Genetic factors

RA is a complex and thus polygenic disease. The heritability of RA has been estimated to be about 60–65% (28). Genetic factors including class II human leukocyte antigens (HLA-II) (29) as well as non-HLA genes have been implicated in the pathogenesis of RA and its outcome (30). Certain gene profiles or signatures have also been associated with response or nonresponse to therapy (31,32). Recent genome-wide association studies (GWAS) have enabled the simultaneous assessment of thousands of genes leading to more consequent results of genetic associations (33) (Table 2).

Table 2

The most relevant susceptibility alleles in RA according to GWAS studies and related population.

HLA-genes. In 1969, researchers noticed that peripheral blood lymphocytes from patients with RA were nonreactive in so-called mixed lymphocyte cultures to cells of the same type from other patients with RA (34). Peter Stastny (29,35) first found the association between the so-called B cell alloantigen DRw4, now known as HLA-DR4, and RA. According to the current nomenclature, HLA-DRB1*04 denominates the allele group corresponding roughly to the archaic serotypical classification DR4, while the next appending digit set defines a specific allele (e.g.,HLA-DRB1*0404) (36). A decade after Stastny’s discoveries, further characterization of the HLA locus identified multiple RA risk alleles within HLA-DRB1. Gregersen et al. (37) showed that molecules encoded by RA associated HLA-DRB1 alleles share a common amino acid (a.a) sequence, comprising residues 70–74 in the third hypervariable of the DRβ1 chain. This finding led to the ‘shared epitope’ (SE) hypothesis. HLA molecules that contain this 5 a.a sequence (i.e., QKRAA, QQRAA, and KKRAA), which is encoded by SE alleles and is arranged around the antigen-binding groove, are associated with the development of anti-citrullinated protein antibodies (ACPA), and, mostly, with ACPA-positive RA (38). SE alleles (HLA-DRB1*01, DRB1*04, DRB1*10) exert the strongest association with disease susceptibility, accounting for about 30% of the total genetic component (39). Thus, SE alleles HLA-DRB1*1001 can accommodate citrulline in their antigen-anchoring pockets and thus stimulate citrullinated protein-specific T cell responses, especially in smoking patients (40). Further investigations have established more RA-associated alleles, mainly HLA-DRB1*0401, *0404, and *0408 in Caucasians; HLA-DRB1*0405 in Spaniards, Japanese, and Jews; HLA-DRB1*0101/2 in Israelis; HLA-DRB1*1402 in some Native Americans; and HLA-DRB1*1001 in Greeks (41). In Latin Americans, RA is associated with SE and DR4 positive HLA-DRB1 alleles, mainly HLA-DRB1*0404 (42). HLA associations with RA were initially related to ACPA-positive patients; however, new perspectives about the SE have recently been raised by Viatte et al. (36) and Mackie et al.(41) including new associations between HLA and ACPA-negative RA. Vignal et al. (43) showed two non-SE alleles strongly associated with RA: HLA-DRB1*0301 with ACPA-negative RA and HLA-DRB1*0701, the latter regardless of autoantibody status.

A new classification system for the SE has been proposed and validated by French researches (44). Briefly, the susceptibility risk represented by the RAA motif is modulated by a.a at positions 70–71. Thus, at position 71, lysine (K) confers the highest risk, arginine (R) an intermediate risk while alanine (A) and glutamic acid (E) confer a lower risk. At position 70, glutamine (Q) and R represent a higher risk than aspartic acid (D). Based on the type of a.a at positions 70–71, the new classification system divides SE alleles into S1, S2, S3P, and S3D groups and denotes all non-RAA motifs as X. A positive association with RA was found for S2 and S3P allele carriers, while S1, S3D, and X are low risk alleles, which are pooled together as L alleles (44). The presence of S2 or S3P alleles has been correlated with ACPA production, whereas the presence of S3D and S1 alleles appeared to be protective. Stahl et al. (45) demonstrated that the risk of RA associated with the HLA-DRB1 gene correlates most strongly with the a.a residue in position 11, located at the bottom of the DRβ1 antigen-binding groove. Viatte et al. (36) found independent RA risk alleles in HLA B and HLA-DPB1. In both cases, signals from these regions were best explained by a variation in a single a.a site at the bottom of their respective antigen-binding grooves. That is, these genetic variants in HLA B, HLA-DRB1, and HLA-DPB1, affecting a total of 5 a.a positions, almost completely explained the variance in RA risk caused by the HLA region (46,47). DRB1*1301, *1302, *1304, *0103, and *0402 alleles carry the DERAA motif, which is rather responsible for protective effects (20,47,48). A large European meta-analysis in 2010 confirmed HLA-DRB1*1301 as a protective allele for RA (44). For further details about HLA, see Chapters 10 and 17.

Non-HLA susceptibility genes. In addition to HLA-DR alleles, several association studies have confirmed the role of non-HLA genes in susceptibility to RA (Table 2). Begovich et al. (49) identified a non-synonymous SNP in the protein tyrosine phosphatase, non receptor type 22 gene (PTPN22), which codes for lymphoid tyrosine phosphatase (Lyp), a downregulator of T cell receptor (TCR) signaling. The PTPN22 C1885T polymorphism leads to an a.a change from arginine (arg) to tryptophan (Trp) at a.a position 620. This variant remains one of the most strongly RA associated SNP identified to date, right after HLA-DRB1, with an odds ratio (OR) of 1.8 for ACPA-positive RA. This SNP has been associated by many groups with ACPA and rheumatoid factor (RF) positive RA and probably worse prognosis. The presence of PTPN22 C1885T polymorphism, in addition to SE and ACPA status, strongly supports the early diagnosis of RA. In contrast to SE, PTPN22 may not be closely associated with smoking (50,51).

Suzuki et al. (52) described a SNP in the third intron of the peptidyl arginine deiminase type 4 enzime (PADI4) gene, responsible for increasing the stability of PADI4 mRNA transcripts and associated with ACPA-positivity in patients with RA. This enzyme mediates the citrullination of proteins (i.e., conversion of arginine residues to citrulline). Citrullinated peptides bind with higher affinity to HLA-DRB1 SE molecules, are naturally processed and, importantly, are immunogenic. Thus, it seems that increased translation of PADI4 mRNA variant boosts production of citrullinated peptides, which act as autoantigens and elicit profound adaptive immune responses (53). Whereas many other risk loci seem to be connected to several ADs, the PADI4 locus seems to be specific to RA (36). However, the association between PADI4 and RA is mostly observed in Asian cohorts (52,54).

On the basis of recent GWAS data, the tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) in the TRAF1-C5 region may be the third most strongly RA associated locus (55). This region has also been associated primarily with ACPA positive RA. TRAF1 is an adaptor protein that links TNF family members, such as TNF-α, to downstream signaling networks. TRAF1 has been implicated in cell growth, proliferation, apoptosis, and in the overall pathogenesis of RA. TRAF1 has been related to increased radiological progression; however, TRAF1-C5 may not be associated with RA mortality (55,56).

The association of RA with the signal transducer and activator of transcription 4 (STAT4) gene is relatively modest in comparison to the previous genetic factors discussed above. STAT4 exerts a distinct role in the signaling of cytokines, primarily interleukin (IL)-12, through janus kinase-2 (JAK-2) enzymes. Interestingly, different SNP in STAT4 gene may increase susceptibility to both ACPA positive and negative RA (57,58).

Other important and confirmed loci include, Fc gamma receptor IIIA (FCGR) (58,59), CD40 (58,60,61), chemokine receptor 6 (CCR6), CTLA4, IRF5, IL6ST, IL2RA, IL2RB, CCL21 MBL2, IL6R, IL-10, IL-18, TNFRS, and TNFAIP3 (48,62,63). For more details, see Table 2. In summary, several HLA and non-HLA genes have been implicated in susceptibility to or protection against RA. To date, more than 40 genes have been associated with the disease and these genetic factors account for about 50% of the genetic variants linked to RA susceptibility (36,38,58).

Epigenetics

The disparity between the presence of susceptibility genes and the development of a disease such as RA in twins clearly states that carrying susceptibility genes is not enough to acquire the disease. Epigenetics may explain the low rate of concordance of RA between identical twins (see chapters 1 and 22). Using variance modeling, RA heritability is about 60% based on the higher monozygotic twin concordance rates (12–15%) compared to dizygotic twins (2–4%) (28,64). In a cohort of 91 monozygotic twins’ pairs, increased concordance for RA was observed in SE positive pairs (RR: 3.7). In addition, a 5-fold risk for RA concordance was seen in twins who were “homozygous” for the SE as compared with those negative for the SE (65). Familial aggregation (i.e., greater disease occurrence in relatives of probands than in healthy controls) has been consistently observed in RA. It is estimated that familial aggregation of RA ranges between 2% and 17%, depending upon the disease prevalence in the population used as reference (20,28,39). However, aggregation of diverse ADs, also known as familial autoimmunity (FA), has been overlooked in RA patients (66). Analysis of DNA methylation in T cells has revealed global hypomethylation in cells derived from patients with RA compared with those from healthy controls (67). DNA hypomethylation has also been observed in RA fibroblast-like synoviocytes (FLS), as compared with normal FLS. Nakano et al. (68) performed a genome-wide evaluation of FLS derived from patients with RA and osteoarthritis (OA). As many as 1,859 loci, relevant to cell movement, adhesion, and trafficking were differentially methylated in RA (732 hypomethylated and 1,127 hypermethylated) (68). In a gene-targeted approach, Nile et al. (69) investigated DNA methylation patterns in the promoter region of IL-6 in peripheral blood mononuclear cells derived from patients with RA and healthy controls. This study identified a single CpG motif 1,099 base pairs upstream from the IL-6 transcription start site that was less methylated in patients with RA than in controls. Increased expression of microRNA 115133 and microRNA 203134 has been observed in RA FLS compared with OA FLS, and this increase correlates with elevated levels of matrix metalloproteinase 1 (MMP 1) and IL-6. MicroRNA (miRNA) is a small non-coding RNA molecule, which functions in transcriptional and post-transcriptional regulation of gene expression (see chapter 1). It is important to note that the expression of miRNA 115132 and of miRNA 203134 is inversely correlated with levels of DNA methylation (Figure 1).

Age

It has been suggested that YORA might have a poorer prognosis as manifested by more persistent disease activity, more radiographic deterioration, systemic involvement, and a rapid functional decline. Aggressive disease is largely restricted to those patients with high titers of RF (70). Pease et al. (71) found that LORA patients had longer stiffness in the morning. It has also been reported that older patients have more acute onset in both large and small joints and usually present polymyalgia rheumatica-like symptoms (72). These patients can present more constitutional features like weight loss, myalgia, rheumatic nodules, and neuropathy (73). Turkcapar et al. (73) reported that proximal interphalangeal (PIP), metacarpophalangeal (MCP), elbow, metatarsophalangeal (MTP), and ankle joints are more associated with YORA. Classical hand deformities, interstitial lung disease, lung disease, and Sjögren syndrome (SS) are observed more frequently at this group. Rojas-Villarraga et al. (74) found ACPA can be detected at early disease stages and may be used as indicators of RA progression and prognosis, as well as, family history of RA and HLA-DRB1 SE are consistently associated with joint damage. Recently, we showed that YORA is associated with female gender, higher educational level, higher joint involvement, and EAM while LORA is related to environmental exposure, CVD, and higher body mass index (BMI) (75).

Gender

Probably, the striking gender differences in RA patients are due to the effects of sex hormones, fetal microchimerism, and sex chromosomes (76,77). Women have an enhanced antibody production and increased cell mediated responses following immunization while men produce a more intense inflammatory response to infectious organisms. Further, women have higher CD4⁺ T cell counts than men contributing to an increased CD4/CD8 ratio, higher levels of plasma IgM, and greater T helper 1 (Th1) cytokine production (77,78). The predominance of RA in females suggests a role for hormonal imbalances. In fact, the peak age at RA onset is the fifth decade, which coincides with hormonal changes in women (77). Estrogens, androgens, and prolactin, have been the first proposed candidates to have important roles in the sex bias observed in RA, due to their capacity of modulating the immune response via androgen and estrogen receptor. Morning activity of RA is correlated with prolactin plasma levels observed at that time (79) (Figure 1). A history of child-bearing may protect against RA while nulliparity has been suggested as a risk factor for the disease (80). Pregnancy results in changes in disease activity. Signs and symptoms of RA decrease during pregnancy while postpartum may favor disease exacerbation (81). Postpartum worsening may be associated with the return to the Th1 environment (82). After pregnancy, a flare may be induced in RA by breastfeeding through the actions of prolactin (83). However, recent data show that, overall, women who breastfeed their infants have a decreased risk for RA (84). In contrast, women who report a postpartum onset of RA, breastfeeding, especially after the first pregnancy, increased the risk of RA fivefold (85).

Environmental factors

Smoking. Tobacco smoke is a widely known risk factor for RA (86–89) (Figure 1 and 2). Tobacco smoking affects both the innate and adaptive immunity. One of the main mechanisms underlying smoking-evoked autoimmune response in RA is via the production of antibodies recognizing citrullinated proteins (77). Citrullination promotes the transformation from self-antigens to autoantigens (90). The number of copies of the SE that an individual carries can modify the risk of acquiring RA in smokers which suggests a gene environment interaction. Smokers who have two copies of the SE have a 21-fold higher risk of developing RA than non-smokers who do not carry the SE (86). The risk of RA increases with the intensity (i.e., pack per day) and duration of cigarette use. Heavy cigarette smoking has been linked to a substantial increase in the susceptibility to RA. A recent metaanalysis disclosed that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity (91).

Figure 2

Gene-environment interaction: Smoking. Long-term smoking induces a local activation of PADI enzymes, with subsequent citrullination of peptides present in the lungs; later the activation of APC, in response to signals delivered by toxic components in (more...)

Alcohol and coffee consumption. Some studies have found alcohol consumption to be associated with significant reduction in the risk of RA, particularly ACPA-positive (92). The observed inverse association between alcohol intake and the risk of RA, and the demonstration of a preventive effect of alcohol in experimental arthritis, indicate that alcohol could protect against RA (93). On the contrary, coffee consumption has been implicated as a risk factor for seropositive RA in longitudinal data from Finland as has decaffeinated coffee in USA (94), but neither of these associations has been replicated.

Vitamin D. A high vitamin D intake has been associated with a lower risk of RA since vitamin D is an important modulator of the inflammatory response through the vitamin D receptor. Despite its confirmed importance in other ADs such as type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS), its role on the risk of RA is not unanimous (95). The Iowa Women’s Health Study (96) analyzed data from a prospective cohort study of 29,368 women aged 55–69 years. The study found that greater intake of vitamin D might be associated with a lower risk of RA.

Diet and other vitamins. The effect of diet on the risk of RA is controversial. A diet rich in fish, olive oil, and cooked vegetables has been shown to protect against RA due to the high content of omega 3 fatty acids (i.e., Mediterranean diet) (77,97). Vitamin C was associated with a reduced risk of inflammatory polyarthritis, suggesting that antioxidants may protect against RA development (98). There is also some evidence suggesting that copper and selenium deficiency are linked to RA.

Others. Silica dust, mineral oils, and other airborne exposures have been included as potential risk factors for RA (77). Air pollution has been associated with increased risk of RA. Populations living near roads of high traffic density show an increased risk of the disease. As with cigarette smoke, inhaled particulate matter may induce both local lung inflammation and systemic inflammation. Indirect support for this hypothesis comes from the established link between air pollution and inflammation. Organic solvents have been shown to increase the risk of ADs (99).

Infectious agents. Several microbial agents have been associated with risk of developing RA (Figure 1), including parvovirus B19, Epstein-Barr virus (EBV), retroviruses, M. tuberculosis, E. coli, P. mirabilis, and mycoplasmas. The evidence for the participation of microorganisms in the induction of RA include the presence of increased serum levels of antibodies against microbial epitopes, a greater number of cells carrying the genome of some of these viruses and the demonstration, by polymerase chain reaction technique, of bacterial or viral genes in the rheumatoid synovium. It is possible that in many cases these agents act triggering the disease, or helping to perpetuate the disease. The most accepted mechanism is the molecular mimicry (100). Mimicry is also possible respect to shared conformational epitopes (see chapter 19). Whether the SE is itself presented as an antigenic peptide to allow molecular mimicry is far from clear. It is much more likely that it governs the antigenic peptides that are presented to the immune system (100). Several studies have shown both P. mirabilis infection (mostly urinary) and antibody titers against these bacteria are higher in RA patients than in healthy controls. In addition, the association with RA and the immune response against the bacteria has been demonstrated at the molecular level (101), mainly as a consequence of the similarity between its α-hemolysin, urease, and self-epitopes. Bioinfomatic analysis has shown that SE (“EQ/KRRAA”) has high structural similarity with a linear peptide from the bacterial hemolysin (“ESRRAL”). Besides, there was also found a molecular similarity between the peptide “IRRET” found in the type XI collagen and a peptide from the bacterial urease (“LRREI”) (102).

Patients with periodontal disease (PD) seem to have an increased likelihood ratio (LR) of suffering RA (103–105). Conversely, RA patients show increased likelihood of PD, a relationship that could not be attributed simply to inadequate tooth cleaning in RA patients (106,107). ACPA titers have been correlated with PD severity (108). Elevated anti-P. gingivalis antibody titers were associated with higher serum concentrations of C-Reactive protein (CRP) and ACPA (109). There are experimental data suggesting that periodontitis and RA influence each other’s pathogenesis (110–113).

Socioeconomic status (SES): The World health organization (WHO) suggests a number of individual and system factors that can influence and determine health outcomes. Among those, access and use of health-care services and SES are recognized as independent determinants of health, and are particularly relevant for patients living with chronic conditions. Disparities in health resulting from lack of access to care are avoidable and unfair, and can therefore be referred to as inequities (114). SES has been associated with the risk of RA although not uniformly.

Immune response

The innate and the adaptive immune response contribute in a highly interactive form to the pathogenesis of RA. The most likely mechanism for the environmental component is repeated activation of innate immunity. This process can take many years with evidence of autoimmunity increasing gradually until some unknown process tips the balance toward clinically apparent disease. It is possible that the initial inciting event involves the product interaction of a microbial agent, bacterial or viral, with receptors on cells of the innate immunity. When they are activated, these cells invoke the adaptive immune response by providing the second signal of stimulation to the lymphocytes T and B. The discovery of Toll-like receptors (TLRs) and other intracellular receptors from nucleotide-binding oligomerization domain (NOD) group, classified within the pattern-recognition receptors (PRR) [i.e., receptors that recgonize pathogen-associated molecular patterns (PAMPs)], allowed to better understand possibe triggers of early events of the disease.The PRR are present on cells of the innate immune response as DCs, monocytes/macrophage. They are activated upon recognition of PAMPs from viruses or bacteria, and generate a promoter cascade of local inflammation. This inflammatory reaction involves engaging adaptative response cells, mainly T and B lymphocytes, generating antibodies against self-molecules and cellular responses mediated by antigen-specific clones in the joint (116) (Figure 3).

Figure 3

Adaptive and innate immune response: synovial interactions in rheumatoid arthritis. The costimulation-dependent interactions among DCs, T cells, and B cells are shown as occurring primarily in the lymph node. Pivotal cytokine pathways are depicted in (more...)

Adaptive immune response. After onset of clinical disease, the normally hypocellular synovial membrane becomes hyperplastic, comprising a superficial lining layer with a high density of FLS and MΦ, overlying an interstitial zone that contains a marked cellular infiltrate, arranged in the subintimal, as diffuse infiltrates, perivascular localization or in germinal centers (106). The inflamed synovium invades adjacent cartilage and promotes articular destruction, which is mediated by the activities of osteoclasts, chondrocytes, and FLS. The underlying bone marrow also exhibits an inflammatory infiltrate, containing T cell–B cell aggregates, and so the bone probably receives a bidirectional insult (117). Articular damage, in turn, probably generates a rich source of neo-antigens to promote further autoimmune reactivity. In addition, the articular environment is profoundly hypoxic and angiogenesis is a characteristic feature of rheumatoid joints (118). All these cells express cytokines, HLA-II, and co-stimulatory molecules. Cytokines are implicated in each phase of the pathogenesis by promoting autoimmunity (including during the pre-articular phase), by maintaining chronic inflammatory synovitis and by driving the destruction of adjacent joint tissue. Therefore, cytokines integrate the immune-regulatory and tissue-destructive events that underlie the clinical presentation and progression of RA (119) (Figure3).

Innate Immune System. A variety of innate effector cells, including MΦ, mast cells, and NKs are found in the synovial membrane, whereas neutrophils reside mainly in synovial fluid (Figure 3). Macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), and granulocyte–macrophage colony stimulating factor (GM-CSF) enhance maturation of these cells, their efflux from the bone marrow, and transfer to the synovium (120). In particular, MΦ are central effectors of synovitis (121) and act through release of cytokines (e.g., TNF-α,IL-1,6,12,15,18,23), reactive oxygen intermediates, nitrogen intermediates, production of prostanoids and matrix-degrading enzymes, phagocytosis, and antigen presentation. This pattern of expression of proinflammatory cytokines and inducible nitric oxide synthase suggests a predominant M1 MΦ phenotype. Macrophages are activated by TLRs (i.e., TLR 2/6, 3,4,8), NOD-like receptors (NLRs), cytokines, immunecomplexes, lipoprotein particles, liver X–receptor agonists [i.e., oxysterols, oxidized low density lipoprotein (LDL), serum amyloid A-rich, and high-density lipoprotein (HDL)] (119,122). Moreover, microRNA species (i.e., microRNA-155) have been implicated in the regulation of synovial cytokine expression (123). Neutrophils, mast cells, and NK cells are present in high concentrations during the process. Mesenchimal tissue responses, soluble products, cytokines, complement activation, immune complexes, and additional factors, including nitric oxide, neuropeptides (e.g. substance P), arachidonic acid metabolites, clotting factors and fibrinolysis play a key role in the pathogenesis of RA (106,115,124-126) (Figure 3).

Autoantibodies

Rheumatoid factors are antibodies directed against the Fc portion of IgG. Initially, the RF was described by Waaler and Rose in 1944, and is commonly measured in clinical practice as an IgM-RF; however, other immunoglobulin types, including IgG and IgA, have been identified (127). An abnormal immune response appears to select, via antigenic stimulation, high affinity RF from the host’s natural antibody repertoire. Testing for RF is primarily used for the diagnosis of RA. However, RF may also be present in a number of inflammatory diseases characterized by chronic antigen exposure (e.g., infections and others AD) (128–131) (Table 4). Normal human lymphoid tissue commonly possesses B lymphocytes with RF expression on the cell surface. Nevertheless, RF is not routinely detectable in the circulation in the absence of an antigenic stimulus. Modified IgG could be a stimulus to RF production and could be an important component of RA pathogenesis; this concept is supported by studies that observed an association of RF and more severe RA with autoantibodies to advanced glycated end product damaged IgG or agalactosyl IgG (132,133). In fact, compared to those with seronegative RA, patients with polyarticular symmetrical arthritis who have a persistently positive test for RF are likely to have more erosions of bones and joints, more EAM, and worse function (134). The production of RF results in part from the help provided from a specific subset of T cells to RF precursor B cells. Since T cells reactive with autologous IgG have not been identified in patients with RA, it is likely that these T cells react with antigen(s), and then bind to specific B lymphocytes, which proliferate. Co-stimulation of B cells, perhaps mediated by TLRs, may allow B cells with low affinity receptors for IgG to become activated (134). Another factor that amplifies the inflammatory potential of RF is the propensity for IgG RF to self-associate into large lattice-like complexes. These complexes can be found in all tissues of the rheumatoid joint, and may help concentrate additional material within this structure (e.g., superficial layers of articular cartilage) (135).

Table 4

Presence of rheumatoid factor.

A high correlation for RF has been noted among identical twins with RA, suggesting that genetic factors influence both RF function and disease development. However, some studies have shown that patients with RF-negative RA have HLA susceptibility alleles similar to those in RF-positive patients. Furthermore, there may be a similar immunogenetic predisposition to RA in these patients that is independent of RF (131). The reported incidence may be higher in older subjects without rheumatic disease, ranging from 3–25%. Part of this wide range may be explained by a higher incidence of RF among chronically ill older adults as compared with healthy older patients (5–25%) (136,137). Population-based studies have shown that some healthy people with a positive RF develop RA over time, especially if more than one isotype is persistently elevated and if the level of RF is high (138). In fact, Nielsen et al. (139), demonstrated that individuals in the general population with elevated RF have up to 26-fold greater long term risk of RA, and and up to 32% 10 year absolute risk of RA.

Estimates of the sensitivity and specificity of RF vary depending upon the populations being examined, and this will also affect the calculated predictive value (130,131) (Table 5). This difference may reflect classification criteria that led published series of patients with RA to be biased toward more severe (and more seropositive) disease, thereby overestimating the sensitivity of RF in RA. The specificity depends substantially upon the choice of the control group (130,137,140). The specificity with respect to disease control populations is substantially lower, especially if the disease control populations include patients with rheumatic and other diseases associated with RF (131) (Table5).

Table 5

Sensitivity and Specificity of autoantibodies.

As with any diagnostic test, the predictive value is also affected by the estimated LR of disease prior to ordering the test and by the proportion of patients with a non-rheumatic disorder associated with RF production. The positive predictive value of RF was 24% for RA and 34% for any rheumatic disease. The calculated negative predictive value of the RF tends to be high in a population with a low pre-test probability of RA. However, a negative RF in this setting may not be particularly useful clinically. The negative predictive values for RA and for any rheumatic disease were 85% and 89% respectively (141). The titer of RF should be considered when analyzing its utility. The higher the titer, the greater is the LR that the patient has a rheumatic disease. There are, however, frequent exceptions to this rule, as noted above. Some have suggested that erosive disease may be accurately predicted by analyzing the combination of HLA-DRB1 and RF status among patients with RA (47). However, these tests are of limited value in an individual patient as almost one-half of “high risk” patients had no erosions at one year.

The presence of RF can be detected by a variety of techniques. These include agglutination of IgG-sensitized sheep red cells or of bentonite or latex particles coated with human IgG, radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and nephelometry (142,143). Measurement of RF is not standardized in many laboratories (leading to problems with inconsistent results). Although no one technique has clear advantage over others, automated methods such as nephelometry and ELISA, tend to be more reproducible than manual methods.

Anti-citrullinated peptide/protein antibodies (ACPA). These include anti-cyclic citrullinated peptides (ant-CCP) which are present in both RF positive and negative RA (144). ACPAs are present in the earliest stages of disease in almost 70% of patients (145). The optimal clinical use of ACPA testing and its relationship to RF testing remain uncertain (146,147). Although ACPA and RF have similar sensitivity for the diagnosis of RA, ACPA is a more specific marker (148) (Table 5). Of note, the 2010 revised classification criteria for RA include both RF and ACPA (149). The immunoreactivity of citrullinated fibrin with IgA and IgM in the RA synovium, and the colocalization of PADI and citrullinated peptides, support the notion that arginine residues on fibrin and fibrinogen may be citrullinated and become potential autoantigens of RA (147,150–152). Intracellular citrullinated proteins colocalized with the deimidase in most of RA synovial samples (153).

The RA-associated HLA-DRB1*0404 allele is also associated with production of antibodies to citrullinated fibrinogen, and T cell proliferation in response to fibrinogen peptides is frequent in RA patients but rare in controls (154). In contrast, in another study the SE was associated with antibodies to a citrullinated peptide derived from vimentin but not to a fibrinogen-derived citrullinated peptide (155,156). Comparisons of the SE frequencies on HLA-DRB1 alleles in healthy populations with RA patients who do or do not harbor ACPA have shown that the SE is associated only with ACPA-positive disease and not with ACPA-negative disease. This indicates that the HLA-DRB1 alleles encoding the SE do not associate with RA as such, but rather with a particular phenotype, disease with ACPA (157).

A strong association between cigarette smoking, a known risk factor for RA, and the presence HLA-DBR1*0404, as mentioned above exists (158,159). In case-control study, Klareskog et al. (158) demonstrated that the RR of developing RA was increased 20-fold in those who had two alleles for the SE, had ever smoked cigarettes, and were anti-CCP.

Gene-environment interaction (e.g., smoking), and its role in the citrullination process (158,159) (Figure 2). The lack of an association between smoking and risk of RA in those who are ACPA-negative, suggests that these disease subsets (i.e., ACPA-positive vs. ACPA-negative) differ in their pathogenesis. However, a large collaborative study that included 2,476 Caucasian RA patients from North America confirmed a strong association between the presence of ACPA and the SE, but found only a weak association between ACPA formation and smoking (160). On the other hand, Verpoort et al. (161) in a study of 216 patients demonstrated a strong association between ACPA and tobacco exposure, irrespective of the presence of the SE. A second system of antibodies against proteins modified by carbamylation rather than citrullination has been described in ACPA-negative patients with RA (162).

Anti-mutated citrullinated vimentin (MCV) antibodies. Anti MCV recognize a naturally occurring isoform of citrullinated vimentin, which can be found in patients with RA and in which arginine residues are replaced by glycine (163,164). Vimentin is a widely expressed intermediate filament. It becomes citrullinated through deamination, which occurs in MΦ undergoing apoptosis. The diagnostic and prognostic value of anti-MCV antibodies in RA was analyzed in a 2010 systematic review of 14 studies, most of which used a commercially available assay. Findings disclosed a similar performance than anti-CCP antibody testing (165). A subsequent report evaluated a longitudinal cohort of 238 patients with RA over 10 years and found that anti-MCV predicted joint damage damage similar to anti-CCP (166). The OR for radiographic progression was increased in the presence of either anti-MCV or anti-CCP. Similar observations were previously made in this cohort with anti-CCP antibodies. In patients with undiagnosed early inflammatory arthritis or established RA, the diagnostic and prognostic value of adding anti-MCV antibody testing to anti-CCP and RF testing, or substituting anti-MCV for other tests, remains uncertain (167).

Other autoantibodies such as anti-galactose IgGs (168,169), and antibodies to glucose-6-phosphateisomerase may be associated with more active disease and correlate with EAMs (170–172)

Neoangiogenesis

One of the earliest histopathologic responses in RA is the generation of new synovial blood vessels, which covers the increased metabolic demands of the proliferating cells that form the pannus (173). This event is accompanied by the transudation of fluid and the transmigration of both lymphocytes into the synovium and of neutrophils into the synovial fluid. In the mature RA synovium, the mass of tissue is too much for even the multiple new capillaries to nourish, and local tissue ischemia is the result (106) (Figure 3). Relative synovial hypoxia is associated with an increased production of hypoxia-inducible factor-1 (HIF-1) that activates transcription of genes that are of fundamental importance for angiogenesis (e.g., VEGF) (174). Without new blood vessels, there would be no scaffold upon which synovitis could grow. RA can therefore be considered an “angiogenesis-dependent disease” (175). RA patients show an imbalance between pro-angiogenic factors and antiangiogenic factors in favor of the first.

Cell migration. As the new vessels develop, cytokines produced in the synovium in response to the driving force of TNF (including IL-1, IL-6, IFN-γ, and substance P) activate endothelial cells to produce adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and E-selectin (176). A positive correlation can be made between the expression of adhesion molecules on endothelial cells and the appearance of these cells on histologic sections. Both vascular proliferation and high endothelial venules are found in rheumatoid joints with proliferating, invasive synovitis, but not in clinically uninvolved joints. Although much attention has been focused on the presence of lymphocytes in the synovium, similar lymphoid accumulation also occurs in the juxta-articular bone marrow (106). Targeting chemokines has been attempted in RA, including anti-chemokine antibodies or chemokine receptor antagonists, but few have been successful. This is most likely due to the redundant nature of the chemokine system, which makes it difficult to block cell recruitment. In one phase II trial, an anti-CXCL10 antibody demonstrated efficacy when used in combination with methotrexate (MTX) (177).

The pannus

The normal synovial membrane consists of two main layers: the inner layer or coating, formed by two cell types of distinct lineages, MΦ or type A synoviocytes, fibroblasts or type B synoviocytes, and subintima layer (1). A feature of RA is the enormous growth of the synovial membrane, which becomes hyperplastic by accumulation of FLS in the inner layer (178). These cells confer to the synovial membrane of RA patients an aggressive behavior at the transition pannus/cartilage by their excessive production of pro-inflammatory cytokines, MMPs and angiogenesis promoting substances. Synovial hyperplasia could also reflect increased influx of mesenchymal cells (179), thus when FLSs are cultured on articular cartilage, MMP-13 (i.e., collagenase-3) is produced by the cells; this may be the mechanism by which the rheumatoid synovial pannus is attracted to and begins invading cartilage at the periphery of inflamed joints (180). The subintimal layer contains the inflammatory aggregates arranged in diffuse form, creating granulomas in some parts or organized in germinal centers in others and gives the rheumatoid synovial the appearance of a secondary lymphoid organ. This layer is the seat of chronic inflammatory component, responsible for intimal hyperplasia due to the effect of cytokine-enriched environment on synoviocytes (106,119). No one knows what causes this phenotypic transformation of synovial fibroblasts; some studies suggest mutations of the antiproliferative protein p53 (178). In this front it is concentrated an increased number of substances with lytic ability of the components of the cartilage extracellular matrix, predominantly MMPs (119).

Structural damage: Erosive disease

Cartilage degradation: Articular cartilage is composed of a non-mineralized surface layer and a deep mineralized layer adjacent to bone. Only the resorption of the mineralized layer is osteoclast mediated. Both layers contain chondrocytes, which determine cartilage metabolism. A hyperplastic synovium is the major contributor to cartilage damage in RA. Loss of the normally protective effects of synovium alter, the protein-binding characteristics of the cartilage surface, promoting FLS adhesion and invasion (115,181). The chondrocytes themselves synthesize cytokines or respond to local cytokine release, particularly IL1-B, 17, 18 and TNF-a; this accelerates the switch from an anabolic matriz-synthetizing state to a catabolic state that is characterized by the formation of MMPs and ADAMTS, which cleave collagen fibers and the cartilage component proteoglycan, respectively, and thus, further diminish cartilage integrity.

Moreover, matrix-degrading enzymes are also released by FLSs, PMNs, and mast cells, which are closely located to articular cartilage (106).

Bone erosions: Bone erosion occurs rapidly, affecting 80% of patients within 1–2 year after diagnosis and is associated with prolonged, increased inflammation (182). Normal physiological processes ensure a balance between bone formation and bone resorption to maintain skeletal homeostasis. This balance is perturbed in RA for bone resorption. Bone resorption depends on osteoclasts (183). In RA, osteoclasts at the interface between synovial tissue and articular bone induce bone resorption, which in turn, permits invasion by cells of the synovial membrane and results in pannus formation, as mentioned above (184). This process depends on the influx of osteoclast precursors into inflamed synovial tissue and the differentiation of these cells into mature osteoclasts. Their metabolic activation to resorb bone requires complex cellular interactions between cells of the osteoclast lineage with mesenchymal cells and lymphocytes. These interactions are controlled by cytokines (Figure 4): M-CSF and RANKL [receptor activator of nuclear factor-kβ (RANK) ligand] wich are essential for the differentiation of osteoclasts from their precursor cells, promote invasion of the periosteal surface adjacent to articular cartilage, and a lack of either molecule is sufficient to block osteoclast formation completely (119,185). RANKL, a member of the TNF superfamily, is expressed by mesenchymal cells, and activated synovial T cells (184). RANKL expression is regulated by inflammatory cytokines such as TNF, IL-1β, 6, and 17, but is also influenced by non-cytokine inflammatory mediators (e.g., PGE2) (186). The interaction of RANKL with its receptor RANK is modulated by osteoprotegerin (OPG), a soluble decoy receptor, which is expressed by mesenchymal cells in the RA synovium (187). In RA, an imbalance between OPG and RANKL expression promotes RANKL-induced bone loss (188). Osteoclasts have the acidic enzymatic machinery necessary to destroy mineralized tissues, including mineralized cartilage and subchondral bone; destruction of these tissues leads to deep resorption pits, which are filled by inflammatory tissue. Mechanical factors predispose particular sites to erosion. Thus, mechanically vulnerable sites such as the second and third metacarpals are prone to erosive changes (189). Breach of cortical bone permits synovial access to the bone marrow, which causes inflammation of the bone marrow [osteitis as observed on magnetic resonance imaging (MRI)], in which T cell and B cell aggregates gradually replace marrow fat (190). Eroded periarticular bone shows little evidence of repair in RA, unlike bone in other inflammatory arthropathies.

Figure 4

Mechanism of erosive disease. Inflammation within synovial tissue induces osteoclastogenesis through increased expression of RANKL, and M-CSF, the essential cytokine mediators of erosive RA, which are expressed by synovial fibroblasts, Th1 and Th17 cells. (more...)

The total process, molecules, and mechanism of the pathogenesis and erosive RA are shown in the Figures 3 and 4, and Table 3 (191-195).

Table 3

Key molecules and signal mediators implicated in the pathogenesis of RA.

Classification criteria

Since 1958 different criteria for classification of RA patients have been established, and have been revised over time, the criteria established by the American College of Rheumatology (ACR) in 1987 are the most used (196). These criteria were developed from a cohort of subjects with long-standing RA. Validation studies conducted in the outpatient clinics confirmed that the criteria were an accurate method of classifying RA with sensitivity in the range of 77–95% and specificity in the range of 85–98%. Because of the nature of the cohort for which the criteria were developed, the criteria performs best at distinguishing subjects with long duration and active RA from those with other arthritis (197).Classification criteria generally allow categorization of patients in those groups with and without AR, providing a basis for a common approach to the definition of the disease and thus allow comparison across different studies (2) (Table 6).

Table 6

The 1987 ACR Criteria.

Recent studies have demonstrated that early aggressive treatment for RA can halt or slow the progression of synovitis and bone erosions, decreasing disease-related disability and increasing the rate of disease remission (198). However, the 1987-ACR criteria do not perform as well for early RA (i.e., arthritis symptoms ranging from 4 weeks to 2 years) (199) compared with long-duration RA. Criteria such as joint erosions and rheumatoid nodules are often absent early in the disease, thus decreasing the sensitivity of the classification criteria. For these reasons, in the 2010, the collaborative work between the ACR and the European League Against Rheumatism (EULAR), has established a new classification criteria for RA (149). These new criteria have not been developed to be considered as a reference by the general practitioner, but as a tool to facilitate the study of patients in early stages of the disease. The goals set for the development of these new criteria were: to identify subjects at high risk of chronic disease and erosive joint damage, and use them as a basis for initiating disease modifying therapy, and not exclude the inclusion of patients who are in late stages of the disease (200). Validation of these criteria in three of the most important global cohorts showed that they were adjusted between the 87–97% of patients in which MTX was chosen as initial treatment (201). In accordance with the above, Radner et al. (200) in a systematic literature review found pooled sensitivity and specificity of 82% and 61%, respectively for these new criteria. The authors of these criteria emphasize that physicians should report whether there is a significant proportion of patients who do not meet the new criteria, but in whom there is a reason to be treated with disease modifying therapy or who in the following, without a change of their classification, developed erosive disease (201). In Table 7, the new criteria, their scores and notes for taking into account to do diagnosis are listed.

Table 7

The 2010 ACR/EULAR classification criteria for RA.

The diagnosis of RA may also be made in patients without all the criteria described above. Examples include the following: seronegative RA (38,202), recent onset RA (71,203), and inactive RA (204).

Differential diagnosis

A number of disorders can closely resemble RA and must be ruled-out when the diagnosis of RA is being made. Infection-related reactive arthropathies, seronegative spondyloarthropathies, and other ADs such as SLE and SS, may have symptoms in common with RA, as may an array of endocrine and other disorders (Table 8).

Table 8

Differential diagnosis of RA.

Quantitative diagnosis and prediction

The art of RA diagnosis is based upon hypotheses generated with the information obtained from the clinical history and physical examination. These assumptions can be strengthened by an objective and percentage calculation of the probabilities of accurate diagnosis before and after performing a maneuver or diagnostic test –pre and post probabilities test (205). The probability that an individual will develop RA is equivalent to the prevalence of disease in the general population (206). This probability varies according to epidemiological data and characteristics of each individual as well as the symptoms, clinical signs, and diagnostic test results that have been requested for the patient. These characteristics have sensitivity and specificity, but by the ratio of these two can be calculated the LR, which increases or reduces the possibility of more accurately diagnosing disease (201).

Prediction models have been developed from prospective observational studies of treated patients with early RA (ERA). These models are designed to forecast outcomes in individuals with early arthritis who do not currently meet the 1987 criteria. Several factors can establish whether patients are likely to develop RA. However, in patients with ERA, the joint manifestations are often difficult to distinguish from other forms of inflammatory polyarthritis. The more distinctive signs of RA such as joint erosions, rheumatoid nodules, and other EAMs are seen primarily in patients with longstanding, poorly-controlled disease but are frequently absent on initial presentation (199). Nevertheless, ERA has not been full defined. Some authors have named it as one of less than a year of development and in some studies defining very early arthritis, as one of less than 3 months (134,207). In Table 9 a score applied to 3 independent cohorts of patients with undifferentiated arthritis is described and has an excellent discriminative ability for assessing the LR of progression to RA. The cut off point for RA is 8 points or more (208).

Table 9

Format used to calculate the patient’s prediction score.

Articular manifestations

The clinical evaluation of RA patients should consider the full joint study, including the systemic exhaustive evaluation given the condition of the disease with the possibility of compromise other than the joints. For this, it is necessary to perform a detailed medical history that extends from the presentation of the disease to the evaluation of the patient’s functional class.

RA is a symmetric and inflammatory disease (arthralgia with morning stiffness, sagging throughout the day). The illness may begin with a monoarticular engagement in 35% of cases, oligoarticularin 25% of cases and polyarticular in 40% of cases (205). The main joint involvement is given at the hands and feet. However, there may be a joint compromise of medium and large size as elbows, ankles, shoulders, knees, and hips. Persistent inflammation leads to destruction of cartilage and bone tissue with the consequent of misalignment and joint deformity (201).

The involvement of RA in hands occurs at different levels. It frequently causes disruption of the MCP joints, leading to the destruction of soft tissue tendon favoring the imbalance and weakness of the active and passive forces with subsequent instability, pain, and deformity. The two most frequently associated deformities with MCP level are volar subluxation and ulnar deviation. The condylar structure of the MCF, which allows movement on two planes, makes them more volatile than the PIP, being then more noticeable the deformities at that level (Figure 5)

Figure 5

Metacarpophalangeal deformities. Ulnar deviation. A: lateral view; B: frontal view. Adapted from Rojas-Villarraga et al. (201).

In initial stages, the MCP capsule and ligamentous structures are expanded by synovial proliferation, leading to collateral ligament loss and decreased motility ligament with decreased stability of the joint. Normally, in the flexed position of the MCP there is a minimal lateral movement but with the increase of laxity of collateral ligament deviations of up to 45° occur. The volar subluxation is also caused by the weakness of the collateral ligaments and the dorsal extensor mechanism, especially when the extenders are displaced between any two heads of the metacarpals. As a result, there are no forces that counteract the flexor and then a bending in the contraction of MCF occurs with an evident prominence of the metacarpal heads (201).

In the early stages of RA, fusiform fingers occur by the presence of synovitis and joint effusion at the PIP. Among the most frequently reported deformities, in advanced stages of RA at finger level, is the boutonnière deformity and the swan-neck finger. These deformities are reversible in the early stages, but not in the advanced stages of the disease (Figure 6). The compromise of DIPs in RA is rare, and when it is present, it is the result of deformities and biomechanical forces given by the alterations of the PIP. At the level of the first finger, the feature deformity of an advanced stage is the finger at “Z” (Figure 7).

Figure 6

Boutonnière deformity and swan-neck finger. A: Boutonnière deformity: Flexion in the proximal interphalangeal and hyperextension in distal interphalangeal; B: Swan-neck finger: Hyperextensión of proximal interphalangeal and hyperflexion (more...)

Figure 7

Finger at “Z” from the first finger. Metacarpophalangeal subluxated and hyperextension of interphalangeal. Adapted from Rojas-Villarraga et al. (201).

The wrist may present a severe involvement and destruction as a result of chronic synovitis preceded by pain, decreased functionality, and impact level of the fingers, by compromising the MCF and PIP. Alteration and destruction of tendons, which stabilize carpal at that level, manifest the ulnar commitment. The distal radioulnar joint can erode and parallel compromise to the dorsal capsule. A distal ulnar dorsal subluxation, subluxation of extensor carpi ulnaris tendon, and supination of proximal carpal bones can occur. In the radial portion scaphoid subluxation, ligamentous instability, ulnar translocation of the carpal bones and collapse with a height decreased of the carpal bones may occur (Figure 8). Clinically, the disease presents radial deviation of the hand with supinated position. The imbalance generates ulnar deviation of the metacarpals and phalanges (197,201,205).

Figure 8

Wrist involvement. Lateral view of distal ulnar dorsal subluxation. Subluxation of extensor carpi ulnaris tendon and supination of proximal carpal bones with imbalance, generating ulnar deviation of metacarpals and phalangeas. Adapted from Rojas-Villarraga (more...)

The compromise on elbow is manifested by pain and limited range of motion, initially extension and then flexion. The ulna-trochlear joint often gets affected at the initiation and then undertakes the rotary motion of the forearm. The loss of bone consistency with or without stabilizer tendon destruction may result in instability symptoms. These alterations may lead to limitation of mechanical forces and mobility. The presence of effusion may be evident between the lateral olecranon and radial head, which can migrate to the capitelum-humeral in advanced stages of cartilage loss, thus limiting flexion and extension. The ulnar synovitis can generate ulnar compressive neuropathy. The presence of rheumatoid nodules is common in the ulnar extensor area of the elbow and in the olecranon area (Figure 9), region in which bursitis can also occur (201,209).

Figure 9

Rheumatoid nodules. Localized at level of elbow in the ulnar area. Adapted from Rojas-Villarraga et al. (201).

At shoulder level, the compromise is variable and often underestimated since in its early stages, it can be subtly evident from the clinical standpoint. This leads in many cases to late diagnosis. Up to 65% of RA patients mention symptomatology at shoulder level at some point in the disease. A hallmark of rheumatoid shoulder is that inflammation is difficult to be clinically recognized; it is evident in isolated cases of bursitis, rotator cuff injury, or severe arthritis (210). As a result of inflammatory involvement, an altered functional component can be found, resulting from the combination of pain, muscle weakness, and decreased range of motion. Chronic synovitis can lead to joint space narrowing (JSN), which predicts erosive involvement to the level that, over time ends in joint destruction. The degree of tendon compromise of the rotator cuff can be variable, even generating complete destruction with superior migration of the humeral head as a consequence. In Figure 10, a severe arthritis of the shoulder, a rare manifestation of RA, is presented (197,201,205).

Figure 10

Shoulder compromise. Severe involvement of the shoulder as rare manifestation of the RA.

Between 5% and 15% of RA patients have hip compromise; this is in some cases a gradual and slow destructive process. In a few cases there is a rapid destruction of the femoral head with a severe inflammatory involvement. Generally the inflammatory process begins with synovitis and effusion, which causes a rearrangement of the femoral head by making it assume a position in flexion, external rotation, and abduction. Between the 15–20% of patients with hip compromise by RA develop acetabular protrusion, complicated with fracture of the acetabulum in some cases.

As in other joints, involvement of the knee has a broad spectrum. In the initial stages, the manifestations may range from secondary articular edema to synovial proliferation and effusion without evidence of cartilage damage. Usually the disease affects both kness symmetrically, but initial monoarticular presentation has been described. Compromise of flexo-extensor movements is concomitantly produced. The valgus deformity is common. Sometimes it is accompanied by flexion contracture; although less frequent, varus deformity may occur. This deformity can also accompany external rotation of the knee with an impact at the foot, leading to severe pronation. In some patients, the inflammatory exuberant compromise with synovial proliferation may persist for long periods, leading to chronic painful conditions. In advanced stages of the disease, there may be instability of the cruciate ligaments and collateral ligaments (201,205).

The foot is involved in 85–90% of patients and is the first manifestation in 15% of them (Figure 11). The rheumatoid foot involves primarily the forefoot. Symptoms begin with MTF joint involvement in 90% of the cases. Synovial chronic inflammation leads to distension of the joint capsule, collateral ligament compromise, and laxity of the plantar fascia leading to subluxation and dislocation of the metatarsal heads, which is a characteristic deformity in advanced stages of the disease. In the forefoot, there are also deformities such as hallux valgus, claw toe, hammertoe, mallet toe, and plantar hyperkeratosis areas that sometimes have perforations and are at risk of osteomyelitis. (197,205).

Figure 11

Severe rheumatoid foot. This involves the forefoot with deformity as hallux valgus, hammertoe and overriding the fourth on the fifth finger bilaterally. Adapted from Rojas-Villarraga et al. (201).

In studies of patients with ERA who have been evaluated for predicting clinical models forecasting the type of arthritis that the patient will follow, the positive lateral compression test of the MTP, i.e., squeeze test, with presence of pain has been found to be predictive of the development of persistent erosive arthritis. Therefore the performance of this simple clinic maneuver during physical examination is very informative (182,201) (Figure 12).

Figure 12

Squeeze test. A: dorsal view. B: plantar view. Adapted from Rojas-Villarraga et al. (201).

The RA also involved the hindfoot and ankle in about 30% to 60% of patients. The hindfoot valgus and flat feet are common. The inflammatory compromise of the subtalar-calcaneal-talar and tibiotalarjoints can also generate hindfoot valgus deformity. Talonavicular joints and calcaneo-cuboid can be seen to be involved in up to 25% of patients. The midfoot is not commonly affected. However, the first metatarso-cuneiform joint is frequently one of the most affected ones, causing instability (197,205).

Abnormalities at the foot are present in 82% of the patients, and the most common findings include hallux valgus (65%), flattening of the longitudinal arch (65%), claw toes, and hammer (39% and 25% respectively). A significant association between pain and physical examination of the forefoot is found, specifically in the subtalar and tibiotalar joints. Another positive association is the presence of the disease activity and disability, is measured through the HAQ and DAS28, respectively. In addition, the squeeze test was significantly associated with the risk of disability (9).

Other joints involved in RA are the temporomandibular, cricoarytenoid (i.e., causing hoarseness), and cervical. The latter may present with occipital pain and headache, neck pain, and, in advanced stages, movement limitation. The involvement of the atlanto-axial joint, given by laxity, presence of pannus and erosions, can lead to the development of subluxations in many directions; those changes could compromise the spinal canal, causing progressive quadriparesis and even endanger life. At the risk of compromise at that level, it is important to evaluate the atlo-axoideo space through radiography (i.e., no more than 3 mm between the atlas arch and odontoid process) and MRI (197).

Extra-articular manifestations (EAM)

A subgroup of patients with AR has been defined as extra-articular AR (EARA), which has been associated with poor prognosis and mortality increase. The presentation of the EAMs have been linked to genetic, clinical, immunological, and environmental factors (211,212). Regarding environmental factors, smoking has been reported as one of the most strongly associated (211,213,214). The EAM most frequently reported are the nodulosis, pleuritis, cutaneous vasculitis, even CVD (1,22,211,213,214) (Figure 13). About 15% of patients with RA during long-term follow-up develop EAM, corresponding to an estimated incidence of 1/100 person per year (215). In a recent study, carried out with 538 Colombian patients with RA, 32% had EAAR, specifically nodules and pulmonary involvement were present in 21% and 4% of patients, respectively. Patients with EAMs were older than those without it, presented longer disease duration, and higher titers of ACPA when compared with patients without EAM. Hypertension and thrombosis were significantly associated with EAM. The absence of smoking was a protective factor for developing these manifestations (214).

Figure 13

Rheumatoid arthritis as systemic disease. Systemic compromise may be observed in blood vessels (e.g., atherogenesis, myocardial infarctions), liver (e.g., elevated acute phase response and iron redistribution), lung (e.g., interstitial lung disease, pleuritis), (more...)

Cardiovascular. The main cause of mortality in patients with RA is CV events, which are the first cause of death in over 50% of patients and two times higher than the general population (214) (see Chapter 38).

Lung. The pulmonary compromise in RA is clinically infrequent; nevertheless, it has been detected in 5–63% of the patients (216). The most common types of described compromise are: interstitial lung disease (Figure 14), pleural effusion, rheumatoid nodules, and compromise of the airway. The pleural involvement is given by pleuritis (20%), pleural effusion, pleural thickening, and pneumothorax. Nodular pleural compromise has also been described (211,216). Other lung manifestations, less frequently presented, are: follicular bronchiolitis, diffuse alveolar damage, lymphoid interstitial pneumonitis, empyema, bronchopleural fistula, cricoarytenoid arthritis, bronchiolitis obliterans, follicular bronchiolitis, Caplan syndrome, vasculitis, pulmonary hemorrhage, pulmonary hypertension, respiratory muscle weakness, and amyloidosis (216).

Figure 14

Interstitial lung disease seen on high resolution computed tomography. A: axial; B: coronal; Adapted from Rojas-Villarraga et al. (201).

Eye. Dry eye, as a manifestation of SS associated with RA, is one of the most common eye compromises (see Chapter 28). This polyautoinmunity occurs in up to 30% of patients with RA. Usually the SS that accompanies RA occurs after RA onset. However, in some adults, the SS may be the initial manifestation. The prevalence of SS in patients with RA varies according to the different populations studied and the criteria used for inclusion (217). We have such a condition (i.e., RA-SS) in 15% (210,218). Other causes of dry eye other than SS in RA patients, include age, use of anticholinergic medication, presence of diabetes, and hypoandrogenism. Clinical manifestations can range from ocular foreign body sensation, to filamentary keratitis, and corneal ulceration in severe cases (217,219). Another serious ocular manifestation in patients with RA is scleritis-episcleritis (211,217,219) (Figure 15). Other ocular complications in patients with RA are uveitis, retinal vasculitis, cataracts, retinal hemorrhage, and iridocyclitis (211,217,219).

Figure 15

Scleritis-episcleritis. Scleral compromise, predominantly left eye. Adapted from Rojas-Villarraga et al. (201).

Dermatology. Rheumatoid nodules (Figure 9) have been considered as classical components of the clinical manifestations of RA (149,196). Nodules have been reported worldwide in 24–34% of the cases (211,212) and recently were found in 29% of our cohortwith RA (5). Clinically, these are subcutaneous, more frequently on the extensor surfaces. Another dermatological manifestation present in RA is vasculitis, which can also occur in different organs. They have been described in 1–5% of patients and, in cases of systemic compromise, a high mortality up to 30% at five years, secondary to the disease or treatment complication has been reported (211,212). The dermal involvement can be skin ulceration, secondary to immobility, steroid or underlying vasculitis or neuropathy, digital arteritis (e.g.,from splinter hemorrhages to gangrene), and palpable purpura, etc. (211) (Figure 16A and 16B). Other skin manifestations present in RA are white atrophy, livedo reticularis, palmar erythema, Raynaud’s phenomenon, opportunistic skin infections, granulomatous neutrophilic dermatitis, psoriasiform lesions, and toxic manifestations associated with immunomodulatory treatment (220).

Figure 16

Skin compromise: Chronic ulcer on internal supramalleolar region.

Hematologic. Anemia may be associated with RA, manifested as normocytic-normochromic. It must be differentiated from hypochromic microcytic anemia resulting from iron deficiency caused by multiple causes, including the use of anti-inflammatory drugs (NSAIDs), secondary gastrointestinal lossess and metrorrhagia (219). Another type of anemia present in RA is macrocytic, associated with folate deficiency by the MTX intake. Additionally, the mean corpuscular volume may be high as the result of deficiency of vitamin B12 secondary to concomitant polyautoimmunity with pernicious anemia or AITD. Autoimmune hemolytic anemia has also been as resulting from the use of some some disease-modifying antirheumatic drug (DMARD) or associated polyautoimmunity (201).

Felty’s syndrome. It has been described as the triad of arthritis, splenomegaly, and neutropenia. The presence of the three components is extremely variable. This syndrome occurs most often in patients with RF, nodular arthritis, and HLA-DRB1 SE (215). The main complication is the presence of infections associated with neutropenia in a third of the patients. Neutropenia can be occasionally found in patientes with DMARD or NSAIDs therapy. (212). Benign lymphadenopathy can be found in patients with active RA. In several retrospective studies it has been shown an increased presence of lymphoid malignancy -non Hodgkin’s and Hodgkin- associated with RA, especially in up to one third of patients with Felty’s syndrome. Other hematologic malignancies associated with RA are multiple myeloma and myeloid leukemia. The leuco-lymphopenia should lead to the study of polyautoimmunity with SLE or medicine reactions. Immune thrombocytopenia may be a manifestation associated with RA with a good response to steroid treatment. Thrombocytosis is usually a common manifestation of RA activity, although there have been reported thrombotic thrombocytopenic purpura cases (201,212,221).

Renal. The renal involvement in RA patients is rare. However, it may be the result of associated comorbidities. For instance, amyloidosis has been reported in up to 20% of patients with long-standing and severe RA. It is the most important cause of end-stage renal disease in some patient series (211). The use of several medicines may have a nephrotoxicity impact such as NSAIDs and DMARDs (e.g, gold salts, penicillamine, anti-TNF). The glomerular involvement in RA is rare and may be mesangial type, followed by minimal-change glomerulopathy and glomerulonephritis associated with ANCA (201,212).

Hepatic. Active RA may be associated with an increase in liver function abnormalities. With control of rheumatoid inflammation, the liver function abnormalities return to normal. Hepatomegaly might be observed (221). Serum alkaline phosphatase is increased in 18–46% of patients and gamma-glutamyl transaminase is raised in 23–77% of patients. Polyautoimmunity with autoimmune hepatitis should be considered in the presence of elevated liver enzymes. In this case hepatic compromise by medicines such as MTX should also be ruled out (218).

Nervous system. For various pathogenic mechanisms, the central and peripheral nervous system can be affected by RA and manifests in different ways, including entrapment neuropathies, (e.g., carpal tunnel, tarsal tunnel syndrome), which tend to occur when the nerve is compressed by the inflamed synovium against a fixed structure. Peripheral neuropathy, presenting as diffuse sensor/motor neuropathy or mononeuritis multiplex, occurs in a small subset of patients with RA. The underlying mechanism is small vessel vasculitis, which involves the vasa nervorum with ischemic neuropathy. Atlanto-axial subluxation caused by erosion of the odontoid process or the transverse ligament of C1 may allow the odontoid process to slip posteriorly and cause a cervical myelopathy. Basilar invagination, with upward impingement of the odontoid process into the foramen magnum, can also result in cord compression. The presence of cord compression is indicated by a positive Babinski sign, hyperreflexia, and weakness. This complication require surgical stabilization (197,211,212).

Other extra articular events and comorbidities. The most common gastrointestinal disorders are related to the use of NSAIDs or steroids which produce gastric ulcer. The intestinal immune compromise associated with RA such as Crohn’s disease and ulcerative colitis, has rarely been described (212,222). Depression, osteoporosis, muscle weakness, and infections are common complications or comorbidities (197,211,212,219,223,224).

Polyautoimmunity and familial autoimmunity

ADs share similar mechanisms. In clinical practice some conditions support these commonalities. One of these corresponds to polyautoimmunity, which is defined as the presence of more than one AD in a single patient (218,225). The importance of these terms is due to the fact that patients with polyautoimmunity may have a modified disease course and a modified clinical presentation (218,226). Several studies have consistently mentioned association and clustering between ADs (227). Recently, we have observed polyautoimmunity in up to 21% of RA patients (5, 218). Later, in a literature review, worldwide prevalence was reported between 0.5% in African population to 27% in Caucasian population (226). AITD was followed by SS, which was associated with RA in 11.8%. The factors associated with these conditions were female gender, CVD, and presence of ANAs. RA is more frequently associated with SLE, antiphospholipid syndrome, T1DM, scleroderma (SSc), biliary inflammatory disease, celiac disease, vitiligo, autoimmune hepatitis, myasthenia gravis, dermatomyositis, and pernicious anemia. (218,228).

FA is defined as the presence of any AD in first-degree relatives (FDRs) of the proband (225,228,229). Amaya-Amaya et al. (5) found 6.7% of FA in a cross-sectional analytical study in which 800 consecutive Colombian patients with RA were assessed. Recently, a systematic review and meta-analysis performed by Cardenas-Roldán et al. (66) found AITD, T1DM, SLE, SS, psoriasis, ankylosing spondylitis, pernicious anemia, SSc, and Wegener’s granulomatosis significantly observd in relatives of RA patients. Moreover, FA confers additional susceptibility to CVD in RA patients (5). Conditions related to FA and CVD include radiographic progression, which denotes high disease activity and persistent increased inflammation. El-Gabalawy et al. (230) indicated that levels of multiple cytokines and high sensitivity CRP are higher in Amerindian patients with RA and their FDRs as compared to individuals from a non-AD. In the same way, familial autoimmune disease or family history of RA is defined as the presence of the disease in at least one FDR (74,228). This condition was found in 7% of the Colombian population and was associated, along with ACPA positivity, with an early erosive compromise, and therefore, a rapid progression of disease (74). Walker et al. (231) found an excess risk for AITD in RA multicase families compared with the general population.

Laboratory findings

Given the physical, social, functional, and psychological aspects of RA, it is necessary to closely monitor patients after the diagnosis, using an excellent and careful history and physical examination [i.e., presence and distribution of swollen joint count (SJC), tender joint count (TJC), visual analogue scale (VAS) of pain, and global assessment of the disease], and objective measures to evaluate the response to treatment. This should be done, usually every three months. For these reasons, several tests can provide objective data that allow disease progression to be followed. In laboratory measurements, it has been demonstrated that some are directly related to poor prognosis or early development of the disease. The ACR Subcommittee recommends that baseline laboratory evaluations include a complete blood cell count with differential, RF, and ESR or CRP. Baseline evaluation of renal and hepatic function is also recommended. Table 10 summarizes the test findings associated with the follow-up of RA (1,22,197).

Table 10

Laboratory tests in rheumatoid arthritis.

Assessment of disease activity

The TJC and SJC are a direct reflection of the amount of inflamed synovial tissue, establishing in a numerical form the joint compromise has certainly proven to be the most specific and simple clinical method to measure the activity of RA (234). Disease activity should be evaluated initially and at all subsequent visits. It is recommended that a structured assessment of disease activity using a composite measure such as those described here, should be performed initially, every three months (234). There are several scoring methods, including TJC, SJC, and it is mathematically combined with laboratory measurements and global evaluations to determine the degree of disease activity (235). Adjustments to treatment regimes should be made to quickly achieve and maintain control of disease activity of targeted treatment goals (i.e., remission or low disease activity), rather than an undefined degree of improvement. Among more than 60 activity measures available for evaluation of patients with RA, the six measures noted below have been identified by the ACR as having the greatest utility in clinical practice because they accurately reflect disease activity; are sensitive to change; discriminate well between low, moderate, and high disease activity; have remission criteria; and are feasible to carry out in clinical settings (236). The choice of measure is based upon clinician preference; some measures require both patient and clinician input while others are based only upon patient-reported data. Measures that require both patient and clinician input as well as calculators for these measures, include the following:

• The Disease Activity Score derivative for 28 joints (DAS28) (237). It is made up of the TJC and SJC on 28 joints determined by physician and CRP (mg/L). The equation is as follows: DAS28 = 0.56* √(TJC28) + 0.28* √(SJC28) + 0.36* ln(CRP + 1)* 1.10 + 1.15.
• The Simplified Disease Activity Index (SDAI) (235) is the algebraic sum of the following parameters: TJC and SJC on 28 joints determined by the physician, CRP level (mg/dL), patient VAS-Global, and MD Global.
• The Clinical Disease Activity Index (CDAI) (238)is the algebraic sum of the SDAI items minus CRP level.

The patient-reported outcome (PRO) measures include:

• The Routine Assessment of Patient Index Data 3, 4, and 5 (RAPID3, 4, 5) (239,240): The RAPID 3 is a PROs-based index that uses the three core set criteria evaluated by the patient, that is, physical function (from MDHAQ), VAS-Pain, and VAS-Global (scale 0–10). The RAPID 4 includes the same variables as RAPID3 plus self-administered, RA disease activity Index (RADAI) (Scale 0–10), and RAPID5 includes the same variables as RAPID4 plus MD-Global (Scale 0–10).
• Similarly, the self-administered index is a tool counting SJC and TJC (Figure 17).

Figure 17

Disease activity index-28: Mannequin.

Recently, in a meta-analysis, PROs demonstrated moderate to high correlations and concordance with the objective measures done by the health care practitioners. These can be administrated in the clinical practice and clinical trials without pretending to replace the clinical concept but aimed at facilitating and optimizing the clinical consult and the patient outcomes (3,241,242). Table 11, summarizes different scales, questionnaires, and indexes used to evaluate RA patients.

Table 11

Patients reported outcomes instruments and clinimetry.

X-Ray

Plain radiography (X-ray) is a valuable tool in dealing with RA; it has different uses, including: diagnostic, structural damage assessment, measurement of the severity and progression, establishment of treatment effects and objective measure of joint involvement. For proper radiographic interpretation it is necessary to have adequate technical aspects in their decision and a correct interpretation (205). For the study of RA application, comparative x-ray of both hands and feet is essential for diagnosis and objective staging since most existing indices of damage quantification are performed at both levels. It is suggested that radiographic study of hands and feet be requested at the beginning of the disease with annual monitoring and then, every six months to asses radiographic progression (i.e., structural damage) (205). Proper radiographic evaluation of the hand, including the wrist and fingers, requires posteroanterior (PA) conventional projections, lateral and oblique. The PA projection is the most useful for the assessment of injuries as bad alignments, space narrowing, erosions, and soft tissue lesions (205). The oblique projection can be used to display other alterations on this plane that cannot be seen on the other two, but its use is not widely validated in follow-up studies of RA as if it is the PA projection (243). When a patient has asymmetric symptoms, it is important to apply a comparative hands study precisely because it allows physicians to compare and evaluate other possible alterations that are not clinically evident in the contralateral joint and so staging the damage. The Norgaard projection evaluates hands in their normal resting state making more visible the presence of subluxations and the appearance of early erosions in the PIP and MCP, but it presents technical difficulties in reproducibility by the position at the time of making the radiography to assess the progression and therefore it is not validated through most radiographic follow-up studies (244). Standard projections for evaluation of the foot are the anteroposterior, lateral and medial oblique, and the lateral load (support) which provide a better assessment of the hind foot. Practically all body areas likely to be compromised by the RA can be studied by plain radiography. The order of frequency of injury in RA is: hands, feet, knees, hips, cervical spine, and shoulders. In the hands mainly undertake MCP joints, wrists PIP, and feet the MTP, PIP, and retro-half foot (245). The assessment of damage (injury or radiographic structural alteration) in RA in small joints is a good proxy for assessing the total radiological damage (243).

Joint injuries visualized by X-ray: the major structural evaluated changes are (246):

1. Soft tissue edema: Usually fusiform and evenly distributed around the joint.
2. Osteopenia: The term refers to a shortage quantity of the bone. The amount of bone to be lost before the osteopenia can be detected in an X-ray is about 33%. When osteopenia is found, it is important to define if it is juxta-articular or generalized (246).
3. Joint space narrowing: It is one of the most important measures of radiographic injuries in AR. JSN indicates loss of articular cartilage. In RA this loss is usually symmetrical. When there is total loss of space, it is called ankylosis (246) (Figure 18).
4. Erosion: It is defined as the loss of definition of the bone surface or loss of the continuity of the cortical in the bones that compromise the joint. Juxta-articular erosions are observed in the “bare spots” of bone, (i.e., in areas within the joint in which the bone is not protected by coating cartilage) (246,247). Erosions constitute one of the key measures to assess radiographic damage in RA.
5. Joint congruency: The loss of the congruency between the bones in a joint may be total (luxation) or partial (subluxation). These bad alignments are components of some of the deformities in RA (i.e., boutonnière deformity and swan-neck finger) (248) (Figure 6 and 7).
6. Subchondral cysts: Radiolucent areas with well-defined edges underlying the articular surface.

Figure 18

Comparative hands x-ray in RA. Posteroanterior view. Erosions are shown as red arrow. Yellow arrows indicate JSN, and loss of the joint congruency is exposed as blue arrow.

Of all the above structural changes, erosions and JSN are those that best reflect the pathophysiological process of joint damage in RA, and therefore, they have been used in most studies and quantified through indexes and validated scoring systems (247–249).

Radiographic indices in RA. Several methods have been developed to quantify radiographic progression in RA. Some of these methods provide a global assessment of joint disorders giving a score group and others provide detailed score based on independent findings (250).

A summary of the characteristics evaluated by different methods is found in Table 12. Sharp methods (251,252) and its modification by Van der Heijde (253) are the most widely used. The Larsen method (254) and its modifications (255,256) (i.e., Scott and Rau) have also been implemented in several studies (245,247,248).

Table 12

Major indexes radiographic scoring in RA.

Sharp-Van der Heijde (S-VdH) Index. The version of Sharp method modified by Van der Heijde Désirée (253,257) (S-VdH) removes an area of erosions in hand, leaving 16 areas to evaluate, and eliminates three wrist areas to qualify the JSN, leaving 15 areas to be evaluated (Figure 19). The rating for erosions in the hands and JSN according to this method is found in Table 13. The maximum score is 160 in hands erosion and for JSN it is 120. This scoring system adds the qualification level of the feet including all MTP joints and the first bilateral PIP to assess erosions with a maximum score of 120 (maximum 10 for each joint) and a maximum score of 48 for evaluating JSN (maximum 4 per joint).

Figure 19

Hands, wrist and feet joints assessed by the method of Sharp - Van der Heijde (S-VdH) Index. Above: O = Erosions (16 areas in hands and 6 areas in feet); Low: X = JSN (15 areas in hands and 6 areas in feet).

Table 13

Score of erosions and JSN by the method of S-VdH.

Simple Erosion Narrowing Score (SENS Index). This scoring system developed by D Van Der Heijde (258) is a simplified score version for erosions and JSN and has been validated and compared with traditional methods founding similar reliability. A total of 32 eligible joint areas of the hands and 12 in the feet are analyzed for erosions (total of 44), and 30 parts of the hands and 12 of the feet are analyzed for JSN (total of 42). Score by area is 1 and a score of 1 for the presence of JSN, for each joint the maximum score is 2 (1 for erosion and 1 for JSN), the total score then can be maximum 86.

Implementation in studies. There is no definitive method for scoring radiographic damage in RA. An important aspect is the reliability of scores that are evaluated by correlation coefficients intra-class and inter-observer when the same reader analyzed the radiographs at different times and several readers analyze and give their scores at the same time. These coefficients have proved to be adequate for detailed scores like Sharp or modification S-VdH. Suitable correlation coefficients for scores of Rau-Larsen and SENS have also been found (259). Sensitivity to change is another measure that can determine the sensitivity of a radiographic scoring method to detect real changes in RA. Over time, this has been validated and implemented by the OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) by the concept of the smallest detectable difference and the concept of the minimum clinical important difference in radiography, or minimal detectable change (260).

Reading time using these scoring methods has been found between 3.9 minutes (Larsen), 19 minutes (Sharp), 25 minutes (S-VdH), and 7 minutes (SENS) (259). Adequate radiological monitoring for a RA patient must take into account the appropriate position at the time of shooting, the exposure time in the film, and the type of film used, and the reproducibility of the shooting, so that these measures ensure the accuracy of the appreciated alterations (259). Some studies have implemented the use of the digitized x-ray using scanning techniques to be read on the screen and can provide measures of bone density and porosity level at the site of the joint, developing indices that are being validated (261). Recently the OMERACT group (262) describes the use of computer programs (software) to accurately measure the JSN in millimeters with good reliability compared to conventional visual methods, hoping to have greater sensitivity and accuracy with the improvement of these programs and their implementation in clinical studies.

Radiographic progression and clinical correlation. Radiographic progression and structural damage are related to the disease activity and may be used to assess treatment effectiveness (250). At the same time, the radiographic damage progression relates to clinical outcome, defined as physical disability. There is also a relationship between clinical measures of disease activity and radiographic progression measures in different studies and a strong correlation between local inflammation and progression of joint damage has been established individually (243,250,263). The erosion and structural damage indicators are presented in the first or second years of disease onset, hence the importance of treating the disease early (264). Radiographic progression was assessed (265) in patients with early RA, and it is possible to classify the outcome as progressive (onset of erosion) or non progressive (stability without radiographic appearance of erosions). This has served as a criterion for establishing the extent of therapeutic effect (both early and established RA) with different medicines, including inducing remission DMARD (i.e., MTX and others), leflunomide, and biological therapy (204,249,264,266,267). The moment the first erosion appears is important because it has prognostic implications. Both MTX (204) as well as new, more specific therapies for the treatment of the disease, have been shown to arrest the progression of radiological damage and repair radiographic erosions, thus improving the prognosis of patients (268).

Early arthritis The use of the x-ray in patients with early arthritis allows to classify the type of the disease and to perform differential diagnosis, especially in early RA predicting when used concomitantly with radiography of hands and feet, the latter increases the sensitivity of prediction (182). Using methods of scoring within the first three months of the disease can detect changes if chronological studies are performed (265,269). In some early arthritis studies, structural damage has not been demonstrated (e.g., erosions or JSN), but simply osteopenia, a finding that has low reliability due to its low reproduction in readings for the same or different observer (268). Therefore, software used to develop mathematical models for predicting early arthritis over time is currently being implemented (270). On contrast, there are studies that have shown that patients with early onset arthritis whom had ACPA have a higher scoring system (Larsen) at two years of the disease. Through logistic regression, predictability to develop more severe disease was demonstrated when these antibodies were positive at the beginning of the disease and caused greater radiological damage (271). The use of radiographic scoring methods, within the first three months of the disease, can detect early changes and, also, can let to begin DMARDs in a timely manner (199).

Weaknesses of the x-ray. The use of x-ray in dealing with RA has several weaknesses, including (250): variability in reading and interpretation by untrained observers, alterations in interpretation when the shooting technique is inadequate (i.e., projection, exposure time, proper film, reproducibility, among others), lack of sensitivity to detect early changes that are not erosive such as synovial thickening, synovial fluid, cartilage abnormalities and bone edema, development of erosions or decrease in space, prolonged reading time for account using a suitable damage index (S-VdH 25 minutes) and lack of standardization of computer methods through software to perform a more accurate measurement of the JSN and erosion; lack of standardization of the daily use of digitized radiographs.

Ultrasound

The indications for use of the ultrasound (US) are addressing the inflammatory joint condition, studying abnormal tendons, bursae, ligaments, muscles and synovial fluid. Furthermore, it enhances studies through ultrasonographically guided procedures, application of US-guided medicine, evaluation of the inflammatory activity of the disease, and monitoring disease progression (272, 273). US has proved to be a promising tool because of its superiority to conventional imaging study for evaluating the joints in RA; this assertion is based on the visualization of inflammatory and destructive changes (e.g., erosions) that are not detected by the clinic or radiography (Figure 20).

Figure 20

A: shows X-ray of a non-erosive left foot; B: US shows an erosion on the fifth metatarsal head.

Alterations in RA evaluated by US

Synovitis. The US can distinguish between arthritis and tenosynovitis from a joint with effusion and also distinguish turbulence caused by mechanical disturbance, at the same time it can visualize structural changes in the synovial membrane (274). Synovial tissue is not seen through US unless there is a thickening of it, in which case it is seen as an intra-articular hypoechoic tissue. However, the exact appearance varies based on the amount of extracellular fluid that is in the synovial tissue. In some areas such as the radial or cubital aspect of MCP joint or prepatellar area, synovitis can be better appreciated. Most authors consider that evaluation of synovitis as a tool to define the therapeutic response (275).

Joint fluid. The US is extremely sensitive in detecting joint fluid, even in small joints (273). The distension of the joint capsule is the main sonographic finding of the articular phlogosis. In recent onset synovitis, synovial fluid is characterized by homogeneous lack of echogenicity. In cases of prolonged flogosis, the presence of irregular echogenicity of the synovial fluid due to the presence of proteinaceous material and/or inflammatory cells is often revealed. These margins are different from those observed in cases in which synovial hypertrophy has a thickening and/or variable irregularity (proliferation) of the articular capsule wall (205,246).

Erosion. Several authors have described the ability of ultrasound to detect erosions (247,272). One of the main benefits of ultrasound is the ability to visualize the joint in different planes and thus obtain greater sensitivity in the detection of erosions (273). The bone surface is a barrier to US and it is seen as a hyperechoic structure with posterior acoustic shadowing. Through US, terosions have been detected 7.5 times more in patients with early RA than through conventional radiography, and 3.4 times more in patients with established RA (246,273). Using second generation probes (i.e., transducers) with high spatial resolution and multiplanar studies, minimal disruptions of the bones may be detected and therefore, microerosions that are not able to grasp in the standard projections of hand for x-ray can be visualized (247). Since the earliest erosive manifestations in patients with RA are located, in most cases, in the second MCP joint, the US study of this anatomical region should be performed routinely in these patients (247). This study as well as the fifth MTP would ensure the best combination of sensitivity, specificity, and suitable time on the US examination (205).

Cartilage. In healthy subjects, the articular cartilage of the metacarpal head appears as a subtle hypoanechoic band bounded by clear margins and homogeneous hyperechoic bands. Normal thickness of articular cartilage of metacarpal heads is between 0.2–0.4 mm. In 85% of RA patients a loss of definition of the articular cartilage (i.e., irregular margins, increased echogenicity, and internal thinning) is observed (273).

Cysts, bursae, ganglions, meniscus injury, solid masses, abnormal ligament, tendon injuries, and tenosynovitis can also be observed by this technique.

OMERACT-7 and US. In 2005, the OMERACT group at its seventh session (276) made of the major alterations that can be evaluated by US; these are presented in Table 14, along with the update from 2009 (277). Results demonstrated good intermachine reliability among multiple examiners, good applicability of the scoring system for the hand on other joints (including shoulder), and helped dispel the myth that US is too subjective.

Table 14

Definitions of articular pathologic findings by ultrasound OMERACT 7 Consensus.

US diagnostic in RA. Through MRI every erosion detected by US that was not detected by X-ray was identified (278). US has demonstrated a high inter-observer correlation between rheumatologists and radiologists when performing US of the small joints of the hand in patients with established RA. Correlations include evaluating erosions (91%), synovitis (86%), joint effusion (79%), and Doppler signal (87)% (279). In a study in which the three methods were compared at the MTP joint, it was found that the US is more sensitive, accurate, and specific than clinical examination and X-ray with a high sensitivity and specificity (i.e., 79% and 97% respectively) for the detection of erosions taking the MRI with contrast as gold standard (280). Some authors have performed measurements in healthy adults through articular US, describing standard reference values in terms of extent and localization of anatomical structures to be used as a guide to the pathological findings (281). Scoring systems have been used in research to describe in a semi-quantitative form the presence of synovitis and joint effusion in RA patients (Table 15).

Table 15

Semiquantitative method for classification of synovitis and joint effusion in rheumatoid arthritis.

Musculoskeletal Doppler in RA. There are different modalities and utilities such as US Doppler mode, pulsed Doppler, color Doppler, duplex, and power Doppler (282-286) (Table 14).

Magnetic resonance imaging (MRI)

MRI is a good tool for evaluation of most musculoskeletal disorders. The absence of ionizing radiation, the best anatomic detail, and functional information are some of the most important advantages of MRI. It has a high sensitivity in detecting radiographic abnormalities that are hidden. It can detect active synovitis and bone erosions earlier than conventional X-rays. It is useful to differentiate early cases of arthritis and other diseases with joint manifestations (248). It is important to note that the accuracy of resonance depends on technical factors such as the magnetic field and surface antennas used, and the selection of specific sequences. The timing of the examinations is another important aspect of precise diagnosis, as the findings are dependent on the stage of the disease.

Structural abnormalities detected by MRI in RA

Synovitis. It is defined as an area in the synovial compartment showing a higher than normal enhancement after the injection of Gd (gadolinium) showing a higher thickness than normal synovium (287). It is correlated with active histologically observed inflammation. These signs are related to three aspects (288,289): increase in volume (“mass”), increase signal intensity following injection of intravenous contrast medium, increase water content, and a combination of the above. Although in MRI the normal synovial membrane is not visible, in RA it can discriminate between effusion, hypervascular pannus, and fibrous pannus (290). After intravenous administration, Gd passes within the interstitial space at a rate dependent on the local capillary permeability and tissue perfusion (287). This substance accumulates in areas of inflammation and can improve detection and differentiation of inflammatory processes from internal liquid. MRI is a more accurate method than clinic for detecting synovitis (287) and it can be a useful and sensitive measure of inflammation in the early stages of the disease, thus improving the accuracy of diagnosis (272).

Erosion. To avoid overestimation, the strict use of its definition is essential. Resonance bone erosion is defined as a marginal lesion with juxtaposed location with typical articular signal intensity in different sequences, visible on two planes with cortical rupture, which must be observed at least on one plane. Erosions are also recognized because they replace fatty marrow (248) and they differentiate from a fluid-filled cyst because erosion takes the contrast (290,291). It has been shown that MRI is superior to identify erosive changes earlier than conventional radiographic studies detect them in patients with early arthritis (272,292). This makes it the method of choice for detecting erosions and it is also more sensitive in monitoring erosive progression.

Bone marrow edema. This phenomenon is reversible; it generally refers to bone edema or osteitis. The exact histological correlation is unknown. It can be alone or around bone erosion. There are frequently detected signs of increased water content in the core compartment (293–295). Bone edema has been shown to be associated with erosive lesion and it is considered to be a precursor of erosion. The effective suppression of synovitis may reverse the pre-erosive changes and subsequent structural damage (296).

Cartilage and destructive changes. The image of the cartilage is more specific than the radiographic visualization of the joint space. Although optimal evaluation of small joints has not been established, it is useful in monitoring and controlling treatment. MRI displays inflammatory and destructive changes of the disease; it is considered to play an important role in the proper monitoring of treatment efficacy. The methods used for its investigation are quantitative (i.e., measured), semiquantitative (i.e., scores), or qualitative (i.e., presence or abscense). Quantitative methods estimate the joint inflammatory activity by measuring and determining the volume of inflamed synovium (i.e., the "inflammatory load”) (293–295). Erosion volumes can also be estimated. Unfortunately, quantization of the volumes is time-consuming (294). Semiquantitative scoring methods require less time. Currently, the best-validated scoring system has been developed by the OMERACT. The OMERACT rheumatoid arthritis magnetic resonance image scoring system (RAMRIS) has shown good correlation between the scores and volumes of synovitis and erosions (36), but there is a lack of data on sensitivity study of minimal changes (Table16).

Table 16

OMERACT MRI in RA group recommendations of a ‘core set’ of basic MRI sequences, MRI definitions of important RA joint pathologies and a RA MRI scoring system.

Prognostic value in early arthritis. MRI may have prognostic value because it provides predictors of poor prognosis and outcome in RA. The findings of erosive disease in the wrist can predict subsequent radiographic damage at 2 years. The proportion of synovitis detected by MRI in early RA is predictive of radiographic injury during monitoring (297). In future clinical practice, MRI can acquire an important role in the differential diagnosis of early-unsorted polyarthritis, in monitoring therapeutic response, and in patient prognosis. Clinicians using MRI can make optimal decisions in less time due to the availability of more accurate information (297).

Computed tomography (CT)

Since was developed of CT in the 1970s, it has been extensively used to image osseous structures. CT provides multiplanar imaging with the benefit of good contrast for cortical and trabecular bone (298). CT viewing perspective obviates projectional superimposition, which can obscure erosions and mimic joint space narrowing on conventional radiograph. However, recent developments in multidetector CT technology and computer-enhanced reformatting of image data have revolutionized this modality and broadened its usage. Images are still generally obtained on the transverse plane, but reformatted images on other planes can now be obtained immediately on advanced workstations, allowing for visualization of structures in any linear or even curvilinear plane(299). However, it has the disadvantage of ionizing radiation (197).

Another strength is the excellent soft tissue resolution in many areas, leading a good definition of bone anatomy (300). CT optimally images bone structures and can easily detect erosions. On CT, erosion is visualized as a local area with decreased density of the cortical joint surface, sometimes including the adjacent subcortical bone. Sclerosis can also be seen with CT and may be indicative of reparative changes following erosion (301). Cortical bone, being very dense, is readily visible, as is the interface with adjacent soft tissues. Thus, these imaging techniques are capable of clearly delineating the borders of erosions and differentiating bone (whether edematous or not) from inflamed synovium (Figure 23). In this way, it is more sensitive than the MRI in the detection of early erosions in the hand (302). Otherwise, this has been increasingly used in patients who cannot tolerate, or have absolute contraindications to MRI (300). Given the advantages of other imaging modalities, the potential of CT in the clinical management and clinical trials of RA patients seems minimal. However, it may be a valuable reference method for validation of bone damage observed on MRI and US (299) (Figure 21).

Figure 21

Computed tomography in RA. A: erosions are observed on fifth metatarsal head; B: erosions in the same place on CT-3D.

While plain radiography has traditionally been used as the gold standard for imaging erosions, there are many regions such as the carpus in which complex 3-dimensional anatomy is very inadequately depicted using a 2-dimensional technique. This was recognized when the Sharp score was developed for scoring erosive damage in rheumatoid patients, as some areas of the carpus were excluded altogether because of poor visibility. This problem is circumvented by multidetector helical CT, which offers the benefits of multiplanar capability, similar to MRI, with the enhanced cortical definition intrinsic to plain radiography (298,299). CT is also significantly less expensive than MRI and is quicker to do (300). New technologies have been developed. High resolution CT provides a sensitive method with high reader agreement in assessment of structural bone damage in RA, including joint space width measurements. Moreover, it has better correlation of erosion measures with disease duration (301,303).

General principles

The overall approach to the treatment of these patients depends upon the timely and judicious use of several types of therapeutic interventions. The appropriate use of these therapies is based upon an understanding of a group of general principles that have been widely accepted by major working groups and by professional organizations of rheumatologists (Figure 22). These principles include:

• Early recognition and diagnosis: Achieving the benefits of early intervention with DMARDs depends upon making the diagnosis of RA as early as possible. The recognition of RA early in the course of inflammatory arthritis, before irreversible injury has occurred, is thus an important element of effective management (304).
• Care by an expert: in the treatment of rheumatic diseases an expert such as a rheumatologist, should participate in the care of patients with inflammatory arthritis who are suspected of having RA and in the ongoing care of patients diagnosed with this condition (149,305).
• Early use of DMARDs for all patients diagnosed with RA: importance of tight control with target of remission or low disease activity, use of anti-inflammatory agents, including NSAIDs and glucocorticoids (GCs), only as adjuncts to therapy (198,306,307).

Figure 22

Algorithm based on the EULAR-2010 recommendations, up to date in EULAR meeting 2013. ^* 2010 ACR-EULAR classification criteria can support early diagnosis ^** The treatment target is remission according to ACR-EULAR definitions or, if remission is unlikely (more...)

The application of these principles has resulted in significant improvement in the outcomes of treatment (308). Such improvements may owe even more to the therapeutic strategies that have been adopted than to the development and use of newer and more potent drugs (309).

Pharmacological intervention

Choices between treatment options are based upon multiple factors, including: level of disease activity, stage of therapy, regulatory restrictions, and patient preferences among others (304,307). It is important to use a combination of the following types of therapies:

• Rapidly acting anti-inflammatory medications, including NSAIDs systemic, and intra-articular GCs, which offer reliable but limited relief of pain, swelling, and stiffness, improving quality of life in the majority of the cases. However, adverse effects are common, and patient education is necessary. Combination of NSAIDs should be avoided (141,205). Selective COX-2 NSAIDs are similar in efficacy to diclofenac or naproxen, and may be of value in patients who cannot tolerate COX-1 NSAIDs. However, many of these medications have been withdrawn from the market due to concerns regarding COX-2 inhibitors and increased of CVD (210).
• DMARDs, which include non-biologic and biologic agents as well as an orally administerd kinase inhibitor, have the potential to reduce or prevent joint damage, and preserve joint integrity and function. The non-biologic DMARDs most frequently used include hydroxychloroquine (HCQ), sulfasalazine (SSZ), MTX, and leflunomide. Biologic DMARDs, produced by recombinant DNA technology, generally target cytokines or their receptors, or are directed towards other cell surface molecules. These include anti-cytokine therapies such as anti-TNF-α (e.g., etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol), IL-1 receptor antagonist (i.e., anakinra), and IL-6 receptor antagonist (i.e., tocilizumab). They also include other biologic response modifiers such as the CTLA-4 blocker, (i.e., abatacept), and the anti-CD20 B cell depleting monoclonal antibody (rituximab). Several kinase inhibitors are in development for use in RA, and one of these, tofacitinib, is available for such clinical use in the USA and is under review for potential approval in Europe. Tofacitinib is an orally administered small molecule DMARD that inhibits cytokine and growth factor signalling through interference with Janus kinases.

All patients diagnosed with RA are started on DMARD therapy as soon as possible. The choice of initial drug therapy depends upon the degree of disease activity. It is necessary to distinguish between those patients with mildly active disease and the majority of patients with more active disease:

• In patients with mildly active RA, initiate anti-inflammatory therapy with a NSAID for rapid symptomatic relief and begin DMARD treatment with either HCQ or SSZ.
• In patients with moderately to severely active RA, initiate anti-inflammatory therapy with either a NSAID or GC, depending upon the degree of disease activity, and generally start DMARD therapy with MTX.
• In patients resistant to initial DMARD therapy (i.e., MTX), treat with a combination of DMARDs (i.e., MTX plus either a TNF-inhibitor or SSZ and HCQ) or, alternatively, switch the patient to a different DMARD of potentially comparable efficacy (e.g. leflunomide or a TNF-inhibitor), while also treating the active inflammation with anti-inflammatory drug therapy.

Concerning to steroid therapy, it should be started initially, with a tapering dose titrated to patient’s response and side effects (198,307).

In 2010, the EULAR issued the recommendations for the treatment of RA with synthetic and biological DMARDs and GCs based on evidence from five systematic literature reviews (SLR) performed for these medications, treatment strategies, and economic issues (304). Fifteen recommendations were developed. Recently, these recommendations were updated at the EULAR-2013 meeting (310) based on three SLR and fourteen recommendations were given (Table 17). According to this latest guidance, treatment with DMARDs should be initiated as soon as a diagnosis of RA is made with the goal of reaching a target of remission or lowering disease activity in every patient; as first-line treatment, EULAR recommends rheumatologists to administer MTX or combination therapy of MTX with other conventional synthetic DMARDs. Low-dose GCs should also be considered in combination with DMARDs for up to six months, but should be tapered as soon as clinically feasible. As already stated in the 2010 guideline, by advocating the use of synthetic DMARDs, rather than biologics, as the first-line treatment, this approach avoids the over-treatment of 20–50% of patients with early RA, who will achieve the treatment target with such initial therapy. In addition, it is recommended that patients who have failed to respond to an initial biologic DMARD should receive another biologic DMARD. Patients who have failed to respond to an initial TNF-inhibitor may receive another TNF-inhibitor, or a biologic with an alternative mode of action. If biologic treatment has failed, tofacitinib may be considered where approved, and it is only recommended after at least one biological has failed – in fact, many Task Force members felt it should be used after two biological treatment failures. (310). If a patient has achieved persistent remission, after having tapered GCs, clinicians should consider tapering the biological DMARD, particularly if the treatment is in combination with a conventional synthetic DMARD. In cases of sustained long-term remission, cautious dose-reduction of conventional synthetic DMARDs should be considered (310). The set of recommendations are summarized in the Figure 22 and Table 17.

Table 17

Recommendations for the management of RA EULAR-2013.

Non-pharmacologic and preventive therapies

Despite advances in pharmacologic therapy for RA, many patients continue to experience some measure of ongoing disease activity and resultant disability. Although measures aimed at identifying early active disease and controlling inflammation are essential, the disease itself and the drugs used for treatment may contribute to increased risks of comorbidities (311). A comprehensive management program for RA includes patient education, exercise and rest, psychosocial interventions, physical and occupational therapy, nutritional and dietary counseling. The management program also includes interventions to reduce the risks of CVD and osteoporosis, and immunizations to decrease the risk of infectious complications in immunosuppressive therapies (312–319).