module3 pa tho genesis and clinical aspects ra

8/6/2019 Module3 Pa Tho Genesis and Clinical Aspects Ra

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Eular On-line Course on Rheumatic Diseases module n3Gerd-Rdiger Burmester , Arthur G Pratt, Hans Ulrich Scherer, Jacob M van Laar

12007-2010 EULAR

PATHOGENESIS AND CLINICAL ASPECTS OF RHEUMATOID ARTHRITIS

Gerd-Rdiger Burmester *, Arthur G Pratt**, Hans Ulrich Scherer***, Jacob M. van Laar **

* Department of Rheumatology and Clinical Immunology

Charit - University Medicine BerlinCharitplatz 1, D - 10117 [email protected]

**Musculoskeletal Research GroupFloor 4 Cookson Building,

Newcastle University,Framligton Place,Newcastle upon Tyne NE2 4HHUnited [email protected]@ncl.ac.uk

***Department of RheumatologyLeiden University Medical CenterP.O. Box 96002300 RC LeidenThe [email protected]
mailto:[email protected]:[email protected]:[email protected]


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LEARNING OBJECTIVES

After following this module on rheumatoid arthritis, pathogenesis and clinical aspects, the students will

be able to:

Describe how environmental, genetic and immunological mechanisms interact in the

pathogenesis of the disease

Explain the relationship between undifferentiated arthritis and RA

Describe the characteristic pattern of joint involvement in early and established disease

State and describe the typical extra-articular manifestations

Describe the most commonly used tests for assessment of disease activity and health-related

quality of life

Use this knowledge in diagnosis and assessment of RA

I - PATHOGENESIS OF RHEUMATOID ARTHRITIS

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder that typically affects small and medium-

sized joints in a symmetric fashion. The primary lesion is synovitis whereby immune cells invade the

normally relatively acellular synovium, leading to the formation of inflammatory pannus. This

hyperplastic, invasive tissue causes cartilage break-down, bony erosion and, ultimately, loss of

function of the affected joint(s). Systemic involvement, for example of the respiratory, cardiovascular

and haematopoietic systems, may also occur. Consequently the risk of atherosclerosis and lymphoma

development is increased in RA, which is associated with a 7 year reduction in life-expectancy.

For the clinician, the striking heterogeneity of RA, in terms of clinical presentation, natural history and

drug responsiveness, means that it remains as challenging to manage as it is fascinating to study.

This heterogeneity extends to a molecular level and, intriguingly, recent analyses of genetic risk

factors, autoantibodies and drug responsiveness indicate that it may one day be possible to stratify

the disease into prognostically and therapeutically meaningful subsets close to the time of symptomonset, permitting individually targeted treatments, with obvious benefits in terms of clinical outcomes

and cost. These ideals remain far off, however, and lie behind the need for an ever improved

understanding of the pathophysiology of RA.

In this section, current and evolving concepts in RA pathogenesis are considered. We focus on RA as

a putative autoimmune disease, the role of autoantibodies in disease stratification, and the associated

genetic epidemiology. We summarise the molecular pathways involved, emphasising established and

emerging therapeutic targets.


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I - 1 Epidemiology of RA

RA affects approximately 0.5-1% of European and North-American adults, with considerable regional

variation. Prevalence estimates for Southern European countries (median of 3.3 cases per 103) are

lower than for Northern Europe (5.0 per 103), and highest rates are found in North America (10.7 per

103) (1). Asian studies report between 2.8 and 3.5 cases per 103, but the disease is said to be absent

from certain parts of rural Africa. In some Native American tribes up to 5% of individuals are affected.

Annual incidence rates are estimated to be 16.5 cases (per 105) in Southern Europe, compared with

29 in Northern Europe and 38 in North America (1). Women are about three times more frequently

affected than men. It has long been documented that RA clusters in families: the likelihood that a first-

degree relative of a patient will share the diagnosis is 210 times the population prevalence of the

disease, and recurrence risks are highest for relatives of the most severely affected index cases (2).

I - 2 Autoantibodies: RA as an autoimmune disease.

Witebsky postulated in 1957 that a disease must fulfil three criteria to be considered autoimmune in

nature. A contemporary understanding of these postulates requires 1) the presence of autoantibodies

or a cell-mediated immune response against an autoantigen, 2) that the respective autoantigen is

known and 3) that a similar disease can be initiated in animals based on an analogous immune

response (3, 4). The status of RA as an autoimmune entity, whilst generally accepted, remains

somewhat controversial based on these requirements. For example, although an array of antibodiestargeting self antigens (including collagen type II, calreticulin, cathepsin, BiP, CH65 and human

collagen glycoprotein 39) has been described, the identity of a dominant arthritogenic autoantigen has

remained elusive. Moreover, whilst inflammatory arthritis of autoimmune aetiology, and with

phenotypic similarities to human RA, may be artificially induced in animals (as in the example of

collagen induced arthritis; CIA), the direct relevance of such models to human disease has been

difficult to demonstrate.

I 2 -1 Rheumatoid FactorThe initial notion that mechanisms of autoimmunity might underlie RA pathogenesis came from the

discovery of autoantibodies targeting the Fc-part of human IgG (so called rheumatoid factors (RFs)

in the blood of affected patients (5,6). RFs, present mostly as IgM-RF, but detectable in subgroups of

patients also as IgG- and IgA-RF, are thought to form immune complexes activating complement in

the joint, which in turn leads to increased vascular permeability and the release of chemotactic factors

recruiting immune-competent effector cells to the joint (7). The mere presence of RF, however, is

insufficient to initiate arthritis development, as RF are also found in infectious diseases, autoimmune

diseases other than RA and in up to 15% of healthy, mostly elderly individuals. Thus, sensitivity and

specificity of RF are, depending on the population studied, 60-70% and 50-90%, respectively, and


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their role in disease aetiology remains unclear. Despite this lack of specificity, presence of RF is one

of 7 diagnostic criteria for RA put forward by the American College of Rheumatology in 1987 (8).

I 2 -2 Anti-citrullinated peptide antibody (ACPA)

Citrullination is a process by which arginine residues in a given protein are post-translationally

modified (deiminated) in the presence of high calcium concentrations by an enzyme called PAD

(peptidyl arginine deiminase). Citrullination is a physiological process, which is believed to be

important for degradation of intracellular proteins during apoptosis. In 1998, two antibodies present in

RA patient sera that had been described already years before (so called antiperinuclear factors,

discovered in 1964 (9), and anti-keratin antibodies, first described in 1979 (10)) were found to share a

common specificity for citrullinated fillagrin (11;12). This observation placed citrullinated proteins at

the center of autoantibody research in RA. Citrulline-specific reactivities against a number of

additional citrullinated proteins (e.g. fibrinogen, vimentin, and -enolase) have since been identified.

Using novel assays that employ synthetic cyclic citrullinated peptides (CCP) as antigens, anti-

citrullinated protein antibodies (ACPA) are found in 60-70% of RA-patients, but hardly ever in other

diseases or healthy subjects (13). Despite their unique (>95%) specificity for the disease, the extent

to which ACPA are directly involved in RA pathogenesis continues to be the subject of intense debate

and investigation.

Circumstantial evidence for their role in disease induction comes from observations that ACPAs canbe detected in sera several years before clinical onset of arthritis (14), that their presence predicts

progression from undifferentiated arthritis (UA) to RA (15) and that they are associated with a more

severe course of disease (16). Longitudinal studies and studies in healthy relatives of ACPA-positive

RA patients have shown that the number of citrullinated epitopes recognized by ACPA increases

during the development of RA (epitope-spreading), and the isotype repertoire of these autoantibodies

concurrently expands (17). Interestingly, IgM-ACPA are detectable in samples from patients with early

as well as long standing RA, indicating that new antibody secreting cells are continuously generated

as a reflection of an ongoing immune response (18). Among the different ACPA specificities identifiedso far, citrullinated vimentin is identical to the previously described and highly RA-specific Sa-antigen

(19). Specific mutations of vimentin have been detected in RA synovial fluid, and serum titres of

antibodies targeting these mutated isoforms (called mutated citrullinated vimentin, MCV) correlate

with disease activity (20). It is currently not clear if measurement of these autoantibodies will add

value over CCP for diagnostic purposes in early arthritis (21, 22).


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Figure 1: Schematic representation of factors relevant for the development of RA. Genetic and

environmental determinants interact to create an adverse immune state in the predisposed individual,

which may include the generation of circulating ACPA. When, how and why a "trigger event"

subsequently causes pathology to become focussed in the synovium, is unknown, but it likely involves

the innate immune system, and further interaction of genetic and environmental factors. A self-

perpetuating inflammatory cascade follows, producing the clinically recognisable, albeit

heterogeneous, RA phenotype. TLR: Toll-like receptor.


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Taken together, these observational findings strongly point to a crucial role for ACPA in RA-

pathogenesis. This is supported by data showing different pathological synovial features of ACPA-

positive versus ACPA-negative disease (23). Indeed, elegant animal studies suggest that ACPA-

positivity may soon be said to define a subgroup of RA with a full set of "autoimmune" credentials as

originally defined by Witebsky. For example, antibodies to a citrullinated, immunodominant B-cell

epitope of collagen type II (CII) which recognize citrullinated CII also in human joints were recently

found to be arthritogenic in the mouse (24). In a similar manner, monoclonal antibodies against

citrullinated fibrinogen were found to enhance arthritis in a mouse model of pre-existing collagen-

induced arthritis (25). Moreover, citrullinated human fibrinogen, but not unmodified fibrinogen, was

able to induce arthritis in HLA-DRB1*0401 (DR4-IE) transgenic mice (26). No induction of arthritis was

seen in wild-type mice lacking the transgene. The important influence of polymorphism at the HLA-

DRB1 locus on ACPA status in humans is outlined in detail below.

I - 3 Genetic Risk Factors

Twin studies permit an estimation of heritability (the extent to which liability to a condition in a

population can be explained by genetic variation), and on the basis of British and Finnish populations

the heritability of RA has been calculated as 60%(27). Many genetic variations that show association

with RA have been identified within the last few years due to technical advances in genotyping, and

they are summarised here. Intriguingly, the majority of these associations apply primarily to ACPA-

positive RA, being either absent or less robust for its ACPA-negative counterpart.

I - 3 - 1 HLA association

The strongest and most relevant genetic risk factor for the development of RA, contributing around

30% to the total genetic effect, is found at the HLA class II molecule-encoding locus (chromosomal

position 6p21.3) and relates to experiments first performed in 1969. In autologous mixed lymphocyte

reactions, lymphocytes from RA-patients proliferated poorly when cultured with lymphocytes from

other RA-patients, whereas their proliferative potential was normal in response to lymphocytes from

healthy donors (28). This finding indicated genetic similarities between RA-patients, which weresubsequently found to reside in the MHC class II locus, namely the HLA-DRB1 alleles. Several HLA-

DRB1 molecules (*0101, *0102, *0401, *0404, *0405, *0408, *1001 and *1402) share a common

amino acid sequence at position 70-74 in the third hypervariable region of the DR1-chain. This

sequence, consisting of glutamine-leucine-arginine-alanine-alanine (QKRAA), QRRAA or RRRAA, is

associated with RA and has been termed the shared epitope. It is situated in the antigen binding

cleft of the respective class II molecule and has thus been implicated in binding of a putative

arthritogenic peptide (shared epitope hypothesis) (29). Multiple efforts aimed at identifying such a

peptide in human RA, however, have failed, and recent availability of the crystal structure of DR

molecules revealed that the shared amino acids actually face away from the antigen binding cleft.


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Thus, alternative explanations for the shared epitope effect have been put forward, favouring a

possible role of the sequence in shaping a T cell repertoire biased towards generation of autoreactive,

non-tolerogenic T-cells.

Many studies underline the strong association between shared epitope and susceptibility to, as well

as severity of, RA. Individuals heterozygous for the shared epitope suffer from more severe and

erosive disease than SE-negative patients, an effect that is further increased by homozygosity. HLA-

DRB1 SE homozygotes, whether simple (having two copies of the same allele) or compound, also

have a higher risk of developing extra-articular disease manifestations including vasculitis. But

perhaps the most significant recent finding concerning the SE is the realisation that, rather than being

a primary risk factor for RA per se, it in fact represents first and foremost a risk factor for ACPA

positivity (30), with these autoantibodies developing preferentially (but not exclusively) in patients that

harbour one or two shared-epitope alleles. Importantly, the presence of two shared-epitope alleles

does not induce higher ACPA-levels than presence of only one allele, indicating a dominant effect of

the shared epitope on the immune response (31). A possible explanation is that deimination of

arginine to citrulline greatly increases the affinity of putative peptide autoantigens for the positively

charged binding groove common to the class-II MHC -chain products which incorporate the SE (32).

Detailed analysis of the shared epitope points to a mechanism whereby the identities of amino acids

at positions 70 and 71 might, by modulating T-cell responses, influence risk of ACPA-positive RA:

Arginine (R) or glutamine (Q) at position 70 and leucine (K) at position 71 confer a higher risk for the

development of RF and ACPA than alanine (A) or glutamic acid (E) at position 71 (33).

With this in mind, it is notable that a distinct amino acid sequence containing the aspartine (D) residue

(DERAA), and encoded by several HLA-DRB1 alleles (*0103, *0402, *1102, *1103, *1301, *1302,

*1304), has been found to independently protect its carriers from the development of RA when

present at the same DR1 position. DERAA-encoding alleles are found in approximately 30% of

healthy Caucasian individuals, and only ~16% of RA-patients. Their protective effect seemingly

remains even in the presence of coexisting SE alleles, and they are associated with less erosive

disease in both ACPA-positive and negative patients. The protective mechanism of DERAA has

remained elusive (34), however, and remains at present no more than a tantalising hypothesis.

Indeed, a recent meta-analysis suggests that, rather than being defined by the amino acid sequence

at positions 70-74 per se, risk is in fact primarily related to the specific DRB1*1301 allele (35).

I - 3 - 2 Non- HLA association

The first robust non-HLA genetic association with RA was found during investigation of the PTPN22

candidate gene, which encodes a lymphoid specific protein tyrosine phosphatase, Lyp. A single

nucleotide polymorphism (SNP) at position 1858 (C->T) leads to a gain-in-function mutation in


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Caucasian populations, whereby enhanced regulation of T-cell receptor (TCR) signalling during

thymic selection is thought to permit autoantigen-specific T cells to escape clonal deletion. This

appears to predispose to autoimmunity in general, and to ACPA-positive (but not ACPA-negative) RA

in particular (36).

Several whole genome association scans have recently been performed on large RA cohorts and

healthy controls originating from different countries. Such genome-wide scans test up to 500,000

SNPs distributed over the entire genome for their association with disease. In addition to confirming

association at HLA-DRB1 and PTPN22 loci, these scans have identified polymorphisms in genetic

regions encoding a large number of protein products that may have pathophysiological relevance in

RA. Initially, polymorphism at STAT4, 6q23 and 9q33.2 loci were identified as novel risk factors for

ACPA-positive disease (37-39). STAT4 (chromosome 2q32) encodes a transcription factor (signal

transducer and activator of transcription 4) involved in the differentiation of both type 1 helper T cells

(Th1) and Th17-cells, discussed later. Although direct evidence for specific gene disruption by risk

alleles at the other 2 loci has not yet been forthcoming, the most biologically compelling candidate

genes remain TNFAIP3 and TRAF1 respectively. TNFAIP3 (tumor necrosis factor- induced protein

3) codes for a protein (A20) that is a negative regulator of NFB and as such involved in the

regulation of TNF- signalling. (40;41). TRAF-1 (tumor necrosis factor receptor associated factor-1

(37;42)) is involved in signalling of TNF- via TNFR-1 and, interestingly, down-stream NFB. A

potential implication of RA association with TNFAIP and TRAF1 is therefore the importance of the

NFB pathway in disease induction, and several additional risk loci containing NFB related geneshave now been identified: CD40, PRKQC and TNFRSF14 (43-46). Functional studies are needed to

confirm and further explore the mechanism of such associations.

Additional RA-associated genetic variants have been found in regions or genes encoding CTLA4,

KIF5A-PIP4K2C, CCL21, CDK6, CD28, PRDM1, CD2/CD58 and IL2RA (43, 47). It is important to

note that the majority of association studies performed to date have been in Caucasian populations,

and some important racial differences exist with regards to risk profiles. For example, the PTPN22

risk allele is not seen in Asian populations(48), where convincing evidence conversely exists for anassociation of RA with a SNP in the PADI4 locus (chromosome 1p36.13), which encodes the enzyme

PAD(49). Moreover, the non-HLA genetic variants described here invariably confer only very modest

independent disease risk, often displaying individual odds ratios of little more than 1. The additive

effects of such minor genetic determinants are unlikely to ever describe all of the unaccounted

heritability of RA, and it seems likely that distinct genetic risk factors may provide multiplicative, rather

than merely additive, combined risk because of their compound molecular consequences, with gene-

environment interactions further completing the picture.


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I - 3 - 3 Smoking, genes, autoantibodies, and the problem of ACPA-negative RA.

Cigarette smoking is the most important environmental risk factor for RA. Several years of smoking

confer an increased risk of the disease, and is associated with more severe disease, that risk

increasing in proportion to the number of pack-years (50). Importantly, and analogous to the case with

SE and PTPN22 risk alleles described above, smoking is seen to represent a risk factor for ACPA-

positive, but not ACPA-negative, RA. Indeed, this risk is further increased in the presence of SE

alleles (up to an estimated 21-fold as compared to shared-epitope negative non-smokers), illustrating

the multiplicative effect of combined risk factors (51, 52). PTPN22 risk alleles also appear to interact

with SE alleles to confer multiplicative risk (51). In the light of these observations, it has been

proposed that cigarette smoke could be involved in the induction of protein-citrullination. Supporting

this hypothesis, citrullinated proteins have been detected in bronchoalveolar lavage fluid from

smokers but not from non-smokers (53). Thus, smoking might induce apoptosis and subsequently

citrullination in alveolar cells, which, by a mechanism so far unknown, induces an anti-citrullin specific

immune response. How and why this response eventually targets the joints, however, remains

unknown and could require additional environmental factors.

It has become tempting to speculate that ACPA status delineates two pathophysiologically distinct

subsets of a clinically defined phenotype which happens to satisfy the ACR criteria for RA. If this is

the case, then we still have a lot to learn about autoantibody negative disease. Certainly, robustly

validatedgenetic risk factors have yet to be convincingly identified for ACPA-negative RA. A possible

such factor is the MHC-class II gene HLA-DR3, which is part of a conserved haplotype (A1; B8;DRB1*03) that includes the MHC class III region, itself comprising many immune-related genes. Thus,

variance at this locus could influence susceptibility to, and degree of, inflammation. Alternatively,

HLA-DR3 could predispose to the development of another, yet unidentified autoantibody distinct from

ACPA (54). In addition, polymorphisms defining several haplotypes in the promoter region of the gene

coding for IRF5 (interferon regulatory factor 5) were found to associate with ACPA-negative RA. IRF-5

is involved in signalling via Toll-like receptors 7 and 9, and the polymorphisms might influence the

induction of IRF-5 dependent type I interferons (55). One partial explanation for the relative lack of

identified risk factors for ACPA-negative RA is the challenge of recruiting sufficient numbers of well-ascertained patients into studies, such that the majority of large-scale association analyses to date

have been biased towards ACPA-positive disease. Nevertheless, family-based studies do show that

the degree of heritability is similar between the two subtypes, indicating that additional, as yet

unidentified genetic factors must exist that predispose to ACPA-negative RA (56).

I - 4 Additional Environmental Risk Factors

Scope for additional robust gene-environment interactions to be found in the aetiology of RA remains,

but that of smoking in relation to the SE is the only one discovered to date. In the context of RA, some

environmental factors may have specific effects directly related to RA-pathogenesis (as suggested for


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smoking), whereas others might have non-specific effects promoting inflammation in general (e.g.

triggers of innate immunity). Thus, the former will only be relevant for subtypes of RA (e.g. ACPA-

positive RA), whereas the latter will influence disease in a broader sense. In addition, these factors

might be relevant at distinct time-points during disease development. Additional proposed

environmental risk factors for RA should be evaluated with caution, as they have generally been

reported in single cohorts, or in cohorts with small sample sizes. Nevertheless it is interesting that

most of them again appear to be most prominent in ACPA-positive disease.

Infections are major candidates for the induction of autoimmunity and have, therefore, been

intensively studied also in RA. Several pathogens (mycobacteria, Ebstein-Barr Virus, Parvovirus B19,

Porphyromonas gingivalis and others) have been debated to trigger the initial immune response

necessary for RA-development in a genetically susceptible host. To date, however, no pathogen-

derived antigen has been clearly linked to RA-pathogenesis, and convincing evidence for cross-

reactivity of self-antigen-specific T- or B-cells with pathogen-derived peptides (molecular mimicry) in

a manner relevant for RA-development is still lacking. Coffee consumption has shown association

with RA in several cohorts, although stratification for smoking usually reduced significance of this

finding. In a Danish cohort, however, coffee consumption did show association with ACPA-positive

RA after adjustment for smoking. Alcohol intake, on the other hand, seemed to have a protective

effect on the development of ACPA-positive RA, whereas no effect was found for ACPA-negative RA

(57). Strong association with ACPA-negative RA has been shown for individuals with high body-mass

index (57), although this finding has been questioned by other studies.. Adipose tissue is receivingincreasing attention due to its recently discovered immune-modulatory properties, as adipocytes are

an abundant source of pro- and anti-inflammatory cytokines. Occupational exposure to mineral oils

(e.g. motor oils, hydraulic oils etc.) was found to be a risk factor for ACPA-positive RA in males in a

Swedish cohort, independent of the presence of shared epitope alleles. This finding is of interest, as

mineral oils are arthritogenic in certain rat-strains due to a yet unknown mechanism (58).

Female predominance in various autoimmune diseases including RA suggests that sex hormones

and reproductive factors influence both RA-development and severity. Women with lower age atmenarche have a comparatively low risk for the development of RA. In the Danish cohort, for example,

women with older age at menarche (15) had an almost 2 -fold risk to develop RA as compared to

women aged 12 years at menarche. Pregnancy is in itself a risk factor for the development of RA, as

around 12% of women with RA experience disease onset within one year after pregnancy. During

pregnancy, most women with RA (in older studies up to 90%) experience a significant reduction in

disease activity (including complete remissions), but almost all patients relapse within six months after

delivery. Multiparity (>3 children) favours a more severe course of disease, but does not additionally

increase the risk for developing RA. Use of oral contraceptives, on the other hand, lowers disease


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severity, but data from initial studies showing a protective effect on RA development could not be

confirmed after adjustment for age (57, 59).

I - 5 Disturbances of the Immune System

The heritability of RA, together with the presence of autoantibodies that precede clinical onset in a

subset of patients, supports a now widely-held pathogenetic model in which autoimmune propensity is

long-established by the time joint inflammation is triggered (Figures 1 & 2). The precise nature of the

trigger(s), and the tendency for


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Figure 2: Suggested mechanism of the development of the immune response. Antigen-specific T cellactivation by DC-T cell interaction usually occurs in lymph nodes. Nave T cells thereby differentiateinto effector T cells that give help to B cells, which leads to production of autoantibodies (e.g.ACPA).These form immune complexes and accumulate in joints, activating complement. This leads torecruitment of effector cells (macrophages, neutrophils, etc.) which secrete proinflammatory cytokinesand chemokines and activate osteoclastogenesis. Note that this figure depicts a hypothesis, as acrucial pathogenetic role for ACPA has not yet been fully demonstrated. (Figure adapted with

modifications from Luross et al. (2001), Immunology 103:407-416)

ensuing inflammatory pathways to converge in peripheral synovial joints, remain tantalisingly

unexplained, however, though innate immune mechanisms undoubtedly play an important role.

Thereafter rheumatoid synovitis is characterized by the infiltration of various immune effector cells,

typically via chemo-attractant gradients. Over time, this process creates a cytokine milieu in the joint

that activates synovial fibroblasts and osteoclasts, which in turn degrade cartilage and bone. Key

cellular mediators as well as important cytokines supporting this process are discussed here.

I - 5 - 1 T cells

T cells are one of the most abundant cell types in RA synovium, comprising 3050% of synovial

tissue cells.The majority are CD4+, T-helper (Th) cells, matured from nave precursors, which have

traditionally been divided into Th1 and Th2 subtypes.In health, Th1 cells secrete interferon- (IFN)

and defend against intracellular bacteria; IL-4-secreting Th2 cells combat extracellular parasites. Only

recently have two novel CD4+ subsets begun to be properly characterised: Th17 cells appear to

defend against extracellular bacteria such as Klebsiella pneumoniae, whilst regulatory T cells (T-regs)

play a vital role in immune tolerance and the modulation of established immune responses.

Along with other immune cellular pathologies such as multiple sclerosis and diabetes, RA has

historically been thought of as a result of immune deviation away from a healthy balance of T-cell

derived cytokines, and characterised by a preponderance of Th1 over Th2 cells. The paucity of

measurable IFN- and IL-2 in RA synovia challenged that dogma, however, and it now seems likely

that newly described Th17 cells are significant players in autoimmune inflammation (60). The

differentiation of this cell-type from nave precursors requires the presence of TGF, IL-23 and pro-

inflammatory cytokines such as IL-6 and IL-1 (61). Lineage commitment of human Th17 cells

appears to be flexible, with sub-populations producing IFN- or IL-10 in addition to IL-17. Apart from

these cytokines, Th17 cells can produce TNF-, IL-6, IL-22 and GM-CSF (62). Th17 cells are critical

orchestrators of CIA in mice (63), and evidence for their importance in human RA comes from the

observation that both IL-17 and IL23 are found in sera, synovial fluid and synovial biopsies of patients,

but are mostly absent from the same compartments in osteoarthritis. IL-17 itself is highly pleiotropic,

acting on a variety of cell-types to perpetuate local inflammation whilst promoting angiogenesis,

osteoclastogenesis and, ultimately, the destruction of cartilage and bone. It has itself therefore

become an interesting novel therapeutic target in RA (64), and the efficacy of tocilizumab, an IL-6


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antagonist approved for the treatment of RA, might in part be explained by an influence on Th17-

development and function.

T-regs appear to be overrepresented in the synovium of RA patients, but controversy remains as to

whether this might simply reflect ongoing methodological challenges in distinguishing cells of this

phenotype from activated T-cells in humans. If the suggested overrepresentation is real, it may

suggest the functional impairment of T-regs within the autoimmune microenvironment they are

supposed to suppress (65). A possible explanation is that Treg cells express TNFR-II, which makes

them susceptible to deleterious effects of TNF- (66). Indeed, functional T-reg defects may be

reversed following treatment with TNF-antagonists (67), apparently through the generation of a

distinct Treg-cell population that secretes TGF- and IL-10 (68). Tregs have been used successfully

to treat murine CIA (69), and an analogous cellular therapy approach in man may not be as far-

fetched as it once seemed.

Of all T-cell targeted approaches to date, the therapeutic efficacy of CTLA4-Ig (abatacept) provides

perhaps the most satisfying evidence that these cells are important drivers of RA. For efficient effector

T-cell maturation, the recognition of antigen by nave T-cells in the context of MHC-molecules

requires additional costimulatory signals, without which T-cells become anergic. Interaction of

surface-expressed CD28 (T-cells) and CD80/86 (antigen presenting cells; APCs) generates one of

the most important such signals, with excessive signalling normally controlled by T-cell derived CTLA-

4. The exploitation of this mechanism using abatacept is now an established treatment option.

I - 5 - 2 B cells

The importance of B cells in RA-pathogenesis has only recently been appreciated. The realisation

that circulating autoantibodies often predate arthritis onset implicates early involvement of

autoantigen-specific B cell activation and plasma cell differentiation. The frequent occurrence of

germinal centre-like structures in RA synovium, ideally suited to humoral immune responses, along

with the recognition that B-cells can themselves present antigenic peptides (even priming naive T-

cells in some cases(70)), has made the case for their role in pathology (71). This is borne out by thesuccess of therapeutic B-cell depletion using, for example, rituximab, which has proven to be highly

effective even in patients with inadequate response to TNF-antagonists.

Far from being mere "antibody producers", accumulating evidence assigns B-cells key roles in many

aspects of immune functions, including the first encounter with antigen. For example, B-cells express

several toll-like receptors (TLRs) on their cell surface which transmit danger signals by binding

bacterial cell wall components or DNA (pathogen associated molecular patterns; PAMPs). Hence,

hypomethylated mitochondrial DNA released from dead cells (which are abundant in RA-synovium)

could conceivably activate autoreactive B-cells, driving autoantibody production and immune complex


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formation. Evidence from mouse models suggests that such a mechanism is plausible in the absence

of T-cell "help" (72), at least where coordinated B-cell receptor ligation occurs, and in the presence of

BAFF (B-cell activating factor, TNF family) (73).

During inflammation, B cells infiltrate RA synovium, although the degree of infiltration and local

structural organization varies significantly between patients. Fibroblast-like synoviocytes and dendritic

cells in synovium secrete factors attracting B cells and influencing their differentiation and survival, as

well as orchestrating the formation of tertiary lymphoid structures in some patients, which themselves

perpetuate autoimmunity. These include BAFF, CXCL12, CXCL13 and APRIL, some of which are

currently being evaluated as therapeutic targets. B cells can also take up antigen via surface Ig and

are very efficient APCs. Moreover, recent evidence suggests that Ig-class switching and somatic

hypermutation, which are classically dependent on CD40-CD40L interactions with CD4+ T-cells, may

also occur independently of T cells. This process again requires BAFF, which is present in elevated

amounts in RA synovium and additionally prolongs B cell survival (71;74).

B-cells are prolific producers of cytokines. By secreting TNF- and IL-6, they contribute to the

activation of macrophages and directly participate in inflammation. IL-6 is also an important autocrine

differentiation factor for B cells themselves. RF from B-cells form immune complexes that can induce

tissue damage and efficiently activate complement. They can also be taken up by macrophages,

thereby perpetuating inflammatory cytokine secretion (75). Finally, as with CD4+ T-cells, a regulatory

B-cell phenotype has recently been described, which produces IL-10 in abundance and may down-regulate immune responses by tolerising T cells (76). The potential for this mechanism to be exploited

for therapeutic ends will be an active field in the coming years.

I - 5 - 3 Mast cells

Mast cells are highly granular cells best known for their role in allergy and anaphylaxis, as

components of the innate immune system. They may be stimulated to degranulate in response to

direct injury, Fc receptor cross-linking, TLR ligation or activated complement, releasing cytokines,

proteases and biogenic amines including histamine. The observation that mice deficient in mast cells

were resistant to experimental arthritis (77) led to a new appreciation of their potential to contribute to

human disease, where their presence indeed correlates with disease progression. TGF-,

complement components C3a and C5a, serum amyloid A and platelet activating factor are important

for mast cell recruitment, and their differentiation is supported by stem-cell factor secreted from

fibroblasts, stromal cells and epithelial cells.

Once activated, the many mediators released by mast cells appear to act in concert, driving

neighbouring immune cells towards an inflammatory phenotype, promoting angiogenesis and, both


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directly and indirectly, degrading cartilage (78). Recently, a previously unrecognised and potentially

crucial role for mast cells has been discovered as producers of IL-17. Indeed, within the rheumatoid

synovium they may be more important in this regard even than Th17 cells (79). In addition, a

prominent role for mast cells in the pathogenesis of ACPA-positive RA in particular is suggested by

the presence of IgE ACPA, and the observation that synovial fluid histamine levels are highest in

seropositive disease, possibly as a result of ACPA IgE-mediated mast cell degranulation(80).

I - 5 - 4 Monocytes/Macrophages

The role of activated macrophages in RA synovium is central to driving and maintaining chronic

inflammation. Macrophages are multipotent effector cells that very efficiently integrate innate and

adaptive immune responses. They are abundantly present in the rheumatoid synovial membrane and

at the cartilage/pannus junction. Important functions include strong phagocytic activity, antigen

processing and presentation, expression of Fc-receptors responsive to (auto-) antibodies and

immune complexes, complement activation and regulation, toll-like receptor (TLR) expression, and

tissue degradation and remodelling. They are important producers of pro-inflammatory cytokines (E.g.

TNF-, IL-1, IL-6), cartilage-degrading enzymes (MMP9 and 12) and growth factors (GM-CSF),

amongst other mediators of pathology. The relative importance of these various macrophage

functions during the course of disease may change over time (81). With such a central role in the

disease process, it is perhaps unsurprising that the abundance of this cell-type in the synovial sub-

lining and, specifically, expression of its CD68 surface marker - has now shown promise as an early

biomarker for drug responsiveness in RA (82).

As macrophages are tissue-resident in most organs they are, along with dendritic cells, likely to be the

first to encounter pathogen-derived antigen, and are well-placed to present it to autoreactive T cells,

providing the initial trigger necessary to start an immune response on the basis of genetic

predisposition. In this regard, synovial macrophages have been shown to respond to direct cell-

contact with T cells and fibroblasts. Co-culture with fibroblasts not only induces secretion of IL-6, IL-8

and GM-CSF, but also enhances cartilage degradation in vitro(83). Bacterial cell wall (e.g. LPS) and

nuclear (e.g. DNA) components, but also cartilage degradation products such as hyaluronic acid, arestrong macrophage activators Macrophages are also responsive to oestrogens, a finding that could

explain changes in disease activity during pregnancy. Interestingly, physiological oestrogen levels

induce IL-1 expression, whereas higher levels (as occur in pregnancy) inhibit IL-1 secretion (84).

Macrophage function is in itself regulated by various cytokines that in some cases have autocrine

effects. IL-4, for example, downregulates macrophage function by reducing the expression of TNF-,

IL-1 and PGE2. IL-10 lowers the expression of HLA-DR and reduces antigen processing and the

expression of Fc-receptors. Both IL-4 and IL-10 have strong anti-arthritic properties in murine models

of arthritis, and some studies have linked polymorphisms in the IL-10 gene to disease susceptibility

(85).


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I - 5 - 5 Inflammatory cytokines

The efficacy of monoclonal antibody therapy directed against the pleitropic, pro-inflammatory

monokine TNF in the 1990s represented a seminal moment in the search for rational drugs in the

treatment of RA. The depletion of IL-1 (e.g. anakinra) proved less of a success story in this setting,

but has found a niche in the management of auto-inflammatory conditions and, potentially, gout. More

recently, anti-IL-6 therapy (tocilizumab) has proved beneficial to patients including those who have not

responded to anti-TNFa drugs. Pro-inflammatory cytokines represent mediators of active disease,

encouraging the recruitment and activation of the adaptive immune system, and inducing synovial

fibroblasts to secrete cartilage degrading matrix metalloproteases but they remain non-specific

targets which may be less important in early disease. With this in mind, it is notable that patients with

early arthritis (symptom duration less than 3 months) that progressed to RA exhibited a different

synovial cytokine profile than patients that remitted or developed other arthritides(86). Patients prone

to develop RA showed elevated levels of T cell-derived cytokines IL-2, IL-4, IL-13 and IL-17 and of

stromal and macrophage related cytokines EGF, bFGF, IL-1 and IL-15. IFN- was not detected in

these samples, and IL-6 seemed to be associated with inflammation independent of underlying

disease phenotype. Interestingly, this profile was absent from patients with established RA and

seemed to be present only transiently. The absence of Th1-cytokine IFN- and the presence of Th2-

cytokines IL-4 and IL-13 together with (presumably) Th17-derived IL-17 in early RA favour an

important role for T cells in particular Th2 and Th17 cells - in the initiation phase of RA.

T cells, macrophages and stromal cells are also the main source of cytokines in established RA.Macrophage derived cytokines, however, predominate, and T cell derived cytokines become less

abundant. Examination of synovial biopsies indicates that disease-subtype specific patterns might

exist. Distinct cytokine profiles were found to correlate with subtypes of lymphocyte infiltration in

active RA. Hence, diffuse lymphocytic infiltrates were associated with RF-negative RA and displayed

low levels of IFN-, IL-4, IL-1 und TNF-. Germinal centre formation, on the other hand, correlated

with high levels of IFN- and IL-10, and absence of IL-4. Patients with extra-articular disease

manifestations showed synovial granuloma formation associated with high levels of IFN-, IL-4, IL-1

and TNF- (87).

Other cytokines such as IL-12, IL-17, IL-23, IFN-, IL-4 and IL-10 have been discussed above. IL-18

needs consideration as proinflammatory cytokine driving macrophage activation together with IL-12

and IL-15. IL-18 is overexpressed in RA synovium, it induces RANKL-expression in T cells (see

below) and strongly aggravates experimental arthritis. The existence of a natural inhibitor, IL-18

binding protein, makes IL-18 an interesting therapeutic target (88). IL-15 attracts T cells and IL-15

activated T cells in turn activate macrophages. It is expressed in the synovial membrane and by

macrophages themselves. Finally, TGF- is an important regulator of tissue degradation and


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remodelling and displays pro- and anti-inflammatory properties. It is produced by macrophages in RA

synovium, and low expression of TGF- due to genetic polymorphisms is associated with disease

severity. In addition, TGF- drives development of regulatory T cells, but can also enhance Th17-

development in the presence of IL-6 (78).

I - 6 Cartilage and Bone Degradation The Role of Fibroblast and Osteoclasts

While immune effector cells discussed above are responsible for initiating and maintaining

inflammation, two cell types are of prime importance for destruction of cartilage and bone. Synovial

fibroblasts (SF) adhere to cartilage and degrade extracellular matrix. Osteoclasts, on the other hand,

are mainly involved in bone destruction. Both cell types closely interact with cells of the immune

system and, by secreting large amounts of cytokines, participate themselves in maintenance of

inflammation. Synovial fibroblasts in RA are characteristically found in the sub-lining layer of the

synovium. Expression of various transcription factors indicates that they proliferate locally in disease,

contributing to synovial hyperplasia. SF in RA-patients show prolonged survival,and resistance to

apoptosis. Intriguingly, they have been shown experimentally to have the potential to migrate between

joints in experimental models, suggesting a possible route to disease progression in humans (89).

Functionally, they adhere to cartilage via attachment to fibronectin, collagen type VI and cartilage

oligomeric matrix protein (COMP), and display an aggressive invasive behaviour. Synovial fibroblasts

are an abundant source of IL-15, -16 and -17. They also secrete CXCL12, CXCL13 and members of

the IL-6 family (e.g. IL-11). These cytokines activate T cells and influence B cell migration and survival.Large amounts of secreted PGE2 additionally support inflammation. In addition, degradation of

cartilage by SFs is due to the secretion of matrix metalloproteinases (MMPs) and cathepsins.

Specifically, SF produce MMP-1, -3, -13, -14 and -15 as well as cathepsins B, K and L. These

enzymes degrade extracellular matrix, providing a rich source of potential neo-antigens for T and B

cell polyclonal proliferation (90).

Bone degradation in RA is mainly mediated by osteoclasts. Osteoclastogenesis, i.e. the differentiation

of osteoclasts from precursor cells, requires M-CSF and the presence of an osteoclast differentiationfactor (ODF). Identification of this factor marked an important step in understanding osteoclast

differentiation, as it was found that ODF and osteoprotegrin ligand (OPG-L) are identical to RANKL

(receptor activator of NFkB ligand) and TRANCE (TNF-related activation induced cytokine),

molecules first identified in activated T cells (91). Meanwhile, RANKL has been found to be

specifically expressed in RA synovium, and RANKL-deficient mice are protected from bone

destruction in experimental arthritis despite active inflammation. RANKL is expressed not only by T

cells, which thereby directly drive osteoclastogenesis (60), but also by neutrophils and in large

amounts by synovial fibroblasts (92). TNF- accelerates this process by inducing RANKL-expression

and enhancing RANKL-signalling. Interestingly, Th1- and Th2-cytokines (IFN-, IL-4, IL-10) as well as


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IL-12 and IL-18 inhibit osteoclastogenesis. IL-17, however, induces RANKL-expression in osteoblasts

and might significantly contribute to osteoclast formation.

Figure 3: Factors contributing to osteoclastogenesis. Macrophages, synovial fibroblasts and T cellsexpress IL-1, TNF- and RANKL, factors important for differentiation of osteoblasts to osteoclasts.Multinucleated osteoclasts degrade bone, thereby creating radiographically detectable erosions.


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I - 7 RA Pathogenesis:

Summary Points:

Rheumatoid arthritis is a heterogeneous disease which can be, based on data combining

genetic risk factors and autoantibodies, sub-classified in ACPA-positive and -negative RA.

Presence of ACPA and RF as well as rising CRP-levels years before onset of clinical

symptoms indicate that relevant immune responses for RA development are initiated very

early.

ACPA are highly specific for RA, whereas RF can also be found among healthy (elderly)

individuals and patients with other autoimmune diseases.

The most important genetic risk factor for RA development, the shared epitope alleles, resides

in the MHC class II region. Shared epitope alleles only predispose to the development of

ACPA-positive RA. Smoking is thus far the most important environmental risk factor associated with the

development of RA. Similar to shared-epitope alleles, smoking is a risk factor only for ACPA-

positive RA.

The concept that RA is a Th1-mediated autoimmune disease is currently under revision. Th17

cells might be more crucially involved, and efficacy of B cell depleting therapy and the ACPA

response indicate that B cells are more relevant than previously anticipated.

RA development requires several factors acting at different points in time in an orchestrated

manner.

I - 8 RA Pathogenesis:

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60. Toh,M.L. and Miossec,P. 2007. The role of T cells in rheumatoid arthritis: new subsets

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II - CLINICAL ASPECTS OF RHEUMATOID ARTHRITIS

II - 1 Introduction

Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory joint disease. No single clinical

sign or symptom or test result distinguishes it from other joint diseases, nor are the pathological

features of synovitis, the hallmark of RA, unique. Rather RA is diagnosed on a combination of clinical

findings and laboratory tests. RA is a heterogeneous condition with a variable mode of disease onset

and disease course. Some patients have a very acute disease onset with fever, polyarthritis and

extra-articular manifestations, whereas other patients have a more gradual and insidious onset. The

latter presentation is more common. Typical articular signs and symptoms include pain, stiffness and

swelling. Redness and warmth of involved joints are less common findings. Concomitant tenosynovitis,

bursitis and even carpal tunnel syndrome may be present. RA is a systemic disease as manifested by

generalized weakness, weight loss or low-grade fever and extra-articular features such as sicca

syndrome, nodules, interstitial lung fibrosis.

A special type of RA has been called palindromic rheumatism. This clinical picture includes variable

episodes of polyarthritis which suddenly may affect one or more large or peripheral joints. The

duration may be hours or a few days and then spontaneous improvement with complete

disappearance of all rheumatic signs between attacks. About one third of these palindromic cases will

eventually evolve into typical RA. Both prevalence and incidence rates are about 2- to 4-fold higher inwomen, and symptoms are more severe than in men (93). The female/male ratio decreases with age.

The reasons for the greater prevalence of RA among women have not been firmly established. A

decline in the incidence of RA over recent decades has been reported in a number of countries (e.g.

Finland, England/Wales, United States and Japan). The decreasing incidence has been especially

apparent in women possibly as a consequence of some environmental factor such as the introduction

of oral contraceptives in the 1960s (94). A shift in the incidence towards a higher age at disease

onset has been observed across several cohorts. The incidence rate seems to increase with age up

to a plateau around 60 years (95).

II 2 Disease onset

II - 2 - 1 Articular Manifestations

The typical joint involvement at disease onset is swelling of the proximal interphalangeal (PIP) joints,

the metacarpophalangeal (MCP) joints, the wrists (Figure 5), and the metatarso-phalangeal (MTP)

joints. However, the disease may also start gradually with involvement of one or few joints and then

over time develop from undifferentiated oligo- or polyarthritis into a more polyarticular, and classically

symmetrical, disease. Sometimes the disease also starts with monoarthritis, e.g. of the knee. The


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differential diagnosis depends on the pattern of joint involvement at disease onset. Sometimes the

disease onset may be similar to reactive arthritis, but polyarticular inflammatory osteoarthritis is a

more common differential diagnostic consideration especially in patients aged 50 or over.

Figure 5: Symmetric swelling of the proximal interphalangeal (PIP) joints, the metacarpo-phalangeal

(MCP) joints, and the wrists are typical in rheumatoid arthritis

II - 2 - 2 Extra-articular Manifestations

The dominating feature at disease onset is usually joint involvement. However, the disease may startmuch more dramatically with fever and inflammatory manifestations of internal organs, e.g. with

pericarditis and pleuritis. In such cases, other systemic diseases may be the most important

differential diagnoses, e.g. systemic lupus erythematosus. Other extra-articular manifestations such

as sicca syndrome, nodules and interstitial lung fibrosis are more commonly seen in establishedRA.

II - 2 - 3 Symptoms

The symptoms of the patient will typically reflect the most prominent disease manifestations at

disease onset. Joints with inflammation are painful, tender and the patient perceives stiffness on

movement. The patients may also observe that the joints are swollen. A general feeling of morning

stiffness is common and typical. Other frequently occurring general symptoms include fatigue and

loss of energy.

II - 2 - 4 Clinical Findings

The typical clinical finding of inflamed joints is soft tissue swelling and tenderness, and frequently also

limited motion (Figure 6). Detection of synovitis is essential for the diagnosis (Figure 7 and 8). The


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joint swelling of the finger joints will often be symmetric and the same may be seen in middle sized

joints, eg the wrists, and in the forefeet. Involvement of shoulders and hips at disease onset is rare.

The clinical examination should include a general physical examination as extra-articular

manifestations may be present. In cases with serositis, clinical signs of pericarditis and pleuritis may

be present. Bibasilar inspiratory crepitations can point to underlying interstitial lung fibrosis.

A general organ examination is also important for the assessment of possible concomitant diseases,

since many of the relevant medications may lead to adverse reactions and interfere with existing

concurrent conditions.

Figure 6: Early synovitis of PIP and MCP joints-sourcehttp://www.lecofer.org-

Figure 7: Detecting synovial effusion with two-finger technique, flexing the proximal phalanx at 30.-sourcehttp://www.lecofer.org-
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Figure 8: Detecting PIP synovial effusion; four-finger technique-sourcehttp://www.lecofer.org-

II - 2 - 5 Laboratory investigations

Typical findings are elevated erythrocyte sedimentation rate and C-reactive protein concentration.

Thrombocytosis and leucocytosis can be seen in active inflammatory disease. Reduced hemoglobin

is also common. Serum iron may be lowered whereas ferritin concentration may be elevated as a

reflection of the acute phase reaction. It is important to do a general laboratory screening including

liver function test and creatinine as well as urine examination to examine whether there are any

indications of liver or kidney abnormalities.

Most importantly, tests for rheumatoid factor and anti-citrullinated peptide/protein antibodies (ACPA

such as anti-CCP antibodies) are important both for the diagnosis and for the staging of the disease

since the presence of rheumatoid factor and ACPA are associated with a more severe disease course.

Other immunological examinations may be important for differential diagnoses. It is common to test

for the presence of antinuclear antibodies (ANA), but the value of this test can be questioned if there

is no clinical evidence of any systemic connective tissue disease. The presence of anti-nuclear

antibodies has not been shown to have any prognostic value. However, secondary Sjgrens

syndrome can be seen together with RA and in some infrequent cases the typical immunological

markers of Sjgrens syndrome (anti-SSA and anti-SSB) may also be present in RA.
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II - 2 - 6 Imaging procedures

Ultrasonography may be helpful at disease onset to demonstrate synovitis of involved joints.

Subclinical synovitis can be detected with ultrasonography and Doppler, but the clinical utility of this

for clinical decision making remains to be established (Figure 9).

Figure 9: Ultrasonography with Doppler to detect synovitis of the MCP joints(S=synovitis, C=capsule, IP=interphalangeal) -sourcehttp://www.lecofer.org-

Ultrasonography may also be useful to detect erosions of smaller joints at an early stage of the

disease.

Conventional radiographic examinations are still the gold standard for diagnosing joint damage, but

the absence of erosions on X-rays does not rule out RA. Radiographic examinations of the hands,

wrist and feet are important as baseline examination for the subsequent monitoring of the disease.

Without the baseline radiographic assessment it will be difficult to assess radiographic progression

which is considered an unfavourable prognostic sign. Scoring systems have been developed and

validated to assess the extent of and changes in radiographic damage, such as the modified Sharp-

van der Heijde score which is commonly used in clinical trials (96).

MRI of wrist and finger joints may be an important tool for early diagnosis and staging of the disease.

Synovitis can be seen when the imaging procedure is performed with gadolinium contrast. Bone

marrow oedema is also a typical finding, which is considered as a predictor of subsequent erosions,

but bone marrow oedema

module3 pa tho genesis and clinical aspects ra

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