflammatory markers should be monitored every 1–2 weeks until they have normalized (usually within 4–6 weeks), and an echocardiogram should be performed after 1 month to determine if there has been progression of carditis. Cases with more severe carditis need close clinical and echocardiographic monitoring in the longer term.