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1/14/23, 1:33 PM FULL-Mod2-Basic Learning | Prediction of outcome of undifferentiated arthritis and early RA
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Prediction of outcome of
undifferentiated arthritis and early RA
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After excluding other diseases and making a diagnosis of probable RA or UA,

the third step is to determine which patients are at risk of developing
persistent and/or erosive arthritis. This prognostic assessment is important
for guiding optimum treatment strategies. Predictors of persistence and
disease progression include demographic, genetic, clinical, serological, and
radiological factors (Landewé, 2007).
Assessment of disease persistence
Targets all patients with very early synovitis, will expose many patients
to unnecessary and potentially toxic treatments: indeed, spontaneous
remission of synovitis in patients with early arthritis (especially those
with symptoms duration less than 3 months) is frequent.
https://esor.eular.org/mod/scorm/player.php?a=2551&currentorg=adapt_scorm&scoid=5102 1/27
Psychological wellbeing also influences the outcome of RA, with

depression and anxiety at baseline being associated with a lower
chance to achieve remission after 1 year, predominantly caused by
subjective markers of disease activity (Michelsen et al. 2017, de Boer et
al. 2019).
On the other hand, seronegativity for RF and fewer active joints at

baseline in early RA have been suggested as markers of a favourable
outcome (Eberhardt and Fex, 1998).
Some factors are associated with disease persistence (box 1).
Assessment of disease severity
Individual factors predicting persistence and disease

severity
 Symptom duration
Several studies have shown longer symptom duration at the first visit to
be a predictor of disease persistence (Tunn and Bacon, 1993;
Schumacher, 2004; Green, 2001), with disease duration ≤12 weeks
associated with a better chance of remission (see part 2.2).
As discussed earlier, symptom duration is also an important predictor of

disease severity, with better clinical and radiographic outcomes seen in
patients with shorter symptom duration at the first visit to the
rheumatologist (van der Linden et al, 2010; Emery et al, 2012).
 Early morning stiffness (EMS)
EMS is an early symptom of inflammatory arthritis. It is, however, a

complex symptom and may be difficult for patients to distinguish from
pain and functional limitation.
It has been used as a clinical marker of disease persistence (Visser et

al, 2002; van der Helm et al, 2007).
Cut-off of EMS, to predict disease persistence, is different depending on

if we considered patients with arthralgia (≥60 min) or with early arthritis
(≥30 min): in patients with arthralgia, EMS ≥60 min was associated with
arthritis, and in the group of patients with early arthritis duration of
morning stiffness ≥30 min discriminated patients with RA (van Nies et
al, 2015).
Moreover, during the first phase of the development of the 2010

ACR/EULAR RA classification criteria, EMS—using the traditional cut-off
point of 60 min—was not found to be predictive of starting methotrexate
in patients with early inflammatory arthritis and was therefore
subsequently not included in the final classification criteria (Funovits et
al, 2010).
 Polyarticular disease and hand involvement
In a cohort of 121 patients with early arthritis followed up for a median

duration of 5 years, those with polyarticular disease and hand
involvement were more likely to have the persistent disease
(Schumacher et al, 2004). These findings have been confirmed by
several other studies (Machold et al, 2002; Sokka et al, 2003).
 Functional disability
Functional disability as measured by the Stanford HAQ disability index is

one of the most reliable predictors of disease outcomes in early arthritis
(Pincus and Callahan, 1985).
In patients with early disease, a high baseline HAQ is an important risk

factor for:
the development of future functional disability (Wiles et al, 2000)
quality of life and work disability (Combe et al, 2003; Eberhardt et al,
2007)
 Acute phase response
A rise in the level of acute phase reactants, such as the ESR and CRP,
provides a surrogate measure of inflammation. The combination of ESR
and CRP yields useful information that is often not apparent when only a
single test is used.
 Rheumatoid factor
Historically, RF has been one of the most consistent markers of disease

persistence and progression of radiographic damage in patients with
inflammatory arthritis (Wolfe et al, 1993; Bukhari et al, 2002; Machold et
al, 2007). Further, RF at a high titre was found to be a predictor of
disability (Harrison and Symmons, 2000).
 Anti-cyclic citrullinated peptide antibodies (ACPA)
The most used test in clinical practice to detect the ACPA is the assay
using the second-generation cyclic citrullinated peptide as an artificial
autoantigen (CCP2).
ACPA are present early in the disease course and can precede the onset
of symptoms by up to 10 years, particularly in the 2 years before
symptom onset (Rantapaa-Dahlqvist et al, 2003; Berglin et al, 2004)
ACPA represents an independent risk factor for developing RA in

patients with undifferentiated arthritis or arthralgia:
In early UA, 93% of patients who were ACPA (CCP2) positive at

baseline were diagnosed with RA at 3 years. Conversely, only 25%
of ACPA-negative patients had a diagnosis of RA at follow-up (van
Gaalen et al, 2004).
In patients with arthralgia but without clinical synovitis, an

expanded ACPA repertoire recognizing different citrullinated
peptides and higher anti-CCP levels was associated with a higher
risk of developing inflammatory arthritis (van de Stadt et al, 2011).
ACPA has a similar sensitivity to RF in early RA but a greater specificity.

The negative and predictive values of ACPA are high (table 4)
The presence of ACPA (and titre of ACPA) is also associated with:
baseline and long-term disease severity in patients with

inflammatory polyarthritis (independently) (Farragher et al, 2010;
Berglin et al, 2006)
radiographic damage and radiographic progression in patients with
RA (Meyer et al, 2003; Seegobin et al, 2014).
Osteoclastogenesis and serum markers for osteoclast-mediated
bone resorption in patients with RA (Harre et al, 2012). ACPA titres
have also been related to disease severity
Following treatment escalation, autoantibody levels dropped markedly,

while they rose following tapering (de Moel et al. 2019).
Nevertheless, measuring ACPA titres has not been proved to be of value

in monitoring treatment outcomes, although the levels of ACPA and
IgM-RF could decrease by up to 30-50% one-two year after initiation of
the treatment in early RA (Ursum et al. 2010).
Seroconversion from seronegative to seropositive seems to occur

seldom, in 2-3% of seronegative patients. The first-year changes of
ACPA and IgM-RF are hardly associated with outcome after two years
as disease activity, functional and radiographic outcome, but seems to
reflect the intensity of immunosuppression.
Despite a lot of data confirming that ACPA should be taking into

account in guiding treatment decisions, treatment of all patients with
early and active RA should focus on rapid relief of symptoms, and there
is no reason to weigh the initial treatment choice based on the presence

of autoantibodies
In the Dutch dynamic treatment strategy study, the BeST trials analysis,
ACPA-negative and RF-negative patients also benefited from initial
combination therapy, with better functional ability at 3- and 6-month
follow-up compared with patients treated with initial methotrexate
monotherapy (Akdemir et al, 2016).
Table 4: Sensitivity, specificity, positive and negative predictive value of

ACPA in early arthritis ((Aggarwal et al, 2009).
 Obesity
Obesity in patients with early RA is associated with higher disease

activity and HAQ score, more pain, worse general health, a lower chance
for sustained remission and higher prevalence of comorbidities
(Ajeganova et al, 2013, Vidal 2015)
 Other autoantibodies and immune markers
Some other autoantibodies and immune markers are associated with

disease persistence and severity but, actually, they are not used in
current practice: carbamylated antigens (anti-CarP), and levels of
cytokines and chemokines, including interleukin (IL)-1α, IL-1β, IL-6, IL-10
and tumour necrosis factor α (TNF-α) (see “to go further”)
Family history and genetic markers

- Family history
Family history of RA is one of the strongest clinical risk factors for

developing RA. Therefore, information on family history should be routinely
collected in clinical practice if RA-disease is suspected. The odds ratio (OR)
for developing RA is about 4-fold higher if a first degree relative reported
having the disease.
OR for developing RA is about 5-fold higher if a female first degree relative

reported having the disease (Koumantaki et al, 1997).
In this study, mothers with RA predisposed their daughters and sons to

develop RA more (OR = 8.6, p < 0.01, for daughters and 4.8, p < 0.05, for
both sexes) than fathers (OR = 1.1 and 1.9, respectively).
The familial risk factors are still not recognized:
The genetic risk factors account for only a limited proportion of the
familial risk of seropositive RA, and (familial) risk factors for
seronegative RA are not identified (Jiang et al 2015).
The presence of both positive family history of RA, in particular

among women, high genetic susceptibility and smoking could
discriminate seropositive and seronegative RA (Sparks et al 2015).
It has been thus suggested that assessing epidemiological and

genetic factors among those with positive family history may
identify individuals suitable for RA prevention proof-of-concept
trials.
- Genetic markers
The shared epitope (SE), a group of HLA-DRB1 alleles that share a similar
amino acid sequence, is strongly associated with RA.
Among the different HLA-DRB1 alleles examined, HLA-DRB1*0401

and DRB1*0404 have been consistently associated with
radiographic erosions in different ethnic groups.
This association appears to be dose dependent as patients with

two RA-associated alleles (DRB1*04 or DRB1*01) have more
radiographic erosions and more joint replacement than patients
with non-disease-associated alleles (Weyand et al, 1992).
Studies have shown that individuals who were homozygous for

HLA-DRB1*0404 were four times more likely to develop erosions
than those who were SE negative (Goronzy et al, 2004). Since ACPA
tests have been included in multivariate analyses, however, HLA-
DRB1 genes have no longer been shown to be independent
predictive factors of severity in RA. In most populations, their effect
is accounted for by the presence of ACPA. (Further discussion on
the association with the SE and smoking and the development of
ACPA can be found in chapter 9, Pathogenesis and Clinical Aspects
of Rheumatoid Arthritis.)
Although discovery of specific genetic risk factors (in particular, SE)

has been essential to our understanding of RA pathogenesis,
testing for these markers is not recommended in routine clinical

practice.
A number of other genetic polymorphisms have been studied in

patients with early RA. We refer for an in-depth discussion to the
chapter on genetics in this EULAR textbook.
Smoking
Smoking is the most recognized environmental risk factor for the

development of RA. It has also been associated with structural damage,
extra-articular manifestations (including rheumatoid nodules, in early
seropositive RA) and a lower response to disease-modifying therapies
(Saevarsdottir et al, 2011) independently of ACPA status.
Former smokers are at an increased risk for RA up to 20 years after stopping

smoking, with a gradually decreasing risk over time (Heliovaara et al, 1993).
The association between smoking and structural damage are controversial:
Several cross-sectional studies have demonstrated significant

associations between smoking and more radiographic damage
progression (Saag et al, 1997; Masdottir et al, 2000)
Other studies, including a large observational study of 2,004 patients

with RA (Finckh et al, 2007), have found no difference in rates of
radiographic progression between current or previous smokers and non-

smokers (Harrison et al, 2001; Forslind et al, 2004).
A large multi-centre study indicated that the effect of smoking on joint

damage is mediated via ACPA and that smoking is not an independent
risk factor for radiological progression in RA (De Rooy et al, 2014).
Smoking increase the risk of developing ACPA:
In the presence of HLA-DRB1 SE alleles, this risk is further increased

(up to 20 times in homozygotes as compared with SE-negative non-
smokers in ACPA-positive individuals)
(Klareskog et al, 2006; Klareskog et al, 2007).
This suggests that smoking in a genetically predisposed individual

triggers apoptosis and protein citrullination, followed by an anti-
citrulline-specific immune response.
However, smoking is associated with the concurrent presence of

multiple autoantibodies in rheumatoid arthritis rather than with anti-
citrullinated protein antibodies per se
(van Wesemael TJ et al 2016).
Imaging
- Conventional radiographs
X-ray examinations are the conventional imaging modality (Figure 17 and

18).
Radiographic erosions have a high specificity in discriminating between self-

limiting and persistent arthritis (Visser et al, 2002):
In a cohort of 518 patients with UA, the presence of two or more erosive
joints at baseline showed a positive predictive value for RA development
of 53% and for persistent disease of 68% (Thabet et al, 2009).
Patients with erosions who did not develop RA were less often ACPA-
positive, RF-positive and had lower CRP/ESR levels and fewer swollen
joints compared with those who developed RA.
Feet erosions were equally predictive compared with hand erosions in
this study.
Early radiographic changes are also predictive of disease progression.
Figure 17: Development of a carpitis in RA
Radiographic examination should include assessment of the hands and feet

as erosions often start in the feet and in about 14%–18% of cases are only
detected in the feet (figure 19) (Fex et al, 1996). The fifth MTP are usually the
first joints where erosions are observed (Tămaş 2014, Siddle 2014)
The proportion of patients with

erosions at the time of diagnosis is
currently decreasing since patients with
RA are detected early (van der Kooij, et
al 2009).
Radiographic damage at baseline is
also the best predictive factor of poor
structural outcome. Irrespective of the
scoring systems (e.g., Sharp van der
Heijde score (SHS) or Larsen score)
used, the initial radiographic score
consistently predicts future radiographic
damage (Jansen et al, 2001).
Joint erosions and joint space
narrowing seen on X-ray examinations,
however, are generally late findings.
Accompanying the 2010 RA criteria, an
additional number of patients being
classified as RA based on solely the
presence of erosion at baseline is very
limited (up to 5%), and only 1/118
patients fulfilled solely the erosion
criterion after 2 years of follow-up
(Brinkmann et al. 2017).
Newer imaging modalities have been shown

to provide additional diagnostic information
at an earlier stage.
Figure 19 Conventional radiograph of the

foot showing erosions of the fifth metatarsal
head
- Magnetic resonance imaging
Magnetic resonance imaging (MRI) can assess all structures of the inflamed
joint (figure 20 and 21) .
It is more sensitive than clinical examination and radiography for the

detection of synovitis and erosions in early RA. Nevertheless, adding
information on the presence of MRI-detected bone marrow oedema and
erosions increase sensitivity but considerably decreases the specificity of
the 2010 EULAR/ACR criteria for RA, and does not improve the accuracy and
discriminative ability of the criteria (Nieuwenhuis et al, 2015).
There is also evidence that MRI findings (synovitis, bone oedema and bone
erosions at baseline and early changes) may predict subsequent
radiographic progression and MRI progression (Baker et al, 2014):
Persistent MRI bone marrow oedema, but not persistent MRI synovitis,
is strongly associated with erosive progression, independently of local
synovitis (Nieuwenhuis et al, 2016).
Changes resembling mild synovitis or small bone erosions, however, are

occasionally found in the joints of healthy subjects:
A review of the literature on 31 MRI studies assessed the occurrence of

MRI features in symptom-free individuals (Mangnus et al, 2015). MRI
erosions were present in 33%–52% of symptom-free individuals,
synovitis in 27% and bone oedema in 0%–16%. The prevalence of MRI-
detected erosions was shown to increase with age. Higher costs, longer
examination times and lower availability are some of the disadvantages
of MRI compared with conventional radiographs.
The role of MRI of joints in clinical practice is yet to be established.
Figure 20: Magnetic resonance imaging picture of the wrist of a patient with
early rheumatoid arthritis.
- T1 3D VIBE with fat suppression sequence - coronal plane showing

synovitis of the wrist. This is seen as a well-defined area of ring
enhancement just proximal to the carpus (blue arrow). There are also a
diffuse hyperintense region within the carpus (**) and the fifth
metacarpophalangeal joint (*). A small erosion can be seen in the scaphoid

(white arrow). LMBRU, University of Leeds, U.K. - T1 3D VIBE with fat
suppression sequence - coronal plane showing synovitis of the wrist. This is
seen as a well-defined area of ring enhancement just proximal to the carpus
(blue arrow). There are also a diffuse hyperintense region within the carpus
(**) and the fifth metacarpophalangeal joint (*). A small erosion can be seen
in the scaphoid (white arrow). LMBRU, University of Leeds, U.K.
- Musculoskeletal ultrasonography (MSUS)
MSUS-guided assessment of disease activity in addition to clinical

examination did not result in better clinical outcomes than Disease
Activity Score (DAS)-guided assessment. Whereas MSUS-driven therapy
led to more intensive treatment (Dale et al, 2016).
The use of MSUS for the management of patients with early arthritis has
increased over the years.
It is useful for detecting synovitis in the small joints of the hands and
feet with greater sensitivity than clinical examination.
It is also more sensitive for visualizing synovitis and bone erosions in

the finger joints than conventional X-ray examinations (figure 22): MSUS
detects 1.4-fold more patients with erosions than X-ray examinations
(Funck-Brentano et al, 2009), and revealed bone erosions in nearly 60%
of early RA patients (Tǎmaş et al, 2014).
Figure 22: Imaging of the second metacarpophalangeal joint of a patient

with rheumatoid arthritis. (A) Conventional radiography shows juxta-articular
osteoporosis. (B) Ultrasonographic examination, in the longitudinal dorsal
scan, shows proliferative synovitis with marked intra-articular power Doppler
signal. m, metacarpal bone; p, proximal phalanx; t, extensor tendon.
Bone erosions seen on MSUS are correlated with the later development
of X-ray erosions (McQueen et al, 2001)
The advantages of US are that it is relatively inexpensive, non-invasive
and allows assessment of many joints. The main disadvantage is its
dependence on the skills of the operator and problems with
reproducibility.
In patients without clinical synovitis, the role of US is not clear.

One of the studies encouragingly reported prediction of the
development of inflammatory arthritis in patients with seropositive
new-onset arthralgia, based on MSUS findings (grey scale, power
Doppler signal and erosions) (Rakieh et al, 2015; Nam et al, 2016).
However, it should be noted that MSUS findings are quite common
in healthy individuals and were reported in 88% of healthy
individuals without joint symptoms (Padovano et al, 2015).
So far it has not been proved that including US examination leads to better
outcomes for patients with early RA (Dale et al, 2016; D’Agostino et al, 2016;
Haavardsholm et al, 2016):
The ARTIC study (Haavardsholm 2016) evaluated MSUS in 122 patients

randomized to an ultrasound tight control strategy targeting clinical and
imaging remission, and 116 patients randomized to a conventional tight
control strategy targeting clinical remission. Patients in both arms were
treated according to the same disease modifying anti-rheumatic drug
escalation strategy, with 13 visits over two years:
26 (22%) of the 118 analysed patients in the ultrasound tight
control arm and 21 (19%) of the 112 analysed patients in the
clinical tight control arm reached the primary endpoint (mean
difference 3.3%, 95% confidence interval −7.1% to 13.7%).
Secondary endpoints (disease activity, physical function, and joint
damage) were similar between the two groups. Six (5%) patients in
the ultrasound tight control arm and seven (6%) patients in the
conventional arm had serious adverse events.
Consequently, the systematic use of ultrasound in the follow-up of
patients with early rheumatoid arthritis treated according to current
recommendations is not justified.
The level of agreement and impact on treatment decision-making of adding

MSUS to clinical assessment of disease activity in early RA patients has
been assessed in the TaSER (Targeting Synovitis in Early Rheumatoid

Arthritis) study (Dale et al, 2014):
MSUS power Doppler was performed in 14 joints on patients with low

disease activity (DAS28<3.2) and with moderate disease activity
(3.2≤DAS28<5.1) without clinically swollen joints.
Data from 414 paired DAS28 and MSUS assessments were pooled to
determine the level of agreement between each method.
MSUS identified persistent disease activity in 1/4 of patients with low
disease activity or clinical remission; on the other hand, MSUS
confirmed active disease only in 1/3of patients with moderate disease
activity.
In 29% of assessments, MSUS findings contradicted the DAS28 score
and led to modified therapeutic decisions.
The authors concluded that compared with the DAS28, global RA disease
activity assessment using a limited MSUS joint set provided additional
disease activity information and led to altered treatment decisions in a
significant minority of occasions.
In a real-life cohort of patients with RA followed for 3–5 years, ‘silent

radiographic progression' in an individual joint without any clinical activity in
any other joint was reported to be very rare, in just 5.8% of the patients,
suggesting that remission assessed clinically is a marker of structural
stability (Gartner et al, 2016).
Mostly, MSUS imaging is currently used for disease monitoring as a part of

clinical investigation. Whether the combination of clinical, serological, and
imaging (ultrasound) findings could potentially help clinicians make more
precise treatment decisions in individual patients with early arthritis is to be
defined.
MSUS imaging should be interpreted cautiously and always in the context of

the clinical situation. In patients with RA, MSUS findings in both large and
small joints reflect synovial histological scores, DAS28 and CRP (Abe et al,
2016).
Histology
Studies using arthroscopy have confirmed imaging findings of subclinical

synovitis when examining asymptomatic joints of newly diagnosed RA.
Distinct macroscopic vascular patterns have been seen in early RA and

psoriatic arthritis (figure 23).
Comparison of the histopathological features of synovial tissue in early RA

and non-RA synovitis has shown subtle differences in histological features,
and cytokine and protease expression patterns, as well as apoptosis:
An analysis of synovial biopsies of 95 patients with early arthritis

showed that higher scores for the number of CD38+ plasma cells and
CD22+ B cells were the best markers for distinguishing between
patients with and without RA.
The number of CD68+ macrophages in the synovial tissue of patients
with RA was also increased (Kraan et al, 1999).
Thus, so far, however, the clinical value of the histopathological

characteristics of synovial tissue in early arthritis has not yet been proved
(Hitchon and el-Gabalawy, 2003).
The widespread use of synovial biopsy in the clinical setting is also limited
by its invasiveness.
Hand bone densitometry
With newer treatments for RA, erosion progression is lower, requiring more
sensitive measures to assess treatment outcomes. In RA, bone loss,
particularly in the hands, takes place early in the disease process. Measuring
hand bone loss may therefore be useful for diagnosis and as a marker of
disease activity. Dual energy X-ray absorptiometry (DEXA) measures bone
density with high precision, making it sufficiently sensitive to detect even

small changes in bone mass.
Studies in RA assessing bone mineral density (BMD) have shown a good

correlation between BMD loss in the spine (Gough et al, 1994) and hand
(Devlin et al, 1996) with disease activity.
DEXA has been found to be a more sensitive tool than radiology for
measuring disease-related bone damage:
Out of 58 patients with early RA of <12 months’ duration, 50% showed

significant individual BMD hand bone loss after 24 weeks compared
with only 22% showing the smallest detectable radiographic progress
evaluated by the SHS method at 48 weeks (Haugeberg et al, 2007).
In an exploratory analysis of patients participating in the IMPROVED

study (a clinical trial in 610 patients with recent onset RA or UA, treated
according to a remission steered strategy) without baseline erosions,
early metacarpal BMD loss after 4 months was found as the main
predictor of radiological progression after 1 year (Wevers-de Boer et al,
2015).
In another study evaluating the role of DEXA in early RA, change in BMD
hand bone loss at 1 year was correlated significantly and inversely with
structural damage (evaluating by the change in Sharp van der Heijde
score (SHS)at 2, 5 and 8 years) during the first year (Forslind et al,
2012).
However, there is no recommendation to use this technique in the

diagnosis, or the management of early RA or RA.
Figure 23: Arthroscopy showing rheumatoid synovitis. Hypertrophic,

rounded, polypoid-like villi with an opaque, ill-defined background due to
congestion and oedema are seen.
Biomarkers of joint destruction
Molecular markers that reflect synovial, bone and cartilage turnover have
been studied as potential tools for the early identification of patients with RA
at high risk of rapid disease progression (Landewé, 2007).
These include:
Urinary glucosyl-galactosyl-pyridinoline, a marker of destruction of the

synovium
C-terminal crosslinking telopeptides of type I and type II collagen (CTX-I

and CTX-II), markers of bone and cartilage destruction:
High baseline levels of CTX-I and CTX-II have been shown to

(weakly) associate with radiographic progression.
Matrix metalloproteinases, enzymes involved in the degradation of

articular cartilage in RA
Raise of matrix metalloproteinases have been found in tissue,

synovial fluid, and the systemic circulation of patients with RA.
Several studies have shown a correlation between increased matrix
metalloproteinase levels and progression of joint damage.
The osteoprotegerin: nuclear factor (NF) kappaB ligand (OPG:RANKL)

ratio, marker of joint destruction (with low levels predictive of more
rapid progression).
Osteoclasts play a key role in the mechanism of joint destruction in

RA.
RANKL and its receptor RANK are central to the stimulation of
osteoclast formation and activation, and the soluble receptor-like
molecule OPG is a natural inhibitor of RANKL.
Bone resorption is regulated by the balance between RANKL and
OPG.
Calprotectin (myeloid-related protein 8/14, expressed in granulocytes

and monocytes)
Calprotectin level in plasma/serum and/or synovial fluid have been

shown to predict erosive joint damage progression and therapeutic
responses (Abildtrup et al, 2015).
However, analysis of cartilage and bone biomarkers is not more useful than
current predictors of clinical and radiographic outcomes in RA—for example,
ACPA and the presence of early radiographic damage. In daily clinical
practice, the role of these biomarkers is not demonstrated.
Phases up to the development of RA
Research at the very earliest stages of RA has led to the formation of a

‘Study Group for Risk Factors for RA’ (Gerlag et al, 2012*). The group has
published recommended terminology to define the specific phases up to the
development of RA to phenotype/characterize these phases and to
standardize further research in the field (box 3). These phenotypes include
certain genetic profiles (e.g., SE), environmental factors (e.g., smoking) and
autoantibodies (e.g., RF and ACPA), known risk factors for the development
of RA.
Predictors of persistence and disease

severity: practical points
In practice, the clinical features and investigations listed in boxes 1 and 2

may be used to identify patients with early inflammatory arthritis who are at
risk of a persistent and more severe disease course. X-ray of the hands and
feet is the mainstay imaging modality, although the use of MSUS, MRI and
DEXA is coming to the fore. Non-HLA genetic markers, histology and
biochemical markers remain more research-based tools than investigations
for day-to-day patient care.
The development of the 2010 ACR/EULAR classification criteria has been an

important step forward, setting a new benchmark for the early identification
of patients with RA, aiming to start effective treatment as early as the
diagnosis is made, thus preventing the adverse sequelae of the disease.
Currently, great efforts are being made with a focus on the identification of
clinical, serological, and genetic factors, MSUS and MRI imaging features
aiming to predict the development of inflammatory arthritis in individuals at
risk (van Steenbergen et al, 2015a).
Prediction of outcome of undifferentiated arthritis and

early RA: Take time for a brief reflection
Insert your take aways from this chapter here:
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1/14/23, 1:33 PM FULL-Mod2-Basic Learning | Prediction of outcome of undifferentiated arthritis and early RA

After excluding other diseases and making a diagnosis of probable RA or UA,

Assessment of disease persistence

Psychological wellbeing also influences the outcome of RA, with

On the other hand, seronegativity for RF and fewer active joints at

Some factors are associated with disease persistence (box 1).

Assessment of disease severity

Individual factors predicting persistence and disease

As discussed earlier, symptom duration is also an important predictor of

 Early morning stiffness (EMS)

EMS is an early symptom of inflammatory arthritis. It is, however, a

It has been used as a clinical marker of disease persistence (Visser et

Cut-off of EMS, to predict disease persistence, is different depending on

Moreover, during the first phase of the development of the 2010

 Polyarticular disease and hand involvement

In a cohort of 121 patients with early arthritis followed up for a median

Functional disability as measured by the Stanford HAQ disability index is

In patients with early disease, a high baseline HAQ is an important risk

 Acute phase response

Historically, RF has been one of the most consistent markers of disease

 Anti-cyclic citrullinated peptide antibodies (ACPA)

ACPA represents an independent risk factor for developing RA in

In early UA, 93% of patients who were ACPA (CCP2) positive at

In patients with arthralgia but without clinical synovitis, an

ACPA has a similar sensitivity to RF in early RA but a greater specificity.

The presence of ACPA (and titre of ACPA) is also associated with:

baseline and long-term disease severity in patients with

Following treatment escalation, autoantibody levels dropped markedly,

Nevertheless, measuring ACPA titres has not been proved to be of value

Seroconversion from seronegative to seropositive seems to occur

Despite a lot of data confirming that ACPA should be taking into

is no reason to weigh the initial treatment choice based on the presence

Table 4: Sensitivity, specificity, positive and negative predictive value of

Obesity in patients with early RA is associated with higher disease

 Other autoantibodies and immune markers

Some other autoantibodies and immune markers are associated with

Family history and genetic markers

Family history of RA is one of the strongest clinical risk factors for

OR for developing RA is about 5-fold higher if a female first degree relative

In this study, mothers with RA predisposed their daughters and sons to

The presence of both positive family history of RA, in particular

It has been thus suggested that assessing epidemiological and

Among the different HLA-DRB1 alleles examined, HLA-DRB1*0401

This association appears to be dose dependent as patients with

Studies have shown that individuals who were homozygous for

Although discovery of specific genetic risk factors (in particular, SE)

testing for these markers is not recommended in routine clinical

A number of other genetic polymorphisms have been studied in

Smoking is the most recognized environmental risk factor for the

Former smokers are at an increased risk for RA up to 20 years after stopping

The association between smoking and structural damage are controversial:

Several cross-sectional studies have demonstrated significant

Other studies, including a large observational study of 2,004 patients

radiographic progression between current or previous smokers and non-

A large multi-centre study indicated that the effect of smoking on joint

Smoking increase the risk of developing ACPA:

In the presence of HLA-DRB1 SE alleles, this risk is further increased

(Klareskog et al, 2006; Klareskog et al, 2007).

This suggests that smoking in a genetically predisposed individual

However, smoking is associated with the concurrent presence of

(van Wesemael TJ et al 2016).

X-ray examinations are the conventional imaging modality (Figure 17 and

Radiographic erosions have a high specificity in discriminating between self-